TW202106689A - Bridged ring-3,4-dihydro-pyrido [1,2-a] pyrazine-1,8-dione compound and pharmaceutical use thereof - Google Patents

Abstract

The disclosure relates to a bridged ring-3,4-dihydro-pyrido [1,2-a] pyrazine-1,8-dione compound and pharmaceutical use thereof. Specifically, the disclosure provides a compound represented by Formula I or a pharmaceutically acceptable salt or stereoisomer, rotamer, or tautomer thereof, wherein R1~R8 are as defined herein. The compound of formula I can be used to treat human immunodeficiency virus (HIV) infection.

Description

Bridged ring-3,4-dihydro-pyrido[1,2-a]pyrazine-1,8-dione compound and its pharmaceutical use

The present disclosure belongs to the field of medicine, and relates to a bridged ring-3,4-dihydro-pyrido[1,2-a]pyrazine-1,8-dione compound.

Human immunodeficiency virus infection ((HIV) is a major public health problem worldwide. Although drugs targeting reverse transcriptase and protease are widely used and have shown some effectiveness, especially when used in combination such as cocktail therapy, they are toxic The development of resistant strains has limited their usefulness (Richman, DD Nature , (2001) 410:995-1001). Therefore, there is a need to develop new HIV inhibitors.

In addition, it is known that the HIV virus will mutate in infected subjects (Tang et al., Drugs , (2012) 72(9)e1-e25), which also leads to complicated HIV infection treatment strategies for patients, and HIV infection Patients may need to receive other medications due to other diseases, and the interaction of medications will cause the evaluation criteria of antiretroviral therapy to become invalid. Therefore, there is a need to develop more effective antiretroviral methods that reduce drug interactions.

The following references can be used as background information:

US2007/0111984 discloses a series of bicyclic pyrimidinone compounds that can be used as HIV integrase inhibitors.

US2006/0276466, US2007/0049606, US2007/0111985, US2007/0112190, US2007/0281917, US2008/0004265 each disclose a series of bicyclic pyrimidinone compounds that can be used as HIV integrase inhibitors.

WO2014/100323, WO2015/048363, and WO2016/106237 each disclose a series of pyridone derivatives or quinazine derivatives that can be used as HIV integrase inhibitors.

The disclosure provides a compound represented by formula I,

或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，

Or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers,

Wherein, ring A is selected from C _5-12 cycloalkyl and 6 to 12 membered heterocyclic group;

R ¹ or R ² are each independently selected from hydrogen, halogen (such as fluorine, chlorine, bromine), alkyl (such as C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl) , Cycloalkyl (such as C _3-12 cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3 to 12 membered heterocycloalkyl, including but not limited to pyrrolyl ), the alkyl group, cycloalkyl group or heterocyclic group is optionally selected from one or more alkyl groups (such as C _1-6 alkyl groups, including but not limited to methyl, ethyl, propyl or isopropyl) , Cycloalkyl (such as C _3-12 cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3 to 12 membered heterocycloalkyl, including but not limited to pyrrolyl ), alkoxy (such as C _1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), alkenyl, alkynyl, aryl, heteroaryl, Nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR' or CONR'(R") substituted, or R ¹ or R ² together with its adjacent carbon atoms form 3 to 12 members Membered carbocyclic or heterocyclic ring, preferably 3 to 8-membered carbocyclic or heterocyclic ring, the carbocyclic or heterocyclic ring is optionally selected from alkyl (such as C _1-6 alkyl, including but not limited to methyl, ethyl , Propyl or isopropyl), halogen (such as fluorine, chlorine, bromine), hydroxyl, amino, oxy, carboxy, nitro, cyano, alkoxy (such as C _1-6 alkoxy, including but Not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl (such as C _3-12 cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), hetero Among cyclic groups (such as 3 to 12-membered heterocycloalkyl groups), aryl groups, heteroaryl groups, haloalkyl groups, haloalkoxy groups, halocycloalkyl groups, haloheterocyclic groups, haloaryl groups or haloheteroaryl groups Substituted by one or more substituents;

R ^{3 is} selected from hydrogen, halogen (such as fluorine, chlorine, bromine), alkyl (such as C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl), and the alkyl group is optional By one or more cycloalkyl (such as C _3-12 cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), alkoxy (such as C _1-6 alkoxy, including but not Limited to methoxy, ethoxy, propoxy or isopropoxy), alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen (such as fluorine, chlorine , Bromo), haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, haloheteroaryl, SR', NR'(R"), COOR' or CONR'(R" ) Replaced by;

R4 or R5 are each independently selected from hydrogen, halogen (such as fluorine, chlorine, bromine), hydroxy, alkyl (such as C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl) , Alkoxy (such as C _1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl (such as C _3-12 cycloalkyl, including But not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3 to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl, heteroaryl, SR', NR'( R"), COOR' or CONR'(R"), the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally selected from one or more alkyl groups (such as C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy (such as C _1-6 alkoxy, including but not limited to methoxy, ethoxy, propyl) Oxy or isopropoxy), cycloalkyl (such as C _3-12 cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3-12 membered heterocycloalkane Groups, including but not limited to pyrrolyl), alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocycle Group, haloaryl, haloheteroaryl, SR', NR'(R"), COOR' or CONR'(R"), alternatively, R ⁴ or R ⁵ together with its adjacent carbon atoms form 5 members to 12-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, preferably 6 to 8-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, the carbocyclic, heterocyclic, aromatic or heteroaromatic ring is optionally Selected from alkyl (such as C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl), halogen (such as fluorine, chlorine, bromine), hydroxyl, amino, oxy, carboxyl , Nitro, cyano, alkoxy (such as C _1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl (such as C _{3- 12} cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3 to 12 membered heterocycloalkyl, including but not limited to pyrrolyl), aryl and heteroaryl Is substituted by one or more substituents;

R ^{6 is} selected from hydrogen, alkyl (such as C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl), cycloalkyl (such as C _3-12 cycloalkyl, including but not limited to) Not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3 to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl or heteroaryl, the alkyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl optionally selected by one or more selected from halogen, hydroxy, alkyl (such as C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl Group), alkoxy (such as C _1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl (such as C _3-12 cycloalkyl , Including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3 to 12 membered heterocycloalkyl, including but not limited to pyrrolyl), aryl, heteroaryl, SR', NR '(R"), OCOR', OCOOR', COOR', CONR'(R") or OCONR'(R");

Each R ⁷ or R ^{8 is} independently selected from hydrogen, halogen (such as fluorine, chlorine, bromine), hydroxy, alkyl (such as C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or iso Propyl), alkoxy (such as C _1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl (such as C _3-12 cycloalkane Group, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3 to 12 membered heterocycloalkyl, including but limited to pyrrolyl), aryl or heteroaryl, the alkyl group, The alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally selected from halogen (such as fluorine, chlorine, bromine), alkyl (such as C _1-6 alkyl, including but Not limited to methyl, ethyl, propyl or isopropyl), cycloalkyl (such as C _3-12 cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), alkoxy (such as C _1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro , Nitrile, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, haloheteroaryl, SR', NR'(R"), OCOR', OCOOR', COOR' , CONR'(R") or OCONR'(R"), or, ^{at least one of R 7} and R ⁸ and one or more adjacent atoms together form a 3-member to 12-member carbocyclic ring, heterocyclic ring, aromatic Ring or heteroaromatic ring, preferably 3-membered to 8-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, the carbocyclic, heterocyclic, aromatic or heteroaromatic ring is optionally selected from alkyl (such as C _{1- 6} Alkyl, including but not limited to methyl, ethyl, propyl or isopropyl), halogen (such as fluorine, chlorine, bromine), hydroxyl, amino, oxy, carboxy, nitro, cyano, alkoxy Group (such as C _1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl (such as C _3-12 cycloalkyl, including but not limited to Cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3-12 membered heterocycloalkyl, including but limited to pyrrolyl), aryl, heteroaryl, haloalkyl, haloalkoxy, halo Cycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl group is substituted by one or more substituents; the sum of n and o is an integer less than or equal to 24 (such as 1, 2, 3, 4, 5 , 6, 7, 8, etc.), including zero;

R'or R" are independently selected from hydrogen, hydroxy, alkyl (such as C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy (such as C _{1- 6} alkoxy, including but not limited to, methoxy, ethoxy, propoxy or isopropoxy), alkenyl, acyl, aryl or heteroaryl group, the alkyl group, alkoxy group, aryl group Or heteroaryl groups are optionally selected by one or more selected from halogen (such as fluorine, chlorine, bromine), alkyl (such as C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl) ), cycloalkyl, alkoxy (such as C _1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile, or substituted with -R ^a; R ^a is selected from aryl or heteroaryl, which aryl or heteroaryl group optionally substituted with one or more substituents selected from halogen (e.g. fluorine, chlorine, bromine) , Alkyl (such as C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl), cycloalkyl (such as C _3-12 cycloalkyl, including but not limited to cyclopropyl , Cyclopentyl, cyclohexyl), alkoxy (such as C _1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), alkenyl, alkynyl, Substituted by oxy, hydroxy, aryl, heteroaryl, nitro, nitrile, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl.

In some alternative embodiments, the compound represented by Formula I is:

Wherein, B is selected from -CONR'-, -COO- or five to six member heterocycles (preferably thiadiazolyl);

R ^{9 is} selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, 3-membered to 8-membered heterocyclic group, 6-membered to 12-membered aryl or heteroaryl, the C _1-6 alkyl group, C _3-8 cycloalkyl, 3-membered to 8-membered heterocyclic group, 6-membered to 12-membered aryl group or heteroaryl group is optionally substituted by one or more halogen, alkyl, cycloalkyl, alkoxy, alkenyl groups , Alkynyl, oxy, hydroxy, nitro, nitrile, aryl or heteroaryl group, the alkyl, cycloalkyl, alkoxy, aryl or heteroaryl group is optionally selected by one or more from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, nitro, nitrile, or substituted with -R ^a;

R ^{a is} selected from aryl or heteroaryl, and the aryl or heteroaryl is optionally selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy or hydroxy. ；

R', R ⁷ or R ⁸ are as defined in the compound of formula I.

^{In some embodiments, R 6} in the compound represented by formula I is selected from hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclic group, the alkyl group, cycloalkyl group Or the heterocyclic group is optionally selected from halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, preferably hydrogen or C _1-6 alkyl.

In some alternative embodiments, the compound represented by Formula I is:

Wherein, Z ¹ , Z ² , Z ³ and Z ⁴ are each independently selected from -O-, -S-, -SO-, -SO ₂ -, -NH ₂ -or -CH ₂ -;

R ^{10 is} selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile, aryl or heteroaryl, the aryl or heteroaryl group as required Substituted by one or more selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile or -R ^b;

R ^{b is} selected from aryl or heteroaryl, and the aryl or heteroaryl is optionally selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy or hydroxy. Replaced by

R ^c or R ^d are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile, halogen Alkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl, or R ^c or ^Rd together with its adjacent carbon atoms form a 3- to 12-membered carbocyclic or heterocyclic ring , Aromatic ring or heteroaromatic ring, preferably 3-membered to 8-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, the carbocyclic, heterocyclic, aromatic or heteroaromatic ring is optionally selected from alkyl, halogen, Substituted by one or more substituents of hydroxyl, amino, oxy, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; the sum of n and o It is an integer less than or equal to 8 (such as 1, 2, 3, 4, 5, 6, 7, 8), including zero.

^{In some embodiments, up to 3 of Z 1} , Z ² , Z ³ and Z ⁴ in the compound of formula III are selected from -O-, -S-, -SO-, -SO ₂ -, -NH ₂ -, Preferably, there are at most two selected from -O-, -S-, -SO-, -SO ₂ -, -NH ₂ -, and the two are not connected.

In some embodiments, Z ¹ , Z ² , Z ³ and Z ^{4 in the} compound of formula III are selected from -O-, -S-, -SO ₂ -, -NH ₂ -or -CH ₂ -.

In some embodiments, Z ¹ , Z ² , Z ³ and Z ^{4 in the} compound of formula III are selected from -O-, -S-, -SO ₂ -or -CH ₂ -.

Some embodiments provide compounds represented by Formula I as follows:

Some embodiments provide compounds represented by Formula I as follows:

Some embodiments provide compounds represented by Formula I as follows:

Other embodiments provide compounds represented by formula I as follows:

Further, some embodiments provide the compound represented by Formula I as follows:

Wherein, R ^{11 is} selected from hydrogen, halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile, haloalkyl, halo Alkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl; p=0 to any integer between 0 and 5 (including 0, 1, 2, 3, 4, 5).

Other embodiments provide compounds represented by formula I as follows:

或

，其中，

or

,among them,

R ¹¹ and p are as defined in the compound represented by formula Va.

Other embodiments provide compounds represented by formula I as follows:

或

，其中，

or

,among them,

R ¹¹ and p are as defined in the compound represented by formula Va.

Other embodiments provide compounds represented by formula I as follows:

或

，其中，

or

,among them,

R ¹¹ and p are as defined in the compound represented by formula Va.

^{In other embodiments, R 4} in the compound represented by formula I is selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy or C _3-7 cycloalkyl. , Alkoxy, cycloalkyl, optionally selected from nitro, nitrile, hydroxyl, halogen, halo C _1-6 alkyl, halo C _1-6 alkoxy, halo C _3-7 ring Alkyl and halo are substituted with a 3- to 7-membered heterocyclic group, preferably hydrogen.

^{In other embodiments, R 3} in the compound represented by formula I is selected from hydrogen or C _1-6 alkyl group, and the alkyl group is optionally substituted by one or more nitro groups, nitrile groups, hydroxyl groups, halogens, and haloalkyl groups. , Haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, haloheteroaryl.

^{In other embodiments, each of R 1} or R ² in the compound represented by formula I is independently selected from hydrogen, halogen, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, 3 to 7 members Heterocyclic group, or, R ¹ or R ² together with its adjacent carbon atoms form a C _3-7 cycloalkyl group, a 3- to 7-membered heterocyclic group, and the alkyl, cycloalkyl or heterocyclic group optionally contains one Or more selected from nitro, nitrile, hydroxyl, halogen substituted.

^{In other embodiments, each R 7} or R ⁸ in the compound represented by formula I is independently selected from hydrogen, halogen, nitrile, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, 3- to 7-membered heterocyclic group, the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally selected from halogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkoxy, hydroxy, nitro, nitrile, halo C _1-6 alkyl, halo C _1-6 alkoxy, halo C _1-6 cycloalkyl, halo 3-membered to 7-membered heterocyclic group, SR', NR'(R"), OCOR', OCOOR', COOR', CONR'(R") or OCONR'(R") substituted, or R ⁷ and R ^{At least one group of 8} and its adjacent one or more atoms together form a C _3-7 cycloalkyl group, a 3- to 7-membered heterocyclic group, and the cycloalkyl group or heterocyclic group is optionally selected from C _1-6 alkane Group, halogen, hydroxy, amino, oxy, carboxy, nitro, cyano, C _1-6 alkyl alkoxy, C _1-6 alkyl cycloalkyl, 3 to 7 member heterocyclic group, aryl Substituted by one or more substituents in the group, heteroaryl, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl; the sum of n and o is An integer less than or equal to 12, such as 1, 2, 3, 4, 5, 6, 7, 8.

^{In other embodiments, each R 7} or R ⁸ in the compound represented by formula I is independently selected from hydrogen, halogen, nitrile, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, 3- to 7-membered heterocyclic group, the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally selected from halogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkoxy, hydroxyl, nitro, nitrile, NR'(R"), OCOR", COOR', CONR'(R") or OCONR'(R") replace.

In other embodiments, in the compound of formula I, R ⁷ or R ⁸ and one or more of its adjacent atoms together form a C _3-7 cycloalkyl group, a 3-membered to 7-membered heterocyclic group, and the cycloalkyl group Or heterocyclic group is optionally selected from C _1-6 alkyl, halogen, hydroxyl, amino, oxy, carboxy, nitro, cyano, C _1-6 alkyl alkoxy, C _1-6 alkyl Cycloalkyl, 3- to 7-membered heterocyclyl, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, or haloheteroaryl is substituted by one or more substituents .

In other embodiments, in the compounds represented by formulas IVa to IVd or formulas IVa-1 to IVd-1, R ^c and R ^d are each independently selected from hydrogen, R ^c and R ^{d are} preferably hydrogen; R ¹⁰ is 1 To 4 halogen substituted phenyl groups. ^{In other embodiments, R 10} in the compounds represented by formulas IVa to IVd or formulas Iva-1 to IVd-1 is phenyl substituted with 2 halogens. ^{In other embodiments, R 10} in the compounds represented by formulas IVa to IVd or formulas Iva-1 to IVd-1 is phenyl substituted with 3 halogens. ^{In other embodiments, R 10} in the compounds represented by formulas IVa to IVd or formulas Iva-1 to IVd-1 is phenyl substituted with 4 halogens.

^{In some embodiments, R 10} in the compounds represented by formulas IVa to IVd or formulas Iva-1 to IVd-1 is selected from 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6- Difluorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl or 3,5-difluorophenyl.

^{In some embodiments, R 10} in the compounds represented by formulas IVa to IVd or formulas IVa-1 to IVd-1 is phenyl substituted with 3 halogens. ^{In some embodiments, R 10} in the compounds represented by formulas IVa to IVd or formulas IVa-1 to IVd-1 is selected from 2,4,6-trifluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl or 2,4-difluoro-3-chlorophenyl.

^{In some embodiments, R 10} in the compounds represented by formulas IVa to IVd or formulas IVa-1 to IVd-1 is phenyl substituted with 4 halogens.

^{In other embodiments, R 10} in the compounds represented by formulas IVa to IVd or formulas IVa-1 to IVd-1 is selected from 2,3,4,5-tetrafluorophenyl or 2,3,4,6- Tetrafluorophenyl.

Typical compounds represented by formula I include but are not limited to:

或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體。

Or a pharmaceutically acceptable salt or stereoisomer, rotamer or tautomer thereof.

In some embodiments, the compound represented by formula I is selected from:

或其可藥用的鹽或其立體異構體。

Or a pharmaceutically acceptable salt or stereoisomer thereof.

The present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned formula I, II, III, IVa, IVb, IVc, IVd, IVa-1, IVb-1, IVc-1, IVd-1, Compounds represented by Va, Vb, Vc, Vd, Va-1, Vb-1, Vc-1 or Vd-1 or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients.

In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned pharmaceutically acceptable salts based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned pharmaceutically acceptable salts. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned pharmaceutically acceptable salts. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned pharmaceutically acceptable salts. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned pharmaceutically acceptable salts.

In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.

On the other hand, the present disclosure also provides a method for treating HIV infection in a patient suffering from infection or at risk of suffering from infection by administering to the patient a therapeutically effective amount of the aforementioned formulas I, II, III, IVa, Compounds shown in IVb, IVc, IVd, IVa-1, IVb-1, IVc-1, IVd-1, Va, Vb, Vc, Vd, Va-1, Vb-1, Vc-1 or Vd-1 or A pharmaceutically acceptable salt or its stereoisomer, rotamer or tautomer, or the aforementioned pharmaceutical composition.

The present disclosure also relates to the compounds described in the above-mentioned schemes or their pharmaceutically acceptable salts or their stereoisomers, rotamers or tautomers, or the aforementioned pharmaceutical compositions for preparing and treating infections or suffering from Use in medicines for HIV infection in patients at risk of infection.

On the other hand, the pharmaceutically acceptable salt of the compound described in the present disclosure is selected from inorganic salts or organic salts, and the compound described in the present disclosure reacts with an acid such as trifluoroacetic acid to form a corresponding salt. Salicylic acid, malic acid, ascorbic acid, phosphoric acid, citric acid, benzoic acid or fumaric acid. As described in this disclosure The compound reacts with a base such as N-methyl-D meglumine or dicyclohexylamine to form the corresponding salt, and the base is selected from but not limited to sodium, alkaline earth metals, amino acids (such as arginine, lysine).

On the other hand, the hydrogen in the functional group of the compound of the present disclosure can be deuterated to obtain the corresponding deuterated compound. The deuterated compound retains the selectivity and potential equivalent to the hydrogen analog; the deuterium bond is more stable, making the "ADME" that is" Toxic pharmacokinetics are different, thereby providing clinically beneficial effects.

Toxic pharmacokinetics refers to the process of absorption, distribution, metabolism, and excretion of foreign chemicals by the body.

The present disclosure also provides a method for preparing the compound represented by formula I,

The method includes the step of reacting a compound represented by formula I-a with a compound represented by formula I-b to form a compound represented by formula I-c,

Among them, ring A, R ¹ -R ⁸ , n, and o are as described above, and PG ₁ , PG ₂ , and PG ₄ are protecting groups.

In some embodiments, the protecting groups of the present disclosure include, but are not limited to, tertiary butyl, tertiary-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1- (2-Chloroethoxy) ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, two Phenyl-methyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyl-di Phenylsilyl (TBDPS), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz), formyl, acetyl, trichloroacetoxy.

Further, the method for preparing the compound represented by formula I further includes the step of converting the compound represented by formula I-c into the compound represented by formula I,

Term explanation:

"Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents that have been approved by the U.S. Food and Drug Administration for use in humans or livestock animals. Agents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.

"Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 12 carbon atoms is preferred, and an alkyl group having 1 to 6 carbon atoms is more preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl Group, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and various branched isomers Body and so on. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from aryl, heteroaryl Group, halogen substituted. "Alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. For example, "C _2-6 alkenyl" means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected with the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , Benzocycloheptanyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (wherein m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, condensed, and bridged heterocyclic groups. Non-limiting examples of "heterocyclyl" include:

和

，等等。

with

,and many more.

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

和

等。

with

Wait.

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.

"Alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or alkene containing aliphatic hydrocarbon groups, or if the number of carbon atoms is specified, it means that specific number. For example, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated π-electron system, preferably 6 to 12 members, for example Phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclic or cycloalkyl ring, where it is connected to the parent structure The ring together is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, The heterocycloalkylthio group, carboxyl group or carboxylate group is preferably phenyl.

，

，

，等等。 The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group preferably has 6 to 12 members, more preferably 5 or 6 members. E.g. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,

,

,

,and many more.

The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups can be optionally substituted or unsubstituted. When substituted, the substituents are more Preferably one or more of the following groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, ring Alkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or carboxylate.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

The term "haloalkyl" refers to an alkyl substituted by halogen, where alkyl is as defined above.

The term "haloaryl" refers to an aryl group substituted by halogen, wherein the aryl group is as defined above.

The term "haloheteroaryl" refers to a heteroaryl group substituted by halogen, wherein the heteroaryl group is as defined above.

The term "haloheterocyclyl" refers to a heterocyclyl substituted by halogen, wherein the heterocyclyl is as defined above.

The term "halocycloalkyl" refers to a cyclic group substituted by halogen, wherein cycloalkyl is as defined above.

The term "hydroxy" refers to the -OH group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "pendant oxy" refers to the =0 substituent.

The term "pendant thio" refers to the =S substituent.

"As needed" or "as needed" means that the event or environment described later can but need not occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "heterocyclic group substituted by an alkyl group as required" means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

It is known in the art to protect reactive groups (including but not limited to hydroxyl and amine groups) from side reactions during the synthesis process. The hydroxyl group and the amino group protected with a protecting group are referred to herein as "protected hydroxyl group" and "protected amino group", respectively. Protecting groups are usually used selectively and/or orthogonally to protect sites during other reactive site reactions and can then be removed leaving the unprotected group intact or participating in further reactions. Protecting groups as known in the art are generally described in Greene and Wuts, Protective Groups in Organic Synthes is, 3rd edition, John Wiley & Sons, New York (1999). Examples of "hydroxy-protecting groups" include, but are not limited to, tertiary butyl, tertiary-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2- (Chloroethoxy) ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenyl -Methyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyl-diphenyl Silyl (TBDPS), triphenylsilyl, benzoyl formate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivaloate , Benzoate, phenyl p-benzoate, 9-Fluorenyl methyl carbonate, mesylate and tosylate. Examples of "amino protecting groups" include, but are not limited to, carbamate protecting groups, such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl) Group)-ethoxy-carbonyl (Bpoc), third-butoxycarbonyl (BOC), allyloxycarbonyl (Al loc), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxy Carbonyl (Cbz); amide protecting groups, such as formamide, acetyl, trichloroacetoxy, benzyl and nitrophenyl acetyl; sulfonamide-protecting group, such as 2-nitro Benzenesulfonyl; and imine and cyclic imine protecting groups, such as xylylenedimethine imine group and dithiabutanedioic group.

"Pharmaceutical composition" means a mixture containing one or more of the compounds herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients Agent. The purpose of the medicinal composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

The compounds in the present disclosure can contain one or more asymmetric centers, so they can produce enantiomers, diastereomers, and can be defined as ( R )- or ( S )- according to absolute stereochemistry or for (D )- or ( L )- other stereoisomeric forms of amino acids. The present disclosure includes all possible isomers and their racemic and optically pure forms. Optically active (+) and (-), ( R )- and ( S )- or ( D )- and ( L )- isomers can be prepared using chiral synthons or chiral reagents, or conventional methods can be used For example, chromatography and fractional crystallization preparation. Conventional methods for the preparation/separation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the use of, for example, chiral high pressure liquid chromatography (HPLC) of racemates (or salts or derivatives). Racemate) resolution. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, it means that the compounds include E and Z geometric isomers. Moreover, all tautomeric forms are also meant to be included.

"Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but with different three-dimensional structures, and they are not interchangeable. Various stereoisomers and mixtures thereof are expected in this disclosure, and It also includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.

"Tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The present disclosure includes any tautomers of the compound.

Synthetic method of compound in the present disclosure

In order to achieve the purpose of the present disclosure, the following technical solutions are adopted in the present disclosure:

The method for preparing the compound represented by formula I or its pharmaceutically acceptable salt or its stereoisomer, rotamer or tautomer in the present disclosure includes the following steps:

Synthesis method 1:

Synthesis method 2:

註：PG₁、PG₂、PG₃、PG₄為保護基團

Note: PG ₁ , PG ₂ , PG ₃ , and PG ₄ are protecting groups

The following further describes the present disclosure in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

In the embodiments of the present disclosure, the experimental methods without specific conditions are usually in accordance with conventional conditions or in accordance with the conditions suggested by the raw material or commodity manufacturers. The reagents without specific sources are the conventional reagents purchased on the market.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of ^{10 -6 (ppm).} NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methyl Silane (TMS). The spatial configuration of optical isomers (isomers) of compounds can be further confirmed by measuring single crystal parameters.

HPLC determination uses Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent 1200 LC high pressure liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM chromatographic column, Ultimate XB-C18 3.0 *150mm chromatographic column or Xtimate C18 2.1*30mm chromatographic column).

The MS is measured with Waters SQD2 mass spectrometer, scanning in positive/negative ion mode, and the mass scanning range is 100~1200.

Chiralpak IC-3 100×4.6mm ID, 3um, Chiralpak AD-3 150×4.6mm ID, 3um, Chiralpak AD-3 50×4.6mm ID, 3um, Chiralpak AS-3 150×4.6mm ID, 3um, Chiralpak AS-3 100×4.6mm ID, 3μm, ChiralCel OD-3 150×4.6mm ID, 3um, Chiralcel OD-3 100×4.6mm ID, 3μm, ChiralCel OJ-H 150×4.6mm ID, 5um, Chiralcel OJ-3 150×4.6mm ID, 3um chromatographic column ；

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm. ~0.5mm.

The fast column purification system uses Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

Forward column chromatography generally uses Yantai Huanghai silicone gel 100~200 mesh, 200~300 mesh or 300~400 mesh silica gel as the carrier, or uses Changzhou Santai pre-filled and pre-filled ultra-pure normal phase silica gel column (40-63μm, 60 , 12g,, 25g, 40g, 80g or other specifications).

Reversed-phase column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45μm, 100Å, 40g, 80g, 120g, 220g or other specifications).

The high-pressure column purification system uses Waters AutoP, with Waters XBridge BEH C18 OBD Prep Column, 130Å, 5μm, 19mm X 150mm or Atlantis T3 OBD Prep Column, 100Å, 5μm, 19mm X 150mm.

The chiral preparation column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).

The known starting materials in the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology ( Accela ChemBio Inc), Darui Chemicals and other companies.

There is no special description in the examples, and the reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.

The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction uses a CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC). The developing reagent used in the reaction, the eluent system of column chromatography used to purify the compound and the developing reagent system of thin-layer chromatography include: A : Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: petroleum ether/ethyl acetate/methanol, the volume ratio of the solvent depends on the polarity of the compound Adjust, you can also add a small amount of triethylamine and acetic acid and other alkaline or acidic reagents to adjust.

Example 1

(7 R ) -N -(2,4-Difluorobenzyl)-12-hydroxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2, 7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide 1

first step

(Z)-2-((Dimethylamino)methylene)-4-methoxy-3-carbonylbutyric acid methyl ester 1c

A mixture of methyl 4-methoxyacetylacetate (26.57mL, 205.28mmol) and N,N -dimethylformamide dimethyl acetal (27.48mL, 205.28mmol) was heated and stirred at 85°C for the reaction until almost The reaction is complete. It was cooled to room temperature and concentrated under reduced pressure to obtain the title compound 1c (40.4 g, yield 98%).

MS(ESI)m/z 224.1[M+H] ⁺

Second step

3-Methoxy-4-carbonyl-4H-pyran-2,5-dicarboxylic acid 2-ethyl ester 5-methyl ester 1d

Sodium tertiary butoxide (13.37g, 139.15mmol) was added to the mixture of compound 1c (10g, 139.1512mmol) and diethyl oxalate (20mL), the reaction was carried out at room temperature until the reaction was almost complete, and acetic acid (20mL) was added . The resulting mixture was directly purified by elution with acetonitrile and water on a C18 reversed-phase column, and then lyophilized to obtain the title compound 1d (4g, yield 11%).

MS(ESI)m/z 257.1[M+H] ⁺

third step

( R )-1-(1-(Third-butoxycarbonyl) azepan-3-yl)-3-methoxy-4-carbonyl-1,4-dihydropyridine-2,5-di Carboxylic acid 2-ethyl ester 5-methyl ester 1f

Compound 1d (100 mg, 0.39 mmol) was dissolved in 8 mL of ethanol, and (3 R )-3-aminohexahydro-1H-azepine-1-carboxylic acid tert-butyl ester (92 mg, 0.43 mmol) was added. The resulting solution was reacted at 70°C until the reaction was almost complete, cooled to room temperature and concentrated under reduced pressure to obtain the title compound 1f (180 mg, yield 102%).

MS(ESI)m/z 453.4[M+H] ⁺

the fourth step

(7 R )- N -(2,4-Difluorobenzyl)-12-methoxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H- 2,7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide 1h

Compound 1f (180 mg, 0.40 mmol) and 2,4 difluorobenzylamine (85 mg, 0.60 mmol) were dissolved in p-xylene (3 mL), and acetic acid (0.22 mL, 3.98 mmol) was added. The resulting mixture was reacted at 200°C for 2 hours, and then p-toluenesulfonic acid (137mg, 0.80mmol) was added to the reaction solution. The reaction was continued at 200°C until the reaction was almost complete. Cooled and concentrated under reduced pressure. The residue was obtained using a C18 reversed-phase tube The column was eluted and purified with acetonitrile and water to obtain the title compound for 1 h (80 mg, yield 48%).

MS(ESI)m/z 418.3[M+H] ⁺

the fifth step

(7 R ) -N -(2,4-Difluorobenzyl)-12-hydroxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2, 7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide 1

To a solution of compound 1h (80 mg, 0.19 mmol) and 1-methyl-2 pyrrolidone (4 mL) was added magnesium diiodide (162 mg, 0.38 mmol). The resulting mixture was reacted at 50° C. until the reaction was almost complete. After cooling, it was directly purified by elution with acetonitrile and water using a C18 reversed-phase column to obtain the title compound 1 (30 mg, yield 39%).

MS(ESI)m/z 404.3[M+H] ⁺

¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.40 (t, J=6.0Hz, 1H), 8.49 (s, 1H), 7.50-7.35 (m, 1H), 7.30-7.20 (m, 1H), 7.10 -6.95(m,1H), 4.80-4.70(m,1H), 4.50(d,J=6.0Hz,2H), 4.20-4.00(m,1H), 3.85(d,J=16.8Hz,1H), 3.65(d,J=14.8Hz,1H),3.10-3.00(m,1H),2.10-1.90(m,1H),1.90-1.65(m,3H),1.65-1.55(m,1H),1.20- 1.05(m,1H).

Example 2

(7 S ) -N -(2,4-Difluorobenzyl)-12-hydroxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2, 7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide 2

first step

( S )-1-(1-(Third-butoxycarbonyl) azepan-3-yl)-3-methoxy-4-carbonyl-1,4-dihydropyridine-2,5-di Carboxylic acid 2-ethyl ester 5-methyl ester 2b

Compound 1d (50 mg, 0.20 mmol) was dissolved in 2 mL of ethanol, and ( S )-tert-butyl 3-aminoazepane-1-carboxylate (41 mg, 0.20 mmol) was added. The resulting solution was reacted at 70°C until the reaction was almost complete, cooled to room temperature and concentrated under reduced pressure to obtain the title compound 2b (100 mg, yield 113%).

MS(ESI)m/z 453.3[M+H] ⁺

Second step

(7 S )- N -(2,4-Difluorobenzyl)-12-methoxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H- 2,7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide 2c

Compound 4 (100 mg, 0.22 mmol) and 1 g (38 mg, 0.27 mmol) of 2,4-difluorobenzylamine were dissolved in p-xylene (2 mL), and acetic acid (0.12 mL, 2.21 mmol) was added. The resulting mixture was reacted at 200°C for 2 hours, and then p-toluenesulfonic acid (76mg, 0.44mmol) was added to the reaction solution. The reaction was continued at 200°C until the reaction was basically complete, cooled and distilled under reduced pressure. The residue obtained was a C18 reversed-phase tube The column was eluted and purified with acetonitrile and water to obtain the title compound 2c (30 mg, yield 33%).

MS(ESI)m/z 418.3[M+H] ⁺

third step

(7 S ) -N -(2,4-Difluorobenzyl)-12-hydroxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2, 7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide 2

Magnesium diiodide (60 mg, 0.14 mmol) was added to the solution of compound 2c (30 mg, 0.07 mmol) in 1-methyl-2 pyrrolidone (4 mL). The resulting mixture was reacted at 50° C. until the reaction was almost complete. After cooling, it was directly purified with acetonitrile and water using a C18 reversed-phase column to obtain the title compound 2 (5 mg, yield 17%).

MS(ESI)m/z 404.2[M+H] ⁺

¹ H NMR (400MHz, DMSO- d6 ) δ 10.65 (br s, 1H), 10.40 (t, J=6.0Hz, 1H), 8.49 (s, 1H), 7.50-7.45 (m, 1H), 7.40-7.30 (m,1H),7.15-7.00(m,1H),4.80-4.70(m,1H),4.55(d,J=6.0Hz,2H),4.20-4.15(m,1H),3.85(d,J =14.8Hz, 1H), 3.65 (d, J=14.0 Hz, 1H), 3.10-3.00 (m, 1H), 2.10-1.95 (m, 1H), 1.95-1.70 (m, 3H), 1.70-1.50 ( m,1H),1.20-1.05(m,1H).

Example 3

N -(2,4-Difluorobenzyl)-12-hydroxy-1,11-dicarbonyl-1,3,4,6,7,11-hexahydro-2,7-methylenepyrido[ 1,2-d][1,4,7]oxadiazononin-10-carboxamide 3

first step

6-Amino-1,4-oxazepan-4-carboxylic acid tert-butyl ester 3b

6-Oxylidene-1,4-oxazepane-4-carboxylic acid tert-butyl ester (150 mg, 0.70 mmol) was dissolved in 5 mL of 7M methanol solution of amine gas, and stirred at room temperature overnight. Sodium cyanoborohydride (88mg, 1.39mmol) was added to the reaction solution and the reaction was continued to stir at room temperature until the reaction was almost complete. The C18 reversed-phase column was used to extract and purify with acetonitrile and water to obtain the title compound 3b (90mg, yield 60 %).

MS(ESI)m/z 161.1[M-55] ⁺

Second step

1-(4-(Third-butoxycarbonyl)-1,4-oxazepan-6-yl)-3-methoxy-4-carbonyl-1,4-dihydropyridine-2,5 -Dicarboxylic acid 2-ethyl ester 5-methyl ester 3c

Compound 3b (106 mg, 0.42 mmol) was dissolved in ethanol (2 mL), and compound 1d (90 mg, 0.42 mmol) was added. The resulting solution was reacted at 80°C until the reaction was almost complete, cooled, and purified by eluting with acetonitrile and water using a C18 reversed-phase column to obtain compound 3c (45 mg, yield 24%).

MS(ESI)m/z 455.4[M+H] ⁺

third step

6-(5-((2,4-Difluorobenzyl)aminomethyl)-2-(carbethoxycarbonyl<ethoxycarbonyl>)-3-methoxy-4-carbonylpyridine-1(4H )-Yl)-1,4-oxazepan-4-carboxylic acid tert-butyl ester 3d

Compound 3c (40 mg, 0.09 mmol) and 1 g (14 mg, 0.10 mmol) of 2,4 difluorobenzylamine were dissolved in p-xylene (4 mL). The resulting solution was reacted at 200°C until the reaction was almost complete, cooled and concentrated under reduced pressure. The resulting residue was purified by eluting with acetonitrile and water on a C18 reversed-phase column to obtain the title compound 3d (45mg, yield 90%).

MS(ESI)m/z 566.4[M+H] ⁺

the fourth step

5-((2,4-Difluorobenzyl)aminomethyl)-3-methoxy-1-(1,4-oxazepin-6-yl)-4-carbonyl-1,4 -Dihydropyridine-2-carboxylic acid 3e

Compound 3d (45 mg, 0.08 mmol) was dissolved in 4 mL of methanol, and lithium hydroxide (7 mg, 0.16 mmol) and water (3 mg, 0.16 mmol) were added to the solution. The resulting solution was reacted at 70°C until the reaction was almost complete, cooled, and distilled under reduced pressure. The resulting residue was dissolved in 4 mL of 4M methanolic hydrogen chloride solution and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title compound 3e (50 mg, yield 132%).

MS(ESI)m/z 438.3[M+H] ⁺

the fifth step

N -(2,4-Difluorobenzyl)-12-methoxy-1,11-dicarbonyl-1,3,4,6,7,11-hexahydro-2,7-methylenepyridine And [1,2-d][1,4,7] oxadiazononin-10-formamide 3f

Compound 3e (40mg, 0.09mmol) was dissolved in 4mL N,N -dimethylformamide, and 2-(7-azobenzotriazole)-tetramethylurea hexafluoro Phosphate (70 mg, 0.18 mmol) and N,N -diisopropylethylamine (35 mg, 0.27 mmol). The resulting solution was reacted at room temperature until the reaction was almost complete, and was purified by eluting with acetonitrile and water using a C18 reversed-phase column to obtain the title compound 3f (20 mg, yield 52%).

MS(ESI)m/z 420.2[M+H] ⁺

Sixth step

N -(2,4-Difluorobenzyl)-12-hydroxy-1,11-dicarbonyl-1,3,4,6,7,11-hexahydro-2,7-methylenepyrido[ 1,2-d][1,4,7]oxadiazononin-10-carboxamide 3

Magnesium diiodide (27 mg, 0.10 mmol) was added to a solution of compound 3f (20 mg, 0.05 mmol) in acetonitrile (4 mL). The resulting mixture was reacted at 60°C until the reaction was almost complete, cooled and concentrated under reduced pressure. The residue obtained was purified by eluting with acetonitrile and water on a C18 reversed-phase column to obtain the title compound 3 (8 mg, yield 41%).

MS(ESI)m/z 406.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d6) d 10.60-10.30 (m, 2H), 8.52 (s, 1H), 7.50-7.35 (m, 1H), 7.35-7.15 (m, 1H), 7.15-7.00 (m ,1H), 4.80-4.70(m,1H),4.55(d,J=5.6Hz,2H), 4.35-4.20(m,1H), 4.20-3.85(m,5H), 3.60-3.50(m,1H) ), 3.20-3.10 (m, 1H).

Example 4

( 3S,7S ) -N -(2,4-Difluorobenzyl)-12-hydroxy-3-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro -3 H -2,7-methylenepyrido[1,2-a][1,4]diazononin-10-carboxamide 4

first step

3-Methoxy-4-carbonyl-4H-pyran-2,5-dicarboxylic acid 2-methyl ester 5-methyl ester 4a

A mixture of methyl 4-methoxyacetylacetate (17.71mL, 136.85mmol) and N,N-dimethylformamide dimethylacetal (18.32mL, 136.85mmol) was heated and stirred at 85°C, and the oxalic acid Dimethyl ester (32.32g, 273.70mmol) was added to the reaction solution, stirred until the reaction was complete, and cooled to room temperature, 30% sodium methoxide methanol solution (52.1542mL, 273.7082mmol) was added to the reaction solution, and the stirring was continued After reacting for 2-4 hours, the reaction was quenched with 50 ml of acetic acid, and purified by a C18 reverse phase chromatography column to obtain the title compound 4a (15.8 g, yield 48%).

MS(ESI)m/z 265.3[M+Na] ⁺

Second step

6-[(2-Ethoxy-2-oxoethyl)amino] ethyl hexanoate 4d

Ethyl 5-oxohexanoate (3g, 18.96mmol) was dissolved in 10mL of methanol, and ethyl 2-aminoacetate hydrochloride (2.65g, 18.96mmol) and triethylamine (2.64mL, 18.96mmol) were added in sequence. ) And sodium cyanoborohydride (2.38g, 37.93mmol), stir the reaction at room temperature until the reaction is almost complete, quench the reaction with 20ml saturated sodium bicarbonate, concentrate the mixed solution, add dichloromethane (20mL×2), saturated brine It was washed, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 4d (4g), which was used directly in the next step.

MS(ESI)m/z 246.2[M+H] ⁺

third step

5-((Third-butoxycarbonyl)(2-ethoxy-2-carbonylethyl)amino) ethyl hexanoate 4e

Compound 4d (4g, 16.30mmol) was dissolved in 20mL of dichloromethane, and di-tertiary butyl dicarbonate (4.19mL, 19.57mmol) and triethylamine (6.80mL, 48.92mmol) were added successively, and the reaction was carried out at room temperature. When the reaction was basically complete, the reaction was quenched by adding water, separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 4e (6g), which was directly used in the next step.

MS(ESI)m/z 368.3[M+H] ⁺

the fourth step

7-Methyl-3-carbonylazepane-1,4-dicarboxylic acid 1-(tert-butyl ester) 4-ethyl ester 4f

7-Methyl-3-carbonylazepane-1,2-dicarboxylic acid 1-(tert-butyl ester) 2-ethyl ester 4g

Compound 4e (4g, 11.5797mmol) was dissolved in 10mL of toluene, and sodium tert-butoxide (1.78g, 18.53mmol) was added to the reaction. The reaction solution was reacted at 110°C until the reaction was almost complete. Concentrated to obtain the crude title compound 4f. The mixture (6g) with compound 4g was used directly in the next step.

MS(ESI)m/z 322.3[M+Na] ⁺

the fifth step

Tert-butyl 2-methyl-6-carbonyl azepine-1-carboxylate 4h

The mixed crude product (6g) of compound 4f and compound 4g was dissolved in a mixed solution of 10mL of water and 10mL of tetrahydrofuran, and sodium hydroxide (2.40g, 60.13mmol) was added, and the reaction was reacted at 70°C until the reaction was almost complete. It was extracted with ethyl acetate (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by C18 reaction to obtain the title compound 4h (0.9g, total yield of 31% in four steps).

MS(ESI)m/z 250.2[M+H] ⁺

Sixth step

6-amino-2-methylazepane-1-carboxylic acid tert-butyl ester 4i

Compound 11 (0.9g, 3.96mmol) was dissolved in 5ml of methanol, and then ammonium formate (2.50g, 39.60mmol) and 10% palladium on carbon (0.18g) were added successively, stirred and heated for reaction, filtered, and concentrated to obtain a crude product. Purified by C18 reverse phase, the title compound 4i (400 mg, yield 44.24%) was obtained.

MS(ESI)m/z 229.3[M+H] ⁺

Seventh step

1-(1-(Third-butoxycarbonyl)-7-methylazepan-3-yl)-3-methoxy-4-carbonyl-1,4-dihydropyridine-2,5- Dimethyl Dicarboxylate 4j

Compound 4i (424.25mg, 1.75mmol) was dissolved in 5ml of ethanol, then compound 12 (400mg, 1.75mmol) was added to the reaction solution, reacted at 80°C until the reaction was almost complete, and concentrated under reduced pressure to obtain the crude product. Phase purification gave the title compound 4j (400mg, yield 50.46%).

MS(ESI)m/z 453.5[M+H] ⁺

Eighth step

1-(1-(Third-butoxycarbonyl)-7-methylazepan-3-yl)-3-methoxy-4-carbonyl-1,4-dihydropyridine-2,5- Dimethyl Dicarboxylate 4k

Compound 4j (400mg, 0.88mmol) was dissolved in 5ml of xylene, and then acetic acid (530.84mg, 8.84mmol) and 2,4-difluorobenzylamine (126.53mg, 0.88mmol) were added sequentially. The reaction was complete and concentrated under reduced pressure to obtain the crude product. The crude product was purified by C18 reverse phase to obtain the title compound 4k (350 mg, 70.25%).

MS(ESI)m/z 564.5[M+H] ⁺

Step 9

5-((2,4-Difluorobenzyl)aminomethyl)-3-methoxy-1-(7-methylazeppan-3-yl)-4-carbonyl-1,4- Dihydropyridine-2-carboxylic acid 4l

Compound 4k (350mg, 0.6210mmol) was dissolved in 10ml of methanol, and lithium hydroxide (52mg, 1.2420mmol) and water (22mg, 1.2420mmol) were added in sequence. The reaction was carried out at 70°C until the reaction was almost complete, and the crude product was obtained by concentration. It was diluted with 4 mol/L of hydrochloric acid methanol solution (10 mL), and the reaction was continued for 3 hours at room temperature. The reaction solution was concentrated to obtain compound 4l (370 mg).

MS(ESI)m/z 450.4[M+H] ⁺

Tenth step

N -(2,4-Difluorobenzyl)-12-methoxy-3-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3H-2 ,7-Methylenepyrido[1,2-a][1,4]diazononinyl-10-carboxamide 4m

Compound 4l (320mg, 0.71mmol) was dissolved in N,N -dimethylformamide (5mL), and O -(7-azabenzotriazole-1-YL) -N,N,N was added sequentially , N -tetramethylurea hexafluorophosphonium salt (541.45mg, 1.42mmol) and N,N -diisopropylethylamine (0.35mL, 2.14mmol), react at room temperature until the reaction is almost complete, and the reaction solution Purified by C18 reverse phase to obtain the title compound 4m (200 mg, yield 65.11%).

MS(ESI)m/z 432.4[M+H] ⁺

Eleventh step

( 3R,7R ) -N -(2,4-Difluorobenzyl)-12-methoxy-3-methyl-1,11-dicarbonyl-1,4,5,6,7,11- Hexahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide 4n

( 3S,7S ) -N -(2,4-Difluorobenzyl)-12-methoxy-3-methyl-1,11-dicarbonyl-1,4,5,6,7,11- Hexahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononin-10-carboxamide 4o

The compound 4m (60 mg, 0.138 mmol) was resolved by supercritical fluid chromatography on a Chiralpak AD chiral column to obtain the title compound 4n (23.3 mg, yield 38.83%) and the title compound 4o (19.4 mg, 32.33%).

Chromatographic conditions:

Chromatographic column: Chiralpak AD-3 50×4.6mm I.D., 3um

Mobile phase: A: carbon dioxide; B: ethanol (0.05% diethylamine)

Twelfth step

( 3S,7S ) -N -(2,4-Difluorobenzyl)-12-hydroxy-3-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro -3 H -2,7-methylenepyrido[1,2-a][1,4]diazononin-10-carboxamide 4

Compound 4o (46mg, 0.11mmol) was dissolved in 3ml of acetonitrile, and magnesium dibromide (39.25mg, 0.21mmol) was added. The reaction was carried out at 50℃ until the reaction was almost complete. The crude product was concentrated and purified by C18 reverse phase. , The title compound 4 (31mg, yield 70%) was obtained

MS(ESI)m/z 418.5[M+H] ⁺

¹ H NMR(400MHz, DMSO- d ₆ )d 10.39-10.46(m,1 H)8.49(s,1 H)7.36-7.45(m,1 H)7.20-7.28(m,1 H)7.02-7.11( m,1 H)4.77(br s,1 H)4.55(br d,J=5.77Hz,2 H)4.42-4.50(m,1 H)3.64-3.75(m,2 H)1.97-2.07(m, 2 H)1.76-1.85(m,1 H)1.57-1.67(m,1 H)1.40-1.51(m,1 H)1.18(d,J=6.53Hz,3 H)0.97-1.01(m,1 H) ).

Example 5

( 3R,7R ) -N -(2,4-Difluorobenzyl)-12-hydroxy-3-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro -3H-2,7-Methylenepyrido[1,2-a][1,4]diazononinyl-10-carboxamide 5

Compound 4n (23mg, 0.05mmol) was dissolved in 3ml of acetonitrile, magnesium dibromide (19.6mg, 0.11mmol) was added, and the reaction was carried out at 50°C for 1 hour. The reaction solution was concentrated to obtain the crude product, which was then purified by C18 reverse phase to obtain the title compound 5 (21 mg, yield 94%).

MS(ESI)m/z 418.5[M+H] ⁺

¹ H NMR (400MHz, DMSO- d ₆ ) d 10.43-10.50 (m, 1 H) 8.44 (s, 1 H) 7.34-7.44 (m, 1 H) 7.19-7.28 (m, 1 H) 7.01-7.10 ( m,1 H)4.75(br s,1 H)4.54(br d,J=5.63Hz,2 H)4.42-4.50(m,1 H)3.61-3.73(m,2 H)1.96-2.07(m, 2 H)1.73-1.86(m,1 H)1.54-1.65(m,1 H)1.39-1.52(m,1 H)1.17(d,J=6.63Hz,3 H)0.96-1.04(m,1 H) ).

Example 6

N -(2,4-Difluorobenzyl)-12-hydroxy-4-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2, 7-Methylenepyrido[1,2-a][1,4]diazononinyl-10-formamide isomer (A) 6

first step

3-(allylamino) ethyl propionate 6c

Dissolve allylamine hydrochloride 6a (50g, 534.44mmol) and 1,8-diazabicycloundec-7-ene (108.5g, 712.59mmol) in 750ml of ethanol, add acrylic acid at room temperature Ethyl ester 6b (35.7g, 356.30mmol), stir the reaction at room temperature until the reaction is almost complete, concentrate the reaction solution, add 400ml of water and adjust the pH to 11 with saturated sodium hydroxide solution, extract with ethyl acetate, brine Washed, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 6c . The product does not require further purification and is used directly in the next step.

Second step

Ethyl 3-(allyl(third-butoxycarbonyl)amino)propionate 6d

The crude compound 6c (56 g, 356 mmol) was dissolved in 600 ml of dichloromethane, and di-tertiary butyl dicarbonate (85.5 g, 391.93 mmol) was added at room temperature. The reaction was stirred at room temperature until the reaction was almost complete, washed with 200 ml of water, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (the eluent was 0~8.5% ethyl acetate petroleum Ether mixed solvent) to obtain the title compound 6d (77.18 g, the total yield of two steps is 84%).

¹ H NMR: (400MHz, CDCl ₃ )5.94-5.59(m,1H), 5.27-4.97(m,2H), 4.13(q,J=7.2Hz,2H), 3.93-3.74(m,2H), 3.55 -3.37(m,2H),2.67-2.44(m,2H),1.45(s,9H),1.25(t,J=7.2Hz,3H).

third step

2-((allyl(third-butoxycarbonyl)amino)methyl)pent-4-enoic acid ethyl ester 6e

Dissolve compound 6d (77.66g, 301.80mmol) in 600ml tetrahydrofuran, cool to -78°C, add bistrimethylsilylamide lithium tetrahydrofuran solution (25.3mL, 1mol/L) in sequence under nitrogen protection, Allyl iodide (60.8 g, 362.16 mmol). The temperature is naturally raised to room temperature and the reaction is stirred until the reaction is basically complete, and 500 ml of saturated ammonium chloride solution is added under ice bath conditions and stirred for 15 minutes. The mixture was extracted with 800 ml of ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (the eluent was 0~5% ethyl acetate in petroleum ether mixed solvent ) To obtain the title compound 6e (42.67 g, yield 47%). MS(ESI)m/z 297.9[M+H] ⁺

¹ H NMR: (400MHz, CDCl ₃ ) 5.87-5.61 (m, 2H), 5.17-4.98 (m, 4H), 4.14-4.10 (m, 2H), 4.02-3.80 (m, 1H), 3.68 (dd, J=6.0, 16.0Hz, 1H), 3.50-3.33 (m, 1H), 3.29 (dd, J=8.8, 14.4Hz, 1H), 2.97-2.70 (m, 1H), 2.38-2.28 (m, 1H) , 2.27-2.12 (m, 1H), 1.45 (br s, 9H), 1.25 (t, J=7.2Hz, 3H).

the fourth step

2,3,4,7-Tetrahydro-1H-azepine-1,3-dicarboxylic acid 1-(tert-butyl ester) 3-ethyl ester 6f

Compound 6e (6.88g, 23.31mmol) was dissolved in 700ml of tetrahydrofuran, and the second generation Grubbs catalyst (1.43g, 1.68mmol) was added. After replacing the gas with a nitrogen balloon for three times, the reaction solution was heated to 55°C and stirred until the reaction was almost complete, concentrated to obtain a crude product, and then purified by column chromatography (the eluent phase is 0.5-15% ethyl acetate and petroleum ether mixed solvent) , The title compound 6f (4.67g, yield 75%) was obtained.

MS(ESI)m/z 269.9[M+H] ⁺

¹ H NMR: (400MHz, CDCl ₃ )5.83-5.53(m,2H),4.21-4.08(m,3H),4.02-3.71(m,2H),3.51(dd,J=8.8,14.0Hz,1H) , 3.00-2.82 (m, 1H), 2.52-2.33 (m, 2H), 1.47-1.44 (m, 9H), 1.28-1.23 (m, 3H).

the fifth step

6-Hydroxyazepane-1,3-dicarboxylic acid 1-(tert-butyl ester) 3-ethyl ester isomer (A) 6g

5-Hydroxyazepane-1,3-dicarboxylic acid 1-(tert-butyl ester) 3-ethyl ester isomer (B) 6h

Compound 6f (4.67 g, 17.34 mmol) was dissolved in 50 ml of tetrahydrofuran, and borane dimethyl sulfide (3.5 mL, 10 mol/L) was slowly added dropwise at 0° C. under nitrogen protection. The reaction solution is reacted for 1-3 hours at 10°C or less. Slowly add sodium hydroxide solution (3.12mL, 3mol/L) at 0°C, and then add hydrogen peroxide (7.86g, 69.36mmol). The reaction was stirred at room temperature until the reaction was almost complete. At 0°C, 60 mL of saturated sodium bisulfite solution was added to the reaction solution to quench the reaction, and then extracted with 40 mL of ethyl acetate and 30 mL of saturated sodium bisulfite. It was washed with sodium bisulfate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of the title compound 6g and 6h (4.22g, crude product), which was used directly in the next step without further purification.

MS(ESI)m/z 309.9[M+Na] ⁺

Sixth step

6-Carbonylazepane-1,3-dicarboxylic acid 1-(tert-butyl ester) 3-ethyl ester isomer (A) 6i

5-Carbonylazepane-1,3-dicarboxylic acid 1-(tert-butyl ester) 3-ethyl ester isomer (B) 6j

The mixture of compound 6g and 6h (4.2g) was dissolved in 85 ml of dichloromethane, and Dess-Martin oxidant (7.44g, 17.54mmol) was added at 0°C, and the reaction was stirred at room temperature until the reaction was almost complete. Filter through celite and wash with 10 ml of dichloromethane. The filtrate was washed with 40 ml saturated sodium bicarbonate solution, then washed with 50 ml saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (the extraction phase is 2~ 4% ethyl acetate in petroleum ether mixed solvent) to obtain title compound 6i (2.14 g, 51% yield), compound 6j (760 mg, yield 18%).

Analytical data of compound 6i : MS(ESI) m/z 229.9[M-56+H] ⁺

¹ H NMR: (400MHz, CDCl ₃ ) 4.68-4.23 (m, 2H), 4.19-4.12 (m, 2H), 3.53 (dd, J=18.8, 47.6 Hz, 1H), 3.01-2.77 (m, 2H) , 2.67-2.51 (m, 2H), 2.27-2.16 (m, 1H), 1.79-1.67 (m, 1H), 1.53-1.44 (m, 9H), 1.29-1.25 (m, 3H).

Analytical data of compound 6j : MS (ESI) m/z 229.8 [M-56+H] ⁺

¹ H NMR: (400MHz, CDCl ₃ ) 4.24-3.72 (m, 4H), 3.59-3.38 (m, 2H), 3.02-2.56 (m, 5H), 1.46 (s, 9H), 1.30-1.24 (m, 3H).

Seventh step

6-methylene azepan-1,3-dicarboxylic acid 1-(tert-butyl ester) 3-ethyl ester 6k

Dissolve methyltriphenylphosphonium bromide (6.0g, 16.82mmol) in 60ml of tetrahydrofuran, add 2.5 moles per liter of n-butyl n-hexane solution (5.6mL ,2.5 mol/liter). React at -20~-10°C for 30 minutes, then add 10 ml of a tetrahydrofuran solution in which compound 6i (2g, 7.00mmol) is dissolved, and then stir the reaction at room temperature until the reaction is almost complete. It was quenched with 30 ml of saturated ammonium chloride solution, extracted with 30 ml of ethyl acetate, washed with 25 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (extracted phase 2~3% ethyl acetate in petroleum ether mixed solvent) to obtain the title compound 6k (1255mg, yield 63%).

MS(ESI)m/z 305.9[M+Na] ⁺

¹ H NMR: (400MHz, CDCl ₃ )5.01-4.78(m,2H), 4.49(dd,J=15.6,81.2Hz,1H), 4.20-3.89(m,3H),3.59(dd,J=15.2, 36.0Hz, 1H), 2.95-2.82 (m, 1H), 2.80-2.55 (m, 1H), 2.55-2.42 (m, 1H), 2.16-2.08 (m, 1H), 2.07-1.95 (m, 1H) ,1.63-1.53(m,1H),1.53-1.41(m,9H),1.25(dt,J=4.0,7.2Hz,3H).

Eighth step

6-Methylazepane-1,3-dicarboxylic acid 1-(tert-butyl ester) 3-ethyl ester 6l

Compound 6k (1.25 g, 4.41 mmol) was dissolved in 30 mL of ethanol, and 10% palladium on carbon (400 mg) was added. The reaction solution was reacted at 60° C. for 3 hours under a hydrogen pressure of 50 psi, filtered through Celite, washed with 20 ml of ethanol, and concentrated under reduced pressure to obtain 6 liters of the title compound (1.2 g, yield 99%).

MS(ESI)m/z 285.9[M+H] ⁺

Step 9

1-(Third-butoxycarbonyl)-6-methylazepane-3-carboxylic acid 6m

Compound 6l (1.25g, 4.37mmol) was dissolved in 10ml of methanol and 10ml of water, potassium hydroxide (0.49g, 8.73mmol) was added, heated to 50°C and stirred until the reaction was almost complete, and concentrated to remove methanol. Dilute with 30 ml of water, adjust the pH to 12 with saturated sodium hydroxide solution, then extract with 15 ml of ethyl acetate, wash with brine, dry with anhydrous sodium sulfate, and filter. Concentrate under reduced pressure to obtain the title compound 6m (1.25 g, crude product).

MS(ESI)m/z 258.0[M+H] ⁺

Tenth step

-3-(((benzyloxy)carbonyl)amino)-6-methylazepane-1-carboxylic acid tert-butyl ester isomer (A) 6n

-3-(((Benzyloxy)carbonyl)amino)-6-methylazepane-1-carboxylic acid tert-butyl ester isomer (B) 6o

Compound 6m (500 mg, 1.94 mmol) was dissolved in 10 mL of toluene, and diphenyl azide phosphate (1.07 g, 3.89 mmol) and triethylamine (393 mg, 3.89 mmol) were added. After replacing the nitrogen with the reaction solution three times, it was heated to 90°C for 2 hours of reaction. Benzyl alcohol (420 mg, 3.89 mmol) was added to the reaction solution, and the reaction was continued to be stirred at 90° C. until the reaction was almost complete. Dilute with 30 ml ethyl acetate, wash with 15 ml brine, dry with anhydrous sodium sulfate, and filter. Concentrate to obtain the crude product, which is purified by column chromatography (the eluent is 6.5-9% ethyl acetate and petroleum ether mixed solvent) to obtain the title compound 6n (150mg, 27% yield) and title compound 6o (170mg, yield 31%).

Analytical data of compound 6n : MS(ESI) m/z 385.0[M+Na] ⁺

¹ H NMR: (400MHz, CDCl ₃ )7.43-7.27(m,5H), 5.20-4.97(m,2H), 4.07-3.64(m,3H), 3.37-3.09(m,1H), 2.45-2.20( m, 1H), 2.18-1.99 (m, 1H), 1.89-1.66 (m, 2H), 1.55-1.40 (m, 9H), 1.36-1.22 (m, 1H), 1.18-1.00 (m, 1H), 0.93-0.79 (m, 3H).

Analytical data of compound 6o : MS(ESI) m/z 385.0[M+Na] ⁺

Eleventh step

Tertiary-butyl-3-amino-6-methylazepane-1-carboxylic acid eluting ester 6p

Compound 6n (150 mg, 0.41 mmol) was dissolved in 10 mL of ethanol, and 10% palladium on carbon (150 mg) was added. The reaction was carried out under the hydrogen pressure of a hydrogen balloon (15 Psi), and the reaction was stirred at room temperature until the reaction was almost complete. Filter through Celite, wash the filter cake, and concentrate under reduced pressure to obtain the title compound 6p (100 mg, yield 100%).

MS(ESI)m/z 229.0[M+H] ⁺

Twelfth step

1-(1-(Third-butoxycarbonyl)-6-methylazepan-3-yl)-3-methoxy-4-carbonyl-1,4-dihydropyridine-2,5- Dicarboxylic acid 2-ethyl ester 5-methyl ester 6q

Compound A1 (89.8 mg, 0.35 mmol) was dissolved in 2 ml of ethanol, and compound 6p (80 mg, 0.35 mmol) and acetic acid (103.4 mg, 1.75 mmol) were added at room temperature. The reaction solution was stirred and reacted at 80°C until the reaction was almost complete, and concentrated to obtain the crude title compound 6q , which was directly used in the next step.

MS(ESI)m/z 467.1[M+H] ⁺

Step 13

-3-(5-((2,4-Difluorobenzyl)aminomethyl)-2-(carbethoxycarbonyl<ethoxycarbonyl>)-3-methoxy-4-carbonylpyridine-1( 4H)-yl)-6-methylazepane-1-carboxylic acid tert-butyl ester 6r

The crude compound 6q from the previous step was dissolved in 2 ml of p-xylene, and 1 g (75 mg, 0.53 mmol) of 2,4-difluorobenzylamine and acetic acid (207 mg, 3.50 mmol) were added at room temperature. After reacting at 180°C for 2 hours, 1 g (30 mg) of 2,4-difluorobenzylamine was added to the reaction solution to continue the reaction until it was almost complete. Concentrate to obtain the crude title compound 6r , which is used directly in the next step.

MS(ESI)m/z 578.1[M+H] ⁺

Step Fourteen

N -(2,4-Difluorobenzyl)-12-methoxy-4-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H- 2,7-Methylenepyrido[1,2-a][1,4]diazononinyl-10-formamide isomer (A) 6s

N -(2,4-Difluorobenzyl)-12-hydroxy-4-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2, 7-Methylenepyrido[1,2-a][1,4]diazononinyl-10-formamide isomer (B) 6t

The crude compound 6r from the previous step was dissolved in 3 ml of p-xylene, and p-toluenesulfonic acid (50 mg, 0.26 mmol) was added at room temperature. The reaction was reacted to almost complete at 180°C, and concentrated to obtain a crude product. Purification by column chromatography (developing solvent is ethyl acetate) to obtain the racemic compound. The racemic compound was resolved by supercritical fluid chromatography on a DAICEL CHIRALCEL OD-H chiral column to obtain the title compound 6s (21.4 mg, the total yield of three steps is 14%) and the title compound 6t (21.2 mg, three steps). Step total yield 14%).

The chiral analysis method is as follows:

Analysis column: Chiralpak AD-3 50×4.6mm I.D., 3um

Mobile phase: A: carbon dioxide B: ethanol (0.05% diethylamine)

Gradient: rise from 5% B phase to 40% B in 5 minutes, then keep 40% B flush for 2.5 minutes, and finally return to 5% B phase rinse for 2.5 minutes

Flow rate: 2.5 ml/min

Column temperature: 35℃

Pressure: 1500psi

Compound 6s retention time 4.852 minutes, MS(ESI) m/z 432.1[M+H] ⁺

¹ H NMR: (400MHz, CDCl ₃ ) 10.49 (t, J=5.6 Hz, 1H), 8.42 (s, 1H), 7.41-7.32 (m, 1H), 6.88-6.74 (m, 2H), 4.71-4.56 (m, 2H), 4.49 (dd, J=5.6, 13.2 Hz, 1H), 4.37-4.29 (m, 1H), 4.10 (s, 3H), 3.89-3.81 (m, 1H), 3.56 (dd, J =2.4, 14.4Hz, 1H), 2.72-2.60 (m, 1H), 2.49 (dd, J=11.2, 13.6Hz, 1H), 2.24-2.09 (m, 1H), 1.85-1.74 (m, 1H), 1.61-1.43(m,2H),1.00(d,J=6.8Hz,3H).

The retention time of compound 6t is 5.788 minutes, MS(ESI) m/z 432.1[M+H] ⁺

¹ H NMR: (400MHz, CDCl3) 10.49 (t, J = 5.6 Hz, 1H), 8.42 (s, 1H), 7.41-7.32 (m, 1H), 6.91-6.69 (m, 2H), 4.71-4.56 ( m,2H), 4.49(dd,J=6.0,14.0Hz,1H), 4.37-4.29(m,1H),4.09(s,3H),3.90-3.81(m,1H),3.56(dd,J= 2.4, 14.8Hz, 1H), 2.73-2.60 (m, 1H), 2.49 (dd, J=11.6, 13.6Hz, 1H), 2.24-2.10 (m, 1H), 1.83-1.75 (m, 1H), 1.61 -1.43(m,2H),1.00(d,J=6.4Hz,3H).

Fifteenth step

N -(2,4-Difluorobenzyl)-12-hydroxy-4-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2, 7-Methylenepyrido[1,2-a][1,4]diazononinyl-10-formamide isomer (A) 6

Compound 6s (21 mg, 0.05 mmol) was dissolved in 3 ml of acetonitrile, magnesium dibromide (18 mg, 0.10 mmol) was added, and the reaction was completed at 50°C. Concentrated to obtain the crude product, and then purified by C18 reverse phase to obtain the title compound 6 (9 mg, yield 45%).

MS(ESI)m/z 418.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d6) 10.38(t,J=5.6Hz,1H), 8.47(s,1H),7.44-7.36(m,1H),7.27-7.20(m,1H),7.09-7.02 (m,1H),4.79-4.70(m,1H),4.54(d,J=5.6Hz,2H), 4.18(dd,J=5.6,13.2Hz,1H),3.86-3.73(m,2H), 2.71-2.56 (m, 2H), 1.91-1.75 (m, 1H), 1.67-1.48 (m, 2H), 1.36-1.25 (m, 1H), 0.89 (d, J=6.4Hz, 3H).

Example 7

N -(2,4-Difluorobenzyl)-12-hydroxy-4-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2, 7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide isomer (B) 7

Compound 7 was synthesized by compound 6t , referring to the synthesis method in the fifteenth step of Example 6.

MS(ESI)m/z 418.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d6)10.38(br t,J=5.6Hz,1H), 8.48(s,1H),7.45-7.36(m,1H),7.27-7.19(m,1H),7.10- 7.02(m,1H),4.79-4.70(m,1H),4.54(br d,J=5.6Hz,2H), 4.18(br dd,J=5.6,13.2Hz,1H),3.87-3.73(m, 2H),2.71-2.54(m,2H),1.91-1.73(m,1H),1.68-1.48(m,2H),1.36-1.25(m,1H),0.89(d,J=6.4Hz,3H)

Example 8

N -(2,4-Difluorobenzyl)-12-hydroxy-4-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2, 7-Methylenepyrido[1,2-a][1,4]diazononinyl-10-formamide isomer (C) 8

Compound 8 was synthesized by intermediate 6o , referring to the synthesis method of Example 6 from step 11 to step 15.

MS(ESI)m/z 418.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d6) 10.40(t,J=6.0Hz,1H), 8.47(s,1H),7.44-7.36(m,1H),7.28-7.20(m,1H),7.10-7.02 (m,1H),4.76(br s,1H),4.54(d,J=6.0Hz,2H),3.87(d,J=14.8Hz,1H),3.73-3.65(m,2H),3.22(dd ,J=7.2,12.8Hz,2H),2.18-2.10(m,1H),2.05-1.97(m,1H),1.96-1.87(m,1H),1.45-1.37(m,1H),1.16-1.00 (m,1H),0.94(d,J=6.4Hz,3H).

Example 9

(4 R ,7 R ) -N -(2,4-Difluorobenzyl)-12-hydroxy-4-methyl-1,11-dicarbonyl-1,4,5,6,7,11- Hexahydro-3 H -2,7-methylenepyrido[1,2-a][1,4]diazononin-10-carboxamide isomer (D) 9

Compound 9 was synthesized by intermediate 6o , referring to the synthesis method of Example 6 from step 11 to step 15.

MS(ESI)m/z 418.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d6) 10.40 (t, J=6.0Hz, 1H), 8.47 (s, 1H), 7.43-7.36 (m, 1H), 7.27-7.20 (m, 1H), 7.09-7.03 (m,1H),4.76(br s,1H),4.54(d,J=6.0Hz,2H),3.90-3.83(m,1H),3.22(br dd,J=6.8,12.8Hz,3H), 2.17-2.10(m,1H),2.05-1.97(m,1H),1.95-1.87(m,1H),1.45-1.37(m,1H),1.12-1.00(m,1H),0.94(d,J =6.8Hz,3H).

Example 10

N -(2,4-Difluorobenzyl)-5,5-difluoro-12-hydroxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H- 2,7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide isomer (A) 10

first step

5,5-Difluoroazepane-1,3-dicarboxylic acid 1-(tert-butyl ester) 3-ethyl ester 10a

Dissolve 5-carbonylazepane-1,3-dicarboxylic acid 1-(tert-butyl ester) 3-ethyl ester 6j (390 mg, 1.37 mmol) in 8 ml of dichloromethane at room temperature Add diethylaminosulfur trifluoride (0.7 mL, 5.47 mmol). The reaction was reacted at room temperature until the reaction was almost complete, 30 ml of saturated sodium bicarbonate solution was added, extracted with 30 ml of dichloromethane, washed with saturated brine, dried, filtered, and concentrated to obtain a crude product. The crude product was purified by column layer (the eluent phase was 0-10% ethyl acetate in petroleum ether mixed solvent) to obtain the title compound 10a (410 mg, yield 48%).

MS(ESI)m/z252.1[M-56+H] ⁺

¹ H NMR: (400MHz, CDCl ₃ ) 4.23-4.14 (m, 2H), 3.93-3.74 (m, 1H), 3.65-3.30 (m, 3H), 3.05-2.89 (m, 1H), 2.55-2.08 ( m, 4H), 1.52-1.46 (m, 9H), 1.27-1.25 (m, 3H).

Second step

1-(Third-butoxycarbonyl)-5,5-difluoroazepane-3-carboxylic acid 10b

Compound 10a (160mg, 0.52mmol) was dissolved in 2ml of methanol, sodium hydroxide (41.6mg, 1.04mmol) was dissolved in 2ml of water and added to the reaction solution at room temperature. The reaction was reacted at 60°C until the reaction was almost complete, concentrated to remove methanol, diluted with 5 ml of water, and extracted with 5 ml of ethyl acetate. The aqueous phase was adjusted to pH 2~3 with 2 moles per liter of hydrochloric acid solution, extracted with 5 ml of ethyl acetate, the combined organic phase was washed with 10 ml of brine, dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound 10b (95 mg, yield 65%) was obtained.

MS(ESI)m/z 223.9[M-56+H] ⁺

¹ H NMR: (400MHz, CDCl ₃ ) 3.83-3.69 (m, 2 H), 3.67-3.48 (m, 1H), 3.35-3.23 (m, 1H), 3.12-2.92 (m, 1H), 2.39-2.15 (m, 4H), 1.51-1.42 (m, 9H).

third step

3-Aminomethyl-5,5-difluoroazepane-1-carboxylic acid tert-butyl ester 10c

Compound 10b (95mg, 0.34mmol) was dissolved in 1 ml of dichloromethane, and ammonium chloride (182.0mg, 3.40mmol), triethylamine (0.07mL, 0.51mmol) and HATU condensing agent ( 168.2mg, 0.44mmol). The reaction was carried out at 25°C until the reaction was almost complete. Add 5 ml of water to dilute, then extract with dichloromethane, wash with brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain crude product. The crude product was purified by column layer (the eluent phase was 0-65% ethyl acetate in petroleum ether mixed solvent) to obtain the title compound 10c (75 mg, yield 79%).

MS(ESI)m/z 222.9[M-56+H] ⁺

¹ H NMR: (400MHz, CDCl ₃ ) 7.08-6.87 (m, 1H), 5.71-5.32 (m, 1H), 3.74-3.61 (m, 2H), 3.60-3.49 (m, 1H), 3.43-3.28 ( m, 1H), 2.93-2.82 (m, 1H), 2.51-2.04 (m, 4H), 1.48 (s, 9H).

the fourth step

3-(((benzyloxy)carbonyl)amino)-5,5-difluoroazepane-1-carboxylic acid tert-butyl ester 10d

Compound 10c (470mg, 1.69mmol) and benzyl alcohol (0.9mL, 8.44mmol) were dissolved in 5ml of dichloromethane, and 1,8-diazabicycloundec- 7-ene (0.8 mL, 5.07 mmol) and N-bromosuccinimide (360.7 mg, 2.03 mmol). The reaction was reacted at room temperature until the reaction was almost complete, diluted with 5 ml of water, and then extracted with 5 ml of dichloromethane respectively, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by C18 (the eluent was methanol and water containing 0.1% ammonia) to obtain the title compound 10d (390 mg, yield 60%).

¹ H NMR: (400MHz, CDCl ₃ ) 7.43-7.30 (m, 5H), 5.87-5.72 (m, 1H), 5.23-5.03 (m, 2H), 4.24-4.15 (m, 1H), 3.81-3.33 ( m, 4H), 2.70-2.38 (m, 1H), 2.37-2.06 (m, 3H), 1.48 (s, 9H).

the fifth step

3-Amino-5,5-difluoroazepane-1-carboxylic acid tert-butyl ester 10e

Compound 10d (410 mg, 1.07 mmol) was dissolved in 4 mL ethyl acetate and 1 mL tetrahydrofuran, and 100 mg palladium carbon was added at room temperature. It was reacted at room temperature under hydrogen atmosphere until the reaction was almost complete, filtered, and concentrated to obtain the title compound 10e (210 mg, yield 78%).

¹ H NMR: (400MHz, CDCl ₃ )δ=3.80-3.07(m,5H), 2.37-1.95(m,4H), 1.54-1.41(m,9H).

Sixth step

1-(1-(Third-butoxycarbonyl)-5,5-difluoroazepan-3-yl)-3-methoxy-4-carbonyl-1,4-dihydropyridine-2, 5-Dicarboxylic acid 2-ethyl ester 5-methyl ester 10f

Compound 1A (184.3 mg, 0.72 mmol) was dissolved in 2 mL of ethanol, and compound 10e (180 mg, 0.72 mmol) and acetic acid (0.2 mL, 3.60 mmol) were added at room temperature. The reaction was carried out at 80°C until the reaction was almost complete, and concentrated to obtain the title compound 10f (520 mg, crude product), which was directly used in the next step.

MS(ESI)m/z 489.4[M+H] ⁺

Seventh step

3-(5-((2,4-Difluorobenzyl)aminomethyl)-2-(carbethoxycarbonyl<ethoxycarbonyl>)-3-methoxy-4-carbonylpyridine-1(4H )-Yl)-5,5-difluoroazepane-1-carboxylic acid tert-butyl ester 10g

Compound 10f (520 mg) was dissolved in 5 ml of p-xylene, and 1 g (0.13 mL, 1.08 mmol) of 2,4-difluorobenzylamine and acetic acid (0.4 mL, 7.19 mmol) were added at room temperature. The reaction solution was reacted at 160°C until the reaction was almost complete, and concentrated to obtain 10 g (520 mg, crude product) of the title compound, which was used directly in the next step without purification.

MS(ESI)m/z 600.2[M+H] ⁺

Eighth step

N -(2,4-difluorobenzyl)-5,5-difluoro-12-methoxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2,7-methylenepyrido[1,2-a][1,4]diazononinyl-10-carboxamide isomer (A) 10h

N-(2,4-Difluorobenzyl)-5,5-difluoro-12-methoxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3H -2,7-Methylenepyrido[1,2-a][1,4]diazononinyl-10-carboxamide isomer (B) 10i

Compound 10g (430mg, 0.72mmol) was dissolved in 5ml of p-xylene, and p-toluenesulfonic acid (409mg, 2.15mmol) was added at room temperature. The reaction solution was reacted at 160°C until the reaction was almost complete, and concentrated to obtain a crude product. The crude product is purified by column layer (the phase is 0-100% ethyl acetate and petroleum ether mixed solvent) to obtain the racemic compound. The racemic compound was resolved by supercritical fluid chromatography on a DAICEL CHIRALCEL OD-H chiral column to obtain the title compound 10h (31.4mg, yield 9.6%) and title compound 10i (30.6mg, yield 9.4%) ).

The chiral analysis method is as follows:

Analysis column: Chiralpak AD-3 50×4.6mm I.D., 3um

Mobile phase: A: carbon dioxide B: ethanol (0.05% diethylamine)

Gradient: Rinse from 5% B phase to 40% B flush in 5 minutes, then keep 40% B flush for 3 minutes, and finally return to 5% B phase flush for 1.5 minutes

Flow rate: 2.5 ml/min

Column temperature: 40℃

Pressure: 100bar

Compound 10h retention time 4.428 minutes, MS(ESI) m/z 454.1[M+H]+

¹ H NMR: (400MHz, DMSO-d6) 10.41 (t, J = 6.0 Hz, 1H), 8.65 (s, 1H), 7.45-7.36 (m, 1H), 7.27-7.20 (m, 1H), 7.06 ( td, J =8.4,1.6Hz,1H),4.81(br d, J =6.0Hz,1H),4.60-4.49(m,2H),4.25-4.15(m,1H),4.03-3.95(m,1H) ), 3.85(s, 3H), 3.84-3.79(m, 1H), 3.16-3.06(m, 1H), 2.84-2.72(m, 1H), 2.65-2.53(m, 3H).

Compound 10i retention time 5.519 minutes, MS(ESI) m/z 454.1[M+H]+

¹ H NMR: (400MHz, DMSO-d6) 10.41 (t, J = 6.0 Hz, 1H), 8.65 (s, 1H), 7.45-7.36 (m, 1H), 7.28-7.20 (m, 1H), 7.07 ( td, J =8.4,1.6Hz,1H), 4.81(br d, J =6.0Hz,1H), 4.60-4.49(m,2H),4.25-4.16(m,1H),4.03-3.95(m,1H) ), 3.86 (s, 3H), 3.85-3.80 (m, 1H), 3.16-3.07 (m, 1H), 2.84-2.72 (m, 1H), 2.66-2.53 (m, 3H).

Step 9

N -(2,4-Difluorobenzyl)-5,5-difluoro-12-hydroxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H- 2,7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide isomer (A) 10

Compound 10h (31mg, 0.07mmol) was dissolved in 3ml of acetonitrile, then magnesium dibromide (26mg, 0.14mmol) was added, and the reaction was carried out at 50°C until the reaction was almost complete. The crude product was concentrated and purified by C18 reverse phase. The title compound 10 was obtained (20mg, 67% yield)

MS(ESI)m/z 440.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ⁶ ) 10.34 (t, J = 6.0 Hz, 1H), 8.55 (s, 1H), 7.46-7.35 (m, 1H), 7.30-7.18 (m, 1H), 7.06 ( dt,J=2.4,8.4Hz,1H),5.03-4.73(m,1H),4.55(d,J=6.0Hz,2H),4.23-4.10(m,1H),4.05-3.93(m,1H) ,3.90-3.81(m,1H),3.23-3.09(m,1H),2.83-2.67(m,2H),2.66-2.57(m,2H).

Example 11

N -(2,4-Difluorobenzyl)-5,5-difluoro-12-hydroxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H- 2,7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide isomer (B) 11

Compound 11 was synthesized from compound 10i , referring to the synthesis method in the ninth step of Example 10.

MS(ESI)m/z 440.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ⁶ ) 10.34 (t, J=6.0 Hz, 1H), 8.55 (s, 1H), 7.45-7.35 (m, 1H), 7.30-7.19 (m, 1H), 7.06 ( dt,J=2.0,8.4Hz,1H),4.94-4.81(m,1H),4.55(d,J=5.6Hz,2H),4.22-4.10(m,1H),4.03-3.94(m,1H) , 3.89-3.82 (m, 1H), 3.24-3.08 (m, 1H), 2.79-2.67 (m, 2H), 2.65-2.59 (m, 2H).

Example 12

N -(2,4-difluorobenzyl)-4,4-difluoro-12-hydroxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H- 2,7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide isomer (A) 12

Compound 12 was synthesized using intermediate 6i as the starting material, referring to the synthesis method of Example 10.

MS(ESI)m/z 440.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d6) 10.34-10.47 (m, 1 H) 8.43 (s, 1 H) 7.34-7.46 (m, 1 H) 7.18-7.28 (m, 1 H) 7.01-7.10 (m, 1 H) 4.81 (br s, 1 H) 4.50-4.64 (m, 3 H) 3.88-3.98 (m, 1 H) 3.72-3.82 (m, 1 H) 3.59-3.64 (m, 1 H) 2.36-2.43 (m, 1 H) 2.26 (br d, J=13.88 Hz, 1 H) 1.99 (br s, 1 H) 1.65-1.78 (m, 1 H).

Example 13

N -(2,4-difluorobenzyl)-4,4-difluoro-12-hydroxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H- 2,7-Methylenepyrido[1,2-a][1,4]diazonononin-10-carboxamide isomer (B) 13

Compound 13 was synthesized using intermediate 6i as the starting material, referring to the synthesis method of Example 10.

MS(ESI)m/z 440.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d6)10.34-10.47(m,1 H)8.43(s,1 H)7.35-7.44(m,1 H)7.18-7.28(m,1 H)7.02-7.11(m, 1 H)4.83(br s,1 H)4.51-4.65(m,3 H)3.88-3.98(m,1 H)3.73-3.84(m,1 H)3.59-3.64(m,1 H)2.36-2.43 (m, 1 H) 2.26 (br d, J=13.88 Hz, 1 H) 2.01 (br s, 1 H) 1.66-1.79 (m, 1 H)

Example 14

N -(2,4-Difluorobenzyl)-12-hydroxy-4,4-dimethyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2,7-Methylenepyrido[1,2-a][1,4]diazononinyl-10-carboxamide isomer (A) 14

first step

2,2-Dimethylhex-5-enenitrile 14c

Dissolve isobutyronitrile 14b (12.2mL, 134.68mmol) in 200ml of tetrahydrofuran, add bistrimethylsilylamide lithium tetrahydrofuran solution (74.1mL, 2mol/L) dropwise under the protection of nitrogen at -78℃ . The reaction was carried out at minus 78°C for 1 hour, and 4-bromo-1-butene 14a (15.0 mL, 148.15 mmol) was added dropwise under this condition. After the addition, the reaction was naturally warmed to room temperature and the reaction was almost complete. It was quenched with 100 ml of saturated ammonium chloride solution, and then extracted with 200 ml of dichloromethane, and washed with 200 ml of water and 200 ml of brine, respectively. , Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 14c (33.5g, yield 91%).

¹ H NMR (400MHz, CDCl ₃ ) 5.89-5.77 (m, 1H), 5.18-4.99 (m, 2H), 2.30-2.20 (m, 2H), 1.66-1.59 (m, 2H), 1.37 (s, 6H) ).

Second step

2,2-Dimethylhex-5-en-1-amine 14d

The crude compound 14c (56 g, 356 mmol) was dissolved in 600 ml of tetrahydrofuran, and lithium aluminum hydride (13.9 g, 367.10 mmol) was added at 0°C. The reaction solution was reacted at 40°C until the reaction was almost complete, the reaction solution was reduced to 0°C, and then 14 ml of water, 15 ml of 15% sodium hydroxide solution and 42 ml of water were added in sequence, stirred for half an hour to obtain a suspension, filtered, The filter cake was washed with 200 ml of tetrahydrofuran, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 14d (15.56 g, crude product), which was used directly in the next step.

third step

(2,2-Dimethylhex-5-en-1-yl) tertiary butyl carbamate 14f

Compound 14d (15.56g) was dissolved in 200 mL of tetrahydrofuran, and di-tertiary butyl dicarbonate (25.1 mL, 117.41 mmol) and triethylamine (27.2 mL, 195.68 mmol) were added at room temperature. Reaction at room temperature until the reaction is almost complete, quenched by adding 300 ml of water, extracted with 200 ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which is purified by column chromatography silica gel column. The extractant is a mixed solvent of 0-10% ethyl acetate in petroleum ether) to obtain the title compound 14f (15.3g, yield 68%).

¹ H NMR (400MHz, CDCl ₃ ) 5.88-5.74 (m, 1H), 5.06-4.89 (m, 2H), 4.55 (br s, 1H), 2.96 (d, J=6.8Hz, 2H), 2.09-1.95 (m, 2H), 1.45 (s, 9H), 1.32-1.25 (m, 2H), 0.87 (s, 6H).

the fourth step

6-Acetyloxy-3,3-dimethylazepane-1-carboxylic acid tert-butyl ester 14g

Compound 14f (5.2g, 22.87mmol) was dissolved in 40ml of glacial acetic acid, and palladium acetate (0.26g, 1.14mmol) and bis(2-pyridyl)methanone (0.32g, 1.72mmol) were added in sequence at room temperature. And hydrogen peroxide (7.78g, 68.62mmol). React at room temperature until the reaction is almost complete, add 300 ml of water to dilute, and extract with 200 ml of ethyl acetate, wash with 300 ml of brine, dry with anhydrous sodium sulfate, filter, concentrate the crude product obtained, and purify by column chromatography ( The extractant is 0-10% ethyl acetate in petroleum ether) to obtain 14 g (554 mg, yield 8.5%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ) 5.08-4.95 (m, 1H), 3.76-3.58 (m, 1H), 3.42-3.30 (m, 1H), 3.24-3.03 (m, 2H), 2.05 (d, J =6.4Hz,3H),1.91-1.79(m,1H),1.78-1.67(m,1H),1.63-1.53(m,1H),1.46(s,9H),1.33-1.22(m,1H), 0.98-0.90 (m, 6H).

the fifth step

6-Hydroxy-3,3-dimethylazepane-1-carboxylic acid tert-butyl ester 14h

Compound 14g (1.63g, 5.71mmol) was dissolved in 10ml of methanol, and sodium hydroxide (2.28g, 57.12mmol) was dissolved in 10ml of water at 0°C and added to the reaction solution. The reaction is almost complete at room temperature. After the reaction, it was concentrated to remove methanol, then diluted with 5 ml of water, and extracted with 10 ml of ethyl acetate, washed with 10 ml of brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 14h (1.32g, yield 95 %).

¹ H NMR (400MHz, CDCl ₃ ) 3.98-3.91 (m, 1H), 3.79-3.68 (m, 1H), 3.44 (d, J=14.4 Hz, 1H), 3.29 (dd, J=15.2, 4.8 Hz, 1H), 2.75 (d, J=14.4 Hz, 1H), 1.95-1.50 (m, 4H), 1.47 (s, 9H), 0.97 (s, 3H), 0.89 (s, 3H).

Sixth step

3,3-Dimethyl-6-carbonyl azepine-1-carboxylic acid tert-butyl ester 14i

Compound 14h (1.3 g, 5.34 mmol) was dissolved in 15 mL of dichloromethane, and Des Martin oxidant (2.72 g, 6.41 mmol) was added. React at room temperature until the reaction is almost complete, filter, and wash with dichloromethane. Add 40 ml of saturated sodium bicarbonate solution to the filtrate, separate the layers, wash with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, and filter. Concentrate under reduced pressure to obtain the crude product, which was purified by column chromatography (the eluent was a mixed solvent of petroleum ether with 0-10% ethyl acetate) to obtain the title compound 14i (950 mg, yield 73%).

¹ H NMR (400MHz, CDCl ₃ ) 3.96-4.13 (m, 2H), 3.13-3.26 (m, 2H), 2.55-2.62 (m, 2H), 1.51-1.56 (m, 2H), 1.43-1.50 (m ,9H),1.01(s,6H).

Steps 7 to 10

N -(2,4-Difluorobenzyl)-12-hydroxy-4,4-dimethyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2,7-Methylenepyrido[1,2-a][1,4]diazononinyl-10-carboxamide isomer (A) 14

Compound 14 uses compound 14i as the starting material, and from the seventh step to the tenth step, refer to the twelfth to fifteenth step synthesis method in Example 6.

MS(ESI)m/z 432.1[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) 10.46-10.54 (m, 1H), 8.44 (s, 1H), 7.32-7.41 (m, 1H), 6.77-6.87 (m, 2H), 4.57-4.72 (m, 3H) ), 4.43(d,J=14.0Hz,1H),4.32-4.38(m,1H),3.81-3.91(m,1H),3.48-3.56(m,1H),2.72(d,J=14.0Hz, 1H), 2.25-2.39 (m, 1H), 1.85-2.10 (m, 2H), 1.12 (s, 6H).

Example 15

( N -(2,4-Difluorobenzyl)-12-hydroxy-4,4-dimethyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3 H -2,7-methylenepyrido[1,2-a][1,4]diazononinyl-10-carboxamide isomer (B) 15

Compound 15 was synthesized from compound 14m , referring to the synthesis method in the fifteenth step of Example 6.

MS(ESI)m/z 432.1[M+H] ⁺

¹ H NMR (400MHz, CHLOROFORM-d) 10.47-10.55 (m, 1H), 8.44 (s, 1H), 7.33-7.42 (m, 1H), 6.76-6.87 (m, 2H), 4.57-4.71 (m, 2H), 4.43 (d, J=14.0 Hz, 1H), 4.32-4.39 (m, 1H), 4.10 (s, 3H), 3.84-3.91 (m, 1H), 3.50-3.57 (m, 1H), 2.72 (d,J=14.0Hz,1H),2.25-2.39(m,1H),1.93-2.09(m,2H),1.12(s,6H).

Example 16

10-(5-(2,4-Difluorobenzyl)-1,3,4-thiadiazol-2-yl)-12-hydroxy-3-methyl-4,5,6,7-tetra Hydrogen-3H-2,7-methylenepyrido[1,2-a][1,4]diazononinin-1,11-dione isomer (A) 16

first step

Tert-butyl 2-(2-(2,4-difluorophenyl)acetoxy)hydrazine-1-carboxylate 16c

2,4-Difluorophenylacetic acid 16a (1g, 5.81mmol) was dissolved in 10ml of N,N -dimethylformamide, HATU condensing agent (2.65g, 6.97mmol) was added sequentially at room temperature, N , N -Diisopropylethylamine (1.9mL, 11.62mmol) and tertiary butyl carbazate 16b (1.15g, 8.71mmol). The reaction was reacted at room temperature until the reaction was almost complete, and the reaction solution was directly purified by a C18 reversed-phase column to obtain the title compound 16c (550 mg, yield 33%).

MS(ESI)m/z 309.3[M+Na] ⁺

Second step

2-(2-(2,4-Difluorophenyl)ethionyl)hydrazine-1-carboxylic acid tert-butyl ester 16d

Compound 16c (500 mg, 1.75 mmol) was dissolved in 5 mL of tetrahydrofuran, and Lawson's reagent (906 mg, 2.24 mmol) was added. The reaction was reacted at 50°C until the reaction was almost complete. The reaction solution was poured into 10ml of 10wt% sodium carbonate solution, then extracted with 10ml of ethyl acetate, washed with 10ml of brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. , The title compound 16d (520 mg, yield 98%) was obtained.

MS(ESI)m/z 247.2[M+H-56] ⁺

third step

2-(2,4-Difluorophenyl)ethylthiohydrazine 16e

Compound 16d (300mg, 0.99mmol) was dissolved in 4ml of hydrochloric acid methanol solution (4mol/L), stirred at room temperature until the reaction was basically complete, concentrated to remove methanol, diluted with 10ml of saturated sodium bicarbonate to neutralize, It was extracted with 10 ml of ethyl acetate, washed with 10 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 16e (150 mg, yield 75%).

MS(ESI)m/z 203.2[M+H] ⁺

the fourth step

3-Methoxy-1-(7-methylazeppan-3-yl)-4-carbonyl-1,4-dihydropyridine-2,5-dicarboxylic acid dimethyl ester 16f

Compound 4j (500mg, 1.11mmol) was dissolved in 5ml of hydrochloric acid methanol solution (4mol/L), stirred at room temperature until the reaction was basically complete, concentrated to remove methanol, diluted with 10ml of saturated sodium bicarbonate to neutralize, It was extracted with 10 mL of ethyl acetate, washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 16f (300 mg, yield 77%).

MS(ESI)m/z 353.4[M+H] ⁺

the fifth step

12-Methoxy-3-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3H-2,7-methylenepyrido[1,2-a ][1,4]Diazononin-10-carboxylic acid methyl ester 16g

Compound 16f (300mg, 0.85mmol) was dissolved in 3ml of p-xylene, and 0.5ml of acetic acid was added. The reaction was reacted at 180°C until the reaction was almost complete. The xylene was concentrated to remove the xylene, and then 10ml of saturated sodium bicarbonate solution was added. It was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 16 g (200 mg, yield 73%) of the title compound.

MS(ESI)m/z 321.4[M+H] ⁺

Sixth step

12-Methoxy-3-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3H-2,7-methylenepyrido[1,2-a ][1,4]diazononinyl-10-carboxylic acid 16h

Compound 16g (300mg, 0.94mmol) was dissolved in 5ml of methanol and 1ml of water, and lithium hydroxide (118mg, 2.81mmol) was added. The reaction was reacted at 80°C until the reaction was almost complete, 1 ml of acetic acid was added, and then purified by a C18 reversed-phase column in an acidic system to obtain the title compound 16h (150 mg, yield 52%).

MS(ESI)m/z 307.4[M+H] ⁺

Seventh step

10-(5-(2,4-Difluorobenzyl)-1,3,4-thiadiazol-2-yl)-12-methoxy-3-methyl-4,5,6,7 -Tetrahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononinin-1,11-dione isomer (A) 16i

10-(5-(2,4-Difluorobenzyl)-1,3,4-thiadiazol-2-yl)-12-methoxy-3-methyl-4,5,6,7 -Tetrahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononinin-1,11-dione isomer (B) 16j

Compound 16h (100mg, 0.33mmol) was dissolved in 3 ml of ethyl acetate, added to 50wt% T ₃ P in ethyl acetate solution (415mg, 0.65mmol), triethylamine (99mg, 0.98mmol) and compound 16e ( 66mg, 0.33mmol). The reaction was reacted at 50° C. until the reaction was almost complete, and 10 ml of ethyl acetate was added, washed with 10 ml of water, and concentrated to obtain a crude product, which was then purified by a C18 reverse phase column to obtain a racemic compound. The racemic compound was resolved by supercritical fluid chromatography on DAICEL CHIRALCEL OD-H chiral column to obtain title compound 16i (14mg, yield 9%) and title compound 16j (14.4mg, yield 9%) .

The chiral analysis method is as follows:

Á4.6mm I.D.,3um Analysis column: Chiralcel OJ-3 100

Á4.6mm ID,3um

Mobile phase: A: carbon dioxide B: ethanol (0.05% diethylamine)

Gradient: Rinse from 5% B phase to 40% B flush in 4 minutes, keep 40% B flush for 2.5 minutes, and finally return to 5% B phase flush for 1.5 minutes

Flow rate: 2.5 ml/min

Column temperature: 35℃

Pressure: 1500psi

Compound 16i retention time 2.979 minutes, MS(ESI) m/z 473.2[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) 8.70 (s, 1H), 7.35-7.28 (m, 1H), 6.93-6.77 (m, 2H), 4.92-4.74 (m, 1H), 4.51-4.38 (m, 3H) ), 4.16 (s, 3H), 3.83-3.68 (m, 1H), 3.49 (dd, J=1.2, 14.8 Hz, 1H), 2.39-2.29 (m, 1H), 2.28-2.17 (m, 1H), 1.93-1.82 (m, 1H), 1.81-1.73 (m, 1H), 1.39-1.29 (m, 2H), 1.25 (d, J=6.8Hz, 3H).

Compound 16j retention time 3.381 minutes, MS(ESI) m/z 473.1[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) 8.70 (s, 1H), 7.35-7.28 (m, 1H), 6.91-6.79 (m, 2H), 4.89-4.77 (m, 1H), 4.49-4.40 (m, 3H) ), 4.16 (s, 3H), 3.81-3.69 (m, 1H), 3.49 (dd, J=1.2, 14.8Hz, 1H), 2.40-2.29 (m, 1H), 2.28-2.18 (m, 1H), 1.94-1.82 (m, 1H), 1.82-1.72 (m, 1H), 1.40-1.29 (m, 2H), 1.25 (d, J=6.8Hz, 3H).

Eighth step

10-(5-(2,4-Difluorobenzyl)-1,3,4-thiadiazol-2-yl)-12-hydroxy-3-methyl-4,5,6,7-tetra Hydrogen-3 H -2,7-methylenepyrido[1,2-a][1,4]diazononinin-1,11-dione isomer (A) 16

Compound 16i (14mg, 0.03mmol) was dissolved in 3ml of acetonitrile, and magnesium dibromide (11mg, 0.06mmol) was added. The reaction was carried out at 50°C until the reaction was almost complete. The crude product was concentrated and purified by C18 reverse phase. The title compound 16 (8mg, yield 58%) was obtained

MS(ESI)m/z 459.4[M+H] ⁺

¹ H NMR: (400MHz,DMSO-d6)8.92(s,1H),7.60-7.49(m,1H),7.30(dt,J=2.4,10.0Hz,1H),7.12(dt,J=2.0,8.4 Hz,1H),4.92-4.81(m,1H),4.54-4.42(m,3H),3.83-3.68(m,2H),2.15-1.97(m,2H),1.91-1.78(m,1H), 1.70-1.58 (m, 1H), 1.56-1.42 (m, 1H), 1.20 (d, J=6.4Hz, 3H), 1.09-0.95 (m, 1H).

Example 17

10-(5-(2,4-Difluorobenzyl)-1,3,4-thiadiazol-2-yl)-12-hydroxy-3-methyl-4,5,6,7-tetra Hydrogen-3 H -2,7-methylenepyrido[1,2-a][1,4]diazononinin-1,11-dione isomer (B) 17

Compound 17 was synthesized from compound 16j , referring to the synthesis method in the fifteenth step of Example 6.

MS(ESI)m/z 459.4[M+H] ⁺

¹ H NMR: (400MHz, DMSO-d6) 8.92 (s, 1H), 7.59-7.47 (m, 1H), 7.34-7.24 (m, 1H), 7.11 (dt, J=2.0, 8.8 Hz, 1H), 4.91-4.81(m,1H),4.53-4.42(m,3H),3.80-3.69(m,2H),2.11-2.00(m,2H),1.92-1.77(m,1H),1.70-1.56(m ,1H), 1.55-1.41(m,1H), 1.19(d,J=6.8Hz,3H), 1.07-0.95(m,1H).

Biological evaluation

The following further describes and explains the present disclosure in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.

Test Example 1. Intergrase enzyme in vitro activity detection experiment: based on time-resolved fluorescence HTRF based strand transfer assay (HTRF based strand transfer assay)

1. Experimental equipment and materials

The N-terminal HIV integrase (IN F185K/C280S ) protein with 6 HIS-tags was expressed in E. coli BL21 (DE3) expression system. Recombinant HIS-IN protein with a purity of 85% and a concentration of 3.85 mg/ml (Nanjing GenScript Biotechnology Co., Ltd.) was purified by affinity chromatography on a nickel column. Store at -80°C after aliquoting.

The N155H mutant HIV integrase (IN F185K/C280S/N155H ) expression method is similar to that of the wild type. Both are produced by Nanjing GenScript Biotechnology Co., Ltd. The purity is 85% and the concentration is 1.95mg/ml.

The deoxynucleotide sequence information required for the experiment is as follows, produced by Nanjing GenScript Biotechnology Co., Ltd

The other reagent information required for the experiment is as follows

2. Experimental steps

Add 50M Cy-5 labeled (donor) two complementary DNA sequences and biotin (biotin) labeled DNA (acceptor) complementary sequences to the annealing solution (50mM Tris[pH 7.6], 10mM MgCl ₂ ) and heat to 95°C for 20 minutes, then slowly cool to room temperature, and store at -20°C before use.

The test compound was dissolved to 10 mM with DMSO. Use the reaction solution (20mM Hepes[pH 7.5], 7.5mM MgCl ₂ , 1mM DTT, 10% glycerol[w/v], 0.1mg/ml bovine serum albumin[BSA], 0.05% Brij-35, 10M ZnSO ₄ , 5mM NaCl) was diluted to different concentrations. The chain transfer experiment based on time-resolved fluorescence was carried out in a 384-well plate. The final concentration of 50nM donor DNA and 200nM 6HIS-IN were mixed in the reaction solution at a volume ratio of 1:1, and incubated on ice for 10 minutes. Mix 12.5μl of the enzyme and substrate mixture with the same volume of the compound to be tested in the same proportion. After incubating on ice for 10 minutes, add 12.5μl of 10nM acceptor DNA and shake at 37°C for 2 hours. Add to each well after termination anyway 25μl 2nM LANCE Eu-W8044-labeled streptavidin detection reagent. Incubate for 3 hours at room temperature. Time-resolved fluorescence signal The fluorescence signal in each well was measured using an Envision plate reader (PerkinElmer excitation light wavelength 330nm, emission light wavelength 665/620nm). _{The IC 50} value of the inhibitory activity of the compound on the enzyme activity was calculated by the four-parameter logit method. In the following formula, x represents the logarithmic form of the compound concentration; F(x) represents the effect value (inhibition rate of enzyme activity under this concentration condition): F(x)=((AD)/(1+((x/C)) ^B)))+D. A, B, C and D are four parameters. Using Primer premier 6.0 to _{further calculate the IC 50} value as the compound concentration required for 50% enzyme activity inhibition in the best-fit curve.

The in vitro activity of the compounds in the present disclosure on HIV Intergrase enzyme was determined by the above test, and the measured IC ₅₀ values are shown in Table 1.

The in vitro activity of the compounds in the present disclosure against the N155H mutant HIV Integrase enzyme was determined by the above test, and the measured IC ₅₀ values are shown in Table 2.

Test Example 2: Anti-HIV virus and cytotoxicity test

1. Experimental equipment and materials

The other reagent information required for the experiment is as follows

2. Experimental steps

The HIV-1 IIIB and MT-4 (NIH AIDS project) cells were _{co-cultured in a 37°C, 5% CO 2} incubator for 1 hour. At the same time, the test compound and the control compound (AZT, sigma) were diluted with DMSO times and then added to the cell culture plate. The infected cells were then seeded in a cell culture plate at a density of 10,000 cells per well. The final concentration of DMSO in the cell culture medium is 0.5%. The cells were cultured in a 37°C, 5% CO ₂ incubator for 5 days. The cytotoxicity test and the antiviral test were carried out in parallel, and the tested cells were uninfected MT-4 cells. Cell viability was determined by CellTiter-Glo (Promega).

The antiviral activity and cytotoxicity of the compound are represented by the inhibition rate (%) and cell viability (%) of the compound on the virus, respectively. The calculation formula is as follows: Inhibition rate (%) = (test hole reading value-virus control average value) / (cell control average value-virus control average value) x 100 Cell viability (%) = (reading value of test well-average value of culture medium control) / (average value of cell control-average value of culture medium control) x 100

GraphPad Prism software (Version 5) was used to calculate the EC ₅₀ and CC ₅₀ values of the compound. The EC ₅₀ and CC ₅₀ values use the four-parameter logit method. In the following formula, x represents the logarithmic form of the compound concentration; F(x) represents the effect value (inhibition rate or cell viability): F(x)=((AD)/( 1+((x/C)^B))+D. A, B, C and D are the four parameters. Different concentrations correspond to different inhibition rates, make a reverse curve, and calculate the compound EC ₅₀ and CC ₅₀ (Primer premier 6.0).

The antiviral activity and cytotoxicity of the compounds in the present disclosure in MT4 cells were determined by the above test, and the measured IC ₅₀ values are shown in Table 3.

Pharmacokinetic evaluation

Test Example 3. Pharmacokinetic test of the compound of the present disclosure

1. Summary

Using rats as test animals, the LC/MS/MS method was used to determine the drug concentration in plasma at different times after intravenous injection and intragastric administration of the compound of the present disclosure in rats. Study the pharmacokinetic behavior of the compound of the present invention in rats and evaluate its pharmacokinetic characteristics.

2. Test plan

2.1 Test drug

Examples 4 and 5 compounds.

2.2 Experimental animals

Each group has 3 male SD rats healthy for 6-8 weeks.

2.3 Drug preparation

Intravenous administration: Weigh a certain amount of medicine, add 10% volume of N,N-dimethylacetamide, 33% volume of triethylene glycol and 57% volume of normal saline to prepare 1mg/mL colorless, clear and transparent liquid;

Gavage administration: Weigh a certain amount of medicine, add 0.5% mass hypromellose, 0.1% volume Tween 80 and 99.6% volume normal saline to prepare a white suspension of 1 mg/mL.

2.4 Administration

After fasting overnight, SD rats were given intravenously by gavage at a dose of 1 mg/kg. Or intragastric administration, the administration dose is 5mg/kg.

3. Operation

The compound of the present disclosure was administered to rats by intravenous injection. 0.2 mL of blood was collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 hours after administration, and placed in a test tube containing EDTA-K2 at 4°C, 4000 The plasma was separated by centrifugation at rpm for 5 minutes and stored at -75°C.

Or rats were given the compound of the present disclosure by intragastric administration, 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, 24 hours after administration, and placed in a test tube containing EDTA-K2 at 4°C, 3500 revolutions Centrifuge for 10 minutes to separate plasma and store at -75°C.

To determine the content of the test compound in rat plasma after oral administration of different concentrations of drugs: Take 30μL of rat plasma at each time after administration, and add 200μL of acetonitrile solution of internal standard dexamethasone (50 ng/mL), vortex and mix for 30 seconds, and centrifuge at 4°C, 4700 rpm for 15 minutes. Take the supernatant of the plasma sample and dilute it three times with water, and take 2.0 μL for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

The pharmacokinetic parameters of the compounds in the present disclosure are as follows:

Claims (24)

A compound represented by formula I or a pharmaceutically acceptable salt thereof or a stereoisomer, rotamer or tautomer,

Wherein, ring A is selected from C _5-12 cycloalkyl and 6 to 12 membered heterocyclic group; R ¹ or R ² are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic group, and the alkyl, cycloalkyl or heterocyclic group is optionally selected from one or more of alkyl, cycloalkane Group, heterocyclic group, alkoxy group, alkenyl group, alkynyl group, aryl group, heteroaryl group, nitro group, nitrile group, hydroxyl group, halogen, SR', NR'(R"), COOR' or CONR'(R ") substituted, alternatively, R ¹ or R ² together with its adjacent carbon atoms form a 3-member to 12-membered carbocyclic or heterocyclic ring, preferably a 3-membered to 8-membered carbocyclic or heterocyclic ring, the carbocyclic or heterocyclic ring as required Is selected from alkyl, halogen, hydroxyl, amino, oxy, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, haloalkoxy Substituted by one or more substituents in the group, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl; R ^{3 is} selected from hydrogen, halogen, alkyl, and the alkyl group is optionally substituted by one or more cycloalkyl, alkoxy, alkenyl, alkynyl, heterocyclic, aryl, heteroaryl, nitro, nitrile Group, hydroxy, halogen, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, haloheteroaryl, SR', NR'(R"), COOR' or CONR'( R") replaced; R ⁴ or R ⁵ are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR', NR'(R"), COOR' Or CONR'(R"), the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally selected from one or more alkyl groups, alkoxy groups, cycloalkyl groups, Heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, Halo heteroaryl, SR', NR'(R"), COOR' or CONR'(R"), or R ⁴ or R ⁵ together with its adjacent carbon atoms form a 5-member to 12-member carbocyclic ring, hetero Ring, aromatic ring or heteroaromatic ring, preferably 6 to 8 member carbocyclic, heterocyclic, aromatic or heteroaromatic ring, the carbocyclic, heterocyclic, aromatic or heteroaromatic ring is optionally selected from alkyl, halogen , Hydroxy, amino, oxy, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents; R ^{6 is} selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally selected from one or more From halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR', NR'(R"), OCOR', OCOOR', COOR', CONR'(R ") or OCONR'(R"); Each R ⁷ or R ^{8 is} independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, the alkyl, alkoxy, cycloalkyl , Heterocyclyl, aryl or heteroaryl optionally selected from one or more of halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxyl, aryl, heteroaryl , Nitro, nitrile, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, haloheteroaryl, SR', NR'(R"), OCOR', OCOOR' , COOR', CONR'(R") or OCONR'(R"), or, ^{at least one of R 7} and R ⁸ and one or more adjacent atoms together form a 3-member to 12-member carbocyclic or heterocyclic ring Ring, aromatic ring or heteroaromatic ring, preferably 3-membered to 8-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, the carbocyclic, heterocyclic, aromatic or heteroaromatic ring is optionally selected from alkyl, halogen , Hydroxy, amino, oxy, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, haloalkoxy, halocycloalkyl, One or more substituents in the haloheterocyclic group, haloaryl group or haloheteroaryl group; the sum of n and o is an integer less than or equal to 24; R'or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl, aryl, aryl or heteroaryl, and the alkyl, alkoxy, aryl or heteroaryl group is optionally selected one or more substituents selected from halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, nitro, nitrile, or substituted with -R ^a; R ^a is selected from aryl or heteroaryl Aryl, the aryl or heteroaryl group is optionally selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, Substituted by nitro, nitrile, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclic, haloaryl, or haloheteroaryl. The compound or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers as described in item 1 of the scope of the patent application, wherein the compound represented by formula I is:

Wherein, B is selected from -CONR'-, -COO- or a five-member to six-member heterocyclic ring; R ^{9 is} selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocyclyl, C _6-12 aryl or C _6-12 heteroaryl, the C _1-6 alkyl Group, C _3-8 cycloalkyl group, 5-membered to 8-membered heterocyclic group, 6-membered to 12-membered aryl or heteroaryl group is optionally substituted by one or more halogen, alkyl, cycloalkyl, alkoxy, Alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile, aryl or heteroaryl group, the alkyl, cycloalkyl, alkoxy, aryl or heteroaryl group is optionally substituted by one or more selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, nitro, nitrile, or substituted with -R ^a; R ^{a is} selected from aryl or heteroaryl, and the aryl or heteroaryl is optionally selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy or hydroxy. ； R'is as described in item 1 of the scope of patent application. The compound described in item 1 or 2 of the scope of the patent application or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers, wherein R ^{6 is} selected from hydrogen, C _1-6 alkyl , C _3-7 cycloalkyl, 3-membered to 7-membered heterocyclic group, the alkyl group, cycloalkyl group or heterocyclic group is optionally selected by one or more selected from halogen, hydroxy, alkyl, alkoxy, ring Alkyl, heterocyclyl, aryl, heteroaryl, preferably hydrogen or C _1-6 alkyl. The compound described in any one of items 1 to 3 in the scope of the patent application or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers, wherein the compound represented by formula I is:

Wherein, Z ¹ , Z ² , Z ³ and Z ⁴ are each independently selected from -O-, -S-, -SO-, -SO ₂ -, -NH ₂ -or -CH ₂ -; R ^{10 is} selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile, aryl or heteroaryl, the aryl or heteroaryl group as required Substituted by one or more selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile or -R ^b; R ^{b is} selected from aryl or heteroaryl, and the aryl or heteroaryl is optionally selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy or hydroxy. Replaced by R ^c or R ^d are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile, halogen Alkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl, or R ^c or ^Rd together with its adjacent carbon atoms form a 3- to 12-membered carbocyclic or heterocyclic ring , Aromatic ring or heteroaromatic ring, preferably 3-membered to 8-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, the carbocyclic, heterocyclic, aromatic or heteroaromatic ring is optionally selected from alkyl, halogen, Substituted by one or more substituents among hydroxyl, amino, oxy, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl; The sum of n and o is an integer less than or equal to 8, such as 1, 2, 3, 4, or 5. The compound or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers as described in item 4 of the scope of the patent application, wherein at most among Z ¹ , Z ² , Z ³ and Z ⁴ 3 selected from -O-, -S-, -SO-, -SO ₂ -, -NH ₂ -, preferably at most 2 selected from -O-, -S-, -SO-, -SO _2- , -NH ₂ -, and the two are not connected. The compound described in any one of items 1 to 5 in the scope of the patent application or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers, wherein the compound represented by formula I is

The compound described in any one of items 1 to 6 in the scope of the patent application or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers, wherein the compound represented by formula I is

The compound or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers as described in any one of items 1 to 7 of the scope of the patent application, wherein the compound represented by formula I is

The compound described in any one of items 1 to 8 in the scope of the patent application or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers, wherein the compound represented by formula I is

The compound described in any one of items 1 to 9 in the scope of the patent application, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein R ^{4 is} selected from hydrogen, halogen, Hydroxy, C _1-6 alkyl, C _1-6 alkoxy or C _3-7 cycloalkyl, the alkyl, alkoxy, and cycloalkyl are optionally selected from nitro and nitrile by one or more , Hydroxy, halogen, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, halogen C _3-7 cycloalkyl, halogen 3-membered to 7-membered heterocyclic group, preferably hydrogen. The compound described in any one of items 1 to 10 in the scope of the patent application, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein R ^{3 is} selected from hydrogen or C _{1 -6} alkyl group, the alkyl group is optionally substituted by one or more nitro, nitrile, hydroxy, halogen, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, halohetero Aryl substituted. The compound described in any one of items 1 to 11 in the scope of the patent application, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein R ¹ or R ² are each independently Selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, 3-member to 7-member heterocyclic group, or, R ¹ or R ² together with its adjacent carbon atoms form C _3-7 Cycloalkyl, 3- to 7-membered heterocyclic group, the alkyl, cycloalkyl or heterocyclic group is optionally substituted with one or more selected from nitro, nitrile, hydroxy, and halogen. The compound described in any one of items 1 to 12 in the scope of the patent application, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein each R ⁷ or R ^{8 is} independent Is selected from hydrogen, halogen, nitrile, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, 3-membered to 7-membered heterocyclic group, the alkyl group, alkoxy group The group, cycloalkyl or heterocyclic group is optionally selected by one or more selected from halogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkoxy, hydroxy, nitro, nitrile , _{Halo C 1-6} alkyl, halo C _1-6 alkoxy, halo C _1-6 cycloalkyl, halo 3 to 7 member heterocyclic group, SR', NR'(R"), OCOR', OCOOR', COOR', CONR'(R") or OCONR'(R") substituted, or ^{at least one group of R 7} and R ⁸ together with one or more adjacent atoms to form a C _3-7 cycloalkyl group , 3-membered to 7-membered heterocyclic group, the cycloalkyl or heterocyclic group is optionally selected from C _1-6 alkyl, halogen, hydroxy, amino, oxy, carboxy, nitro, cyano, C _{1 -6} alkyl alkoxy, C _1-6 alkyl cycloalkyl, 3- to 7-membered heterocyclic group, aryl, heteroaryl, haloalkyl, haloalkoxy, halocycloalkyl, halo One or more substituents in the cyclic group, haloaryl group or haloheteroaryl group; the sum of n and o is an integer less than or equal to 12, such as 1, 2, 3, 4, 5, 6, 7, 8 . The compound or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers as described in item 13 of the scope of the patent application, wherein each R ⁷ or R ^{8 is} independently selected from hydrogen and halogen , Nitrile group, hydroxy group, C _1-6 alkyl group, C _1-6 alkoxy group, C _3-7 cycloalkyl group, 3 to 7 member heterocyclic group, the alkyl group, alkoxy group, cycloalkyl group or The heterocyclic group is optionally selected by one or more selected from halogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkoxy, hydroxy, nitro, nitrile, NR'(R" ), OCOR", COOR', CONR'(R") or OCONR'(R"), or R ⁷ or R ^{8 together} with one or more adjacent atoms to form a C _3-7 cycloalkyl, 3-member To 7-membered heterocyclic group, the cycloalkyl or heterocyclic group is optionally selected from C _1-6 alkyl, halogen, hydroxyl, amino, oxy, carboxy, nitro, cyano, C _1-6 alkane Alkyl alkoxy, C _1-6 alkylcycloalkyl, 3- to 7-membered heterocyclyl, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl One or more substituents in the group are substituted. The compound described in any one of items 4 to 9 in the scope of the patent application, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein R ^c and R ^d are each independently selected From hydrogen, R ^c and R ^{d are} preferably hydrogen; R ¹⁰ is phenyl substituted with 1 to 4 halogens. The compound or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers as described in item 15 of the scope of the patent application, wherein R ¹⁰ is a phenyl substituted with 2 halogens, preferably 2,4-Difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl or 3,5- Difluorophenyl. The compound or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers as described in item 15 of the scope of the patent application, wherein R ¹⁰ is a phenyl substituted with 3 halogens, preferably 2,4,6-trifluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl or 2,4-difluoro-3-chlorophenyl. The compound or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers as described in item 15 of the scope of the patent application, wherein R ¹⁰ is a phenyl substituted with 4 halogens, preferably 2,3,4,5-tetrafluorophenyl or 2,3,4,6-tetrafluorophenyl. The compound or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers as described in item 1 of the scope of the patent application are selected from:

Or a pharmaceutically acceptable salt or stereoisomer, rotamer or tautomer thereof. The compound or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers as described in item 1 of the scope of the patent application are selected from:

Or a pharmaceutically acceptable salt or stereoisomer thereof. A method for preparing the compound represented by formula I or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers,

Including the step of reacting a compound represented by formula I-a with a compound represented by formula I-b to form a compound represented by formula I-c,

Among them, rings A, R ¹ -R ⁸ , n, and o are as described in item 1 of the scope of patent application; PG ₁ , PG ₂ , and PG ₄ are protecting groups. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomers, rotamers or tautomers described in any one of items 1 to 20 in the scope of the patent application Constructs and pharmaceutically acceptable excipients. A method for treating HIV infection in a patient suffering from infection or at risk of suffering from infection, by administering to the patient a therapeutically effective amount of a compound as described in any one of items 1 to 20 in the scope of the patent application or its available Pharmaceutical salt or its stereoisomers, rotamers or tautomers or the pharmaceutical composition described in item 21 of the scope of the patent application. A compound or a pharmaceutically acceptable salt or stereoisomer, rotamer or tautomer described in any one of items 1 to 20 in the scope of the patent application or the compound described in item 21 in the scope of the patent application The use of the pharmaceutical composition in the preparation of medicines for treating HIV infections suffering from infections or at risk of suffering from infections.