TW202227445A - Use of inhibiting genetically defective hiv virus - Google Patents

Abstract

The present disclosure relates to the use of inhibiting genetically defective HIV virus. Specifically, provide an active agent for inhibiting genetically defective HIV virus such as N155H, and the active agent is used to prepare drugs for the treatment of diseases caused by genetically defective HIV viruses such as N155H, etc.

Description

Use of suppressing genetically defective HIV viruses

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

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 HIV can further improve or improve the quality of life of HIV patients.

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 infection, the HIV virus including N155H, E92Q, G140S, Q148H, Y143H, Y143C have a defect in one or more of the genes,

Wherein, R ¹ is selected from hydrogen or C _6-10 aryl, the aryl is optionally substituted by one or more R ^A1 , R ^A1 is 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 ² is selected from hydrogen, deuterium, halogen or alkyl optionally substituted by one or more nitro, nitrile, hydroxyl 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

或

，較佳

；

or

, preferably

;

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 group optionally substituted with one or more R ^A2 , R ^A2 Each is independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, the 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"), the alkyl or alkoxy is optionally replaced by halogen, nitro, cyano or C _1-6 alkane substituted by oxy;

Alternatively, any two of 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 which is optionally replaced by a or multiple R ^A3 substituted, R ^A3 are each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, the alkyl or alkoxy is optionally halogenated , nitro, cyano or C _1-6 alkoxy substituted;

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 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 of which 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, the alkyl or alkoxy optionally 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, the alkyl or alkoxy optionally being substituted by halogen, nitro, cyano or C _1-6 alkoxy;

Alternatively, R ^8a , R ^8b and adjacent carbon atoms together form a 3- to 7-membered cycloalkyl or heterocycloalkyl, the cycloalkyl or heterocycloalkyl may be optionally substituted by one or more R ^A5 , R ^A5 each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, the alkyl or alkoxy optionally replaced by halogen, nitro, cyano or C _{1- 6} alkoxy substituted;

Alternatively, R ^8b is taken together with any of R ^5a , R ^5b , R ^5c , R ^5d and R ⁷ to form a 3- to 7-membered cycloalkyl or heterocycloalkyl, optionally Replaced 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, the alkyl or alkoxy is optional substituted by halogen, nitro, cyano or C _1-6 alkoxy;

Alternatively, R ^8b and R ² 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 Each is independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, the 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 group optionally separated by one or more R Replaced by ^A5 , R and ^A5 are each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, and the alkyl or alkoxy is optionally substituted by halogen, nitro, substituted by cyano or C _1-6 alkoxy;

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, the 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 group optionally separated by one or more R Replaced by ^A6 , R and ^A6 are each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, and the alkyl or alkoxy is optionally substituted by halogen, nitro, substituted by cyano or C _1-6 alkoxy;

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, 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 , 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, hydroxyl, halogen, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, the alkyl or alkoxy optionally being substituted by halogen, nitro, cyano or C _1-6 alkoxy;

Alternatively, R ^10a , R ^10b together with adjacent carbon atoms form a 5- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, optionally substituted with one or more R ^A7 , each 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, hydroxyl, 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, 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, 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, and the phenyl group is optionally substituted by one or more R ^A1 , and R ^A1 is independently selected from deuterium, halogen, Nitro group, cyano group, C _1-6 alkyl group, C _1-6 alkoxy group, the alkyl or alkoxy group is optionally substituted by halogen, nitro group, cyano group or C _1-6 alkoxy group.

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, halo 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 , and R ^A1 is independently selected from halogen or C _{1 -6} alkoxy; further, R ¹ is preferred

,

,

,

,

,

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, R ¹ is selected from

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

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, L is selected from _-CH2- , -CH( _CH3 )-, _-C (O)- or _-CH2CH2- .

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

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

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

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

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

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 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(CH ₃ )-, preferably a bond, -CH ₂ -, -CF ₂ - or -CH(F)-.

On the other hand, in some embodiments, in the compound shown in 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, halo C _1-6 alkyl or C _1-6 alkoxy base;

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 group optionally substituted by one or more R Replaced by ^A3 , R and ^A3 are each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, halogen 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 halo C _1-6 alkyl;

Alternatively, R ^6a , R ^6b 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 of which 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 halogen C _1-6 alkyl;

n is selected from 0, 1 or 2.

In some embodiments, in the compound shown in 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;

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

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

n is selected from 0, 1 or 2.

In some embodiments, in the compound shown in 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;

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

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

n is selected from 0, 1 or 2.

In some embodiments, in the compound shown in 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 halogen C _1-6 alkyl; R ⁷ is selected from hydrogen, deuterium, C _1-6 alkyl or halo 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, the alkyl or alkoxy is optionally substituted by 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 heterocycloalkyl, The heterocycloalkyl 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 optionally need to be replaced by 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 , R ^8b and adjacent carbon atoms together form a 3- to 6-membered cycloalkyl, 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 optionally substituted by 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 cycloalkane Radical 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 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( _CH3 )- or -CF( _CH3 )-.

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 by 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, the compound of formula I or a pharmaceutically acceptable salt thereof is

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

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, the alkyl group 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 .

、

、

、

或

。 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 -,

,

,

,

or

.

、

、

。 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 of 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 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 halo C _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 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 halo C _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 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 halo C _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 .

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 groups , 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 groups.

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 halo 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, cabot Wei. 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 virus strain is resistant to the integrase inhibitor bictegravir or dolutegravir sex. 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, enfuvirtide , albovir, darunavir, tipranavir, fosamprenavir, atazanavir, lopinavir, amprenavir, nelfinavir, indinavir, ritonavir , saquinavir, fostamsavir, zidovudine, lamivudine, abacavir, efavirenz, stavudine, zalcitabine, emtricitabine, rilpivir Lin, 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 triplet mutation.

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 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, indinavir Navir, 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, lecithin Fudine, 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 the group consisting of raltegravir, elvitegravir, bictegravir, dolutegravir, cabotevir, Trizivir, Nevirapine, enfuvirtide, albumin Vitavir, darunavir, tipranavir, fosamprenavir, atazanavir, lopinavir, amprenavir, nelfinavir, indinavir, ritonavir, saqui Navir, fostamsavir.

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

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 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.

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 protease inhibitors.

The HIV viral infection 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, 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.

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 an 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. Or, when points When the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then the non-stereomeric salt is carried out by conventional methods known in the art. The enantiomers are resolved and then recovered to give the pure enantiomer. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (eg from amine to amine carboxylate).

Although all of the above 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 by a chemical reaction called 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-lactamide. An example of a lactam-lactamine 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 that are identical to those described herein, but wherein one or more atoms are 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 10 times greater than the natural abundance of deuterium, which is 0.015%), at least 1000 times greater % deuterium incorporation). 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. One of ordinary skill in the art can refer to the 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" is meant to mean that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "optionally substituted C _1-6 alkyl 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.

”或“

”，或者同時包含“

”和“

”兩種構型。 In the chemical structure of the compounds described in the present invention, the bond "/" represents an unspecified configuration, that is, if there is a chiral isomer 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 patient's general health condition, route of administration and dosage, and 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 base, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers thereof. Alkyl groups 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 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 group, hydroxyl group, cyano group, C _1-6 alkyl group, C _1-6 alkoxy group.

The cycloalkyl ring can 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, benzocycloheptyl Alkyl 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, C _1-6 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. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 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:

，

，

和

等等。

,

,

and

and many more.

The heterocycloalkyl ring can 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:

和

等。

and

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 sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, e.g. Phenyl and Naphthalene base. 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 can 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, C _1-6 Alkyl, C _1-6 alkoxy, optionally substituted by halogen, nitro, cyano or C _1-6 alkoxy.

，

，

，等等。 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 members, more preferably 5 or 6 members. E.g. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,

,

,

,and many more.

The heteroaryl ring 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, C _1-6 alkyl, C _1-6 alkoxy, the alkyl or alkoxy is 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, C _1-6 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 are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those of ordinary skill in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.

The present disclosure is further described below with reference to the embodiments, but these embodiments do not limit the scope of the present disclosure.

The experimental methods for which specific conditions are not indicated in the embodiments of the present disclosure are generally based on 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, and 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 with a Waters Micromass Quattro micro API triple quadrupole mass spectrometer, scanned in positive/negative ion mode, with a mass scan 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 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, Accela ChemBio Inc, Bide Medicine 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 temperature of the reaction 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-carbamide

first step

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

A mixture of methyl 4-methoxyacetate acetate (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, and the oxalic acid Dimethyl ester (32.32 g, 273.70 mmol) was added to the reaction solution, and the reaction was stirred until the reaction was complete, then lowered to room temperature, and a methanol solution of sodium methoxide (52.1542 mL, 273.7082 mmol) with a content of 30% was added to the reaction solution, and the stirring was continued. The reaction was carried out for 2-4 h, quenched with 50 ml of acetic acid, and purified by C18 reverse phase chromatography column to obtain 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 (2.38 g, 37.93 mmol), stirred at room temperature for 18-24 h, quenched with 20 ml of saturated sodium bicarbonate, concentrated the mixed solution, added dichloromethane (20 mL×2), saturated brine Washed, 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] ⁺

third step

Ethyl 5-((3-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, at room temperature The reaction was carried out for 4-6 hours, 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 directly used in the next step.

MS(ESI)m/z 368.3[M+H] ⁺

the fourth step

1-(Third-butyl) 4-ethyl 7-methyl-3-carbonylazepan-1,4-dicarboxylate 4f

1-(Third-butyl) 2-ethyl 7-methyl-3-carbonyl azepan-1,2-dicarboxylate 4g

Compound 4e (4 g, 11.5797 mmol) was dissolved in 10 mL of toluene, sodium tertiary 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

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

The mixed crude product (6g) 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 reverse phase 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

3-butyl 6-amino-2-methylazepan-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 the crude product, the 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-(3-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-(3-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)aminocarbamide)-3-methoxy-1-(7-methylazeptan-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 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 then 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]diazononin-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 hexafluorophosphine 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 reverse-phase purified by C18 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]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:

Chromatography 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-carbamide 4

Compound 4o (46 mg, 0.11 mmol) was dissolved in 3 mL of acetonitrile, magnesium dibromide (39.25 mg, 0.21 mmol) was added, and the reaction was carried out at 50° C. for 1 hour. The reaction solution was concentrated to obtain the crude product, which was then purified by C18 reverse phase to obtain the title compound 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 present disclosure is further described and explained below in conjunction with test examples, but these examples are not intended 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 pNL4.3△ which was deleted in the HIV integrase coding region. Compound activity ( _EC50 ) was determined in MT-4 cell infection system after virus stock preparation on IN vector.

virus strain

Note: Five virus 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 the specific concentration of the test compound and wild-type or integrase mutant virus was added, and incubated at 37 °C, 5% CO ₂ After 6 days of incubation in the box, the antiviral activity of the compounds was determined by detecting the protective ability of the compounds on cells by MTS (CellTiter® 96 Reagent, Promega) staining. 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 strains 4736_4, 1556_1 and 8070_1, and compared with raltegravir, compound 4 exhibited superior drug resistance in strains 4736_4, 1556_1 and 8070_1, 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 (55)

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

Wherein, R ¹ is selected from hydrogen or C _6-10 aryl group, the aryl group 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 ² is selected from hydrogen, deuterium, halogen or alkyl optionally substituted by one or more nitro, nitrile, hydroxyl 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

or

, preferably

; 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 group optionally substituted with one or more R ^A2 , R ^A2 Each is independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, the 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"), the alkyl or alkoxy is optionally replaced by halogen, nitro, cyano or C _1-6 alkane substituted by oxy; Alternatively, any two of 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 which is optionally replaced by a or multiple R ^A3 substituted, R ^A3 are each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, the alkyl or alkoxy is optionally halogenated , nitro, cyano or C _1-6 alkoxy substituted; 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 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 of which 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, the alkyl or alkoxy optionally 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, the alkyl or alkoxy optionally being substituted by halogen, nitro, cyano or C _1-6 alkoxy; Alternatively, R ^8a , R ^8b and adjacent carbon atoms together form a 3- to 7-membered cycloalkyl or heterocycloalkyl, the cycloalkyl or heterocycloalkyl may be optionally substituted by one or more R ^A5 , R ^A5 Each is independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, the alkyl or alkoxy optionally being replaced by halogen, nitro, cyano or C _{1- 6} alkoxy substituted; Alternatively, R ^8b is taken together with any of R ^5a , R ^5b , R ^5c , R ^5d and R ⁷ to form a 3- to 7-membered cycloalkyl or heterocycloalkyl, optionally Replaced 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, the alkyl or alkoxy is optional substituted by halogen, nitro, cyano or C _1-6 alkoxy; Alternatively, R ^8b and R ² 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 Each is independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, the 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 group optionally separated by one or more R Replaced by ^A5 , R and ^A5 are each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, and the alkyl or alkoxy is optionally substituted by halogen, nitro, substituted by cyano or C _1-6 alkoxy; 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, the 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 group optionally separated by one or more R Replaced by ^A6 , R and ^A6 are each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, and the alkyl or alkoxy is optionally substituted by halogen, nitro, substituted by cyano or C _1-6 alkoxy; 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, 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 , 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, hydroxyl, halogen, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, the alkyl or alkoxy optionally being substituted by halogen, nitro, cyano or C _1-6 alkoxy; Alternatively, R ^10a , R ^10b together with adjacent carbon atoms form a 5- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, optionally substituted with one or more R ^A7 , each 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, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy; n is selected from an integer between 0-2, such as 1 or 2. The use according to claim 1, wherein R ² is selected from hydrogen, deuterium, methyl, ethyl or fluoromethyl, preferably hydrogen or methyl, more preferably hydrogen. The use as claimed in claim 1 or 2, wherein Y is selected from -C(O)NH-. The use as described in any one of claims 1- to 3, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is

The use according to any one of claims 1 to 4, wherein R ¹ is selected from phenyl, and the phenyl group is 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, the alkyl or alkoxy is optionally substituted by halogen, nitro, cyano or C _1-6 alkoxy. The use according to any one of claims 1 to 5, wherein 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 deuterium, halogen, nitro , cyano, C _1-6 alkyl, halo C _1-6 alkyl or C _1-6 alkoxy. The use according to any one of claims 1 to 6, wherein R ¹ is selected from phenyl, 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 preferred

,

,

,

,

,

,

,

,

or

, better

,

,

or

,optimal

,

or

. The use as described in any one of claims 1 to 7, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is

The use according to any one of claims 1 to 8, wherein L is selected from -CH ₂ -, -C(CH ₃ )-, -CH(CH ₃ ) ₂ -, -C(O)-, -CH ₂ CH ₂ -or

. The use as claimed in any one of claims 1 to 9, wherein L is selected from -CH ₂ -. The use as described in any one of claims 1 to 10, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is

The use according to any one of claims 1 to 11, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is

The use according to any one of claims 1 to 8, wherein L is selected from -CH ₂ CH ₂ -. The use as described in any one of claims 1 to 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 to 8 or 13 to 14, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is

The use as claimed in any one of claims 1 to 15, wherein Z ³ is selected from a bond or -CR ^4a R ^4b -, R ^4a and R ^4b are each independently selected from hydrogen, deuterium, halogen or C _1-6 alkyl . The use as claimed in any one of claims 1 to 16, wherein Z ³ is selected from a bond or -CR ^4a R ^4b -, R ^4a and R ^4b are each independently selected from hydrogen, deuterium, halogen or methyl. The use according to any one of claims 1 to 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 to 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, halo C _1-6 alkyl or C _1-6 alkoxy base; 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 which is optionally substituted by one or more R ^A3 Substituted, R ^A3 are each independently selected from deuterium, halogen, nitro, cyano, C _1-6 alkyl, halogen 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 halo C _1-6 alkyl; Alternatively, R ^6a , R ^6b 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 of which 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 halogen C _1-6 alkyl; n is selected from 0, 1 or 2. The use according to any one of claims 1 to 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 R ^5a , R ^5b , R ^5c and R ^5d together with adjacent carbon atoms form a 3-membered cycloalkyl, which is optionally substituted by one or more R ^A3 , each R ^A3 is independently selected from deuterium, halogen , C _1-6 alkyl or halogen C _1-6 alkyl; R ^6a and R ^6b are each independently selected from hydrogen, deuterium, halogen or C _1-6 alkyl or halo 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 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 halo C _1-6 alkyl; n is selected from 0, 1 or 2. The use according to any one of claims 1 to 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, which is ^{optionally substituted by one or more R A3 selected} from deuterium , halogen, C _1-6 alkyl or halogen C _1-6 alkyl; R ^6a and R ^6b are each independently selected from hydrogen, deuterium, halogen or C _1-6 alkyl or halo 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 by 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 halo C _1-6 alkyl; n is selected from 0, 1 or 2. The use according to any one of claims 1 to 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 each 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 halogen C _1-6 alkyl; R ⁷ is selected from hydrogen, deuterium, C _1-6 alkyl or halo C _1-6 alkyl; n is selected from 0, 1 or 2. The use as claimed in 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 as claimed in any one of claims 1 to 23, wherein Z ¹ is selected from a bond. The use according to any one of claims 1 to 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 Alkyl, C _1-6 alkoxy, and the alkyl or alkoxy is optionally substituted with halogen. The use according to any one of claims 1 to 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 , and R ^A5 is independently selected from deuterium, halogen, C _1-6 alkyl, C _1-6 alkoxy, and the alkyl or alkoxy is optionally substituted by substituted by halogen. The use according to any one of claims 1 to 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 base 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 optionally replaced by halogen. replace. The use as claimed in any one of claims 1 to 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, and the alkyl or alkoxy is as required replaced by halogen. The use according to any one of claims 1 to 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 according to any one of claims 1 to 29, wherein Z ⁴ is selected from -CR ^9a R ^9b -. The use according to any one of claims 1 to 29, wherein Z ⁴ is selected from -CR ^9a R ^9b CR ^9c R ^9d -. The use according to any one of claims 1 to 31, wherein R ^9a , R ^9b , R ^9c and R ^9d are each independently selected from hydrogen, deuterium, hydroxyl, halogen, hydroxyl, C _1-6 alkyl, C _{1 -6Alkoxy} , the alkyl or alkoxy is optionally substituted by halogen. The use according to any one of claims 1 to 32, wherein R ^9a , R ^9b , R ^9c and R ^9d are each independently selected from hydrogen, deuterium, hydroxyl, fluoro, methyl, ethyl, -CHF ₂ or - CH ₂ F. The use according to any one of claims 1 to 15, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is

The use as described in any one of claim 1 to 15 or 34, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is

The use as claimed in claim 34 or 35, wherein Z ⁴ is selected from -CR ^9a R ^9b -. The use as claimed in claim 34 or 35, wherein Z ⁴ is selected from -CR ^9a R ^9b CR ^9c R ^9d -. The use according to any one of claims 34 to 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 -6Alkoxy} , the alkyl or alkoxy is optionally substituted by halogen. The use of any one of claims 34 to 38, wherein R ^9a , R ^9b , R ^9c and R ^9d are each independently selected from hydrogen, deuterium, hydroxy, fluoro, methyl, ethyl, _-CHF or - CH ₂ F. The use according to any one of claims 1 to 15, wherein Z ⁴ is selected from -CH ₂ -, -CH(CH ₃ )-, -CH ₂ CH ₂ -,

,

,

,

or

. The use according to any one of claims 1 to 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 to 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 halo C _1-6 alkyl. The use as claimed in any one of claims 1 to 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 halo C _1-6 alkyl. The use as claimed in any one of claims 1 to 15 or 42 to 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 halo C _1-6 alkyl. The use according to any one of claims 1 to 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 is selected from methyl, ethyl or propyl. The use according to any one of claims 1 to 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 replaced by 1 to 3 deuterium, halogen, cyano, C _1-6 alkyl substituted. The use according to any one of claims 1 to 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 together with adjacent carbon atoms A 3 to 7 membered cycloalkyl group is formed, optionally substituted with 1 to 3 deuterium, halogen, cyano, _C1-6 alkyl groups. The use as claimed in any one of claims 1 to 15, wherein L is selected from -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ - or

. The use according to any one of claims 1 to 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 halo C _1-6 alkyl, n=0, 1 or 2. A compound shown in formula I or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

The use according to any one of claims 1 to 50, wherein the HIV virus is resistant to an integrase inhibitor selected from the group consisting of raltegravir, elvitegravir, bicteira Wei, dolutegravir, cabotegravir, preferably raltegravir or elvitegravir. The use as claimed in any one of claims 1 to 51, wherein the virus is a virus strain resistant to an integrase inhibitor, the virus strain comprising HIV integrase, the HIV integrase preferably comprising the Y143C mutation, E92Q /N155H double mutation or G140S/Y143H/Q148H triple mutation. The purposes of a compound shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for HIV infection with resistance to AIDS drugs,

Wherein, R ¹ , R ² , L, Z ¹ , Z ² , Z ³ , Z ⁴ , Y are as defined in any one of claims 1 to 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 raltegravir, elvitegravir, bictegravir, dolutegravir, cabotevir, Trizivir, Nevirapine, enfuvirtide, albovirtide, darunavir, tipranavir, Fosamprenavir, atazanavir, lopinavir, amprenavir, nelfinavir, indinavir, ritonavir, saquinavir, fostamsavir, zidovudine , lamivudine, abacavir, efavirenz, stavudine, zalcitabine, emtricitabine, rilpivirine, doravirine, preferably raltegravir or eltivir Lave. The use of any one of claims 1 to 54, wherein the defect is a mutation in the gene, a deletion in the gene or defective expression.