CN113795491B - Bridged ring-3, 4-dihydro-pyrido [1,2-a ] pyrazine-1, 8-dione compounds and pharmaceutical uses thereof - Google Patents

Abstract

A bridged-ring-3,4-dihydro-pyrido[1,2-a]pyrazine-1,8-dione compound and its pharmaceutical use. Specifically, a compound of formula I or a pharmaceutically acceptable salt thereof or a stereoisomer, a rotamer or a tautomer thereof is provided, wherein R ¹ to R ⁸ 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

Technical Field

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

Background Art

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 as cocktail therapy, toxicity and the development of resistant strains limit their usefulness (Richman, D.D. Nature, (2001) 410:995-1001). Therefore, there is a need to develop new HIV inhibitors.

In addition, it is known that HIV virus will mutate in infected subjects (Tang et al., Drugs, (2012) 72(9) e1-e25), which also makes the treatment strategy of HIV infection in patients complicated. Moreover, HIV-infected patients may need to receive other drugs due to other diseases, and drug interactions will make the evaluation criteria of antiretroviral treatment invalid. Therefore, it is necessary to develop more effective antiretroviral methods that reduce drug interactions.

The following references may be used as background information:

US2007/0111984 discloses a series of bicyclic pyrimidinone compounds useful as HIV integrase inhibitors.

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

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

Summary of the invention

The present disclosure provides a compound of formula I,

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

wherein Ring A is selected from C _5-12 cycloalkyl and 6 to 12 membered heterocyclyl;

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 heterocyclyl, including but not limited to pyrrolyl), the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more selected from 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 heterocyclyl, including but not limited to pyrrolyl), alkoxy (such as C _{R 1} or R 2 together with its adjacent carbon atom forms a 3- to 12-membered carbocyclic or heterocyclic ring, preferably a 3- to 8-membered carbocyclic or heterocyclic ring, wherein 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, oxo, carboxyl, nitro, cyano, alkoxy (such as C _1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl (such as C _1-6 alk ... substituted by one or more substituents selected from the group consisting of _3-12- membered cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3-12-membered heterocyclyl), aryl, heteroaryl, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl;

^R3 is selected from hydrogen, halogen (such as fluorine, chlorine, bromine), alkyl (such as _C1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl), the alkyl is optionally substituted with one or more cycloalkyl (such as _C3-12 cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), alkoxy (such as _C1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen (such as fluorine, chlorine, bromine), haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, haloheteroaryl, SR′, NR′(R″), COOR′ or CONR′(R″);

^R4 or ^R5 are each independently selected from hydrogen, halogen (such as fluorine, chlorine, bromine), hydroxyl, alkyl (such as _C1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy (such as _C1-6 alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl (such as _C3-12 cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3 to 12 membered heterocyclyl, including but not limited to pyrrolyl), aryl, heteroaryl, SR', NR'(R"), COOR' or CONR'(R"), wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more selected from alkyl (such as _{C1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy (such as C1-6} alkoxy, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl (such as C3-12 cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as _{3 to 12 membered} heterocyclyl, including but not limited to pyrrolyl), aryl, heteroaryl, SR', NR'(R"), COOR' or CONR'(R") wherein R ₄ or R 5 is substituted with a 3- to 12-membered cycloalkyl group, including but not limited to cyclopropyl, cyclopentyl, and cyclohexyl), a heterocyclic group (such as a 3- to 12-membered heterocyclic group, including but not limited to pyrrolyl), an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a nitro group, a nitrile group, a hydroxyl group, a halogen group, a haloalkyl group, a haloalkoxy group, a halocycloalkyl group, a haloheterocyclic group, a haloaryl group, a haloheteroaryl group, SR′, NR′(R″), COOR′, or CONR′(R″); or, R ⁴ or R ⁵ together with its adjacent carbon atoms form a 5- to 12-membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring, preferably a 6- to 8-membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring, wherein the carbocyclic, heterocyclic, aromatic, or heteroaromatic ring is optionally selected from an alkyl group (such as a C _1-6 alkyl group, including but not limited to methyl, ethyl, propyl, or isopropyl), a halogen group (such as fluorine, chlorine, or bromine), a hydroxyl group, an amino group, an oxo group, a carboxyl group, a nitro group, a cyano group, an alkoxy group (such as C 1-6 substituted by one or more substituents selected from the group consisting of _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 heterocyclyl, including but not limited to pyrrolyl), aryl and heteroaryl;

^R 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 cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (such as 3 to 12 membered heterocyclyl, including but not limited to pyrrolyl), aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more selected from halogen, hydroxyl, 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 heterocyclyl, 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), hydroxyl, 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 heterocyclyl, including but not limited to pyrrolyl), aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more 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 wherein the carbonyl group is selected from the group consisting of alkyl (e.g., C _1-6 alkyl, 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 together with one or more adjacent atoms forms a 3- to 12-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, preferably a 3- to 8-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein the carbocyclic, heterocyclic, aromatic or heteroaromatic ring is optionally selected from alkyl (e.g., C _1-6 alkyl, including but not limited to methyl, ethyl, propyl or isopropyl), halogen (e.g., fluorine, chlorine, bromine), hydroxy, amino, oxy, carboxyl, nitro, cyano, alkoxy (e.g., C 1-6 The present invention is substituted by one or more substituents selected from the group consisting of 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 heterocyclyl, including but not limited to pyrrolyl), aryl, heteroaryl, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl; 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″ is 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, wherein the alkyl, alkoxy, aryl or heteroaryl is optionally substituted 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 ^-Ra ; Ra ^is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted 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 (such as C _1-6 alkyl), The invention may be substituted with a _{C 3-12} cycloalkyl group, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), an alkoxy group (such as a C _1-6 alkoxy group, including but not limited to methoxy, ethoxy, propoxy or isopropoxy), an alkenyl group, an alkynyl group, an oxy group, a hydroxyl group, an aryl group, a heteroaryl group, a nitro group, a nitrile group, a haloalkyl group, a haloalkoxy group, a halocycloalkyl group, a haloheterocyclyl group, a haloaryl group or a haloheteroaryl group.

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

Wherein, B is selected from -CONR′-, -COO-, or a five-membered to six-membered heterocyclic ring (preferably thiadiazolyl);

^R is selected from hydrogen, _C1-6 alkyl, _C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 12-membered aryl or heteroaryl, wherein the _C1-6 alkyl, _C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 12-membered aryl or heteroaryl is optionally substituted with one or more halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile, aryl or heteroaryl, wherein the alkyl, cycloalkyl, alkoxy, aryl or heteroaryl is optionally substituted with one or more halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile or ^-R ;

R ^a is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxo or hydroxy;

R', ^R7 or ^R8 are as defined in the compound of formula I.

In some embodiments, in the compound of Formula I, ^R6 is selected from hydrogen, _C1-6 alkyl, _C3-7 cycloalkyl, 3-membered to 7-membered heterocyclyl, and the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more selected from halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, preferably hydrogen or _C1-6 alkyl.

In some optional 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-, -8O ₂ -, -NH ₂ - or -CH ₂ -;

R ¹⁰ is selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 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, wherein the aryl or heteroaryl is optionally substituted by one or more selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxo or hydroxy;

R ^c or R ^{d is} each independently selected from hydrogen, halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile, haloalkyl, haloalkoxy, halocycloalkyl, halogenated heterocyclyl, halogenated aryl or halogenated heteroaryl, or R ^c or R ^d together with its adjacent carbon atom forms a 3- to 12-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, preferably a 3- to 8-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, which is optionally substituted with one or more substituents selected from alkyl, halogen, hydroxy, amino, oxy, carboxyl, 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, 5, 6, 7, 8), including zero.

In some embodiments, in the compound of formula III, at most three of Z ¹ , Z ² , Z ³ and Z ⁴ are selected from -O-, -S-, -SO-, -SO ₂ -, and -NH ₂ -, preferably at most two are selected from -O-, -S-, -SO-, -SO ₂ -, and -NH ₂ -, and the two are not connected.

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

In some embodiments, in the compound of formula III, Z ¹ , Z ² , Z ³ and Z ⁴ 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:

Some other embodiments provide compounds shown in Formula I as follows:

Further, some embodiments provide compounds 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, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or substituted with haloheteroaryl; p=any integer between 0 and 5 (including 0, 1, 2, 3, 4, 5).

Some other embodiments provide compounds shown in Formula I as follows:

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

Some other embodiments provide compounds shown in Formula I as follows:

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

Some other embodiments provide compounds shown in Formula I as follows:

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

In other embodiments, in the compound of Formula I, ^R4 is selected from hydrogen, halogen, hydroxyl, _C1-6 alkyl, _C1-6 alkoxy or _C3-7 cycloalkyl, and the alkyl, alkoxy, cycloalkyl is optionally substituted with one or more selected from nitro, nitrile, hydroxyl, halogen, halogenated _C1-6 alkyl, halogenated _C1-6 alkoxy, halogenated _C3-7 cycloalkyl, halogenated 3-membered to 7-membered heterocyclic group, preferably hydrogen.

In other embodiments, in the compound of Formula I, R ³ is selected from hydrogen or C _1-6 alkyl, and the alkyl is optionally substituted with one or more nitro, nitrile, hydroxyl, halogen, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, or haloheteroaryl.

In other embodiments, in the compound of Formula I, ^R1 or ^R2 is independently selected from hydrogen, halogen, hydroxyl, _C1-6 alkyl, _C3-7 cycloalkyl, 3-membered to 7-membered heterocyclyl, or, ^R1 or ^R2 together with its adjacent carbon atom forms a _C3-7 cycloalkyl, 3-membered to 7-membered heterocyclyl, and the alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more selected from nitro, nitrile, hydroxyl, halogen.

In other embodiments, each R ⁷ or R ⁸ in the compound of Formula I is independently selected from hydrogen, halogen, nitrile, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, 3-membered to 7-membered heterocyclyl, and the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by one or more selected from halogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkoxy, hydroxyl, nitro, nitrile, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, halogenated C _1-6 cycloalkyl, halogenated 3-membered to 7-membered heterocyclyl, SR′, NR′(R″), OCOR′, OCOOR′, COOR′, CONR′(R″) or OCONR′(R″), or, at least one of R ⁷ and R ⁸ and its adjacent one or more atoms together form a C _3-7 cycloalkyl, 3-membered to 7-membered heterocyclyl, and the cycloalkyl or heterocyclyl is optionally selected from C The invention relates to _{an alkyl group comprising: an alkyl group, a halogen group, a hydroxyl group, an amino group, an oxo group, a carboxyl group, a nitro group, a cyano group, a C 1-6 alkyl alkoxy group, a C 1-6 alkyl cycloalkyl} group, a 3-membered to 7-membered heterocyclyl group, an aryl group, a heteroaryl group, a haloalkyl group, a haloalkoxy group, a halocycloalkyl group, a haloheterocyclyl group, a haloaryl group or a haloheteroaryl group; and the sum of n and o is an integer less than or equal to 12, for example, 1, 2, 3, 4, 5, 6, 7, 8.

In other embodiments, each ^R7 or ^R8 in the compound of Formula I is independently selected from hydrogen, halogen, nitrile, hydroxyl, _C1-6 alkyl, _C1-6 alkoxy, _C3-7 cycloalkyl, 3-membered to 7-membered heterocyclyl, and the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted with one or more selected from halogen, _C1-6 alkyl, _C3-7 cycloalkyl, _C1-6 alkoxy, hydroxyl, nitro, nitrile, NR′(R″), OCOR″, COOR′, CONR′(R″) or OCONR′(R″).

In other embodiments, in the compound shown in Formula I, ^R7 or ^R8 together with one or more adjacent atoms form a _C3-7 cycloalkyl or a 3-membered to 7-membered heterocyclyl, and the cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from _C1-6 alkyl, halogen, hydroxyl, amino, oxo, carboxyl, nitro, cyano, _C1-6 alkylalkoxy, _C1-6 alkylcycloalkyl, a 3-membered to 7-membered heterocyclyl, haloalkyl, haloalkoxy, halocycloalkyl, halogenated heterocyclyl, halogenated aryl or halogenated heteroaryl.

In other embodiments, in the compounds of formula IVa to IVd or formula IVa-1 to IVd-1, R ^c and R ^d are each independently selected from hydrogen, and R ^c and R ^d are preferably hydrogen; R ¹⁰ is a phenyl substituted by 1 to 4 halogens. In other embodiments, in the compounds of formula IVa to IVd or formula Iva-1 to IVd-1, R ¹⁰ is a phenyl substituted by 2 halogens. In other embodiments, in the compounds of formula IVa to IVd or formula Iva-1 to IVd-1, R ¹⁰ is a phenyl substituted by 3 halogens. In other embodiments, in the compounds of formula IVa to IVd or formula Iva-1 to IVd-1, R ¹⁰ is a phenyl substituted by 4 halogens.

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

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

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

Typical compounds of formula I include, but are not limited to:

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

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

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

The present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound represented by the aforementioned formula I, II, III, IVa, 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 thereof, and a pharmaceutically acceptable excipient.

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

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

On the other hand, the present disclosure also provides a method for treating HIV infection in a patient suffering from the infection or at risk of the infection, by administering to the patient a therapeutically effective amount of a compound represented by the aforementioned formula I, II, III, IVa, 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 thereof, or a stereoisomer, rotamer or tautomer thereof, or the aforementioned pharmaceutical composition.

The present disclosure also relates to the use of the compound described in the above scheme or its pharmaceutically acceptable salt or its stereoisomer, rotational isomer or tautomer, or the aforementioned pharmaceutical composition in the preparation of a drug for treating HIV infection in patients suffering from or at risk of infection.

On the other hand, the pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts, and the compounds described in the present disclosure react with acids such as trifluoroacetic acid to form corresponding salts, and the acids are selected from, but not limited to, acetic acid, hydrochloric acid, salicylic acid, malic acid, ascorbic acid, phosphoric acid, citric acid, benzoic acid or fumaric acid. The compounds described in the present disclosure react with bases such as N-methyl-D meglumine or dicyclohexylamine to form corresponding salts, and the bases are selected from, but not limited to, sodium, alkaline earth metals, and amino acids (such as arginine and lysine).

On the other hand, hydrogen in the functional groups of the compounds disclosed herein can be deuterated to obtain corresponding deuterated compounds, which retain the selectivity and potential comparable to hydrogen analogs; the deuterium bond is more stable, resulting in different "ADME" or "toxico-pharmacokinetics", thereby providing clinically beneficial effects.

Toxicological pharmacokinetics refers to the body's absorption, distribution, metabolism and excretion of exogenous chemicals.

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

The method comprises the steps 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,

Wherein, 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, protecting groups disclosed herein include, but are not limited to, tert-butyl, tert-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-diphenylsilyl (TBDPS), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz), formyl, acetyl, trichloroacetyl.

Furthermore, the method for preparing the compound of formula I also includes the step of converting the compound of formula I-c into the compound of formula I,

Terminology explanation:

"Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

"Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 20 carbon atoms. Preferably, the alkyl group contains 1 to 12 carbon atoms, and more preferably, the alkyl group contains 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and various branched isomers thereof. Alkyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available connection point, preferably one or more of the following groups, independently selected from aryl, heteroaryl, halogen substituted. "Alkenyl" includes branched and straight chain olefins with 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. For example, " _C2-6 alkenyl" means an alkenyl group with 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 containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

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 a heteroatom selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it 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 heterocyclyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spirocyclic, fused ring and bridged heterocyclyls. Non-limiting examples of "heterocyclyl" include:

etc.

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

wait.

The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

"Alkynyl" includes branched and straight chain alkynyl or aliphatic hydrocarbon-containing olefins having 2 to 12 carbon atoms, or if a specific number of carbon atoms is specified, that specific number is intended, 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 (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate, preferably phenyl.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12 members, more preferably 5 or 6 members. For example. Non-limiting examples include: imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazine, etc.

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

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

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

The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

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

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

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

The term "halocycloalkyl" refers to a ring radical substituted with halogen, wherein cycloalkyl is as defined above.

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

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

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" refers to a =0 substituent.

The term "thio" refers to a =S substituent.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

It is known in the art that it protects reactive groups (including but not limited to hydroxyl and amino) from side reactions during the building-up process. The hydroxyl and amino protected with protecting groups are referred to as "protected hydroxyl" and "protected amino" respectively in this article. Protecting groups are usually used selectively and/or orthogonally to protect sites during other reactive sites and can then be removed to leave unprotected groups to remain intact or participate 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, tert-butyl, tert-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-diphenylsilyl (TBDPS), triphenylsilyl, benzoylformate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivaloate, benzoate, p-benzoic acid phenyl ester, 9-fluorenylmethyl 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)-ethoxy-carbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl and nitrophenylacetyl; sulfonamide-protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups such as phthalimido and dithiasuccinyl.

"Pharmaceutical composition" means a mixture containing one or more compounds described 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. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

The compounds of the present disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined by absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids. The present disclosure includes all possible isomers as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be prepared using conventional methods such as chromatography and fractional crystallization. Conventional methods for preparing/separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, it is intended that the compounds include both E and Z geometric isomers. Furthermore, all tautomeric forms are also meant to be included.

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

"Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. Included in the present disclosure are tautomers of any of the described compounds.

Methods for synthesizing compounds disclosed herein

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

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

Synthesis method 1:

Synthesis method 2:

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

DETAILED DESCRIPTION

The present disclosure is further described below in conjunction with embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

The experimental methods in the examples of this disclosure that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR measurement is performed using a Bruker AVANCE-400 NMR spectrometer, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard is tetramethylsilane (TMS). The spatial configuration of the optical isomers (isomers) of the compound 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 1200LC high pressure liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).

MS was determined using a Waters SQD2 mass spectrometer in positive/negative ion mode with a mass scan range of 100-1200.

Chiral HPLC analysis was performed using Chiralpak IC-3 100×4.6mm I.D., 3um, Chiralpak AD-3 150×4.6mm I.D., 3um, Chiralpak AD-3 50×4.6mm I.D., 3um, Chiralpak AS-3 150×4.6mm I.D., 3um, Chiralpak AS-3 100×4.6mm I.D., 3μm, ChiralCel OD-3 150×4.6mmI.D., 3um, Chiralcel OD-3 100×4.6mm I.D., 3μm, ChiralCel OJ-H 150×4.6mm I.D., 5um, Chiralcel OJ-3 150×4.6mm I.D., 3um columns;

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

The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

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

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

The high-pressure column purification system uses Waters AutoP in combination with Waters XBridge BEH C18 OBDPrep Column. 5μm, 19mm X 150mm or Atlantis T3OBD Prep Column, 5μm, 19mmX 150mm.

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

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

Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

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

The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

Unless otherwise specified in the examples, the solution refers to an aqueous solution.

Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent 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 is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

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

first step

Methyl (Z)-2-((dimethylamino)methylene)-4-methoxy-3-oxobutyrate 1c

A mixture of methyl 4-methoxyacetoacetate (26.57 mL, 205.28 mmol) and N,N-dimethylformamide dimethyl acetal (27.48 mL, 205.28 mmol) was heated and stirred at 85°C until the reaction was substantially complete, 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] ⁺

Step 2

2-Ethyl 5-methyl 3-methoxy-4-carbonyl-4H-pyran-2,5-dicarboxylate 1d

Sodium tert-butoxide (13.37 g, 139.15 mmol) was added to a mixture of compound 1c (10 g, 139.1512 mmol) and diethyl oxalate (20 mL), and the mixture was reacted at room temperature until the reaction was almost complete, and acetic acid (20 mL) was added. The resulting mixture was directly purified by C18 reverse phase column with acetonitrile and water, and the title compound 1d (4 g, yield 11%) was obtained after freeze drying.

MS (ESI) m/z 257.1 [M+H] ⁺

Step 3

2-Ethyl 5-methyl (R)-1-(1-(tert-butoxycarbonyl)azepan-3-yl)-3-methoxy-4-carbonyl-1,4-dihydropyridine-2,5-dicarboxylate 1f

Compound 1d (100 mg, 0.39 mmol) was dissolved in 8 mL of ethanol, and (3R)-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 substantially 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] ⁺

Step 4

(7R)-N-(2,4-difluorobenzyl)-12-methoxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-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 (137 mg, 0.80 mmol) was added to the reaction solution, and the reaction was continued at 200°C until the reaction was basically completed, cooled and concentrated under reduced pressure, and the resulting residue was purified using a C18 reverse phase column with acetonitrile and water to obtain the title compound 1h (80 mg, yield 48%).

MS (ESI) m/z 418.3 [M + H] ⁺

Step 5

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

Magnesium diiodide (162 mg, 0.38 mmol) was added to a solution of compound 1h (80 mg, 0.19 mmol) and 1-methyl-2-pyrrolidone (4 mL). The resulting mixture was reacted at 50°C until the reaction was substantially complete, and after cooling, it was directly purified using a C18 reverse phase column with acetonitrile and water 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 ) δ10.40 (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

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

first step

2-Ethyl 5-methyl (S)-1-(1-(tert-butoxycarbonyl)azepan-3-yl)-3-methoxy-4-carbonyl-1,4-dihydropyridine-2,5-dicarboxylate 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 substantially 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] ⁺

Step 2

(7S)-N-(2,4-difluorobenzyl)-12-methoxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-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 (76 mg, 0.44 mmol) was added to the reaction solution. The reaction was continued at 200° C. until the reaction was substantially complete, and the mixture was cooled and distilled under reduced pressure. The resulting residue was purified using a C18 reverse phase column with acetonitrile and water to obtain the title compound 2c (30 mg, yield 33%).

MS (ESI) m/z 418.3 [M + H] ⁺

Step 3

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

Magnesium diiodide (60 mg, 0.14 mmol) was added to a 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 substantially complete, and after cooling, it was directly purified using a C18 reverse phase column with acetonitrile and water to obtain the title compound 2 (5 mg, yield 17%).

MS (ESI) m/z 404.2 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d6) δ10.65 (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), 4.20-4.1 5 (m, 1H), 3.85 (d, J = 14.8Hz, 1H), 3.65 (d, J = 14.0Hz, 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]oxadiazonoinane-10-carboxamide

first step

Tert-butyl 6-amino-1,4-oxazepane-4-carboxylate 3b

Tert-butyl 6-oxydeoxy-1,4-oxazepane-4-carboxylate (150 mg, 0.70 mmol) was dissolved in 5 mL of 7 M ammonia methanol solution and stirred at room temperature overnight. Sodium cyanoborohydride (88 mg, 1.39 mmol) was added to the reaction solution and continued to stir at room temperature until the reaction was substantially complete. The title compound 3b (90 mg, yield 60%) was obtained by eluting with acetonitrile and water using a C18 reverse phase column.

MS (ESI) m/z 161.1 [M-55] ⁺

Step 2

2-Ethyl 5-methyl 1-(4-(tert-butoxycarbonyl)-1,4-oxazepan-6-yl)-3-methoxy-4-carbonyl-1,4-dihydropyridine-2,5-dicarboxylate 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 substantially complete, cooled, and purified using a C18 reverse phase column with acetonitrile and water to obtain compound 3c (45 mg, yield 24%).

MS (ESI) m/z 455.4 [M+H] ⁺

Step 3

Tert-butyl 6-(5-((2,4-difluorobenzyl)carbamoyl)-2-(ethoxycarbonyl<ethoxycarbonyl>)-3-methoxy-4-carbonylpyridin-1(4H)-yl)-1,4-oxazepane-4-carboxylate 3d

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

MS (ESI) m/z 566.4 [M+H] ⁺

Step 4

5-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-1-(1,4-oxazepan-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 substantially complete, cooled, and distilled under reduced pressure. The resulting residue was dissolved in 4 mL of 4M hydrogen chloride methanol 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] ⁺

Step 5

N-(2,4-difluorobenzyl)-12-methoxy-1,11-dicarbonyl-1,3,4,6,7,11-hexahydro-2,7-methylenepyrido[1,2-d][1,4,7]oxadiazonoinane-10-carboxamide 3f

Compound 3e (40 mg, 0.09 mmol) was dissolved in 4 mL of N,N-dimethylformamide, and 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (70 mg, 0.18 mmol) and N,N-diisopropylethylamine (35 mg, 0.27 mmol) were added to the solution in sequence. The resulting solution was reacted at room temperature until the reaction was substantially complete, and purified using a C18 reverse phase column with acetonitrile and water to obtain the title compound 3f (20 mg, yield 52%).

MS (ESI) m/z 420.2 [M + H] ⁺

Step 6

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]oxadiazonoinane-10-carboxamide

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 substantially complete, cooled and concentrated under reduced pressure, and the resulting residue was purified by C18 reverse phase column eluted with acetonitrile and water 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-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-10-carboxamide

first step

2-Methyl 5-methyl 3-methoxy-4-carbonyl-4H-pyran-2,5-dicarboxylate 4a

A mixture of methyl 4-methoxyacetoacetate (17.71 mL, 136.85 mmol) and N,N-dimethylformamide dimethyl acetal (18.32 mL, 136.85 mmol) was heated and stirred at 85°C, dimethyl oxalate (32.32 g, 273.70 mmol) was added to the reaction solution, and the reaction was stirred until the reaction was complete. The mixture was cooled to room temperature, and a 30% sodium methoxide methanol solution (52.1542 mL, 273.7082 mmol) was added to the reaction solution. The reaction was continued to be stirred for 2-4 h, and the reaction was quenched with 50 ml of acetic acid. The title compound 4a (15.8 g, yield 48%) was obtained by purification via a C18 reverse phase chromatography column.

MS (ESI) m/z 265.3 [M + Na] ⁺

Step 2

Ethyl 6-[(2-ethoxy-2-oxoethyl)amino]hexanoate 4d

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

MS (ESI) m/z 246.2 [M+H] ⁺

Step 3

Ethyl 5-((tert-butoxycarbonyl)(2-ethoxy-2-carbonylethyl)amino)hexanoate 4e

Compound 4d (4 g, 16.30 mmol) was dissolved in 20 mL of dichloromethane, and di-tert-butyl dicarbonate (4.19 mL, 19.57 mmol) and triethylamine (6.80 mL, 48.92 mmol) were added in sequence. The mixture was reacted at room temperature until the reaction was almost complete. Water was added to quench the reaction. The mixture was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 4e (6 g), which was used directly in the next step.

MS (ESI) m/z 368.3 [M + H] ⁺

Step 4

1-(tert-Butyl) 4-ethyl 7-methyl-3-carbonylazepane-1,4-dicarboxylate 4f

1-(tert-butyl) 2-ethyl 7-methyl-3-carbonylazepane-1,2-dicarboxylate 4g

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

MS (ESI) m/z 322.3 [M + Na] ⁺

Step 5

Tert-butyl 2-methyl-6-carbonylazepane-1-carboxylate 4h

The crude mixture of compound 4f and compound 4g (6 g) was dissolved in a mixed solution of 10 mL of water and 10 mL of tetrahydrofuran, and sodium hydroxide (2.40 g, 60.13 mmol) was added, and the reaction was carried out at 70°C until the reaction was substantially complete. The mixture 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 (0.9 g, 31% total yield in four steps).

MS (ESI) m/z 250.2 [M+H] ⁺

Step 6

Tert-butyl 6-amino-2-methylazepane-1-carboxylate 4i

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

MS (ESI) m/z 229.3 [M + H] ⁺

Step 7

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

Compound 4i (424.25 mg, 1.75 mmol) was dissolved in 5 ml of ethanol, and compound 12 (400 mg, 1.75 mmol) was added to the reaction solution. The reaction was carried out at 80°C until the reaction was basically completed. The crude product was concentrated under reduced pressure and purified by C18 reverse phase to obtain the title compound 4j (400 mg, yield 50.46%).

MS (ESI) m/z 453.5 [M + H] ⁺

Step 8

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

Compound 4j (400 mg, 0.88 mmol) was dissolved in 5 ml of xylene, and then acetic acid (530.84 mg, 8.84 mmol) and 2,4-difluorobenzylamine (126.53 mg, 0.88 mmol) were added in sequence. The reaction was heated under reflux until the reaction was substantially completed, and concentrated under reduced pressure to obtain a 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)carbamoyl)-3-methoxy-1-(7-methylazepan-3-yl)-4-carbonyl-1,4-dihydropyridine-2-carboxylic acid 4l

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

MS (ESI) m/z 450.4 [M+H] ⁺

Step 10

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]diazononane-10-carboxamide 4m

Compound 4l (320 mg, 0.71 mmol) was dissolved in N,N-dimethylformamide (5 mL), and O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (541.45 mg, 1.42 mmol) and N,N-diisopropylethylamine (0.35 mL, 2.14 mmol) were added in sequence. The reaction was carried out at room temperature until the reaction was basically completed. The reaction solution was purified by C18 reverse phase to obtain the title compound 4m (200 mg, yield 65.11%).

MS (ESI) m/z 432.4 [M+H] ⁺

Step 11

(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]diazononane-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]diazononane-10-carboxamide 4o

Compound 4m (60 mg, 0.138 mmol) was separated 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-350×4.6mm I.D., 3um

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

Step 12

(3S,7S)-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]diazononane-10-carboxamide

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

MS (ESI) m/z 418.5 [M+H] ⁺

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

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]diazononane-10-carboxamide 5

Compound 4n (23 mg, 0.05 mmol) was dissolved in 3 ml of acetonitrile, and magnesium dibromide (19.6 mg, 0.11 mmol) was added and reacted at 50° C. for 1 hour. The reaction solution was concentrated to obtain a 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, 1H) 8.44 (s, 1H) 7.34-7.44 (m, 1H) 7.19-7.28 (m, 1H) 7.01-7.10 (m, 1H) 4.75(br s,1H)4.54(br d, J＝5.63Hz, 2H) 4.42-4.50 (m, 1H) 3.61-3.73 (m, 2H) 1.96-2.07 (m, 2H) 1.73-1.86 (m, 1H) 1.54-1.65 (m, 1H) 1.39 -1.52 (m, 1H) 1.17 (d, J=6.63Hz, 3H) 0.96-1.04 (m, 1H).

Example 6

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

first step

Ethyl 3-(allylamino)propionate 6c

Allylamine hydrochloride 6a (50 g, 534.44 mmol) and 1,8-diazabicycloundec-7-ene (108.5 g, 712.59 mmol) were dissolved in 750 ml of ethanol, ethyl acrylate 6b (35.7 g, 356.30 mmol) was added at room temperature, and the mixture was stirred at room temperature until the reaction was almost complete. The reaction solution was concentrated, 400 ml of water was added, and the pH value was adjusted to 11 with saturated sodium hydroxide solution, and the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate.

Filtration and concentration gave the title compound 6c, which was used directly in the next step without further purification.

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

The crude compound 6c (56 g, 356 mmol) was dissolved in 600 ml of dichloromethane, and di-tert-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 over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (eluting phase was a mixed solvent of 0-8.5% ethyl acetate in petroleum ether) to obtain the title compound 6d (77.18 g, total yield of two steps 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).

Step 3

Ethyl 2-((allyl(tert-butoxycarbonyl)amino)methyl)pent-4-enoate 6e

Compound 6d (77.66 g, 301.80 mmol) was dissolved in 600 ml of tetrahydrofuran, cooled to -78 °C, and lithium bis(trimethylsilyl)amide tetrahydrofuran solution (25.3 mL, 1 mol/L) and allyl iodide (60.8 g, 362.16 mmol) were added in sequence under nitrogen protection. The mixture was naturally heated to room temperature and stirred until the reaction was basically complete. 500 ml of saturated ammonium chloride solution was added under ice bath conditions and stirred for 15 minutes. The mixed solution was extracted with 800 ml of ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (eluting phase was a mixed solvent of 0-5% ethyl acetate and petroleum ether) 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).

Step 4

1-(tert-Butyl) 3-ethyl 2,3,4,7-tetrahydro-1H-azepine-1,3-dicarboxylate 6f

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

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).

Step 5

1-(tert-butyl) 3-ethyl 6-hydroxyazepane-1,3-dicarboxylate isomer (A) 6g

1-(tert-Butyl) 3-ethyl 5-hydroxyazepane-1,3-dicarboxylate 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 was reacted for 1-3 hours at a temperature below 10°C. Sodium hydroxide solution (3.12 mL, 3 mol/L) was slowly added dropwise at 0°C, and then hydrogen peroxide (7.86 g, 69.36 mmol) was added. The reaction was stirred at room temperature until the reaction was basically 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, washed with 30 ml of saturated sodium bisulfite, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of the title compounds 6g and 6h (4.22 g, crude product), which was directly used in the next step without further purification.

MS (ESI) m/z 309.9 [M + Na] ⁺

Step 6

1-(tert-Butyl) 3-ethyl 6-carbonylazepane-1,3-dicarboxylate Isomer (A) 6i

1-(tert-Butyl) 3-ethyl 5-carbonylazepane-1,3-dicarboxylate Isomer (B) 6j

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

Compound 6i analytical data: 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, 47.6Hz, 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).

Compound 6j analytical data: 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).

Step 7

1-(tert-Butyl) 3-ethyl 6-methyleneazepane-1,3-dicarboxylate 6k

Methyltriphenylphosphonium bromide (6.0 g, 16.82 mmol) was dissolved in 60 ml of tetrahydrofuran, and 2.5 mol/L of n-butyl hexane solution (5.6 mL, 2.5 mol/L) was added at -20 to -10 °C under nitrogen protection. The mixture was reacted for 30 minutes at -20 to -10 °C, and 10 ml of tetrahydrofuran solution containing compound 6i (2 g, 7.00 mmol) was added, and then stirred at room temperature until the reaction was almost complete. The mixture 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 a crude product, which was purified by column chromatography (eluting phase was a mixed solvent of 2 to 3% ethyl acetate in petroleum ether) to obtain the title compound 6k (1255 mg, 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).

Step 8

1-(tert-butyl) 3-ethyl 6-methylazepane-1,3-dicarboxylate

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. under 50 psi hydrogen pressure for 3 hours, filtered through celite, washed with 20 ml of ethanol, and concentrated under reduced pressure to obtain the title compound 6l (1.2 g, yield 99%).

MS (ESI) m/z 285.9 [M + H] ⁺

Step 9

1-(tert-Butoxycarbonyl)-6-methylazepane-3-carboxylic acid 6m

Dissolve compound 6l (1.25 g, 4.37 mmol) in 10 ml of methanol and 10 ml of water, add potassium hydroxide (0.49 g, 8.73 mmol), heat to 50°C and stir to react until the reaction is almost complete, and concentrate to remove methanol. Dilute with 30 ml of water, adjust the pH value to 12 with saturated sodium hydroxide solution, extract with 15 ml of ethyl acetate, wash with brine, dry over 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] ⁺

Step 10

Tert-butyl-3-(((benzyloxy)carbonyl)amino)-6-methylazepane-1-carboxylate Isomer (A) 6n

Tert-butyl-3-(((benzyloxy)carbonyl)amino)-6-methylazepane-1-carboxylate Isomer (B) 6o

Compound 6m (500 mg, 1.94 mmol) was dissolved in 10 ml of toluene, and diphenylphosphoryl azide (1.07 g, 3.89 mmol) and triethylamine (393 mg, 3.89 mmol) were added. After the reaction solution was replaced with nitrogen three times, it was heated to 90°C for 2 hours. 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 basically complete. Dilute with 30 ml of ethyl acetate, wash with 15 ml of brine, dry with anhydrous sodium sulfate, and filter. Concentrate to obtain a crude product, which was purified by column chromatography (eluting phase was a petroleum ether mixed solvent of 6.5-9% ethyl acetate) to obtain the title compound 6n (150 mg, 27% yield) and the title compound 6o (170 mg, 31% yield).

Compound 6n analytical data: 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] ⁺

Step 11

Tert-butyl-3-amino-6-methylazepane-1-carboxylate 6p

Dissolve compound 6n (150 mg, 0.41 mmol) in 10 ml of ethanol, add 10% palladium carbon (150 mg). The reaction is stirred at room temperature under hydrogen pressure (15 Psi) of a hydrogen balloon until the reaction is substantially complete. Filter through diatomaceous earth, 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] ⁺

Step 12

2-Ethyl 5-methyl 1-(1-(tert-butoxycarbonyl)-6-methylazepan-3-yl)-3-methoxy-4-carbonyl-1,4-dihydropyridine-2,5-dicarboxylate 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 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

Tert-butyl-3-(5-((2,4-difluorobenzyl)carbamoyl)-2-(ethoxycarbonyl<ethoxycarbonyl>)-3-methoxy-4-carbonylpyridin-1(4H)-yl)-6-methylazepane-1-carboxylate 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 207 mg, 3.50 mmol) of acetic acid 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 and the reaction was continued until it was almost complete. The crude product of the title compound 6r was obtained by concentration, and the product was directly used in the next step.

MS (ESI) m/z 578.1 [M+H] ⁺

Step 14

N-(2,4-difluorobenzyl)-12-methoxy-4-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-10-carboxamide Isomer (A) 6s

N-(2,4-difluorobenzyl)-12-hydroxy-4-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-10-carboxamide 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 at 180°C until it was substantially complete, and the crude product was concentrated. Column chromatography purification (developing solvent: ethyl acetate) gave a racemic compound. The racemic compound was separated by supercritical fluid chromatography on a DAICEL CHIRALCEL OD-H chiral column to give the title compound 6s (21.4 mg, 14% total yield in three steps) and the title compound 6t (21.2 mg, 14% total yield in three steps).

The chiral analysis method is as follows:

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

Mobile phase: A: Carbon dioxide B: Ethanol (0.05% diethylamine)

Gradient: 5 min from 5% B to 40% B, then rinse at 40% B for 2.5 min, then return to 5% B for 2.5 min

Flow rate: 2.5 ml/min

Column temperature: 35°C

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=5.6Hz, 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, 13.2Hz, 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).

Compound 6t retention time 5.782 minutes, MS (ESI) m/z 432.1 [M+H] ⁺

¹ H NMR: (400MHz, CDCl3) 10.49 (t, J=5.6Hz, 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).

Step 15

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

Compound 6s (21 mg, 0.05 mmol) was dissolved in 3 ml of acetonitrile, and magnesium dibromide (18 mg, 0.10 mmol) was added and reacted at 50°C until almost complete. The crude product was concentrated 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-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-10-carboxamide isomer (B) 7

Compound 7 was synthesized via compound 6t, referring to the synthesis method of step 15 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-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-10-carboxamide isomer (C) 8

Compound 8 was synthesized via intermediate 6o, referring to the synthesis method of steps 11 to 15 of Example 6.

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).

Embodiment 9

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

Compound 9 was synthesized via intermediate 6o, referring to the synthesis method of steps 11 to 15 of Example 6.

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-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-10-carboxamide isomer (A) 10

first step

1-(tert-Butyl) 3-ethyl 5,5-difluoroazepane-1,3-dicarboxylate 10a

1-(tert-butyl) 3-ethyl 5-carbonylazepane-1,3-dicarboxylate 6j (390 mg, 1.37 mmol) was dissolved in 8 ml of dichloromethane, and diethylaminosulfur trifluoride (0.7 mL, 5.47 mmol) was added at room temperature. The reaction was allowed to proceed until the reaction was substantially complete at room temperature, 30 ml of saturated sodium bicarbonate solution was added, and the mixture was 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 chromatography (the elution phase was a mixed solvent of 0-10% ethyl acetate in petroleum ether) to obtain the title compound 10a (410 mg, yield 48%).

MS (ESI) m/z 252.1 [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).

Step 2

1-(tert-Butoxycarbonyl)-5,5-difluoroazepane-3-carboxylic acid 10b

Compound 10a (160 mg, 0.52 mmol) was dissolved in 2 ml of methanol, and sodium hydroxide (41.6 mg, 1.04 mmol) was dissolved in 2 ml of water and added to the reaction solution at room temperature. The reaction was carried out at 60°C until the reaction was basically complete, and the methanol was concentrated to remove the methanol, and 5 ml of water was added to dilute, and then extracted with 5 ml of ethyl acetate. The aqueous phase was adjusted to pH 2-3 by 2 mol/L hydrochloric acid solution, extracted with 5 ml of ethyl acetate, and the combined organic phase was washed with 10 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 10b (95 mg, yield 65%).

MS (ESI) m/z 223.9 [M-56+H] ⁺

¹ H NMR: (400MHz, CDCl ₃ )3.83-3.69(m, 2H), 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).

Step 3

Tert-butyl 3-carbamoyl-5,5-difluoroazepane-1-carboxylate 10c

Compound 10b (95 mg, 0.34 mmol) was dissolved in 1 ml of dichloromethane, and ammonium chloride (182.0 mg, 3.40 mmol), triethylamine (0.07 mL, 0.51 mmol) and HATU condensing agent (168.2 mg, 0.44 mmol) were added in sequence at room temperature. The reaction was carried out at 25°C until the reaction was basically completed. 5 ml of water was added for dilution, and then extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (eluting phase was a mixed solvent of 0-65% ethyl acetate in petroleum ether) 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).

Step 4

Tert-butyl 3-(((benzyloxy)carbonyl)amino)-5,5-difluoroazepane-1-carboxylate 10d

Compound 10c (470 mg, 1.69 mmol) and benzyl alcohol (0.9 mL, 8.44 mmol) were dissolved in 5 mL of dichloromethane, and 1,8-diazabicycloundec-7-ene (0.8 mL, 5.07 mmol) and N-bromosuccinimide (360.7 mg, 2.03 mmol) were added in sequence at 0°C under nitrogen protection. The reaction was allowed to proceed to substantially complete reaction at room temperature, and then 5 mL of water was added for dilution, and then the mixture was extracted with 5 mL of dichloromethane, washed with saline, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by C18 (eluting phase was methanol and water containing 0.1% ammonia water) 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).

Step 5

Tert-butyl 3-amino-5,5-difluoroazepane-1-carboxylate 10e

Compound 10d (410 mg, 1.07 mmol) was dissolved in 4 ml of ethyl acetate and 1 ml of tetrahydrofuran, and 100 mg of palladium carbon was added at room temperature. The mixture was reacted at room temperature under a hydrogen atmosphere until the reaction was substantially completed, and then 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).

Step 6

2-ethyl 5-methyl 1-(1-(tert-butoxycarbonyl)-5,5-difluoroazepan-3-yl)-3-methoxy-4-carbonyl

-1,4-dihydropyridine-2,5-dicarboxylate 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 substantially completed, and the title compound 10f (520 mg, crude product) was obtained by concentration, and the product was used directly in the next step.

MS (ESI) m/z 489.4 [M+H] ⁺

Step 7

tert-Butyl 3-(5-((2,4-difluorobenzyl)carbamoyl)-2-(ethoxycarbonyl)-3-methoxy-4-

Carbonylpyridin-1(4H)-yl)-5,5-difluoroazepane-1-carboxylate 10g

Compound 10f (520 mg) was dissolved in 5 ml of p-xylene, and 2,4-difluorobenzylamine 1 g (0.13 mL, 1.08 mmol) 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 substantially completed, and concentrated to obtain the title compound 10 g (520 mg, crude product), which was used directly in the next step without purification.

MS (ESI) m/z 600.2 [M+H] ⁺

Step 8

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]diazononane-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]diazononane-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 basically complete, and concentrated to obtain a crude product. The crude product was purified by column chromatography (the elution phase was a petroleum ether mixed solvent of 0-100% ethyl acetate) to obtain a racemic compound. The racemic compound was separated by supercritical fluid chromatography on a DAICEL CHIRALCEL OD-H chiral column to obtain the title compound 10h (31.4mg, yield 9.6%) and the title compound 10i (30.6mg, yield 9.4%).

The chiral analysis method is as follows:

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

Mobile phase: A: Carbon dioxide B: Ethanol (0.05% diethylamine)

Gradient: 5 min from 5% B to 40% B, then 3 min at 40% B, then back to 5% B for 1.5 min

Flow rate: 2.5 ml/min

Column temperature: 40°C

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=6.0Hz, 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=6.0Hz, 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-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-10-carboxamide isomer (A) 10

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

MS (ESI) m/z 440.1 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d6) 10.34 (t, J=6.0Hz, 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).

Embodiment 11

N-(2,4-difluorobenzyl)-5,5-difluoro-12-hydroxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3H-2,7-

Methylenepyrido[1,2-a][1,4]diazononanoin-10-carboxamide isomer (B) 11

Compound 11 was synthesized via compound 10i, referring to the synthesis method of step 9 of Example 10.

MS (ESI) m/z 440.1 [M+H] ⁺

¹ H NMR (400MHz, DMSO-d ⁶ ) 10.34 (t, J=6.0Hz, 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-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-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, 1H) 8.43 (s, 1H) 7.34-7.46 (m, 1H) 7.18-7.28 (m, 1H) 7.01-7.10 (m, 1H) 4.81 ( br s, 1H) 4.50-4.64 (m, 3H) 3.88-3.98 (m, 1H) 3.72-3.82 (m, 1H) 3.59-3.64 (m, 1H) 2.36-2.43 (m, 1H) 2.26 (br d, J=13.88Hz, 1H) 1.99 (br s, 1H) 1.65-1.78 (m, 1H).

Embodiment 13

N-(2,4-difluorobenzyl)-4,4-difluoro-12-hydroxy-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-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, 1H) 8.43 (s, 1H) 7.35-7.44 (m, 1H) 7.18-7.28 (m, 1H) 7.02-7.11 (m, 1H) 4.83 ( br s, 1H) 4.51-4.65 (m, 3H) 3.88-3.98 (m, 1H) 3.73-3.84 (m, 1H) 3.59-3.64 (m, 1H) 2.36-2.43 (m, 1H) 2.26 (br d, J＝13.88Hz, 1H) 2.01 (br s, 1H) 1.66-1.79 (m, 1H)

Embodiment 14

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

first step

2,2-Dimethylhex-5-enenitrile 14c

Isobutyronitrile 14b (12.2 mL, 134.68 mmol) was dissolved in 200 mL of tetrahydrofuran, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (74.1 mL, 2 mol/L) was added dropwise at -78°C under nitrogen protection. The reaction was allowed to proceed at -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 was completed, the reaction was naturally heated to room temperature until the reaction was substantially complete, and the reaction was quenched with 100 mL of saturated ammonium chloride solution, and then extracted with 200 mL of dichloromethane, 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 (33.5 g, 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 ).

Step 2

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 substantially complete, the reaction solution was cooled 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, and stirred for half an hour to obtain a suspension, which was filtered, and 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 directly used in the next step.

Step 3

Tert-butyl (2,2-dimethylhex-5-en-1-yl) carbamate 14f

Compound 14d (15.56 g) was dissolved in 200 ml of tetrahydrofuran, and di-tert-butyl dicarbonate (25.1 mL, 117.41 mmol) and triethylamine (27.2 mL, 195.68 mmol) were added at room temperature. The reaction was carried out until the reaction was basically completed at room temperature, and 300 ml of water was added to quench the reaction, and the mixture was extracted with 200 ml of ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography on a silica gel column (the eluent was a mixed solvent of 0-10% ethyl acetate in petroleum ether) to obtain the title compound 14f (15.3 g, 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).

Step 4

Tert-butyl 6-acetoxy-3,3-dimethylazepane-1-carboxylate 14g

Compound 14f (5.2 g, 22.87 mmol) was dissolved in 40 ml of glacial acetic acid, and palladium acetate (0.26 g, 1.14 mmol), di(2-pyridyl)methanone (0.32 g, 1.72 mmol) and hydrogen peroxide (7.78 g, 68.62 mmol) were added in sequence at room temperature. The reaction was carried out until the reaction was basically completed at room temperature, 300 ml of water was added for dilution, and the mixture was extracted with 200 ml of ethyl acetate, washed with 300 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (eluent: 0-10% ethyl acetate in petroleum ether) to obtain the title compound 14g (554 mg, yield 8.5%).

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).

Step 5

Tert-butyl 6-hydroxy-3,3-dimethylazepane-1-carboxylate 14h

Compound 14g (1.63 g, 5.71 mmol) was dissolved in 10 ml of methanol. At 0°C, sodium hydroxide (2.28 g, 57.12 mmol) was dissolved in 10 ml of water and added to the reaction solution. The reaction was carried out at room temperature until the reaction was basically completed. After the reaction was completed, the methanol was removed by concentration, and 5 ml of water was added to dilute it, and 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 14h (1.32 g, yield 95%).

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

Step 6

Tert-butyl 3,3-dimethyl-6-carbonylazepane-1-carboxylate 14i

Compound 14h (1.3 g, 5.34 mmol) was dissolved in 15 ml of dichloromethane, and Dess-Martin periodinane (2.72 g, 6.41 mmol) was added. The reaction was carried out at room temperature until the reaction was basically complete, filtered, and washed with dichloromethane. 40 ml of saturated sodium bicarbonate solution was added to the filtrate, the liquid was separated, and then washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and filtered. The crude product was concentrated under reduced pressure and purified by column chromatography (the eluent was a mixed solvent of 0-10% ethyl acetate in petroleum ether) 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).

Step 7 to Step 10

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

Compound 14 was prepared using compound 14i as the starting material, and the synthesis method from step 7 to step 10 was followed by steps 12 to 15 of 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).

Embodiment 15

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

Compound 15 was synthesized via compound 14m, referring to the synthesis method of step 15 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=14.0Hz, 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-tetrahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-1,11-dione isomer (A) 16

first step

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

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

MS (ESI) m/z 309.3 [M + Na] ⁺

Step 2

Tert-butyl 2-(2-(2,4-difluorophenyl)ethylthioyl)hydrazine-1-carboxylate 16d

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

MS (ESI) m/z 247.2 [M+H-56] ⁺

Step 3

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

Compound 16d (300 mg, 0.99 mmol) was dissolved in 4 ml of methanolic hydrochloric acid solution (4 mol/L), stirred at room temperature until the reaction was almost complete, concentrated to remove methanol, diluted and neutralized with 10 ml of saturated sodium bicarbonate, 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] ⁺

Step 4

Dimethyl 3-methoxy-1-(7-methylazepan-3-yl)-4-carbonyl-1,4-dihydropyridine-2,5-dicarboxylate 16f

Compound 4j (500 mg, 1.11 mmol) was dissolved in 5 ml of methanolic hydrochloric acid solution (4 mol/L), stirred at room temperature until the reaction was almost complete, concentrated to remove methanol, diluted and neutralized with 10 ml of saturated sodium bicarbonate, 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] ⁺

Step 5

Methyl 12-methoxy-3-methyl-1,11-dicarbonyl-1,4,5,6,7,11-hexahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-10-carboxylate 16g

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

MS (ESI) m/z 321.4 [M+H] ⁺

Step 6

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

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

MS (ESI) m/z 307.4 [M+H] ⁺

Step 7

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]diazononane-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]diazononane-1,11-dione isomer (B) 16j

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

The chiral analysis method is as follows:

Analytical column: Chiralcel OJ-3 ID, 3um

Mobile phase: A: Carbon dioxide B: Ethanol (0.05% diethylamine)

Gradient: 4 minutes from 5% B to 40% B, 2.5 minutes at 40% B, and 1.5 minutes back to 5% B

Flow rate: 2.5 ml/min

Column temperature: 35°C

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, 14.8Hz, 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).

Step 8

10-(5-(2,4-difluorobenzyl)-1,3,4-thiadiazol-2-yl)-12-hydroxy-3-methyl-4,5,6,7-tetrahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-1,11-dione isomer (A) 16

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

MS (ESI) m/z 459.4 [M+H] ⁺

¹ H NMR: (400MHz, DMS0-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).

Embodiment 17

10-(5-(2,4-difluorobenzyl)-1,3,4-thiadiazol-2-yl)-12-hydroxy-3-methyl-4,5,6,7-tetrahydro-3H-2,7-methylenepyrido[1,2-a][1,4]diazononane-1,11-dione isomer (B) 17

Compound 17 was synthesized via compound 16j, referring to the synthesis method of step 15 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, 8.8Hz, 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 present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

Test Example 1: Intergrase enzyme in vitro activity detection experiment: HTRF based strand transfer assay

1. Experimental instruments and materials

Instrument Name Equipment manufacturers model Constant temperature thermostat oscillator IMB MB-1002A Plate Reader PerkinElmer Envision

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

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

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

Sequence (5′to3′) Number of bases 5′ end modification 3′ end modification ATGTGGAAAATCTCTAGCA 19 CY5 ACTGCTAGAGATTTTCCACAT twenty one CY5 ACAGGCCTAGCACGCGTCG 19 Biotin CGACGCGTGCTAGGCCTGT 19 Biotin

The information of other reagents required for the experiment is as follows

2. Experimental steps

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

The test compound was dissolved in DMSO to 10 mM. The compound was diluted to different concentrations using a reaction solution (20 mM Hepes [pH 7.5], 7.5 mM MgCl ₂ , 1 mM DTT, 10% glycerol [w/v], 0.1 mg/ml bovine serum albumin [BSA], 0.05% Brij-35, 10 M ZnSO ₄ , 5 mM NaCl). The strand transfer assay based on time-resolved fluorescence was performed in a 384-well plate. A final concentration of 50 nM donor DNA and 200 nM 6HIS-IN were mixed in a 1:1 volume ratio in the reaction solution and incubated on ice for 10 minutes. 12.5 μl of the enzyme and substrate mixture was mixed with the same volume of the test compound in the same proportion, incubated on ice for 10 minutes, and then 12.5 μl of 10 nM acceptor DNA was added and mixed at 37°C for 2 hours. After termination, 25 μl of 2 nM LANCE Eu-W8044-labeled streptavidin detection reagent was added to each well. Incubated at room temperature for 3 hours. The time-resolved fluorescence signal was measured using an Envision plate reader (PerkinElmer, excitation wavelength 330 nm, emission wavelength 665/620 nm). The IC ₅₀ value of the inhibitory activity of the compound on enzyme activity was calculated using the four-parameter logit method. In the following formula, x represents the logarithmic form of the compound concentration; F(x) represents the effect value (the 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. _IC50 values were further calculated as the compound concentration required for 50% inhibition of enzyme activity in the best-fit curve using Primer premier 6.0.

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

Table 1

serial number IC ₅₀ (nM) Dolutegravir 20.25 Bictegravir 13.17 1 14.02 2 16.98 3 28.77 4 8.01 5 8.62 6 6.04 7 4.79 8 13.16 9 9.3 10 9.2 11 13.43 12 1.83 13 7.60 14 40.58 16 2.81 17 7.45

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

Table 2

Test Example 2: Anti-HIV virus and cytotoxicity experiments

1. Experimental instruments and materials

Instrument Name Equipment manufacturers model Microplate Readers PerkinElmer 2105 C02 Incubator Thermo 3111 Class II Biological Safety Cabinet Thermo 1389

The information of other reagents required for the experiment is as follows

Reagents brand Part Number Bovine Serum Albumin Sigma B2064-50G Dimethyl sulfoxide Sigma C34557 CellTiter-Glo Promega G7570 96-well plate cornmg 3599 384-well plate cornmg 3573

2. Experimental steps

HIV-1IIIB and MT-4 (NIH AIDS Project) cells were co-cultured in a 37°C, 5% _CO2 incubator for 1 hour. At the same time, the test compound and the reference compound (AZT, sigma) were diluted with DMSO in multiples and added to the cell culture plate. The infected cells were then inoculated in the cell culture plate at a density of 10,000 cells per well. The final concentration of DMSO in the cell culture medium was 0.5%. The cells were cultured in a 37°C, 5% _CO2 incubator for 5 days. The cytotoxicity test and antiviral experiment were carried out in parallel, and the experimental cells were uninfected MT-4 cells. Cell viability was determined by CellTiter-Glo (Promega).

The antiviral activity and cytotoxicity of the compound are respectively expressed by the inhibition rate (%) and cell viability (%) of the compound on the virus. The calculation formula is as follows:

Inhibition rate (%) = (test well reading - virus control average) / (cell control average - virus control average) x 100

Cell viability (%) = (test well reading - 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 compounds. EC ₅₀ and CC ₅₀ values were calculated using 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 four parameters. Different concentrations correspond to different inhibition rates, and an inverse curve is drawn. The EC ₅₀ and CC ₅₀ of the test compound are calculated from the curve (Primer premier 6.0).

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

Table 3

serial number _EC50 (nM) CC ₅₀ (uM) Dolutegravir 0.881 7.45 Bictegravir 0.343 1.36 2 0.168 >10 4 0.843 11.79

Pharmacokinetic evaluation

Test Example 3: Pharmacokinetic Test of the Disclosed Compounds

1. Summary

Rats were used as test animals, and the drug concentration in plasma at different times after intravenous injection and oral administration of the disclosed compound was determined by LC/MS/MS method to study the pharmacokinetic behavior of the disclosed compound in rats and evaluate its pharmacokinetic characteristics.

2. Experimental plan

2.1 Trial Drugs

Compounds of Examples 4 and 5.

2.2 Experimental animals

Each group included 3 healthy 6-8 week old male SD rats.

2.3 Drug preparation

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

Intragastric administration: Weigh a certain amount of drug, add 0.5% by mass of hydroxypropyl methylcellulose, 0.1% by volume of Tween 80 and 99.6% by volume of normal saline to prepare a 1 mg/mL white suspension.

2.4 Administration

After SD rats fasted overnight, the drug was administered intravenously by gavage at a dose of 1 mg/kg. Alternatively, the drug was administered by gavage at a dose of 5 mg/kg.

3. Operation

Rats were intravenously administered with the disclosed compound, and 0.2 mL of blood was collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The blood was placed in a tube containing EDTA-K2, centrifuged at 4°C and 4000 rpm for 5 minutes to separate the plasma, and stored at -75°C.

Alternatively, rats were intragastrically administered with the disclosed compounds, and 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, placed in a test tube containing EDTA-K2, centrifuged at 4°C, 3500 rpm for 10 minutes to separate plasma, and stored at -75°C.

Determine the content of the test compound in rat plasma after oral administration of different concentrations of the drug: take 30 μL of rat plasma at each time after administration, add 200 μL (50 ng/mL) of acetonitrile solution of internal standard dexamethasone, vortex mix for 30 seconds, centrifuge at 4°C and 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. Pharmacokinetic parameter results

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

Conclusion: The compounds disclosed in the present invention have a long pharmacokinetic half-life, a low apparent clearance rate, and excellent pharmacokinetics.

Claims (11)

1. The compound of the formula III is shown in the specification,

Or a pharmaceutically acceptable salt thereof,

Wherein Z ¹、Z³ and Z ⁴ are each independently selected from-CH ₂-,Z² from-CH ₂ -or-O-;

R ¹、R² is selected from hydrogen;

R ³ is selected from hydrogen;

R ⁴ is selected from hydrogen;

Each R ⁷ or R ⁸ is independently selected from hydrogen, halogen, or C _1-6 alkyl optionally substituted with one or more groups selected from halogen, hydroxy, oxo, cyano, C _1-6 alkyl, or C _1-6 alkoxy;

B is selected from-CONR' -, -COO-, or five-membered heteroaromatic ring;

R' is selected from hydrogen;

R ^c or R ^d is selected from hydrogen;

R ¹⁰ is selected from phenyl substituted with 1 to 4 halogens;

The sum of n and o is an integer less than or equal to 8.

2. The compound of claim 1, wherein the compound of formula III is

3. The compound of claim 1, wherein R ¹⁰ is phenyl substituted with 2 halogens.

4. A compound according to claim 3 wherein R ¹⁰ is selected from 2, 4-difluorophenyl, 2, 3-difluorophenyl, 2, 6-difluorophenyl, 3, 4-difluorophenyl, 2-fluoro-4-chlorophenyl or 3, 5-difluorophenyl.

5. The compound of claim 1, wherein R ¹⁰ is phenyl substituted with 3 halogens.

6. The compound of claim 5, wherein R ¹⁰ is selected from 2,4, 6-trifluorophenyl, 2,3, 4-trifluorophenyl, 2,4, 5-trifluorophenyl, or 2, 4-difluoro-3-chlorophenyl.

7. The compound of claim 1, wherein R ¹⁰ is phenyl substituted with 4 halogens.

8. The compound of claim 7, wherein R ¹⁰ is selected from 2,3,4, 5-tetrafluorophenyl or 2,3,4, 6-tetrafluorophenyl.

9. The compound of claim 1, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. Use of a compound according to any one of claims 1-9 or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for the treatment of HIV infection in a patient suffering from or at risk of suffering from an infection.