WO2022089562A1

WO2022089562A1 - Use of inhibiting genetically defective hiv virus

Info

Publication number: WO2022089562A1
Application number: PCT/CN2021/127270
Authority: WO
Inventors: 王亚娟; 黄晓星; 刘彪; 祝伟; 李正涛
Original assignee: 上海拓界生物医药科技有限公司
Priority date: 2020-10-30
Filing date: 2021-10-29
Publication date: 2022-05-05
Also published as: TW202227445A

Abstract

The present invention relates to the use of inhibiting genetically defective HIV virus. In particular, provided are an active agent for inhibiting genetically defective HIV virus such as N155H and the use of the active agent for preparing a medicament for treating diseases caused by genetically defective HIV virus such as N155H.

Description

Use of suppressing genetically defective HIV viruses

technical field

The present disclosure belongs to the field of medicine, and relates to the use of inhibiting gene-deficient HIV virus.

Background technique

HIV retroviruses are causative agents of complex diseases that progressively destroy the immune system. Features of retroviral replication include reverse transcription of the viral genome into proviral DNA and its integration into the host cell genome. Among others, the integration of the proviral genome into the host cell genome requires the action of an integrase, which performs this process in at least three or four steps. Step one involves assembling the viral genome into a stable nucleoprotein complex, step two involves processing two nucleotides from the 3' end of the genome to create staggered ends with free 3'OH residues, and step three involves adding These ends are transferred into the host cell genome, and finally gap filling and repair of the insertion site in the host genome.

Currently, HIV infection can be treated with a number of inhibitors on the market that target reverse transcriptase, protease, or entry into cells. Treatment of HIV infection with these drugs or combinations of these drugs is known to be effective in the treatment of AIDS and similar diseases. Disadvantages of current inhibitors include drug resistance and the rapid onset and increased incidence of many side effects.

Certain mutations in wild-type viral integrases are known to confer resistance to known inhibitors of integration. For example, treatment with Raltegravir or MK-0518 was ineffective in patients represented by viral variants containing the Q148H/G140S double mutation in the integrase and N155H/E92Q double mutations in the integrase (see WO2010000032) . This complicates treatment strategies for patients with HIV infection, and HIV-infected patients may require additional drug treatment due to other medical conditions, and drug interactions can render the evaluation criteria for antiretroviral therapy invalid. There is a need to develop more effective antiretroviral methods with reduced drug interactions.

WO2020197991 and WO2020221294 describe a class of HIV integrase inhibitor compounds. The inventors of the present disclosure have found that these subclasses of compounds show excellent drug resistance in viral pathogens containing integrase mutation sites, and are expected to be used to develop resistance to certain drugs. The treatment of patients with drugs can further improve or improve the quality of life of HIV patients.

SUMMARY OF THE INVENTION

The disclosure (The disclosure) provides the use of a compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of HIV virus infection, wherein the HIV virus includes N155H, E92Q, G140S, Q148H, Y143H, Defects in one or more genes in Y143C,

Wherein, R ¹ is selected from hydrogen or C _6-10 aryl, the aryl is optionally substituted by one or more R ^A1 , and R ^A1 is selected from deuterium, halogen, nitro, cyano, C _1-6 alkane base, C _1-6 alkoxy, the alkyl or alkoxy is optionally substituted by halogen, nitro, cyano or C _1-6 alkoxy;

R is selected from ^hydrogen , deuterium, halogen or alkyl optionally substituted with one or more nitro, nitrile, hydroxy or halogen;

L is selected from -CR ^3a R ^3b -, -C(O)-, -SO ₂ -, -CH ₂ -CH ₂ - or -N(R ^a )-;

Z ³ is selected from a bond or -CR ^4a R ^4b -;

Z ² is selected from a bond or -CR ^5a R ^5b -, -CR ^5a R ^5b CR ^5c R ^5d -, -CR ^6a =CR ^6b -, -N(R ⁷ )-, -O-, -C(O)- , -SO _n -, -C(O)O-, -C(O)NH-, -CR ^5a R ^5b -N(R ⁷ )-, -OCR ^5a R ^5b -, -C(O)-CR ^5a R ^5b -, -SO _n -CR ^5a R ^5b -, -C(O)O-CR ^5a R ^5b -, -OC(O)O-CR ^5a R ^5b -, -(O)NH-CR ^5a R ^5b - or -NHC(O)-CR ^5a R ^5b -;

Z ¹ is selected from a bond or -CR ^8a R ^8b -;

Y is selected from -C(O)NH- or a five- to six-membered heterocycle selected from

preferred

Z ⁴ is selected from -CR ^9a R ^9b -, -CR ^9a R ^9b CR ^9c R ^9d - or -CR ^10a =CR ^10b -;

R ^3a and R ^3b are each independently selected from hydrogen, deuterium, halogen or C _1-6 alkyl;

Alternatively, R ^3a and R ^3b together with adjacent carbon atoms form a 3- to 7-membered cycloalkyl or heterocycloalkyl optionally substituted with one or more R ^A2 , R ^A2 is each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, said alkyl or alkoxy optionally being replaced by halogen, nitro, cyano or C _1-6 alkoxy substituted;

R ^4a and R ^4b are each independently selected from hydrogen, deuterium, halogen or alkyl optionally substituted with one or more nitro, nitrile, hydroxy or halogen;

R ^5a , R ^5b , R ^5c and R ^5d are each independently selected from deuterium, hydrogen, halogen, nitro, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, SR', NR' ( R"), OCOR', OCOOR', COOR', CONR'(R") or OCONR'(R"), said alkyl or alkoxy optionally being replaced by halogen, nitro, cyano or C _1-6 substituted by alkoxy;

Alternatively, any two of R ^5a , R ^5b , R ^5c and R ^5d are taken with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or heterocycloalkyl, optionally Replaced by one or more R ^A3 , each R ^A3 is independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, and the alkyl or alkoxy is optional substituted by halogen, nitro, cyano or C _1-6 alkoxy;

R ^6a and R ^6b are each independently selected from hydrogen, deuterium, halogen or alkyl optionally substituted with one or more nitro, nitrile, hydroxy or halogen;

Alternatively, R ^6a , R ^6b taken together with adjacent carbon atoms form a 5- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, optionally substituted with one or more R ^A4 , each R ^A4 independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy;

R ⁷ is selected from hydrogen, deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, said alkyl or alkoxy optionally being replaced by halogen, nitro, cyano or C _1-6 alkoxy substituted;

R ^8a and R ^8b are each independently selected from hydrogen, deuterium, hydroxy, halogen, nitro, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, said alkyl or alkoxy optionally substituted by halogen, nitro, cyano or C _1-6 alkoxy;

Alternatively, R ^8a , R ^8b together with adjacent carbon atoms form a 3- to 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with one or more R ^A5 , R ^A5 is each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, said alkyl or alkoxy optionally being replaced by halogen, nitro, cyano or C _1-6 alkoxy substituted;

Alternatively, R ^8b is taken together with any one of R ^5a , R ^5b , R ^5c , R ^5d and R ⁷ to form a 3- to 7-membered cycloalkyl or heterocycloalkyl group, either is optionally substituted by one or more R ^A5 , each R ^A5 is independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, said alkyl or alkoxy optionally substituted by halogen, nitro, cyano or C _1-6 alkoxy;

Alternatively, ^R and R together with adjacent carbon atoms form a 3- to ⁷ -membered cycloalkyl or heterocycloalkyl ^optionally substituted with one or more R, R ^A5 is each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, said alkyl or alkoxy optionally being replaced by halogen, nitro, cyano or C _1-6 alkoxy substituted;

Alternatively, R ^8a and R ^4a or R ^8b and R ^4b are taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or heterocycloalkyl optionally substituted by one or more R ^A5 is substituted, R ^A5 is each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, and the alkyl or alkoxy is optionally halogen, nitro substituted with cyano group, cyano group or C _1-6 alkoxy group;

R ^9a , R ^9b , R ^9c and R ^9d are each independently selected from hydrogen, deuterium, hydroxy, halogen, nitro, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, said alkyl Or alkoxy is optionally substituted by halogen, nitro, cyano or C _1-6 alkoxy;

Alternatively, R ^9a and R ^9b or R ^9c and R ^9d are taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or heterocycloalkyl optionally substituted by one or more R ^A6 is substituted, and R ^A6 is independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, and the alkyl or alkoxy is optionally halogen, nitro substituted with cyano group, cyano group or C _1-6 alkoxy group;

Alternatively, any of R ^9a , R ^9b , R ^9c and R ^9d together with any of R ^4a , R ^4b , R ^5a , R ^5b and R ⁷ form a 3- to 7-membered cycloalkyl or heterocycloalkyl, so The cycloalkyl or heterocycloalkyl is optionally substituted by one or more R ^A6 , each R ^A6 is independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy group, the alkyl or alkoxy is optionally substituted by halogen, nitro, cyano or C _1-6 alkoxy;

R ^10a and R ^10b are each independently selected from hydrogen, deuterium, hydroxy, halogen, nitro, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, said alkyl or alkoxy optionally substituted by halogen, nitro, cyano or C _1-6 alkoxy;

Alternatively, R ^10a , R ^10b are taken together with adjacent carbon atoms to form a 5- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group optionally substituted with one or more R ^A7 , each of R ^A7 independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy;

R ^b is selected from hydrogen or C _1-6 alkyl;

R' or R" is independently selected from hydrogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy;

n is selected from an integer between 0-2, such as 1 or 2.

The defect in the present disclosure is a mutation in the gene, a deletion in the gene, or defective expression.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, R ² is selected from hydrogen, deuterium, methyl, ethyl or fluoromethyl. In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, R ² is selected from hydrogen or methyl, more preferably hydrogen.

In some embodiments, Y in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from -C(O)NH-.

In some embodiments, Y in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R ¹ is selected from phenyl, the phenyl is optionally substituted by one or more R ^A1 , and R ^A1 is independently selected from deuterium, halogen , nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy optionally substituted by halogen, nitro, cyano or C _1-6 alkoxy .

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R ¹ is selected from phenyl, and the phenyl group is optionally substituted by 1 to 4 R ^A1 , and R ^A1 is independently selected from deuterium, halogen , nitro, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl or C _1-6 alkoxy.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R ¹ is selected from phenyl, and the phenyl group is optionally substituted by 1 to 4 R ^A1 , each R ^A1 is independently selected from halogen or C _1-6 alkoxy; further, R ¹ is preferably

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, R ¹ is selected from

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, L is selected from -CH ₂ -, -CH(CH ₃ )-, -C(O)- or -CH ₂ CH ₂ -.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, L is selected from _-CH2- .

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, L is selected from -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ - or

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, L is selected from -CH ₂ CH ₂ -.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, Z ³ is selected from a bond or -CR ^4a R ^4b -, and R ^4a and R ^4b are each independently selected from hydrogen, deuterium, halogen or C _1-6 alkyl.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ³ is selected from a bond or -CR ^4a R ^4b -, and R ^4a and R ^4b are each independently selected from hydrogen, deuterium, halogen or methyl.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ³ is selected from bond, -CH ₂ -, -CF ₂ -, -CH(F)-, -CH(CH ₃ )- or - CF( _CH3 )-, preferably a bond, _-CH2- , _-CF2- or -CH(F)-.

On the other hand, in some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ² is selected from -CR ^5a R ^5b -, -CR ^5a R ^5b CR ^5c R ^5d -, -CR ^6a =CR ^6b -, -N(R ⁷ )-, -O-, -C(O)-, -SO _n -, -C(O)O-, -O-CR ^5a R ^5b - or -C(O)-CR ^5a R ^5b -,

R ^5a , R ^5b , R ^5c and R ^5d are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl or C _1-6 alkane Oxygen;

Alternatively, R ^5a , R ^5b , R ^5c and R ^5d are taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or heterocycloalkyl optionally substituted by one or more R ^A3 is substituted, and R ^A3 is independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy;

R ^6a and R ^6b are each independently selected from hydrogen, deuterium, halogen, C _1-6 alkyl or haloC _1-6 alkyl;

Alternatively, R ^6a , R ^6b taken together with adjacent carbon atoms form a 5- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, optionally substituted with one or more R ^A4 , each R ^A4 independently selected from deuterium, halogen, cyano, C _1-6 alkyl;

R ⁷ is selected from hydrogen, deuterium, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl;

n is selected from 0, 1 or 2.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ² is selected from -CR ^5a R ^5b -, -CR ^5a R ^5b CR ^5c R ^5d -, -CR ^6a =CR ^6b -, -N (R ⁷ )-, -O-, -C(O)-, -SO _n -, -C(O)O- or -O-CR ^5a R ^5b -,

R ^5a , R ^5b , R ^5c and R ^5d are each independently selected from hydrogen, deuterium, halogen, hydroxy or C _1-6 alkyl;

Alternatively R ^5a , R ^5b , R ^5c and R ^5d together with adjacent carbon atoms form a ^{3-membered cycloalkyl optionally substituted with one or more R A3} ^each independently selected from deuterium, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl;

R ^6a and R ^6b are each independently selected from hydrogen, deuterium, halogen or C _1-6 alkyl or halogenated C _1-6 alkyl;

Alternatively, R ^6a , R ^6b together with adjacent carbon atoms form a 5- to 6-membered heterocycloalkyl or heteroaryl group, which is optionally substituted by one or more R ^A4 ^, each independently selected from deuterium, halogen or C _1-6 alkyl;

R ⁷ is selected from hydrogen, deuterium, C _1-6 alkyl or halogenated C _1-6 alkyl;

n is selected from 0, 1 or 2.

Or any two of R ^5a , R ^5b , R ^5c and R ^5d together with adjacent carbon atoms form a 5-membered cycloalkyl group optionally substituted by one or more R ^A3 , each independently R ^A3 selected from deuterium, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl;

Alternatively, R ^6a , R ^6b together with adjacent carbon atoms form a 5- to 6-membered heterocycloalkyl or heteroaryl group optionally substituted with one or more R ^A4 ^selected from deuterium, halogen or C _{1 -6} alkyl;

n is selected from 0, 1 or 2.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ² is selected from -CR ^5a R ^5b -, -CR ^5a R ^5b CR ^5c R ^5d -, -CR ^6a =CR ^6b -, -N (R ⁷ )-, -O-, -C(O)-, -SO _n -, -C(O)O- or -O-CR ^5a R ^5b -, R ^5a , R ^5b , R ^5c and R ^5d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl or C _1-6 alkyl; R ^6a and R ^6b are each independently selected from hydrogen, deuterium, halogen or C _1-6 alkyl or halogenated C _1-6 alkyl; R ⁷ is selected from hydrogen, deuterium, C _1-6 alkyl or halogenated C _1-6 alkyl; n is selected from 0, 1 or 2.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ² is selected from -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ =CH ₂ -, -NH-, -N(CH ₃ )-, -N(CH(CH ₃ ) ₂ )-, -N(C(O)CH ₃ )-, -N(SO ₂ CH ₃ )-, -O-, -OCH ₂ - or

In some embodiments, Z ¹ in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from a bond.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, Z ¹ is selected from -CR ^8a R ^8b -, and R ^8a and R ^8b are each independently selected from hydrogen, deuterium, hydroxyl, halogen, hydroxyl, C _{1 -6} alkyl, C _1-6 alkoxy, said alkyl or alkoxy optionally substituted by halogen.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ¹ is selected from -CR ^8a R ^8b -, R ^8a and R ^8b together with adjacent carbon atoms form a 3- to 6-membered heterocycloalkyl, Said heterocycloalkyl is optionally substituted by one or more R ^A5 , each R ^A5 is independently selected from deuterium, halogen, C _1-6 alkyl, C _1-6 alkoxy, said alkyl or alkoxy group is optionally substituted with halogen.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, Z ¹ is selected from -CR ^8a R ^8b -, R ^8a and R ^8b together with adjacent carbon atoms form a 3- to 6-membered cycloalkyl, so The cycloalkyl is optionally substituted by one or more R ^A5 , and R ^A5 is independently selected from deuterium, halogen, C _1-6 alkyl, C _1-6 alkoxy, and the alkyl or alkoxy is any Optionally substituted by halogen.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ¹ is selected from R ^8b and R ² together with adjacent carbon atoms form a 3- to 6-membered cycloalkyl or heterocycloalkyl, the ring Alkyl or heterocycloalkyl is optionally substituted by one or more R ^A5 , each R ^A5 is independently selected from deuterium, halogen, C _1-6 alkyl, C _1-6 alkoxy, said alkyl or alkane Oxygen is optionally substituted with halogen.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ¹ is selected from -CH ₂ -, -CF ₂ -, -CHF-, -CH(OH)-, -CH(CH ₃ )- , -CH(CH ₂ F)-, -C(CH ₂ F)(OH)-, -C(CH ₃ )(OH)-, -C(CH ₂ CH ₃ )(OCH ₃ )-, -CH( CH ₂ CH ₃ )-, -C(CH ₃ )(OCH ₃ )- or -CF(CH ₃ )-, preferably -CH ₂ -, -CF ₂ -, -CHF-, -CH(OH)-, - CH(CH ₃ )- or -CF(CH ₃ )-.

On the other hand, in some embodiments, Z ⁴ in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from -CR ^9a R ^9b -.

In some embodiments, Z ⁴ in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from -CR ^9a R ^9b CR ^9c R ^9d -.

In some embodiments, each of R ^9a , R ^9b , R ^9c and R ^9d in the compound of formula I or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, hydroxyl, halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, the alkyl or alkoxy is optionally substituted with halogen.

In some embodiments, each of R ^9a , R ^9b , R ^9c and R ^9d in the compound of formula I or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, hydroxyl, fluorine, methyl, ethyl, -CHF ₂ or -CH ₂ F.

In some embodiments, Z ⁴ in the compound of formula Va or Vb or a pharmaceutically acceptable salt thereof is selected from -CR ^9a R ^9b -.

In some embodiments, Z ⁴ in the compound of formula Va or Vb or a pharmaceutically acceptable salt thereof is selected from -CR ^9a R ^9b CR ^9c R ^9d -.

In some embodiments, each of R ^9a , R ^9b , R ^9c and R ^9d in the compound represented by formula Va or Vb or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, hydroxyl, halogen, hydroxyl, C _1-6 alkane group, C _1-6 alkoxy group, said alkyl or alkoxy group is optionally substituted by halogen.

In some embodiments, each of R ^9a , R ^9b , R ^9c and R ^9d in the compound of formula Va or Vb or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, hydroxyl, fluorine, methyl, and ethyl. _-CHF2 or _-CH2F .

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ⁴ is selected from -CH ₂ -, -CH(CH ₃ )-, -CH ₂ CH ₂ -,

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ⁴ is selected from -CH ₂ -, -CH(CH ₃ )-, -CH ₂ CH ₂ -.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ⁴ is selected from -CH ₂ -, -CF ₂ -, -CHF-, -CH(OH)-, -CH(CH ₃ )- , -CH(CH ₂ F)-, -C(CH ₂ F)(OH)-, -C(CH ₃ )(OH)-, -C(CH ₂ CH ₃ )(OCH ₃ )-, -CH( _CH2CH3 )-, -C( _CH3 )( _OCH3 )- or -CF( _CH3 ₎ -. In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, Z ⁴ is selected from -CH ₂ -, -CF ₂ -, -CHF-, -CH(OH)-, -CH(CH ₃ )- or -CF(CH ₃ )-.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, Z ⁴ is selected from -N(R ⁷ )-, -O-, -C(O)-, -SO _n -, and n is selected from 0 , 1 or 2.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R ^5a , R ^5b and adjacent carbon atoms together form a 3- to 6-membered cycloalkyl or heterocycloalkyl, the cycloalkyl or heterocycloalkyl Cycloalkyl is optionally substituted with 1 to 3 R ^A3 , each independently selected from deuterium, halogen, C _1-6 alkyl or ^haloC _1-6 alkyl.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R ^4a , R ^4b and adjacent carbon atoms together form a 3- to 6-membered cycloalkyl or heterocycloalkyl, the cycloalkyl or heterocycloalkyl Cycloalkyl is optionally substituted with 1 to 3 R ^A3 , each independently selected from deuterium, halogen, C _1-6 alkyl or ^haloC _1-6 alkyl.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, R ^8a , R ^8b and adjacent carbon atoms together form a 3- to 6-membered cycloalkyl or heterocycloalkyl, the cycloalkyl or heterocycloalkyl Cycloalkyl is optionally substituted with 1 to 3 R ^A3 , each independently selected from deuterium, halogen, C _1-6 alkyl or ^haloC _1-6 alkyl.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, Z ² is selected from -CR ^5a R ^5b -, and R ^5a and R ^5b are each selected from OCOC _1-6 alkyl, OCOOC _1-6 alkyl , COOC _1-6 alkyl, CONH (C _1-6 alkyl) or OCONC _1-6 alkyl (C _1-6 alkyl), the C _1-6 alkyl is selected from methyl, ethyl or propyl base.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, Z ¹ is selected from a bond, Z ² is selected from -OCR ^5a R ^5b -, and Z ⁴ is selected from -CR ^9a R ^9b -, wherein R ^5a and R ^9a or R ^5b and R ^9b together with adjacent carbon atoms form a 3- to 7-membered cycloalkyl or heterocycloalkyl group optionally substituted by 1 to 3 deuterium, halogen, cyano base, C _1-6 alkyl substituted.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, Z ¹ is selected from -CR ^8a R ^8b -, and Z ³ is selected from -CR ^4a R ^4b -, wherein R ^8a and R ^4a are adjacent to the adjacent carbon The atoms together form a 3 to 7 membered cycloalkyl group optionally substituted with 1 to 3 deuterium, halogen, cyano, _C1-6 alkyl.

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, Z ² is selected from -N(R ⁷ )-, -O-, -C(O)-, -SO _n -, and R ⁷ is selected from Hydrogen, C _1-6 alkyl or halogenated C _1-6 alkyl, n=0, 1 or 2.

In some embodiments, typical compounds of formula I or pharmaceutically acceptable salts thereof include, but are not limited to:

In some embodiments, the HIV virus is resistant to an integrase inhibitor selected from the group consisting of raltegravir, elvitegravir, bictegravir, dolutegravir, bottway. In some embodiments, the HIV virus is resistant to raltegravir or elvitegravir.

In some embodiments, the HIV virus is a cabotevir resistant strain, or the virus strain is resistant to the integrase inhibitor cabotevir.

In some embodiments, the HIV virus is a strain resistant to bictegravir or dolutegravir, or the strain is resistant to the integrase inhibitor bictegravir or dolutegravir Resistant. In some embodiments, the HIV virus is resistant to an integrase inhibitor, preferably raltegravir or elvitegravir.

The HIV virus is resistant to anti-AIDS drugs, including raltegravir, elvitegravir, bictegravir, dolutegravir, cabotevir, Trizivir, Nevirapine, Enf Vitide, albovirtide, darunavir, tipranavir, fosamprenavir, atazanavir, lopinavir, amprenavir, nelfinavir, indinavir, rito Navir, Saquinavir, Fostamsavir, Zidovudine, Lamivudine, Abacavir, Efavirenz, Stavudine, Zalcitabine, Emtricitabine, Lithium Pevirine, doravirine.

In some embodiments, the virus is a strain resistant to an integrase inhibitor, the strain comprising HIV integrase comprising the Y143C mutation, the E92Q/N155H double mutation, or the G140S/Y143H /Q148H triple mutation.

The present disclosure also provides the use of a compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for HIV infection with resistance to an anti-AIDS drug,

Wherein, R ¹ , R ² , L, Z ¹ , Z ² , Z ³ , Z ⁴ , and Y are as defined above.

In some embodiments, the anti-AIDS drug is selected from integrase inhibitors, protease inhibitors, non-nucleoside reverse transcriptase inhibitors or nucleoside reverse transcriptase inhibitors.

In some embodiments, the protease inhibition includes, but is not limited to, darunavir, tipranavir, fosamprenavir, atazanavir, lopinavir, amprenavir, nelfinavir, indene Dinavir, ritonavir, saquinavir.

In some embodiments, the non-nucleoside reverse transcriptase inhibitor or nucleoside reverse transcriptase inhibitor includes, but is not limited to, zidovudine, lamivudine, abacavir, efavirenz , stavudine, zalcitabine, emtricitabine, rilpivirine, doravirine.

In some embodiments, the integrase inhibitor is selected from but not limited to raltegravir, elvitegravir, bictegravir, dolutegravir, cabotevir, preferably raltegravir or elvitegravir Telavir.

In other embodiments, the anti-AIDS drug is selected from raltegravir, elvitegravir, bictegravir, dolutegravir, cabotevir, Trizivir, Nevirapine, enfuvirtide, elvitegravir Bovirtide, darunavir, tipranavir, fosamprenavir, atazanavir, lopinavir, amprenavir, nelfinavir, indinavir, ritonavir, sand Quinavir, tamshavir.

In some embodiments, the anti-AIDS drug is selected from raltegravir or elvitegravir.

The present disclosure also provides the use of the compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for HIV infection resistant to an integrase inhibitor.

The present disclosure also provides a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for HIV infection resistant to non-nucleoside reverse transcriptase inhibitors or nucleoside reverse transcriptase inhibitors use in.

The present disclosure also provides use of the compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for HIV virus infection resistant to protease inhibitors.

HIV viral infection as described in the present disclosure includes HIV-1 viral infection.

In another aspect, the pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts.

On the other hand, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.

In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversions via migration of protons, such as keto-enol and imine-enamine isomerizations.

The compounds of the present disclosure may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as enantiomers and diastereomers. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).

Although all of the above structural formulae are drawn as certain isomeric forms for simplicity, the present invention encompasses all isomers such as tautomers, rotamers, geometric isomers, diastereomers isomers, racemates and enantiomers.

Tautomers are structural isomers of organic compounds that are readily interconverted through a chemical reaction known as tautomerization. This reaction often results in the transfer of hydrogen atoms or protons in the form of a single bond and an adjacent double bond. Some common tautomeric pairs are: keto-enol, lactam-lactam. An example of a lactam-lactam equilibrium is between A and B as shown below.

All compounds in the present invention can be drawn as A or B type. All tautomeric forms are within the scope of the present invention. The naming of compounds does not exclude any tautomers. "

The present disclosure also includes certain isotopically-labeled compounds of the present disclosure which are identical to those described herein, except that one or more atoms have been replaced by an atom having an atomic weight or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, ^3H , ^11C , ^13C , ^14C , ¹³ , ^respectively N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl and the like.

Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (ie, at least 1000 times greater than the natural abundance of deuterium (which is 0.015%)) % of deuterium incorporated). Exemplary compounds having natural abundance greater than deuterium may be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 4000 times more abundant 5000 times more abundant deuterium, at least 6000 times more abundant deuterium or more abundant deuterium. The present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize the compound of formula (I) in deuterated form. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.

"Optionally" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "C _1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.

In the chemical structure of the compound of the present invention, the bond

Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond

can be

or

or both

and

Two configurations.

Terminology Explanation:

An "effective amount" or "therapeutically effective amount" as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

"Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 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 and various branched chain isomers, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from deuterium, halogen, nitro, Hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy.

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 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro Ring, fused and bridged cycloalkyl groups. Cycloalkyl may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from deuterium, halogen, nitro , hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy.

The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzo rings Heptyl, etc. Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, nitro, hydroxyl, cyano, _{C1 -6} alkyl, C _1-6 alkoxy.

The term "Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or Heteroatoms of S(O) _m (where m is an integer from 0 to 2), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piper pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyl groups include spiro, fused and bridged ring heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:

and many more.

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

Wait.

Heterocycloalkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 12 membered, such as benzene base and naphthyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:

Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, nitro, hydroxyl, cyano, _C1-6alkane group, C _1-6 alkoxy, said alkyl or alkoxy optionally substituted with halogen, nitro, cyano or C _1-6 alkoxy.

The term "heteroaryl" refers to a heteroaromatic system comprising 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-membered, more preferably 5- or 6-membered. E.g. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,

and many more.

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

Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, nitro, hydroxyl, cyano, _{C1 -6} alkyl, C _1-6 alkoxy optionally substituted by halogen, nitro, cyano or C _1-6 alkoxy.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, nitro, hydroxyl, cyano, _{C1 -6} alkyl, C _1-6 alkoxy.

The term "heterocycle" refers to the atoms that make up the ring in addition to carbon atoms, and includes heterocycloalkyl and heteroaromatic rings.

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

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

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.

Detailed ways

The present disclosure is further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure.

The experimental methods without specific conditions in the examples of the present disclosure generally follow conventional conditions or conditions suggested by raw material or commodity manufacturers. Reagents with no specific source indicated are conventional reagents purchased in the market.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (Methanol-d ₄ ), and the internal standard was Tetramethylsilane (TMS).

MS was measured using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer, scanning in positive/negative ion mode, with a mass scanning range of 120-1300.

The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 silica gel plate, the thin-layer chromatography (TLC) uses the silica gel plate with a specification of 0.2mm±0.03mm, and the thin-layer chromatography separation and purification product adopts a specification of 0.4mm-0.5mm.

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

Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-packed pre-packed ultra-pure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

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

There is no special description in the examples, and the reactions can all be carried out under nitrogen atmosphere.

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

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

Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Company.

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

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

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

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC).

Example 1

(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]diazononin-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 dimethylacetal (18.32 mL, 136.85 mmol) was heated and stirred at 85°C, and dimethyl oxalate was heated and stirred at 85°C. The ester (32.32g, 273.70mmol) was added to the reaction solution, and the reaction was stirred until the reaction was complete, and then lowered to room temperature. The methanol solution of sodium methoxide (52.1542mL, 273.7082mmol) with a content of 30% was added to the reaction solution, and the reaction was continued to stir for 2- After 4 h, the reaction was quenched with 50 ml of acetic acid and purified by C18 reverse phase chromatography to give the title compound 4a (15.8 g, 48% yield).

MS(ESI)m/z 265.3[M+Na] ⁺

second step

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

Ethyl 5-oxohexanoate (3 g, 18.96 mmol) was dissolved in 10 mL of methanol, followed by adding 2-aminoethyl acetate hydrochloride (2.65 g, 18.96 mmol), triethylamine (2.64 mL, 18.96 mmol) and sodium cyanoborohydride (2.38g, 37.93mmol), stirred at room temperature for 18-24h, quenched with 20ml of saturated sodium bicarbonate, concentrated the mixed solution, added dichloromethane (20mL×2), washed with saturated brine, Dry over anhydrous sodium sulfate and concentrate to give the title compound 4d (4 g), which is used directly in the next step.

MS(ESI)m/z 246.2[M+H] ⁺

third step

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 successively, and the reaction was carried out at room temperature for 4 -6 hours, add water to quench the reaction, separate the layers, wash with water, dry over anhydrous sodium sulfate, and concentrate to obtain the title compound 4e (6g), which is directly used in the next step.

MS(ESI)m/z 368.3[M+H] ⁺

the fourth step

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

1-(tert-butyl) 2-ethyl 7-methyl-3-carbonyl azepine-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, and the reaction solution was reacted at 110° C. for 4 hours. Concentration directly gave a mixture of crude title compound 4f and compound 4g (6g), which was used directly in the next step.

MS(ESI)m/z 322.3[M+Na] ⁺

the fifth step

tert-Butyl 2-methyl-6-carbonylazepine-1-carboxylate 4h

The mixed crude product (6 g) of compound 4f and compound 4g was dissolved in a mixed solution of 10 mL of water and 10 mL of tetrahydrofuran, sodium hydroxide (2.40 g, 60.13 mmol) was added, and the reaction was carried out at 70° C. for 12 hours. Extract with ethyl acetate (20 mL×2), dry over anhydrous sodium sulfate, and concentrate to obtain crude product. The crude product was purified by C18 reaction to give the title compound 4h (0.9 g, 31% overall yield over four steps).

MS(ESI)m/z 250.2[M+H] ⁺

Step 6

tert-Butyl 6-amino-2-methylazepine-1-carboxylate 4i

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

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, and the reaction was carried out at 80° C. for 5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was 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, then acetic acid (530.84 mg, 8.84 mmol) and 2,4-difluorobenzylamine (126.53 mg, 0.88 mmol) were added successively, and the reaction was heated to reflux for 5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, and 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-di Hydropyridine-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 sequentially added, and the reaction was carried out at 70° C. for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was further diluted with a 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 41 (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 41 (320 mg, 0.71 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by adding O-(7-azabenzotriazole-1-YL)-N,N,N, N-tetramethylurea hexafluorophosphonium salt (541.45 mg, 1.42 mmol) and N,N-diisopropylethylamine (0.35 mL, 2.14 mmol) were reacted at room temperature for 1-2 hours. The reaction solution was purified by C18 reverse phase to obtain the title compound 4m (200 mg, 65.11% yield).

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]diazononin-10-carboxamide 4n

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

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

Chromatographic conditions:

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

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

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]diazononin-10-carboxamide 4

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 to react at 50° C. for 1 hour. The reaction solution was concentrated to obtain the crude product, which was then purified by C18 reverse phase to obtain the title compound 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).

Biological evaluation

The following is further described in conjunction with test examples to explain the present disclosure, but these examples are not meant to limit the scope of the present disclosure.

Test Example 1

HIV integrase mutant virus:

According to literature reports (ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol.54, No.2, p.934–936), the cDNA of the integrase coding region derived from HIV-infected patients was ligated into the pNL4.3ΔIN vector with the deletion of the HIV integrase coding region Above, the activity ( _EC50 ) of the compounds was determined in the MT-4 cell infection system after preparation of viral stocks.

virus strain

	主要突变位点main mutation site
8070-18070-1	G140S,Y143H,Q148HG140S, Y143H, Q148H
4736_44736_4	E92Q,N155HE92Q,N155H
1556_11556_1	Y143CY143C

Note: Five strains 4736_2, 4736_4, 8070_1, 8070_2 and 1556_1 were contributed by Dr. Robert W. Shafer (Stanford University).

Wild-type HIV NL4-3 virus was used as a control in the study.

test methods:

MT-4 cells in logarithmic growth phase were plated into 96-well plates at a concentration of 5000 cells/well, and specific concentrations of test compounds and wild-type or integrase mutant virus were added at 37°C, 5% _CO After 6 days of incubation in the incubator, MTS (

Reagent, Promega) staining method to detect the protective ability of the compound on cells, so as to determine the antiviral activity of the compound. The fold resistance was determined based on the ratio of the _EC50 of the compound against the wild-type virus and the mutant virus.

Note: DTG dolutegravir; RAL raltegravir or raltegravir; AZT zidovudine; NA not yet calculated.

In the present disclosure, compound 4 exhibited drug resistance in 4736_4, 1556_1 and 8070_1 strains, and compared with raltegravir, compound 4 exhibited superior drug resistance in 4736_4, 1556_1 and 8070_1 strains, especially against Y143C Mutant and G140S, Y143H, Q148H triple mutant strains.

Other compounds can be prepared with reference to the method of WO2020197991 or WO2020221294, and the corresponding drug resistance is tested, and it is expected to exhibit drug resistance.

Claims

Use of a compound shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicine for the treatment or prevention of HIV virus infection, the HIV virus comprising one or more of N155H, E92Q, G140S, Q148H, Y143H, Y143C defects in genes,

Wherein, R 1 is selected from hydrogen or C 6-10 aryl, the aryl is optionally substituted by one or more R A1 , and R A1 is independently selected from deuterium, halogen, nitro, cyano, C 1- 6 alkyl, C 1-6 alkoxy, the alkyl or alkoxy is optionally substituted by halogen, nitro, cyano or C 1-6 alkoxy;

R is selected from hydrogen , deuterium, halogen or alkyl optionally substituted with one or more nitro, nitrile, hydroxy or halogen;

L is selected from -CR 3a R 3b -, -C(O)-, -SO 2 -, -CH 2 -CH 2 - or -N(R 3a )-;

Z 3 is selected from a bond or -CR 4a R 4b -;

Z 2 is selected from a bond or -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -C(O)- , -SO n -, -C(O)O-, -C(O)NH-, -CR 5a R 5b -N(R 7 )-, -OCR 5a R 5b -, -C(O)-CR 5a R 5b -, -SO n -CR 5a R 5b -, -C(O)O-CR 5a R 5b -, -OC(O)O-CR 5a R 5b -, -(O)NH-CR 5a R 5b - or -NHC(O)-CR 5a R 5b -;

Z 1 is selected from a bond or -CR 8a R 8b -;

Y is selected from -C(O)NH- or a five- to six-membered heterocycle selected from

preferred

Z 4 is selected from -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d - or -CR 10a =CR 10b -;

R 3a and R 3b are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

Alternatively, R 3a and R 3b together with adjacent carbon atoms form a 3- to 7-membered cycloalkyl or heterocycloalkyl optionally substituted with one or more R A2 , R A2 is each independently selected from deuterium, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, said alkyl or alkoxy optionally being replaced by halogen, nitro, cyano or C 1-6 alkoxy substituted;

R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen or alkyl optionally substituted with one or more nitro, nitrile, hydroxy or halogen;

R 5a , R 5b , R 5c and R 5d are each independently selected from deuterium, hydrogen, halogen, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, SR', NR' ( R"), OCOR', OCOOR', COOR', CONR'(R") or OCONR'(R"), said alkyl or alkoxy optionally being replaced by halogen, nitro, cyano or C 1-6 substituted by alkoxy;

Alternatively, any two of R 5a , R 5b , R 5c and R 5d are taken with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or heterocycloalkyl, optionally Replaced by one or more R A3 , each R A3 is independently selected from deuterium, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, and the alkyl or alkoxy is optional substituted by halogen, nitro, cyano or C 1-6 alkoxy;

R 6a and R 6b are each independently selected from hydrogen, deuterium, halogen or alkyl optionally substituted with one or more nitro, nitrile, hydroxy or halogen;

Alternatively, R 6a , R 6b taken together with adjacent carbon atoms form a 5- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, optionally substituted with one or more R A4 , each R A4 independently selected from deuterium, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy;

R 7 is selected from hydrogen, deuterium, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, said alkyl or alkoxy optionally being replaced by halogen, nitro, cyano or C 1-6 alkoxy substituted;

R 8a and R 8b are each independently selected from hydrogen, deuterium, hydroxy, halogen, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, said alkyl or alkoxy optionally substituted by halogen, nitro, cyano or C 1-6 alkoxy;

Alternatively, R 8a , R 8b together with adjacent carbon atoms form a 3- to 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with one or more R A5 , R A5 is each independently selected from deuterium, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, said alkyl or alkoxy optionally being replaced by halogen, nitro, cyano or C 1-6 alkoxy substituted;

Alternatively, R 8b is taken together with any one of R 5a , R 5b , R 5c , R 5d and R 7 to form a 3- to 7-membered cycloalkyl or heterocycloalkyl group, either is optionally substituted by one or more R A5 , each R A5 is independently selected from deuterium, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, said alkyl or alkoxy optionally substituted by halogen, nitro, cyano or C 1-6 alkoxy;

Alternatively, R and R together with adjacent carbon atoms form a 3- to 7 -membered cycloalkyl or heterocycloalkyl optionally substituted with one or more R, R A5 is each independently selected from deuterium, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, said alkyl or alkoxy optionally being replaced by halogen, nitro, cyano or C 1-6 alkoxy substituted;

Alternatively, R 8a and R 4a or R 8b and R 4b are taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or heterocycloalkyl optionally substituted by one or more R A5 is substituted, R A5 is each independently selected from deuterium, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, and the alkyl or alkoxy is optionally halogen, nitro substituted with cyano group, cyano group or C 1-6 alkoxy group;

R 9a , R 9b , R 9c and R 9d are each independently selected from hydrogen, deuterium, hydroxy, halogen, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, said alkyl Or alkoxy is optionally substituted by halogen, nitro, cyano or C 1-6 alkoxy;

Alternatively, R 9a and R 9b or R 9c and R 9d are taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or heterocycloalkyl optionally substituted by one or more R A6 is substituted, and R A6 is independently selected from deuterium, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, and the alkyl or alkoxy is optionally halogen, nitro substituted with cyano group, cyano group or C 1-6 alkoxy group;

Alternatively, any of R 9a , R 9b , R 9c and R 9d together with any of R 4a , R 4b , R 5a , R 5b and R 7 form a 3- to 7-membered cycloalkyl or heterocycloalkyl, so The cycloalkyl or heterocycloalkyl is optionally substituted by one or more R A6 , each R A6 is independently selected from deuterium, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy group, the alkyl or alkoxy is optionally substituted by halogen, nitro, cyano or C 1-6 alkoxy;

R 10a and R 10b are each independently selected from hydrogen, deuterium, hydroxy, halogen, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, said alkyl or alkoxy optionally substituted by halogen, nitro, cyano or C 1-6 alkoxy;

Alternatively, R 10a , R 10b are taken together with adjacent carbon atoms to form a 5- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group optionally substituted with one or more R A7 , each of R A7 independently selected from deuterium, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy;

R b is selected from hydrogen or C 1-6 alkyl;

R' or R" is independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy;

n is selected from an integer between 0-2, such as 1 or 2.
Use according to claim 1 , wherein R2 is selected from hydrogen, deuterium, methyl, ethyl or fluoromethyl, preferably hydrogen or methyl, more preferably hydrogen.
Use according to claim 1 or 2, wherein Y is selected from -C(O)NH-.
The use according to any one of claims 1-3, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is
The use according to any one of claims 1-4, wherein R 1 is selected from phenyl optionally substituted by one or more R A1 , each R A1 is independently selected from deuterium, halogen, nitro , cyano, C 1-6 alkyl, C 1-6 alkoxy, said alkyl or alkoxy optionally substituted by halogen, nitro, cyano or C 1-6 alkoxy.
The use according to any one of claims 1-5, wherein R 1 is selected from phenyl optionally substituted by 1 to 4 R A1 , each R A1 is independently selected from deuterium, halogen, nitro , cyano, C 1-6 alkyl, halogenated C 1-6 alkyl or C 1-6 alkoxy.
The use according to any one of claims 1-6, wherein R 1 is selected from phenyl optionally substituted by 1 to 4 R A1 , each R A1 is independently selected from halogen or C 1-6 Alkoxy; further, R 1 is preferably

more preferred

most preferred
The use according to any one of claims 1-7, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is
Use according to any one of claims 1-8, wherein L is selected from -CH2- , -C( CH3 )-, -CH( CH3 ) 2- , -C(O)-, -CH2 CH 2 - or
The use of any one of claims 1-9, wherein L is selected from -CH2- .
The use according to any one of claims 1-10, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is
The use according to any one of claims 1-11, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is
The use of any one of claims 1-8 , wherein L is selected from -CH2CH2- .
The use according to any one of claims 1-8 or 13, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is
The use according to any one of claims 1-8 or 13-14, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is
The use of any one of claims 1-15, wherein Z 3 is selected from a bond or -CR 4a R 4b -, and R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl.
The use of any one of claims 1-16, wherein Z3 is selected from a bond or -CR4aR4b- , and R4a and R4b are each independently selected from hydrogen, deuterium, halogen or methyl.
The use of any one of claims 1-16 or 17, wherein Z 3 is selected from a bond, -CH 2 -, -CF 2 -, -CH(F)-, -CH(CH 3 )- or -CF (CH 3 )-, preferably a bond, -CH 2 -, -CF 2 - or -CH(F)-.
The use according to any one of claims 1-18, wherein Z 2 is selected from -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -C(O)-, -SO n -, -C(O)O-, -O-CR 5a R 5b - or -C(O)-CR 5a R 5b -,

R 5a , R 5b , R 5c and R 5d are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl or C 1-6 alkane Oxygen;

R 5a , R 5b , R 5c and R 5d are taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or heterocycloalkyl group optionally surrounded by one or more R A3 substituted, R A3 are each independently selected from deuterium, halogen, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy;

R 6a and R 6b are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl or haloC 1-6 alkyl;

Alternatively, R 6a , R 6b taken together with adjacent carbon atoms form a 5- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, optionally substituted with one or more R A4 , each R A4 independently selected from deuterium, halogen, cyano, C 1-6 alkyl;

R 7 is selected from hydrogen, deuterium, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl;

n is selected from 0, 1 or 2.
The use according to any one of claims 1-19, wherein Z 2 is selected from -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -C(O)-, -SO n -, -C(O)O- or -O-CR 5a R 5b -,

R 5a , R 5b , R 5c and R 5d are each independently selected from hydrogen, deuterium, halogen, hydroxy or C 1-6 alkyl;

Alternatively R 5a , R 5b , R 5c and R 5d together with adjacent carbon atoms form a 3-membered cycloalkyl optionally substituted with one or more R A3 each independently selected from deuterium, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl;

R 6a and R 6b are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl or halogenated C 1-6 alkyl;

Alternatively, R 6a , R 6b together with adjacent carbon atoms form a 5- to 6-membered heterocycloalkyl or heteroaryl group, which is optionally substituted by one or more R A4 , each independently selected from deuterium, halogen or C 1-6 alkyl;

R 7 is selected from hydrogen, deuterium, C 1-6 alkyl or halogenated C 1-6 alkyl;

n is selected from 0, 1 or 2.
The use according to any one of claims 1-19, wherein Z 2 is selected from -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -C(O)-, -SO n -, -C(O)O- or -O-CR 5a R 5b -,

R 5a , R 5b , R 5c and R 5d are each independently selected from hydrogen, deuterium, halogen, hydroxy or C 1-6 alkyl;

Or any two of R 5a , R 5b , R 5c and R 5d together with adjacent carbon atoms form a 5-membered cycloalkyl group optionally substituted by one or more R A3 selected from Deuterium, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl;

R 6a and R 6b are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl or halogenated C 1-6 alkyl;

Alternatively, R 6a , R 6b together with adjacent carbon atoms form a 5- to 6-membered heterocycloalkyl or heteroaryl group optionally substituted with one or more R A4 selected from deuterium, halogen or C 1 -6 alkyl;

R 7 is selected from hydrogen, deuterium, C 1-6 alkyl or halogenated C 1-6 alkyl;

n is selected from 0, 1 or 2.
The use according to any one of claims 1-21, wherein Z 2 is selected from -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -C(O)-, -SO n -, -C(O)O- or -O-CR 5a R 5b -, R 5a , R 5b , R 5c and R 5d are independently selected From hydrogen, deuterium, halogen, hydroxyl or C 1-6 alkyl; R 6a and R 6b are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl or halogenated C 1-6 alkyl; R 7 is selected from hydrogen, deuterium, C 1-6 alkyl or halogenated C 1-6 alkyl; n is selected from 0, 1 or 2.
The use of claim 1, wherein Z 2 is selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 =CH 2 -, -NH-, -N(CH 3 )-, -N(CH (CH 3 ) 2 )-, -N(C(O)CH 3 )-, -N(SO 2 CH 3 )-, -O-, -OCH 2 - or
The use of any one of claims 1-23, wherein Z 1 is selected from a bond.
The use according to any one of claims 1-23, wherein Z 1 is selected from -CR 8a R 8b -, and R 8a and R 8b are each independently selected from hydrogen, deuterium, hydroxyl, halogen, hydroxyl, C 1-6 alkane group, C 1-6 alkoxy group, said alkyl or alkoxy group is optionally substituted by halogen.
The use according to any one of claims 1-23, wherein Z 1 is selected from -CR 8a R 8b -, R 8a , R 8b together with adjacent carbon atoms form a 3- to 6-membered heterocycloalkyl, the heterocycloalkyl Cycloalkyl is optionally substituted by one or more R A5 , each R A5 is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, and the alkyl or alkoxy is optionally replaced by halogen.
The use according to any one of claims 1-23, wherein Z 1 is selected from -CR 8a R 8b -, R 8a , R 8b together with adjacent carbon atoms form a 3- to 6-membered cycloalkyl, the cycloalkane The group is optionally substituted by one or more R A5 , each R A5 is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, and the alkyl or alkoxy is optionally halogen replaced.
Use according to any one of claims 1-23, wherein Z 1 is selected from R 8b and R 2 together with adjacent carbon atoms form a 3- to 6-membered cycloalkyl or heterocycloalkyl, the cycloalkyl or Heterocycloalkyl is optionally substituted by one or more R A5 , each R A5 is independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, the alkyl or alkoxy is any Optionally substituted by halogen.
The use of any one of claims 1-23, wherein Z 1 is selected from -CH 2 -, -CF 2 -, -CHF-, -CH(OH)-, -CH(CH 3 )-, -CH (CH 2 F)-, -C(CH 2 F)(OH)-, -C(CH 3 )(OH)-, -C(CH 2 CH 3 )(OCH 3 )-, -CH(CH 2 CH 3 )-, -C(CH 3 )(OCH 3 )- or -CF(CH 3 )-, preferably -CH 2 -, -CF 2 -, -CHF-, -CH(OH)-, -CH(CH 3 )- or -CF(CH 3 )-.
The use of any one of claims 1-29, wherein Z 4 is selected from -CR 9a R 9b -.
The use of any one of claims 1-29, wherein Z 4 is selected from -CR 9a R 9b CR 9c R 9d -.
The use of any one of claims 1-31, wherein R 9a , R 9b , R 9c and R 9d are each independently selected from hydrogen, deuterium, hydroxy, halogen, hydroxy, C 1-6 alkyl, C 1- 6 alkoxy, said alkyl or alkoxy optionally substituted by halogen.
The use of any one of claims 1-32, wherein R 9a , R 9b , R 9c and R 9d are each independently selected from hydrogen, deuterium, hydroxy, fluoro, methyl, ethyl, -CHF 2 or -CH 2F .
The use according to any one of claims 1-15, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is
The use according to any one of claims 1-15 or 34, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is
The use of claim 34 or 35, wherein Z 4 is selected from -CR 9a R 9b -.
The use of claim 34 or 35, wherein Z 4 is selected from -CR 9a R 9b CR 9c R 9d -.
The use of any one of claims 34-37, wherein R 9a , R 9b , R 9c and R 9d are each independently selected from hydrogen, deuterium, hydroxy, halogen, hydroxy, C 1-6 alkyl, C 1- 6 alkoxy, said alkyl or alkoxy optionally substituted by halogen.
The use of any one of claims 34-38, wherein R 9a , R 9b , R 9c and R 9d are each independently selected from hydrogen, deuterium, hydroxy, fluoro, methyl, ethyl, -CHF 2 or -CH 2F .
The use according to any one of claims 1-15, wherein Z 4 is selected from -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -,
The use according to any one of claims 1-15, wherein Z 4 is selected from -N(R 7 )-, -O-, -C(O)-, -SO n -, and n is selected from 0, 1 or 2.
The use as claimed in any one of claims 1-15, wherein R 5a , R 5b together with adjacent carbon atoms form a 3- to 6-membered cycloalkyl or heterocycloalkyl, which cycloalkyl or heterocycloalkyl Optionally substituted with 1 to 3 R A3 , each R A3 is independently selected from deuterium, halogen, C 1-6 alkyl or haloC 1-6 alkyl.
The use according to any one of claims 1-15 or 42, wherein R 4a , R 4b together with adjacent carbon atoms form a 3- to 6-membered cycloalkyl or heterocycloalkyl, the cycloalkyl or heterocycle The alkyl group is optionally substituted with 1 to 3 R A3 , each R A3 is independently selected from deuterium, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
The use according to any one of claims 1-15 or 42-43, wherein R 8a , R 8b together with adjacent carbon atoms form a 3- to 6-membered cycloalkyl or heterocycloalkyl, the cycloalkyl or Heterocycloalkyl is optionally substituted with 1 to 3 R A3 , each R A3 is independently selected from deuterium, halogen, C 1-6 alkyl or haloC 1-6 alkyl.
The use according to any one of claims 1-15, wherein Z 2 is selected from -CR 5a R 5b -, and R 5a and R 5b are each selected from OCOC 1-6 alkyl, OCOOC 1-6 alkyl, COOC 1 -6 alkyl, CONH(C 1-6 alkyl) or OCONC 1-6 alkyl (C 1-6 alkyl), the C 1-6 alkyl being selected from methyl, ethyl or propyl.
The use according to any one of claims 1-15, wherein Z 1 is selected from a bond, Z 2 is selected from -OCR 5a R 5b -, Z 4 is selected from -CR 9a R 9b -, wherein R 5a and R 9a or R 5b and R 9b together with adjacent carbon atoms form a 3- to 7-membered cycloalkyl or heterocycloalkyl group optionally substituted by 1 to 3 deuterium, halogen, cyano, C 1-6 alkyl substituted.
Use according to any one of claims 1-15, wherein Z 1 is selected from -CR 8a R 8b -, Z 3 is selected from -CR 4a R 4b -, wherein R 8a and R 4a are formed together with adjacent carbon atoms 3 to 7 membered cycloalkyl optionally substituted with 1 to 3 deuterium, halogen, cyano, C 1-6 alkyl.
The use of any one of claims 1-15, wherein L is selected from -CH2- , -CH( CH3 )-, -C( CH3 ) 2- or
The use according to any one of claims 1-15, wherein Z 2 is selected from -N(R 7 )-, -O-, -C(O)-, -SO n -, and R 7 is selected from hydrogen, C 1-6 alkyl or halogenated C 1-6 alkyl, n=0, 1 or 2.
A compound represented by formula I or a pharmaceutically acceptable salt thereof
The use of any one of claims 1-50, wherein the HIV virus is resistant to an integrase inhibitor selected from the group consisting of raltegravir, elvitegravir, bictegra Lasvir, dolutegravir, cabotevir, preferably raltegravir or elvitegravir.
The use of any one of claims 1-51, wherein the virus is a strain resistant to an integrase inhibitor, the strain comprising HIV integrase preferably comprising the Y143C mutation, E92Q/N155H double mutation or G140S/Y143H/Q148H triple mutation.
The purposes of the compound shown in any one of claim 1-50 in formula I or its pharmaceutically acceptable salt in the preparation of the medicine for the HIV virus infection that is resistant to AIDS medicine,

wherein R 1 , R 2 , L, Z 1 , Z 2 , Z 3 , Z 4 , Y are as defined in any one of claims 1-50.
The use according to claim 53, wherein the anti-AIDS drug is selected from integrase inhibitors, protease inhibitors, non-nucleoside reverse transcriptase inhibitors or nucleoside reverse transcriptase inhibitors, preferably Retiger Wei, elvitegravir, bictegravir, dolutegravir, cabotevir, Trizivir, Nevirapine, enfuvirtide, albovirtide, darunavir, tipranavir, fosampre Wei, atazanavir, lopinavir, amprenavir, nelfinavir, indinavir, ritonavir, saquinavir, fostamsavir, zidovudine, lamic Vudine, abacavir, efavirenz, stavudine, zalcitabine, emtricitabine, rilpivirine, doravirine, more preferably raltegravir or elvitegravir.
The use of any one of claims 1-54, wherein the defect is a mutation in the gene, a deletion in the gene, or defective expression.