WO2023134730A1 - Amide antiviral compound - Google Patents

Abstract

The present invention provides a pyrrolidine compound represented by formula (I) and a pharmaceutically acceptable salt thereof, and a use thereof as a coronavirus 3CL protease inhibitor in the prevention or treatment of related diseases caused by coronavirus infection.

Description

A kind of amide antiviral compound

This disclosure claims the priority and rights of the Chinese patent application with the patent application number 202210037787.3 and the title of the invention "an amide antiviral compound" submitted to the State Intellectual Property Office of China on January 13, 2022. The entirety of the aforementioned prior application is hereby incorporated by reference in its entirety.

technical field

The disclosure relates to the field of medicine, in particular to a novel amide compound and a pharmaceutically acceptable salt thereof, and its use as a coronavirus 3CL protease inhibitor in the prevention or treatment of related diseases caused by coronavirus infection.

Background technique

Coronaviruses are a class of RNA viruses that can cause disease in mammals and birds, ranging from mild to severe and even fatal respiratory infections. The epidemics of diseases such as SARS, MERS and SARS-CoV-2 (COVID-19) are all caused by coronaviruses. The SARS-CoV-2 (COVID-19) coronavirus contains four nonstructural proteins: papain-like protease (PLPro) and 3C-like protease (3CLPro), RNA polymerase and helicase. Among them, 3CLpro can hydrolyze viral polyproteins pp1a and pp1ab during coronavirus replication to produce functional proteins. 3C-like proteases are therefore critical for viral replication. At present, a number of preclinical and clinical studies have shown that 3CL protease inhibition can effectively inhibit virus replication and reduce intracellular and in vivo virus titers, but so far no 3CL protease inhibitor has been approved for clinical use. In view of the fact that the severe pneumonia disease caused by coronavirus has seriously affected people's life and health, small molecule antiviral drugs with good effect are imminent in clinical practice, so the research and development of 3CL protease inhibitors with novel structure, low toxicity and high efficiency have great social significance.

Contents of the invention

The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

in,

R ¹ is selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, 4-14 membered heterocyclyl, C ₁ -C ₁₀ alkoxy, C ₃ -C ₁₂ cycloalkyloxy or 4 -14-membered heterocyclyloxy, the C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, 4-14 membered heterocyclyl, C ₁ -C ₁₀ alkoxy, C ₃ -C ₁₂ Cycloalkyloxy or 4-14 membered heterocyclyloxy is optionally substituted by one or more R ^1a ;

Alternatively, R ¹ is selected from N(R ⁴ )(R ⁵ ), said R ⁴ and R ⁵ are independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered Heterocyclic group, or R ⁴ , R ⁵ and the N atom they are connected to together form a 4-7 membered heterocyclic group, the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclic group The cyclic group is optionally substituted by one or more R ^4a ;

Each R ^1a is independently selected from C ₁ -C ₆ alkyl, halogen, CN, =O, OH, NHC(=O)R ^m or N(R ^j )(R ^k ), C ₃ -C ₆ cycloalkane radical or 4-7 membered heterocyclic group, wherein R ^m , R ^j , R ^k are independently selected from H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, said C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl, OH, C ₃ -C ₆ cycloalkyl, 4-7 membered hetero Cyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl are optionally substituted by one or more R ^1b ;

Each R ^4a is independently selected from C ₁ -C ₆ alkyl, halogen, CN, =O, OH, NH ₂ , C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl, the OH, NH _2. C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl are optionally substituted by one or more R ^4b ;

R ² is selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl or 4-14 membered heterocyclic group, the C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl or 4- 14-membered heterocyclyl is optionally substituted by one or more R ^2a ;

Each R ^2a is independently selected from F, Cl, Br, I, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl or 4-7 membered Heterocyclic group, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl or 4-7 membered heterocyclic group are optionally substituted by one or more R ^2b ;

R ³ is selected from 4-14 membered heterocyclic groups, and the 4-14 membered heterocyclic groups are optionally substituted by one or more R ^3a ;

Each R ^3a is independently selected from F, Cl, Br, I, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl , the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclic group are optionally substituted by one or more R ^3b ;

Each R ^1b , R ^2b , R ^3b , R ^4b is independently selected from F, Cl, Br, I, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkane radical, 4-7 membered heterocyclyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyloxy or 4-7 membered heterocyclyloxy.

In some embodiments, R ¹ is selected from C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyloxy, said C ₁ -C ₃ alkyl, C ₃ - C _Cycloalkyl or 4-7 membered heterocyclyloxy is optionally substituted by one or more (for example, 1, 2 or 3) R ^1a ; or, R ¹ is selected from N(R ⁴ )( R ⁵ ), said R ⁴ and R ⁵ are independently selected from H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, or R ⁴ , R ⁵ and their connected N atoms together form 4- 7-membered heterocyclic group, the C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group or 4-7 membered heterocyclic group is optionally replaced by one or more (for example, 1, 2 or 3 ) R ^4a is substituted.

In some embodiments, R ^1a is independently selected from F, CF ₃ ,

In some embodiments, R ^4a is independently selected from halogen, such as F.

In some embodiments, ^R is selected from methyl,

In some embodiments, ^R is selected from methyl,

In some embodiments, R ² is selected from C ₁ -C ₆ alkyl or _4-10 membered heterocyclyl, which is _optionally replaced by one or more (eg, 1, 2 or 3) C ₁ -C ₃ alkyl or phenyl substitution.

In some embodiments, ^R is selected from

In some embodiments, R ^is selected from 5-12 membered heterocyclyl optionally substituted with one or more (eg, 1, 2 or 3) R ^3a .

In some embodiments, ^R is selected from said Optionally substituted with one or more (eg, 1, 2 or 3) R ^3a .

In some embodiments, ^R is selected from said Optionally substituted with one or more (eg, 1, 2 or 3) R ^3a .

In some embodiments, R ^3a is selected from halogen, CN, =O or C ₁ -C ₃ alkyl.

In some embodiments, R ^3a is selected from F, =0, or C ₁ -C ₃ alkyl.

In some embodiments, R ^3a is selected from F or =O.

In some embodiments, ^R is selected from

In some embodiments, ^R is selected from

In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof:

Wherein, R ¹ , R ² , R ³ are as defined above.

In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

The present disclosure also provides a pharmaceutical composition, which comprises the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.

Further, the present disclosure relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating coronavirus 3CL protease-related diseases.

Further, the present disclosure relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of diseases related to coronavirus 3CL protease.

Further, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating diseases related to coronavirus 3CL protease.

The present disclosure also relates to a method for preventing or treating coronavirus 3CL protease-related diseases, the method comprising administering to the patient a therapeutically effective dose of a pharmaceutical preparation comprising the compound of formula (I) described in the present disclosure or a pharmaceutically acceptable salt thereof.

Further, the present disclosure relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating related diseases caused by coronavirus infection.

Further, the present disclosure relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of related diseases caused by coronavirus infection.

Further, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating related diseases caused by coronavirus infection.

The present disclosure also relates to a method for preventing or treating related diseases caused by coronavirus infection, the method comprising administering to the patient a therapeutically effective dose of a drug comprising the compound of formula (I) described in the present disclosure or a pharmaceutically acceptable salt thereof preparation.

In some embodiments, the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and 2019 novel coronavirus (2019-nCoV or SARS-CoV- 2).

In some embodiments, the coronavirus 3CL protease-associated disease is selected from respiratory tract infection, pneumonia or complications thereof.

In some embodiments, the related diseases caused by the coronavirus infection are selected from respiratory tract infection, pneumonia or complications thereof.

Definitions and Explanations of Terms

Unless otherwise stated, terms used in this disclosure have the following meanings, definitions of groups and terms recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, examples The definitions of specific compounds in and etc. may be combined and combined with each other arbitrarily. A specific term should not be regarded as indeterminate or unclear if there is no special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

In this article Indicates the junction site.

Graphical representations of racemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, with wedge and dotted keys Indicates the absolute configuration of a stereocenter with black real and virtual bonds Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

The term "tautomer" refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. Compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. This disclosure encompasses all tautomeric forms of the compounds.

The term "stereoisomer" refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers and diastereomers.

The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof are within the definition of the disclosed compounds. There may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included in Compounds of the disclosure are within the definition. Compounds of the present disclosure containing asymmetric atoms can be isolated in optically pure form or in racemic form, the optically active form can be resolved from a racemic mixture, or by using a chiral starting material or a chiral Reagent synthesis.

The term "substituted" means that any one or more hydrogen atoms on the specified atom are replaced by substituents, as long as the valence of the specified atom is normal and the substituted compound is stable. When a substituent is oxo (ie, =0), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

The term "optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that description includes that said event or circumstance occurs and that it does not. For example, an ethyl group "optionally" substituted with one or more halogens means that the ethyl group can be _{unsubstituted} ( _CH2CH3 ) _, monosubstituted ( _{CH2CH2F , CH2CH2Cl} , etc.) , multi-substituted (CHFCH ₂ F, CH ₂ CHF ₂ , CHFCH ₂ Cl, CH ₂ CHCl _{2 ,} etc.) or fully substituted (CF ₂ CF ₃ , CF ₂ CCl ₃ , CCl ₂ CCl ₃ , etc.). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.

When any variable (eg R ^a , R ^b ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. For example, if a group is substituted by 2 R ^b , each R ^b has independent options.

When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a bond.

When one of the variables is selected from chemical bond or absence, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a bond, it means that the structure is actually A-Z.

When the linking group mentioned herein does not indicate its linking direction, its linking direction is arbitrary. For example when the structural unit When L ¹ in is selected from "C ₁ -C ₃ alkylene-O", at this time L ¹ can connect ring Q and R ¹ in the direction from left to right to form "ring QC ₁ -C ₃ alkylene Group -OR ¹ ", and ring Q and R ¹ can also be connected from right to left to form "ring QOC ₁ -C ₃ alkylene-R ¹ ".

When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring. For example, the structural unit Indicates that R ⁵ can be substituted at any position on the benzene ring.

_Cm - _Cn herein refers to having an integer number of carbon atoms in the range of mn. For example, "C ₁ -C ₁₀ " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

The term "alkyl" refers to a hydrocarbon group having the general formula C _n H _2n+1 , and the alkyl group may be straight or branched. The term "C ₁ -C ₁₀ alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. The term "C ₁ -C ₆ alkyl" can be understood to mean an alkyl group having 1 to 6 carbon atoms, specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C ₁ -C ₃ alkyl" is understood to mean a linear or branched saturated alkyl group having 1 to 3 carbon atoms. The "C ₁ -C ₁₀ alkyl" may include "C ₁ -C ₆ alkyl" or "C ₁ -C ₃ alkyl", and the "C ₁ -C ₆ alkyl" may further include " C ₁ -C ₃ alkyl".

The term "alkoxy" refers to the group produced by the loss of the hydrogen atom on the hydroxyl group of straight-chain or branched alcohols, which can be understood as "alkyloxy" or "alkyl-O-". The term "C ₁ -C ₁₀ alkoxy" can be understood as "C ₁ -C ₁₀ alkyloxy" or "C ₁ -C ₁₀ alkyl-O-"; the term "C ₁ -C ₆ alkoxy" It can be understood as "C ₁ -C ₆ alkyloxy" or "C ₁ -C ₆ alkyl-O-". The "C ₁ -C ₁₀ alkoxy" may include "C ₁ -C ₆ alkoxy" and "C ₁ -C ₃ alkoxy" and other ranges, and the "C ₁ -C ₆ alkoxy""C ₁ -C ₃ alkoxy" may be further included.

The term "cycloalkyl" refers to a fully saturated carbocyclic group in the form of a monocyclic ring, a fused ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 20 membered ring. The term "C ₃ -C ₁₂ cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring carbon atoms, specific examples of the cycloalkyl group Including but not limited to cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, Spiro[4.5]decyl, etc. The term "C ₃ -C ₁₂ cycloalkyl" may include "C ₅ -C ₁₂ cycloalkyl", "C ₃ -C ₁₀ cycloalkyl", "C ₆ -C ₁₀ cycloalkyl" and "C ₃ - C ₆ cycloalkyl" and other ranges. The term "C ₅ -C ₁₂ cycloalkyl" refers to a cycloalkyl group having 5, 6, 7, 8, 9, 10, 11 or 12 ring carbon atoms. The term "C ₃ -C ₁₀ cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms. The term "C ₆ -C ₁₀ cycloalkyl" refers to a cycloalkyl group having 6, 7, 8, 9 or 10 ring carbon atoms. The term " _C3 - _C6 cycloalkyl" refers to a cycloalkyl group having 3, 4, 5 or 6 ring carbon atoms.

The term "C ₃ -C ₁₂ cycloalkyloxy" can be understood as "C ₃ -C ₁₂ cycloalkyl-O-".

The term "C ₃ -C ₆ cycloalkyloxy" can be understood as "C ₃ -C ₆ cycloalkyl-O-".

The term "cycloalkenyl" refers to a non-aromatic carbocyclic group that is not fully saturated and exists in the form of a monocyclic ring, a condensed ring, a bridged ring, or a spiro ring. The term "C ₄ -C ₁₂ cycloalkenyl" refers to a cycloalkenyl group having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, specific examples include but are not limited to cyclopentyl alkenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl and the like.

The term "heterocyclic group" refers to a fully saturated or partially saturated monocyclic, condensed ring, spiro ring or bridged ring group, which contains 1-5 heteroatoms or heteroatom groups in its ring atoms (that is, heteroatom-containing Atomic group), the "heteroatom or heteroatom group" includes but not limited to nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S (= O) ₂ -, -S(=O)-, -P(=O) ₂ -, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(= O)NH- or -NHC(=O)NH- and the like. The term "4-14 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, and its ring atoms contain 1-5 independently selected from the heteroatoms or heteroatom groups described above. Among them, specific examples of 4-membered heterocyclic groups include but are not limited to azetidinyl or oxetanyl; specific examples of 5-membered heterocyclic groups include but are not limited to tetrahydrofuranyl, dioxolyl , pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include but Not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridyl or 4H-[1,3,4] Thiadiazinyl; specific examples of 7-membered heterocyclyl include, but are not limited to, diazepanyl. The heterocyclic group can also be a bicyclic heterocyclic group and a tricyclic heterocyclic group, wherein specific examples of 5 and 5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl ; Specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2 ,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzofused cyclic group of the above-mentioned 4-7 membered heterocyclic group, specific examples include but not limited to dihydroisoquinolyl and the like. "4-14 membered heterocyclic group" may include "4-10 membered heterocyclic group", "5-10 membered heterocyclic group", "4-7 membered heterocyclic group", "5-6 membered heterocyclic group" , "4-7 membered monoheterocyclic group", "4-14 membered fused heterocyclic group", "4-14 membered spiroheterocyclic group" or "4-14 membered bridged heterocyclic group".

The "heterocyclyl" in the present disclosure may include "heterocycloalkyl", for example, "4-14 membered heterocyclyl" may include "4-14 membered heterocycloalkyl".

The term "heterocyclyloxy" can be understood as "heterocyclyl-O-", for example, "4-14 membered heterocyclyloxy" can be understood as "4-14 membered heterocyclyl-O-".

The term "heterocycloalkyl" refers to a fully saturated cyclic group that exists in the form of a monocyclic ring, a condensed ring, a bridged ring or a spiro ring, etc., and its ring atoms contain 1-5 heteroatoms or heteroatom groups (that is, atomic groups containing heteroatoms), the "heteroatoms or heteroatom groups" include but are not limited to nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S), phosphorus atoms (P), boron atoms (B ), -S(=O) ₂ -, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O) NH-et al. The term "3-10 membered heterocycloalkyl" refers to a heterocycloalkyl group with 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1-5 ring atoms independently selected from A heteroatom or heteroatom group as described above. The term "3-10 membered heterocycloalkyl" may include "4-10 membered heterocycloalkyl" or "4-7 membered heterocycloalkyl", wherein specific examples of 4-membered heterocycloalkyl include but are not limited to Azetidinyl, oxetanyl, or thibutanyl; specific examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, iso Thiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydropyrazolyl; specific examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl , piperazinyl, 1,4-thiaxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl or 1,4-dithianyl; 7-membered Specific examples of heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, or thiepanyl.

The term "heterocycloalkyloxy" is understood to mean "heterocycloalkyl-O-".

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. The aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms. The term "C ₆ -C ₂₀ aryl" is understood to mean an aryl group having 6 to 20 carbon atoms. Especially rings with 6 carbon atoms (“C _aryl ”), such as phenyl; or rings with ₉ carbon atoms (“C aryl”), such as indanyl or indenyl; or rings with 10 a ring of 3 carbon atoms (“C ₁₀ aryl”), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl; or a ring of 13 carbon atoms (“C ₁₃ aryl”), such as fluorenyl; or is a ring having 14 carbon atoms ("C ₁₄ aryl"), such as anthracenyl. The term "C ₆ -C ₁₀ aryl" is understood to mean an aryl group having 6 to 10 carbon atoms. Especially rings with 6 carbon atoms (“C _aryl ”), such as phenyl; or rings with ₉ carbon atoms (“C aryl”), such as indanyl or indenyl; or rings with 10 carbon atoms (“C ₁₀ aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

The term "aryloxy" is understood to mean "aryl-O-".

The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazole Linyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthalene Pyridyl, pteridyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, etc.

The term "heteroaryloxy" is understood to mean "heteroaryl-O-".

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

The term "hydroxyl" refers to a -OH group.

The term "cyano" refers to a -CN group.

The term "mercapto" refers to a -SH group.

The term "amino" refers to a _-NH2 group.

The term "nitro" refers to a _-NO2 group.

In this paper, the bonds depicted by solid and dashed lines Indicates a single or double bond. For example, the structural unit Include

The term "therapeutically effective amount" means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying Amounts of a compound of the disclosure for the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art according to its own knowledge and this disclosure.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts formed between compounds and inorganic or organic acids, and salts formed between compounds and inorganic or organic bases.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, Water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The word "comprise" or "comprise" and its English variants such as comprises or comprising can be interpreted in an open and non-exclusive sense, ie "including but not limited to".

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

Certain isotopically labeled compounds of the disclosure (eg, ^{with3H and14C} ) are useful in compound and/or substrate tissue distribution assays. Tritiated ( ^ie3H ) and carbon-14 ( ^ie14C ) isotopes are especially preferred for their ease of preparation and detectability. Positron-emitting isotopes, such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The pharmaceutical composition of the present disclosure can be prepared by combining the compound of the present disclosure with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

Typical routes of administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.

The pharmaceutical composition of the present disclosure can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, emulsifying methods, freeze-drying methods and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to patients.

Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating. Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.

The pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.

In all methods of administration of the compound of general formula I described herein, the daily dosage is 0.01 mg/kg to 200 mg/kg body weight, preferably 0.05 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 30 mg /kg body weight, in single or divided doses.

The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art As an equivalent alternative, preferred embodiments include but are not limited to the examples of the present disclosure.

The chemical reactions of the embodiments of the present disclosure are performed in suitable solvents that are suitable for the chemical changes of the present disclosure and the reagents and materials required therefor. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes on the basis of existing embodiments.

Detailed ways

The invention will be described in detail through the following examples, but it does not imply any adverse limitation on the present disclosure. The present disclosure has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. will be obvious. All reagents used in this disclosure are commercially available and used without further purification.

Unless otherwise specified, the ratios indicated for mixed solvents are volume mixing ratios.

Unless otherwise stated, % means weight percent wt%.

compound by hand or The software is named, and the commercially available compounds adopt the supplier catalog name.

Compound structures were determined by nuclear magnetic resonance (NMR) and/or mass spectroscopy (MS). The unit of NMR shift is 10 ^-6 (ppm). The solvents measured by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is _{tetramethylsilane} (TMS); concentration.

The eluent or mobile phase can be a mixed eluent or mobile phase composed of two or more solvents, and the ratio is the volume ratio of each solvent, such as "0-10% methanol/dichloromethane" means a mixed eluent Or the volume ratio of methanol and dichloromethane in the mobile phase is 0:100-10:100.

Example 1: (1R,2S,5S)-N-((1S)-1-cyano-2-(2-oxoindoline-3-yl)ethyl)-3-((S)- 2-(3-cyclopropylurea)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 1 ) preparation

The synthetic route is as follows:

Step 1: tert-butyl ((2S)-1-amino-1-oxo-3-(2-oxoindol-3-yl)propan-2-yl)carbamate (1b)

Compound 1a (0.30 g, 0.90 mmol) was dissolved in methanol (1 mL) at 20°C, and ammonia methanol solution (7N, 3 mL) was added. The reaction solution was reacted at 40° C. for 24 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C ₁₈ flash silica gel column, gradient elution under the condition of 0.05% formic acid aqueous solution: acetonitrile=20:1～1:2) to obtain compound 1b (0.09g).

m/z (ESI): 320[M+H] ⁺ .

Step 2: (2S)-2-Amino-3-(2-carbonylindolin-3-yl)propanamide hydrochloride (1c)

At 20°C, compound 1b (0.090g, 0.28mmol) was dissolved in 1,4-dioxane (1mL), and 1,4-dioxane hydrochloride solution (4M, 1mL, 4.0mmol) was added to react The solution was reacted at room temperature for 2 hours. The reaction solution was lyophilized under reduced pressure to obtain compound 1c (0.070 g).

m/z(ESI):220[M+H] ⁺ .

Step 3: tert-butyl ((2S)-1-((1R,2S,5S)-2-(((2S)-1-amino-1-oxo-3-(2-oxoindoline- 3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl)-3,3-dimethyl-1- Oxobutyl-2-yl)carbamate (1e)

At room temperature, compound 1d (0.18g, 0.5mmol), compound 1c (0.13g, 0.5mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13g , 0.7mmol), 2-hydroxypyridine oxide (0.013g, 0.1mmol) was dissolved in N,N-dimethylformamide (2mL), and then diisopropylethylamine (0.19g, 1.5mmol) was added, The reaction solution was reacted at 20° C. for 16 hours. The reaction mixture was purified by reverse phase chromatography ( C ₁₈ column, water: acetonitrile = 20:1 ~ 1:4 gradient elution) to obtain compound 1e (0.18g).

m/z (ESI): 570[M+H] ⁺ .

Step 4: (1R,2S,5S)-Nitro-((2S)-1-amino-1-oxo-3-(2-oxoindolin-3-yl)propan-2-yl)-3 -((S)-2-Amino-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (1f)

Compound 1e (0.18g, 0.3mmol) was dissolved in dichloromethane (2ml) at room temperature, and then 4M dioxane hydrochloride solution (2mL, 8.0mmol) was added, followed by reaction at room temperature for 16h. Compound 1f (0.16 g) was obtained after removing the solvent under reduced pressure. m/z (ESI): 470[M+H] ⁺ .

Step 5: (1R,2S,5S)-Nitro-((2S)-1-amino-1-oxo-3-(2-oxoindolin-3-yl)propan-2-yl)-3 -((S)-2-(3-cyclopropylurea)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2 -Formamide (1g)

At room temperature, cyclopropylamine (9.0mg, 0.16mmol) was dissolved in N,N-dimethylformamide (0.4mL), N,N-carbonyldiimidazole (22.7mg, 0.16mmol) was added, and tris Ethylamine (0.016g, 0.16mmol), the reaction solution was reacted at 20°C for 2h. The above solution was then injected into a solution of compound 1f (0.08 g, 0.16 mmol) and triethylamine (0.016 g, 0.16 mmol) in N,N-dimethylformamide (2 mL). After reacting at room temperature for 16 hours, the reaction mixture was purified by reverse phase chromatography ( C ₁₈ column, water: acetonitrile = 20:1 ~ 2:3 gradient elution) to obtain compound 1g (0.03g).

m/z(ESI):553[M+H] ⁺ .

Step 6: (1R,2S,5S)-N-((1S)-1-cyano-2-(2-oxoindolin-3-yl)ethyl)-3-((S)-2 -(3-cyclopropylurea)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (1)

Compound 1g (0.03g, 0.05mmol) was dissolved in dichloromethane (1mL) and acetonitrile (1mL) at room temperature, Burgess reagent (31.1mg, 0.13mmol) was added thereto, and stirred at room temperature for 16 hours. After quenching with water, the reaction mixture was purified by reverse phase chromatography ( C ₁₈ column, water: acetonitrile = 20:1 ~ 3:7 gradient elution) to obtain compound 1 (7.9 mg).

m/z (ESI): 535[M+H] ⁺ .

¹ HNMR: (400MHz,DMSO-d ₆ )δ10.49(s,0.6H),10.48(s,0.4H),9.27(d,J=8.3Hz,0.6H),8.97(d,J=7.5Hz ,0.4H),7.33(d,J=7.5Hz,0.6H),7.29(d,J=7.3Hz,0.4H),7.22–7.15(m,1H),6.99(t,J=7.5Hz,0.4 H), 6.88(t, J=7.6Hz, 0.6H), 6.82(d, J=7.7Hz, 1H), 6.27–6.19(m, 1H), 5.84–5.70(m, 1H), 5.27–5.14( m,1H),4.18(s,1H),4.16–4.06(m,1H),3.92–3.80(m,2H),3.60–3.50(m,1H),2.37–2.32(m,1H),2.32– 2.27(m,1H),1.59–1.52(m,1H),1.32(d,J＝7.6Hz,1H),1.04(s,3H),0.87(s,3H),0.85(s,4H),0.73 (s,5H),0.57–0.50(m,2H),0.26–0.18(m,2H).

Example 2: (1R,2S,5S)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutyryl)-N-((1S) -1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methanol Preparation of Amide (Compound 2)

For the synthesis steps of Example 2, refer to Example 1, wherein the compound 2 was prepared by replacing cyclopropylamine in Step 5 of Example 1 with tert-butylamine.

m/z (ESI): 551[M+H] ⁺ .

¹ HNMR: (400MHz,DMSO-d ₆ )δ10.49(s,0.67H),10.47(s,0.33H),9.26(d,J=7.6Hz,0.67H),8.95(d,J=7.6Hz ,0.33H),7.34(d,J=7.6Hz,0.67H),7.29(d,J=7.6Hz,0.33H),7.21-7.15(m,1H),6.88(t,J=7.6Hz,1H ),6.81(d,J=7.6Hz,1H),5.93(s,0.33H),5.90(s,0.67H),5.82(d,J=10.4Hz,0.33H),5.77(d,J=10.4 Hz, 0.67H), 4.18(s, 1H), 4.08(d, J=10.0Hz, 0.33H), 4.02(d, J=10.0Hz, 0.67H), 3.98(d, J=10.0Hz, 0.33H ), 3.94(d, J＝10.0Hz, 0.67H), 3.83-3.77(m, 1H), 3.62-3.51(m, 1H), 2.35-2.27(m, 1H), 2.20(d, J＝4.8Hz ,0.33H),2.16-2.09(m,0.67H),1.56-1.52(m,1H),1.30(d,J＝7.6Hz,1H),1.19-1.14(m,9H),1.06-0.92(m ,4H),0.86-0.82(m,6H),0.71(s,6H).

Example 3: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-3-((S )-2-(3,3-Difluoroazetidine-1-carboxalylamino<oxalylamino>)-3,3-dimethylbutyryl)-6,6-dimethyl-3 - Preparation of azabicyclo[3.1.0]hexane-2-carboxamide (compound 3)

For the synthesis steps of Example 3, refer to Example 1, wherein 1c in Step 3 of Example 1 is replaced with 6d (see Example 6), and cyclopropylamine in Step 5 of Example 1 is replaced with 3,3-difluoroazetidine Compound 3 was prepared.

¹ HNMR: (400MHz, DMSO-d ₆ )δ8.99(d, J＝8.8Hz, 1H), 7.67(s, 1H), 6.69(d, J＝8.8Hz, 1H), 5.00-4.94(m, 1H),4.32-4.10(m,6H),3.88-3.78(m,2H),3.20-3.11(m,2H),3.06-2.99(m,1H),2.46-2.40(m,1H),2.18- 2.02(m,1H),1.76-1.68(m,2H),1.56-1.52(m,1H),1.29(d,J＝7.6Hz,1H),1.02(s,3H),0.93(s,9H) ,0.86(s,3H).

m/z (ESI): 571[M+H] ⁺ .

Example 4: (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-3-((S)- 2-((S)-2-(cyclopropaneoxalylamino<oxalylamino>)propionylamino)-3,3-dimethylbutyryl)-6,6-dimethyl-3- Preparation of azabicyclo[3.1.0]hexane-2-carboxamide (compound 4)

The synthetic route is as follows:

Step 1: Methyl(1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyryl)-6,6-di Methyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4c)

At room temperature, compound 4a (2.0g, 9.8mmol) and compound 4b (2.3g, 10mmol) were dissolved in N,N-dimethylformamide (10mL), and 2-(7-azabenzotriazepine was added Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.8g, 10mmol), then N,N-diisopropylethylamine (3.0g, 23mmol) was added, and the reaction solution was React at 20°C for 10 minutes. The reaction mixture was purified by reverse phase chromatography ( _C18 flash silica gel column, 0.05% formic acid aqueous solution: acetonitrile=20:1～1:20 gradient elution) to obtain compound 4c (3.1g).

m/z(ESI):383[M+H] ⁺ .

Step 2: Methyl(1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[ 3.1.0] Hexane-2-carboxylate hydrochloride (4d)

At 20°C, compound 4c (1.8g, 4.7mmol) was dissolved in 1,4-dioxane (5.0mL), and hydrochloric acid 1,4-dioxane solution (4.0M, 5.0mL, 20mmol) was added , the reaction solution was reacted at room temperature for 12 hours. The reaction solution was lyophilized under reduced pressure to obtain compound 4d (1.1 g).

m/z(ESI):283[M+H] ⁺ .

Step 3: Methyl(1R,2S,5S)-3-((S)-2-((S)-2-((tert-butoxycarbonyl)amino)propionylamino)-3,3-di Methylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4f)

At room temperature, compound 4d (1.1g, 3.4mmol) and compound 4e (0.71g, 3.7mmol) were dissolved in N,N-dimethylformamide (10mL), and 2-(7-azabenzotri Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.4g, 3.7mmol), then add N,N-diisopropylethylamine (1.4g, 11mmol), react The solution was reacted at 20°C for 10 min. The reaction mixture was purified by reverse phase chromatography ( _C18 flash silica gel column, 0.05% formic acid aqueous solution: acetonitrile=20:1～1:20 gradient elution) to obtain compound 4f (0.97g).

m/z(ESI):454[M+H] ⁺ .

Step 4: Methyl(1R,2S,5S)-3-((S)-2-((S)-2-aminopropionylamino)-3,3-dimethylbutyryl)-6,6- Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (4g)

At 20°C, compound 4f (0.50 g, 1.1 mmol) was dissolved in 1,4-dioxane (10 mL), and 1,4-dioxane hydrochloride solution (4.0 M, 1.0 mL, 4 mmol) was added, The reaction solution was reacted at room temperature for 12 hours. The reaction solution was lyophilized under reduced pressure to obtain compound 4g (0.36g).

m/z(ESI):353[M+H] ⁺ .

Step 5: Methyl(1R,2S,5S)-3-((S)-2-((S)-2-(Cyclopropaneoxalylamino<oxalylamino>)propionylamino)-3 ,3-Dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4i)

At room temperature, compound 4g (0.20g, 0.57mmol) and compound 4h (54mg, 0.63mmol) were dissolved in N,N-dimethylformamide (5.0mL), and 2-(7-azabenzotri Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.24g, 0.63mmol), then add N,N-diisopropylethylamine (0.24g, 1.9mmol), The reaction solution was reacted at 20° C. for 10 min. The reaction mixture was purified by reverse phase chromatography ( _C18 flash silica gel column, 0.05% formic acid aqueous solution: acetonitrile=20:1～1:20 gradient elution) to obtain compound 4i (0.19g).

m/z(ESI):422[M+H] ⁺ .

Step 6: (1R,2S,5S)-3-((S)-2-((S)-2-(cyclopropaneoxalylamino<oxalylamino>)propionylamino)-3,3 -Dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (4j)

Compound 4i (0.19g, 0.44mmol) was dissolved in tetrahydrofuran (5.0mL) and water (5.0mL), then lithium hydroxide (0.10g, 2.2mmol) was added, and the reaction solution was reacted at 20°C for 2 hours. 1M hydrochloric acid was added to adjust the reaction solution to pH=5, extracted with ethyl acetate (3×50ml), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 4j (0.15g). m/z (ESI): 408[M+H] ⁺ .

Step 7: (1R,2S,5S)-N-((2S)-1-amino-1-carbonyl-3-(2-carbonylindolin-3-yl)propan-2-yl)-3- ((S)-2-((S)-2-(cyclopropaneoxalylamino<oxalylamino>)propionylamino)-3,3-dimethylbutyryl)-6,6-di Methyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (4k)

At room temperature, compound 4j (66mg, 0.16mmol) and compound 1c (40mg, 0.18mmol) were dissolved in N,N-dimethylformamide (4.0mL), and 2-(7-azabenzotriazine was added Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (61mg, 0.16mmol), then N,N-diisopropylethylamine (65mg, 0.5mmol) was added, and the reaction solution was React at 20°C for 10 minutes. The reaction mixture was purified by reverse phase chromatography ( _C18 flash silica gel column, 0.05% formic acid aqueous solution: acetonitrile=20:1～1:20 gradient elution) to obtain compound 4k (52 mg).

m/z(ESI):609[M+H] ⁺ .

Step 8: (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-3-((S)-2 -((S)-2-(cyclopropaneoxalylamino<oxalylamino>)propionylamino)-3,3-dimethylbutyryl)-6,6-dimethyl-3-nitrogen Heterobicyclo[3.1.0]hexane-2-carboxamide (4)

Compound 4k (30mg, 0.05mmol) was dissolved in dichloromethane (1.0mL) at 20°C, and methyl-N-(triethylsulfamoyl)carbamate inner salt (23mg ,0.10mmol). The reaction solution was reacted at 20°C for 12h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C ₁₈ flash silica gel column, 0.05% ammonia solution: acetonitrile = 20:1 ~ 1:2 elution) to obtain compound 4 (10 mg).

m/z(ESI):591[M+H] ⁺ .

¹ HNMR: (400MHz,DMSO-d ₆ )δ10.51(s,0.6H),10.49(s,0.4H),9.29(d,J＝8.3Hz,0.6H),8.99(d,J＝7.6Hz ,0.4H),8.34–8.20(m,1H),7.83–7.68(m,1H),7.36–7.28(m,1H),7.24–7.14(m,1H),7.02–6.86(m,1H), 6.82(d,J＝7.8Hz,1H),5.28–5.13(m,1H),4.43–4.34(m,1H),4.33–4.23(m,1H),4.18(s,1H),3.92–3.83( m,1H),3.81–3.72(m,1H),3.61–3.48(m,1H),2.36–2.26(m,1H),2.20–2.04(m,1H),1.68–1.53(m,2H), 1.32(d,J=7.6Hz,1H),1.13–0.90(m,8H),0.89–0.76(m,6H),0.75(s,3H),0.68–0.54(m,4H).

Example 5: (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-3-((S)- 3,3-Dimethyl-2-((S)-2-(2,2,2-trifluoroacetylamino)propionylamino)butyryl)-6,6-dimethyl-3-azabis Preparation of cyclo[3.1.0]hexane-2-carboxamide (compound 5)

For the synthesis steps of Example 5, refer to Example 4, wherein compound 5 was prepared by replacing Compound 4h in Step 5 in Example 4 with trifluoroacetic acid.

m/z(ESI):619[M+H] ⁺ .

Example 6: 3-(trifluoromethyl)oxetan-3-yl ((S)-1-((1R,2S,5S)-2-(((S)-1-1-cyano- 2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl )-3,3-dimethyl-1-carbonylbutane-2-yl) carbamate (compound 6) preparation

The synthetic route is as follows:

Step 1: (1R,2S,5S)-3-((S)-3,3-Dimethyl-2-((((3-(trifluoromethyl)oxetan-3-yl)oxo )carbonyl)amino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (6c)

Compound 6a (20 mg, 0.074 mmol) was dissolved in water (2 mL) and acetonitrile (2 mL), and then compound 6b (24 mg, 0.068 mmol) and sodium bicarbonate (12 mg, 0.14 mmol) were added. The reaction was stirred at 25C for 16 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C18 flash silica gel column, gradient elution under the condition of 0.05% formic acid aqueous solution: acetonitrile=20:1～1:2) to obtain compound 6c (29 mg).

m/z (ESI): 435[M+H] ⁺ .

Step 2: 3-(Trifluoromethyl)oxetan-3-yl((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-carbonyl- 3-((S)-2-carbonylpyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 3-yl)-3,3-dimethyl-1-carbonylbutan-2-yl)carbamate (6e)

Compound 6c (29 mg, 0.66 mmol) was dissolved in N, N-dimethylformamide (1 mL), and compound 6 d (12 mg, 0.070 mmol), N, N-diisopropylethylamine (26 mg, 0.20 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25mg, 0.066mmol). The reaction was stirred at 25C for 2 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C18 flash silica gel column, gradient elution under the condition of 0.05% ammonia solution: acetonitrile=20:1～1:2) to obtain compound 6e (39 mg).

m/z (ESI): 590[M+H] ⁺ .

Step 3: 3-(Trifluoromethyl)oxetan-3-yl((S)-1-((1R,2S,5S)-2-(((S)-1-1-cyano-2 -((S)-2-carbonylpyrrolidin-3-yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl) -3,3-Dimethyl-1-carbonylbutan-2-yl)carbamate (6)

Compound 6e (39 mg, 0.066 mmol) was dissolved in dichloromethane (1 mL), and then Burgess reagent (39 mg, 0.17 mmol) was added. The reaction solution was stirred at 25°C for 2 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C18 flash silica gel column, gradient elution under the condition of 0.05% ammonia solution: acetonitrile=20:1～1:2) to obtain compound 6 (12 mg).

m/z (ESI): 572[M+H] ⁺ .

¹ HNMR: (400MHz, DMSO-d ₆ )δ9.03(d, J＝8.6Hz, 1H), 8.03(d, J＝9.0Hz, 1H), 7.68(s, 1H), 5.01–4.92(m, 1H), 4.88(d, J＝8.7Hz, 1H), 4.79–4.70(m, 3H), 4.16(s, 1H), 4.04(d, J＝9.0Hz, 1H), 3.89–3.82(m, 1H ),3.75(d,J=10.4Hz,1H),3.13(t,J=9.1Hz,1H),3.07–2.98(m,1H),2.46–2.35(m,1H),2.20–2.02(m, 2H),1.76–1.65(m,2H),1.57–1.50(m,1H),1.29(d,J＝7.6Hz,1H),1.02(s,3H),0.94(s,9H),0.84(s ,3H).

Example 7 and Example 8: (1R,2S,5S)-N-((1S)-1-cyano-2-(3-fluoro-2-carbonylindolin-3-yl)ethyl) -3-((S)-3,3-Dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1 .0] Preparation of hexane-2-carboxamide (compound 7 and compound 8)

The synthetic route is as follows:

Step 1: Methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-2-carbonylindolin-3-yl)propionate (7a)

At 20°C, N-fluorobisbenzenesulfonamide (NFSI, 104mg, 0.54mmol), 1-((1R)-((2R,4R,5S)-5-ethylquinuclidin-2-yl )(6-methoxyquinolin-4-yl)methoxy)-4-((1R)-((2R,4S,5R)-5-ethylquinuclidin-2-yl)(6- Methoxyquinolin-4-yl)methoxy)phthalazine (35 mg, 0.045 mmol) and sodium carbonate (57 mg, 0.54 mmol) were added to a solution of compound 1a (0.15 g, 0.45 mmol) in ethyl acetate (10 mL) , the reaction solution was reacted at 20°C for 48 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C ₁₈ flash silica gel column, gradient elution under the condition of 0.05% ammonia solution: acetonitrile=20:1～1:20) to obtain compound 7a (0.16g).

m/z (ESI): 353[M+H] ⁺ .

Step 2: tert-Butyl((2S)-1-amino-3-(3-fluoro-2-carbonylindolin-3-yl)-1-carbonylpropan-2-yl)carbamate (7b)

Compound 7a (0.10 g, 0.28 mmol) was dissolved in methanol (1 mL) at 20°C, and ammonia methanol solution (7N, 1 mL) was added. The reaction solution was reacted at 40° C. for 16 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C ₁₈ flash silica gel column, gradient elution under the condition of 0.05% ammonia solution: acetonitrile=20:1～1:20) to obtain compound 7b (0.06g).

m/z(ESI):338[M+H] ⁺ .

Step 3: (2S)-2-Amino-3-(3-fluoro-2-carbonylindolin-3-yl)propanamide hydrochloride (7c)

Compound 7b (0.04g, 0.18mmol) was dissolved in dichloromethane (4ml) at room temperature, and 4M dioxane hydrochloride solution (1mL, 8.0mmol) was added, followed by reaction at room temperature for 16h. Compound 7c (0.024 g) was obtained after removing the solvent under reduced pressure.

m/z(ESI):238[M+H] ⁺ .

Step 4: (1R,2S,5S)-N-((2S)-1-amino-3-(3-fluoro-2-carbonylindolin-3-yl)-1-carbonylpropan-2-yl )-3-((S)-3,3-

Dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (7e ) Dissolve compound 7c (0.04g, 0.15mmol) and compound 7d (0.077g, 0.21mmol) in N,N-dimethylformamide (5mL), then add triethylamine (0.032g, 0.32mmol) and 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.08 g, 0.21 mmol). The reaction was stirred at 25C for 20 minutes. The reaction solution was purified by reverse phase chromatography ( C18 flash silica gel column, gradient elution under the condition of 0.05% ammonia solution: acetonitrile=20:1～1:20) to obtain compound 7e (69 mg).

m/z (ESI): 584[M+H] ⁺ .

Step 5: (1R,2S,5S)-N-((1S)-1-cyano-2-(3-fluoro-2-carbonylindolin-3-yl)ethyl)-3-(( S)-3,3-Dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-formamide (7 and 8)

Compound 7e (0.04 g, 0.068 mmol) was dissolved in dichloromethane (2 mL) at room temperature, Burgess reagent (0.032 g, 0.14 mmol) was added thereto, and stirred at room temperature for 12 hours. After quenching with water, the reaction mixture was purified by reverse phase chromatography ( C ₁₈ column, water: acetonitrile = 20:1 ~ 1:20 gradient elution) to obtain compound 7 (4.8 mg) and compound 8 (5.1 mg).

In high performance liquid chromatography (the condition is that the column is Xtimate C18 2.1*50mm, the mobile phase A is 0.05% trifluoroacetic acid aqueous solution, the mobile phase B is the acetonitrile solution of 0.05% trifluoroacetic acid, the flow rate is 0.7ml/min, and B% is 5%-95%), the retention time of compound 7 is 1.73min, and the retention time of compound 8 is 1.78min.

Compound 7: m/z (ESI): 566 [M+H] ⁺ .

¹ HNMR: (400MHz,DMSO-d ₆ )δ10.88(s,1H),9.38(s,1H),9.05(d,J=7.3Hz,1H),7.55(d,J=7.3Hz,1H) ,7.39(t,J=7.6Hz,1H),7.05(t,J=7.5Hz,1H),6.92(d,J=7.6Hz,1H),5.09–4.99(m,1H),4.40(s, 1H), 4.18(s, 1H), 3.90(dd, J＝10.2, 5.4Hz, 1H), 3.67(d, J＝10.3Hz, 1H), 2.95–2.77(m, 1H), 2.49–2.41(m ,1H),1.58–1.52(m,1H),1.29–1.21(m,1H),1.02(s,3H),0.99(s,9H),0.84(s,3H).

Compound 8: m/z (ESI): 566 [M+H] ⁺ .

¹ HNMR: (400MHz,DMSO-d ₆ )δ10.76(s,1H),9.39(s,1H),8.93(d,J=7.5Hz,1H),7.56(d,J=7.4Hz,1H) ,7.38(t,J=7.7Hz,1H),7.10(t,J=7.6Hz,1H),6.91(d,J=7.8Hz,1H),4.80(q,J=7.0Hz,1H),4.40 (s,1H),4.16(s,1H),3.89(dd,J=10.4,5.3Hz,1H),3.66(d,J=10.5Hz,1H),2.85–2.72(m,1H),2.69– 2.55(m,1H),1.57–1.52(m,1H),1.29(d,J=7.6Hz,1H),1.02(s,3H),0.98(s,9H),0.83(s,3H).

Example 9 and Example 10: (1R,2S,5S)-N-((1S)-1-cyano-2-(3-fluoro-2-carbonylindolin-3-yl)ethyl) -3-((S)-3,3-Dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1 .0] Preparation of hexane-2-carboxamide (compound 9 and compound 10)

For the synthesis steps of Example 9 and Example 10, refer to Example 7 and Example 8, wherein methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(2-carbonyl-2, 3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)propionate was prepared by substituting step 1 compound 1a in Example 7 and Example 8 to obtain Compound 9 and Compound 10.

m/z (ESI): 567[M+H] ⁺ .

Example 11: (1R,2S,5S)-N-((1S)-1-cyano-2-(6-carbonyl-6,7-dihydro-5H-[1,3]dioxazolo[ 4,5-f]indol-7-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)- Preparation of 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 11)

For the synthesis steps of Example 11, see Example 7 and Example 8, wherein methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(6-carbonyl-6,7-dihydro -5H-[1,3]dioxazolo[4,5-f]indol-7-yl)propionate was replaced by intermediate 7a in step 2 to obtain compound 11.

m/z (ESI): 592[M+H] ⁺ .

Example 12 and Example 13: (1R,2S,5S)-N-((1S)-1-cyano-2-(7-fluoro-6-carbonyl-6,7-dihydro-5H-[1 ,3] Dioxazolo[4,5-f]indol-7-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-tri Preparation of fluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 12 and compound 13)

For the synthesis steps of Example 12 and Example 13, refer to Example 7 and Example 8, wherein methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(6-carbonyl-6, 7-dihydro-5H-[1,3]dioxazolo[4,5-f]indol-7-yl)propionate was prepared by replacing compound 1a in step 1 to obtain compound 12 and compound 13.

m/z (ESI): 610[M+H] ⁺ .

Example 14: (1R,2S,5S)-N-((1S)-1-cyano-2-(2,2-difluoro-6-carbonyl-6,7-dihydro-5H-[1, 3] Dioxazolo[4,5-f]indol-7-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoro Preparation of acetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 14)

For the synthesis steps of Example 14, see Example 7 and Example 8, wherein methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-6-carbonyl Compound 14 was prepared by replacing intermediate 7a in step 2 with -6,7-dihydro-5H-[1,3]dioxazolo[4,5-f]indol-7-yl)propionate.

m/z(ESI):628[M+H] ⁺ .

Example 15 and Example 16: (1R,2S,5S)-N-((1S)-1-cyano-2-(2,2,7-trifluoro-6-carbonyl-6,7-dihydro -5H-[1,3]dioxazolo[4,5-f]indol-7-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2, Preparation of 2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 15 and compound 16)

For the synthesis steps of Example 15 and Example 16, refer to Example 7 and Example 8, wherein methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro -6-carbonyl-6,7-dihydro-5H-[1,3]dioxazolo[4,5-f]indol-7-yl)propionate to replace step 1 compound 1a to obtain the aforementioned compound 15 and compound 16.

m/z(ESI):646[M+H] ⁺ .

Example 17: (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-3-((S)- 2-(Cyclopropanoxalylamino<oxalylamino>)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane - Preparation of 2-formamide (compound 17)

The synthetic route is as follows:

Step 1: Perfluorophenyl cyclopropanecarboxylate (17b)

Compound 17a (1.0g, 12mmol), pentafluorophenol (2.4g, 13mmol) and 4-dimethylaminopyridine (0.14g, 1.2mmol) were dissolved in dichloromethane (5mL), and N,N' - Diisopropylcarbodiimide (1.6 g, 13 mmol). The reaction was stirred at 25C for 2 hours. After the reaction, the reaction solution was filtered, the filter cake was washed with dichloromethane (20 mL), the filtrate was collected, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound 17b (2.0 g).

Step 2: (1R,2S,5S)-3-((S)-2-(Cyclopropaneoxalylamino<oxalylamino>)-3,3-dimethylbutyryl)-6,6 -Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (17d)

Compound 17b (30 mg, 0.12 mmol) was dissolved in water (2 mL) and acetonitrile (2 mL), and then compound 17c (30 mg, 0.12 mmol) and sodium bicarbonate (20 mg, 0.24 mmol) were added. The reaction was stirred at 25C for 16 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C18 flash silica gel column, gradient elution under the condition of 0.05% formic acid aqueous solution: acetonitrile=20:1～1:2) to obtain compound 17d (10 mg).

Step 3: (1R,2S,5S)-N-((2S)-1-Amino-1-carbonyl-3-(2-carbonylindolin-3-yl)propan-2-yl)-3- ((S)-2-(cyclopropaneoxalylamino<oxalylamino>)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1 .0] hexane-2-carboxamide (17e)

Compound 17d (10 mg, 30 μM) was dissolved in N, N-dimethylformamide (1 mL), and compound 1c (8 mg, 31 μM), N, N-diisopropylethylamine (11 mg, 89 μM) and 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (13 mg, 35 μM). The reaction was stirred at 25C for 2 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C18 flash silica gel column, gradient elution under the condition of 0.05% ammonia solution: acetonitrile=20:1～1:2) to obtain compound 17e (16 mg).

Step 4: (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-3-((S)-2 -(cyclopropaneoxalylamino<oxalylamino>)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-Formamide (17)

Compound 17e (16 mg, 30 μM) was dissolved in dichloromethane (1 mL), and then Burgess reagent (17 mg, 74 μM) was added. The reaction was stirred at 25C for 4 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C18 flash silica gel column, gradient elution under the condition of 0.05% ammonia solution: acetonitrile=20:1～1:2) to obtain compound 17 (6.5 mg).

m/z (ESI): 520[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.52(s,0.6H),10.50(s,0.4H),9.29(d,J=8.3Hz,0.6H),9.00(d,J=7.6Hz ,0.4H),8.07(d,J=8.9Hz,0.4H),8.02(d,J=8.8Hz,0.6H),7.34(d,J=7.4Hz,0.6H),7.30(d,J= 7.5Hz,0.4H),7.23–7.14(m,1H),7.02–6.96(m,0.4H),6.92–6.86(m,0.6H),6.83(d,J＝7.8Hz,1H),5.28– 5.18(m,1H),4.34(d,J=9.0Hz,0.4H),4.29(d,J=8.9Hz,0.6H),4.18(s,1H),3.91–3.75(m,2H),3.60 –3.52(m,1H),2.35–2.28(m,1H),2.18–2.07(m,1H),1.84–1.75(m,1H),1.58–1.51(m,1H),1.31(d,J= 7.6Hz,1H),1.02(s,3H),0.90(s,3H),0.83(s,2H),0.78(s,5H),0.67–0.47(m,4H).

Example 18: (1R,2S,5S)-3-((S)-2-Acetamido-3,3-dimethylbutyryl)-N-((1S)-1-cyano-2-( Preparation of 2-carbonylindolin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 18)

For the synthesis steps of Example 18, refer to Example 17. Compound 18 was prepared by replacing 17a in step 1 with acetic acid.

m/z (ESI): 494[M+H] ⁺ .

Example 19: (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-3-((S)- 2-(2,2-difluoropropionylamino)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methanol Preparation of Amide (Compound 19)

For the synthesis steps of Example 19, refer to Example 17. Compound 19 was prepared by substituting difluoroacetic acid for 17a in step 1.

m/z (ESI): 544[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.52(s,1H),9.33-9.26(m,1H),8.15-8.07(m,1H),7.40-7.31(m,1H),7.25-7.12 (m,1H),6.82(d,J=7.8Hz,1H),6.59-6.55(m,1H),4.21(s,1H),4.11(d,J=5.1Hz,1H),3.94-3.87( m,2H),3.65-3.56(m,2H),3.17(d,J＝5.3Hz,1H),2.67(s,1H),2.33(s,1H),1.86-1.65(m,3H),1.23 (s,3H),1.04(s,3H),0.92(s,1H),0.88-0.77(m,9H).

Example 20: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-6,6-di Methyl-3-((S)-3-methyl-3-phenyl-2-(2,2,2-trifluoroacetylamino)butyryl)-3-azabicyclo[3.1.0]hexyl Preparation of alkane-2-carboxamide (compound 20)

Referring to the preparation methods of the foregoing Examples 1-19, compound 20 was synthesized.

m/z(ESI):562[M+H] ⁺ .

Example 21: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-6,6-di Methyl-3-((S)-2-(2-methylbenzo[d][1,3]dioxazol-2-yl)-2-(2,2,2-trifluoroacetylamino) Preparation of acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 21)

Referring to the preparation methods of the foregoing Examples 1-19, compound 21 was synthesized.

m/z (ESI): 578[M+H] ⁺ .

Example 22: (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-6,6-dimethyl -3-((S)-2-(4-methyl-2-oxabicyclo[2.1.1]hexane-1-yl)-2-(2,2,2-trifluoroacetylamino)acetyl base)-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 22)

Referring to the preparation methods of the foregoing Examples 1-19, compound 22 was synthesized.

m/z(ESI):588[M+H] ⁺ .

Example 23: (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-6,6-dimethyl -3-((S)-2-(1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)-2-(2,2,2-trifluoroacetylamino)acetyl base)-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 23)

Referring to the preparation methods of the foregoing Examples 1-19, compound 23 was synthesized.

m/z(ESI):588[M+H] ⁺ .

Example 24: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-3-((S )-2-((S)-2-((2,6-difluorophenyl)amino)propionylamino)-3,3-dimethylbutyryl)-6,6-dimethyl-3- Preparation of azabicyclo[3.1.0]hexane-2-carboxamide (compound 24)

The synthetic route is as follows:

Step 1: (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyryl)-6,6-dimethyl -3-Azabicyclo[3.1.0]hexane-2-carboxylic acid (24a)

Compound 4c (1.6g, 4.2mmol) was dissolved in tetrahydrofuran (20mL) and water (20mL), and lithium hydroxide (0.30g, 12.6mmol) was slowly added at 0°C. The reaction solution was stirred at 25°C for 2 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C18 fast silica gel column, 0.05% aqueous formic acid: acetonitrile = 20: Gradient elution under the condition of 1～1:2) to obtain compound 24a (1.2g).

m/z(ESI):369[M+H] ⁺ .

Step 2: tert-butyl ((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-carbonyl-3-((S)-2-carbonylpyrrolidine -3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)-3,3-dimethyl -1-carbonylbutan-2-yl)carbamate (24b)

Compound 24a (0.30g, 0.8mmol) was dissolved in N,N-dimethylformamide (10mL), then compound 6d (0.14g, 0.80mmol), N,N-diisopropylethylamine (0.32 g, 2.5 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.37 g, 0.90 mmol). The reaction solution was stirred at 25°C for 2 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C18 flash silica gel column, gradient elution under the condition of 0.05% ammonia solution: acetonitrile=20:1～1:2) to obtain compound 24b (0.42g).

m/z(ESI):522[M+H] ⁺ .

Step 3: (1R,2S,5S)-N-((S)-1-amino-1-carbonyl-3-((S)-2-carbonylpyrrolidin-3-yl)propan-2-yl)- 3-((S)-2-amino-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride salt (24c)

Compound 24b (0.42g, 0.80mmol) was dissolved in dichloromethane (3mL) and hydrogen chloride dioxane solution (3mL, 4M) was added. The reaction solution was stirred at 25°C for 16 hours. The solvent was distilled off from the reaction solution under reduced pressure to obtain Compound 24c (0.34 g).

m/z(ESI):422[M+H] ⁺ .

Step 4: (2,6-Difluorophenyl)-L-alanine (24f)

Compound 24d (1.0g, 4.2mmol), 24e (0.37g, 4.2mmol), cuprous iodide (0.16g, 0.83mmol) and cesium carbonate (2.7g, 8.3mmol) were added to the reaction flask and replaced 3 times N,N-Dimethylformamide (5 mL) was added after nitrogen. The reaction solution was stirred at 90°C for 24 hours. After the reaction, add water (30mL) to the reaction liquid, then use hydrochloric acid (1M) to adjust the pH to about 5, then use ethyl acetate (30mL*3) to extract the reaction liquid, collect the organic phase, and saturated saline (30mL) Wash, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The crude product was purified by reverse phase chromatography ( C18 flash silica gel column, gradient elution under the condition of 0.05% formic acid aqueous solution: acetonitrile=20:1～1:2) to obtain compound 24f (0.15 g).

m/z(ESI):202[M+H] ⁺ .

Step 5: (1R,2S,5S)-N-((S)-1-amino-1-carbonyl-3-((S)-2-carbonylpyrrolidin-3-yl)propan-2-yl)- 3-((S)-2-((S)-2-((2,6-difluorophenyl)amino)propionylamino)-3,3-dimethylbutyryl)-6,6-di Methyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (24g)

Compound 24f (0.014g, 0.070mmol) was dissolved in N,N-dimethylformamide (1mL), then compound 24c (0.030g, 0.065mmol), N,N-diisopropylethylamine (0.025 g, 0.20 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.029 g, 0.078 mmol). The reaction solution was stirred at 25°C for 2 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C18 flash silica gel column, gradient elution under the condition of 0.05% ammonia solution: acetonitrile=20:1～1:2) to obtain compound 24g (0.039g).

m/z (ESI): 605[M+H] ⁺ .

Step 6: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-3-((S) -2-((S)-2-((2,6-difluorophenyl)amino)propionylamino)-3,3-dimethylbutyryl)-6,6-dimethyl-3-nitrogen Heterobicyclo[3.1.0]hexane-2-carboxamide (24)

Compound 24g (0.039g, 64mmol) was dissolved in dichloromethane (1mL), and then Burgess reagent (0.038g, 0.16mmol) was added. The reaction solution was stirred at 25°C for 4 hours. The reaction solution was distilled off the solvent under reduced pressure, and the resulting residue was purified by reverse phase chromatography ( C18 flash silica gel column, gradient elution under the condition of 0.05% ammonia solution: acetonitrile=20:1～1:2) to obtain compound 24 (4.2 mg).

m/z (ESI): 587[M+H] ⁺ .

¹ HNMR: (400MHz, DMSO-d ₆ )δ8.92(d, J＝8.5Hz, 1H), 7.96(d, J＝9.2Hz, 1H), 7.61(s, 1H), 6.89–6.82(m, 2H),6.68–6.58(m,1H),4.93–4.85(m,1H),4.79–4.73(m,1H),4.32(d,J＝9.4Hz,1H),4.26–4.19(m,1H) ,4.04(s,1H),3.80(dd,J=10.4,5.5Hz,1H),3.65(d,J=10.3Hz,1H),3.07(t,J=9.1Hz,1H),2.96(q, J＝9.0Hz,1H),2.12–1.96(m,2H),1.68–1.59(m,2H),1.51–1.43(m,1H),1.23–1.10(m,5H),0.95(s,3H) ,0.80(s,9H),0.72(s,3H).

Example 25: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-3-((S )-2-((S)-2-((2,4-difluorophenyl)amino)propionylamino)-3,3-dimethylbutyryl)-6,6-dimethyl-3- Preparation of azabicyclo[3.1.0]hexane-2-carboxamide (compound 25)

For the synthesis steps of Example 25, refer to Example 24, wherein Compound 25 was prepared by substituting 2,4-difluoro-1-iodobenzene for Compound 24d.

m/z (ESI): 587[M+H] ⁺ .

Example 26: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-3-((S )-2-((S)-2-((2,4,6-trifluorophenyl)amino)propionylamino)-3,3-dimethylbutyryl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 26)

For the synthesis steps of Example 26, refer to Example 24, wherein Compound 26 was prepared by substituting 2,4,6-trifluoro-1-iodobenzene for Compound 24d.

m/z (ESI): 605[M+H] ⁺ .

Example 27: (1R,2S,5S)-3-((S)-2-((S)-2-((4-chloro-2-fluorophenyl)amino)propionylamino)-3,3 -Dimethylbutyryl)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-6,6-dimethyl-3 -Preparation of azabicyclo[3.1.0]hexane-2-carboxamide (compound 27)

For the synthesis procedure of Example 27, refer to Example 24, wherein Compound 27 was prepared by substituting 4-chloro-2-fluoro-1-iodobenzene for Compound 24d.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.99(d, J=8.7Hz, 1H), 7.98(d, J=9.4Hz, 1H), 7.68(s, 1H), 7.21(d, J= 11.5Hz, 1H), 6.96(d, J=8.8Hz, 1H), 6.54(t, J=9.1Hz, 1H), 5.71(d, J=8.6Hz, 1H), 4.95(s, 1H), 4.40 (d,J=9.3Hz,1H),4.12–3.93(m,2H),3.91–3.81(m,1H),3.65(d,J=10.3Hz,1H),3.20–3.09(m,1H), 3.09–2.99(m,1H),2.21–1.99(m,2H),1.78–1.64(m,2H),1.56–1.46(m,1H),1.28(d,J＝7.1Hz,4H),1.00( s,3H),0.96–0.78(m,10H),0.71(s,3H).

m/z(ESI):603[M+H] ⁺ .

Example 28: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-3-((S )-3,3-Dimethyl-2-((S)-2-((2,2,2-trifluoroethyl)amino)propionylamino)butyryl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 28)

For the synthesis steps of Example 28, refer to Example 24, in which 2,2,2-trifluoroethyltrifluoromethanesulfonic acid was used instead of Compound 24d to obtain the aforementioned Example 28.

m/z (ESI): 557[M+H] ⁺ .

Example 29: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-3-((S )-2-((S)-2-((4-cyano-2-fluorophenyl)amino)propionylamino)-3,3-dimethylbutyryl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 29)

For the synthesis steps of Example 29, refer to Example 24, wherein 3-fluoro-4-iodobenzonitrile was used to replace Compound 24d to obtain the aforementioned Example 29.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.99(d, J=8.8Hz, 1H), 8.08(d, J=8.8Hz, 1H), 7.68(s, 1H), 7.57(dd, J= 12.0,2.0Hz,1H),7.40(dd,J=8.8,2.0Hz,1H),6.61(t,J=8.8Hz,1H),6.56(d,J=8.0Hz,1H),4.99-4.92( m,1H),4.40(d,J=9.2Hz,1H),4.20-4.16(m,1H),4.06(s,1H),3.88–3.84(m,1H),3.65(d,J=10.4Hz ,1H),3.17-3.12(m,1H),3.07-3.03(m,1H),2.46-2.38(m,1H),2.17-2.05(m,2H),1.76-1.67(m,2H),1.54 -1.50(m,1H),1.35-1.23(m,4H),1.01(s,3H),0.91(m,9H),0.72(s,3H).

m/z (ESI): 594[M+H] ⁺ .

Biological activity and related properties test cases

Test example 1, SARS-CoV-2 3CL protease inhibitory activity test

1. Experimental instruments and materials

The detection system includes 3CL protease, Beyotime fluorescent substrate Dabcyl-KTSAVLQSGFRKME-Edans, the reaction buffer is 20mM Tris-HCl (pH7.3), 100mM NaCl, 1mM EDTA, 0.01% BSA (bivine serum albumin), 1mM DTT. The detection principle is fluorescence resonance energy transfer: 3CL protease hydrolyzes the fluorescent substrate to generate a detectable fluorescent product, and the detection of the fluorescent product reflects the protease activity.

Other reagents and consumables required for the experiment are as follows:

2. Experimental steps

100 nL of 3-fold serially diluted compound (final concentration 1 μM-0.05 nM) was incubated with 10 μL of 50 nM 3CL protease for 30 minutes at room temperature. Add 10 μL of 20 μM fluorescent substrate to the reaction plate to start the reaction, read the fluorescence signal (Ex360/Em490) every 1 minute in continuous reading mode on the FlexStation 3, and collect the Vmax value of the original fluorescence value for 30 minutes. The substrate wells were used as the 100% inhibition control, and the enzyme reaction wells were used as the 0% inhibition control to calculate the compound inhibition rate. _IC50 was calculated using IDBS XLfit.

3. Data analysis

The formula for calculating the inhibitory rate of the compound on 3CL protease activity is:

Inhibition rate% = (Average 0% inhibition well - sample well) / (Average 0% inhibition well - Average 100% inhibition well) x 100%.

The data was analyzed and processed by XLfit, the concentration-effect curve was fitted with a nonlinear four-parameter curve, and the IC ₅₀ of the compound was calculated:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))

in:

X: Log value of compound concentration;

Y: percentage inhibition rate (%inhibition);

Bottom is the minimum suppression percentage;

Top is the maximum inhibition percentage;

HillSlope is the slope coefficient of the curve.

The inhibitory effect of the disclosed compounds on 3CL protease activity was determined by the above test, and the measured IC ₅₀ values are shown in Table 1.

Table 1

A: <50nM; B: ≥50nM and <500nM.

Claims (11)

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

   in,

   R ¹ is selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, 4-14 membered heterocyclyl, C ₁ -C ₁₀ alkoxy, C ₃ -C ₁₂ cycloalkyloxy or 4 -14-membered heterocyclyloxy, the C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, 4-14 membered heterocyclyl, C ₁ -C ₁₀ alkoxy, C ₃ -C ₁₂ Cycloalkyloxy or 4-14 membered heterocyclyloxy is optionally substituted by one or more R ^1a ;

   Alternatively, R ¹ is selected from N(R ⁴ )(R ⁵ ), said R ⁴ and R ⁵ are independently selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered Heterocyclic group, or R ⁴ , R ⁵ and the N atom they are connected to together form a 4-7 membered heterocyclic group, the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclic group The cyclic group is optionally substituted by one or more R ^4a ;

   Each R ^1a is independently selected from C ₁ -C ₆ alkyl, halogen, CN, =O, OH, NHC(=O)R ^m or N(R ^j )(R ^k ), C ₃ -C ₆ cycloalkane radical or 4-7 membered heterocyclic group, wherein R ^m , R ^j , R ^k are independently selected from H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, said C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl, OH, C ₃ -C ₆ cycloalkyl, 4-7 membered hetero Cyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl are optionally substituted by one or more R ^1b ;

   Each R ^4a is independently selected from C ₁ -C ₆ alkyl, halogen, CN, =O, OH, NH ₂ , C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl, the OH, NH _2. C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl are optionally substituted by one or more R ^4b ;

   R ² is selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl or 4-14 membered heterocyclic group, the C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl or 4- 14-membered heterocyclyl is optionally substituted by one or more R ^2a ;

   Each R ^2a is independently selected from F, Cl, Br, I, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl or 4-7 membered Heterocyclic group, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl or 4-7 membered heterocyclic group are optionally substituted by one or more R ^2b ;

   R ³ is selected from 4-14 membered heterocyclic groups, and the 4-14 membered heterocyclic groups are optionally substituted by one or more R ^3a ;

   Each R ^3a is independently selected from F, Cl, Br, I, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl , the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclic group are optionally substituted by one or more R ^3b ;

   Each R ^1b , R ^2b , R ^3b , R ^4b is independently selected from F, Cl, Br, I, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkane radical, 4-7 membered heterocyclyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyloxy or 4-7 membered heterocyclyloxy.
2. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is selected from C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered Heterocyclyloxy, the C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyloxy are optionally replaced by one or more (for example, 1, 2 or 3) R ^1a is substituted; or, R ¹ is selected from N(R ⁴ )(R ⁵ ), said R ⁴ and R ⁵ are independently selected from H, C ₁ -C ₆ alkyl or C ₃ -C ₆ ring Alkyl, or R ⁴ , R ⁵ and the N atom they are connected to together form a 4-7 membered heterocyclic group, the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclic The group is optionally substituted by one or more (eg, 1, 2 or 3) R ^4a ; or

   R ¹ is selected from methyl, or

   R ¹ is selected from methyl,
3. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, R ² is selected from C ₁ -C ₆ alkyl or 4-10 membered heterocyclic group, said C ₁ -C ₆ alkyl or 4-10 membered heterocyclic group is optionally substituted by one or more (for example, 1, 2 or 3) C ₁ -C ₃ alkyl or phenyl; or

   ^R2 is selected from
4. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein,

   R ³ is selected from 5-12 membered heterocyclic groups optionally replaced by one or more (for example, 1, 2 or 3) R ^3a replace; or

   ^R3 is selected from said Optionally substituted with one or more (eg, 1, 2 or 3) R ^3a .
5. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R ^3a is selected from halogen, CN, =O or C ₁ -C ₃ alkyl; or

   R ^3a is selected from F, =O or C ₁ -C ₃ alkyl; or

   R ^3a is selected from F or =0.
6. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein R ^is selected from or

   ^R3 is selected from
7. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of formula (Ia) Compound or its pharmaceutically acceptable salt:
   

   Wherein, R ¹ , R ² , R ³ are as defined in claim 1.
8. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof Acceptable salts:
   
   
9. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof Acceptable salts:
   
   
   
10. A pharmaceutical composition, which comprises the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials.
11. The use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 10 in the preparation of medicines for preventing or treating coronavirus 3CL protease-related diseases; preferably, the The coronavirus 3CL protease-related disease is selected from respiratory tract infection, pneumonia or its complications.