CN115785083A - Cathepsin C small-molecule inhibitor and preparation method thereof - Google Patents

Abstract

The disclosure relates to a cathepsin C small-molecule inhibitor and a preparation method thereof. Specifically, the disclosure provides an amidonitrile compound represented by formula I, and these compounds have a certain inhibitory effect on cathepsin C.

Description

A small molecule inhibitor of cathepsin C and its preparation method

technical field

The disclosure belongs to the field of medicine, and relates to a cathepsin C small molecule inhibitor and a preparation method thereof.

Background technique

Cathepsins are a class of proteolytic enzymes that widely exist in the lysosomes of various tissue cells. D and E) and class 3 of cysteine proteases. Among them, cysteine proteases are the largest cathepsin family, including 11 proteases: cathepsins B, C, F, H, K, L, O, S, W, V and Z.

Cathepsin C (cathepsin C), also known as dipeptidyl peptidase I or "DPPI", DPP1 is constitutively expressed in many tissues, with the highest levels in lung, kidney, liver and spleen. Several recently published studies have begun to describe the role played by cathepsin C in certain inflammatory processes. For example: J Clin Invest.2002Feb published by Adkison et al.; 109(3):363-71; Archives of Biochemistry and Biophysics.2002 403:160-170 published by Tinh et al.; From these studies, cathepsin C is associated with certain Serine proteases are co-expressed in granules and function to process the precursor forms of these proteases into active forms, which are then released from inflammatory cell granules recruited to sites of inflammation. Once activated, these proteases have numerous functions, including the degradation of various extracellular matrix components, which together can propagate tissue damage and chronic inflammation.

WO 2004/110988 relates to certain nitrile derivatives and their use as DPP1 inhibitors.

WO 2009/074829 relates to peptidylnitriles and their use as DPP1 inhibitors.

WO 2010/128324 relates to α-aminoamide nitriles and their use as DPP1 inhibitors.

WO 2012/119941 relates to peptidyl nitrile compounds and their use as DPP1 inhibitors.

WO 2013/041497 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide and its use as DPP1 inhibitors.

WO 2001/096285 and WO 2003/048123 relate to beta-aminoamide nitriles having inhibitory activity against cysteine proteases.

WO 2015/110826 relates to α-aminoamide nitriles and their use as DPP1 inhibitors.

However, the amide nitrile compound represented by formula I of the present disclosure has not been disclosed in any literature.

Contents of the invention

The disclosure (The disclosure) provides a compound shown in formula I or a pharmaceutically acceptable salt thereof

in

A is a C _1-6 alkylene group, and the C _1-6 alkylene group is optionally replaced by one or more deuterium, C _1-6 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy; C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy are optional Replaced by 1-3 R _5a ;

B is selected from 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C _6-10 aryl, the 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C _{6- 10} Aryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amido, oxo, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy or C _1-6 alkoxy; said C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy or C _1-6 alkoxy optionally substituted by 1-3 R _5b ;

_R is independently selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy , C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy , C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy are optionally substituted by 1-3 R _5e ;

n is an integer selected from 0-3;

_R is selected from deuterium, halogen, hydroxyl, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 Alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy; said C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 Alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 deuterium, halogen, cyano, nitro, C _3-6 cycloalkyl, C _1-6 alkane base replaced;

所取代，和/或者所述C_6-10芳基或5-10元杂芳基与C_3-6环烷基或3-6元杂环烷基稠合形成稠合环，所述C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6环烷基、3-6元杂环烷基、C_3-6环烷氧基、3-6元杂环烷氧基、环烯氧基或稠合环任选被一个或多个R_5c所取代；R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, and the C _6-10 aryl or 5-10 membered heteroaryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl, Cyano, nitro, C _1-6 alkyl, amino, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 Member heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 heterocycloalkoxy, cycloalkenyloxy or

Substituted, and/or the C _6-10 aryl or 5-10 membered heteroaryl is fused with a C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl to form a fused ring, the C _{1 -6} alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, cycloalkenyloxy or fused rings are optionally substituted by one or more R _5c ;

Or R ₃ and R ₂ form 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl, described 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl is optionally replaced by one or more deuterium , C _1-6 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 alkenyloxy Base, C _2-6 alkynyloxy, C _3-6 cycloalkoxy substituted;

Or R ₃ and R ₂ form 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl, described 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl and C _6-10 aryl or 5-10 membered heteroaryls are fused to form a fused ring optionally substituted by 1-3 R _5d

所述C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6环烷基、3-6元杂环烷基、C_3-6环烷氧基、3-6元杂环烷氧基、C_3-8环烯氧基、6-10元芳基或5-10元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基取代；R _5d is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _{2 -6} alkynyloxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy , 6-10 membered aryl or 5-10 membered heteroaryl, methanesulfonyl,

The C _1-6 alkyl, C _1-6 alkoxy _{, C 2-6 alkenyloxy, C 2-6 alkynyloxy} , C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 heterocycloalkoxy, C _3-8 cycloalkenyloxy, 6-10 aryl or 5-10 heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, oxo, nitro, cyano;

R _is independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl;

R _5a is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 heterocycloalkoxy, C _3-8 cycloalkene Oxygen, 6-10 membered aryl, 5-10 membered heteroaryl or methylsulfonyl;

R _5b is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 heterocycloalkoxy, C _3-8 cycloalkene Oxygen, 6-10 membered aryl or 5-10 membered heteroaryl, methylsulfonyl;

R _5c is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 heterocycloalkoxy, C _3-8 cycloalkene Oxygen, 6-10 membered aryl or 5-10 membered heteroaryl, methylsulfonyl;

R _is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 heterocycloalkoxy, C _3-8 cycloalkene Oxygen, 6-10 membered aryl or 5-10 membered heteroaryl, methylsulfonyl;

*The configuration of the marked carbon atoms is S or R.

In some embodiments, A in the compound shown in formula I or a pharmaceutically acceptable salt thereof is a C _1-6 alkylene group, and the C _1-6 alkylene group is optionally replaced by one or more deuterium, C _{1 -4} Alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy; said C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy and C _3-6 cycloalkoxy are optionally substituted by 1-3 R _5a .

In some embodiments, A in the compound shown in formula I or a pharmaceutically acceptable salt thereof is a C _1-4 alkylene group, and the C _1-4 alkylene group is optionally replaced by one or more deuterium, C _{1 -4} Alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _3-6 cycloalkoxy ; The C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally substituted by 1-3 R _5a .

In some embodiments, A in the compound shown in formula I or a pharmaceutically acceptable salt thereof is a C _1-4 alkylene group, and the C _1-4 alkylene group is optionally replaced by one or more deuterium, C _{1 -4} alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, C _1-4 alkoxy, C _3-6 cycloalkoxy; the C _{1 -4} alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _3-6 cycloalkoxy are optionally substituted by 1-3 R _5a .

In some embodiments, A in the compound shown in formula I or its pharmaceutically acceptable salt is methylene, and the methylene is optionally replaced by one or more deuterium, C _1-4 alkyl, halogen, hydroxyl, oxygen Substitution, nitro, cyano, C _3-6 cycloalkyl, amino, C _1-4 alkoxy, C _3-6 cycloalkoxy; the C _1-4 alkyl, C _3-6 ring Alkyl, C _1-4 alkoxy, C _3-6 cycloalkoxy are optionally substituted by 1-3 R _5a .

In some embodiments, A in the compound shown in formula I or a pharmaceutically acceptable salt thereof is a C _1-4 alkylene group, and the C _1-4 alkylene group is optionally replaced by one or more deuterium, methyl , ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, halogen, hydroxyl, oxo, nitro, cyano, amino; the methyl, ethyl, cyclopropyl, methyl Cyclopropyl, ethylcyclopropyl are optionally substituted by 1-3 R _5a .

In some embodiments, A in the compound shown in formula I or its pharmaceutically acceptable salt is methylene, and the methylene is optionally replaced by one or more deuterium, methyl, ethyl, cyclopropyl, methyl Cyclopropyl, ethylcyclopropyl, halogen, hydroxyl, oxo, nitro, cyano, amino substitution; the methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl any Optionally replaced by 1-3 R _5a .

In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, B is selected from 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, _C6-10 aryl, the 3- 15 membered heterocycloalkyl, 5-10 membered heteroaryl, C _6-10 aryl are optionally replaced by one or more selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amido, oxygen Substituted, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy or C _1-6 alkoxy; said C _1-6 alkyl, C _3-6 cycloalkane Group, C _3-6 cycloalkoxy or C _1-6 alkoxy is optionally substituted by 1-3 R _5b .

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, B is selected from 3-15 membered heterocycloalkyl groups, and the 3-15 membered heterocycloalkyl groups are optionally selected from 1-3 members selected from Deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amido, oxo, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy or C _1-6 Alkoxy substitution; the C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy or C _1-6 alkoxy is optionally substituted by 1-3 R _5b .

In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, B is selected from 3-15 membered heterocycloalkyl groups, and the 3-15 membered heterocycloalkyl groups are optionally selected from 1-3 members selected from Deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _1-6 alkyl, C _3-6 cycloalkyl; the C _1-6 alkyl, C _3-6 cycloalkyl are optional Optionally replaced by 1-3 R _5b .

In some embodiments, B in the compound represented by formula I or a pharmaceutically acceptable salt thereof is selected from 3-15 membered heterocycloalkyl groups containing 1-3 heteroatoms, and any of the 3-15 membered heterocycloalkyl groups selected from 1-3 selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _1-6 alkyl, C _3-6 cycloalkyl substituted; said C _1-6 alkyl, C _3-6 cycloalkyl is optionally substituted by 1-3 R _5b ; the heteroatom is selected from a nitrogen atom or an oxygen atom.

In some embodiments, B in the compound represented by formula I or a pharmaceutically acceptable salt thereof is selected from 5-10 membered heterocycloalkyl groups containing 1-3 heteroatoms, and any of the 5-10 membered heterocycloalkyl groups selected from 1-3 selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _1-6 alkyl, C _3-6 cycloalkyl substituted; said C _1-6 alkyl, C _3-6 cycloalkyl is optionally substituted by 1-3 R _5b ; the heteroatom is selected from a nitrogen atom or an oxygen atom.

In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, B is selected from the group consisting of deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _{1-3 6} alkyl, C _3-6 cycloalkyl substituted

The C _1-6 alkyl and C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b .

In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, B is selected from the group consisting of deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _{1-3 6} alkyl, C _3-6 cycloalkyl substituted

The C _1-6 alkyl and C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b .

所述C_1-6烷基、C_3-6环烷基任选被1-3个R_5b取代。In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, B is selected from the group consisting of deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _{1-3 6} alkyl, C _3-6 cycloalkyl substituted

The C _1-6 alkyl and C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b .

所述C_1-6烷基、C_3-6环烷基任选被1-3个R_5b取代。In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, B is selected from the group consisting of deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _{1-3 6} alkyl, C _3-6 cycloalkyl substituted

The C _1-6 alkyl and C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b .

所述C_1-6烷基、C_3-6环烷基任选被1-3个R_5b取代。In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, B is selected from the group consisting of deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _{1-3 6} alkyl, C _3-6 cycloalkyl substituted

The C _1-6 alkyl and C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b .

所取代，和/或者所述C_6-10芳基或5-10元杂芳基与C_3-6环烷基或3-6元杂环烷基稠合形成稠合环，所述C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6环烷基、3-6元杂环烷基、C_3-6环烷氧基、3-6元杂环烷氧基、环烯氧基或稠合环任选被一个或多个R_5c所取代；In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, said C _6-10 aryl or 5-10 membered heteroaryl Heteroaryl is optionally replaced by 1-3 members selected from deuterium, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, amino, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 heterocycloalkoxy, cycloalkenyloxy or

Substituted, and/or the C _6-10 aryl or 5-10 membered heteroaryl is fused with a C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl to form a fused ring, the C _{1 -6} alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, cycloalkenyloxy or fused rings are optionally substituted by one or more R _5c ;

R ₂ is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy; said C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 deuterium, halogen, cyano, nitro, C _3-6 cycloalkyl, C _{1 -6} alkyl substituted;

R _is independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl.

所取代，和/或者所述C_6-10芳基或5-10元杂芳基与C_3-6环烷基或3-6元杂环烷基稠合形成稠合环，所述C_1-6烷基、C_1-6烷氧基、C_3-6环烷基、3-6元杂环烷基、C_3-6环烷氧基、3-6元杂环烷氧基或稠合环任选被一个或多个R_5c所取代；In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, said C _6-10 aryl or 5-10 membered heteroaryl Heteroaryl is optionally replaced by 1-3 members selected from deuterium, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, amino, C _1-6 alkoxy, C _3-6 cycloalkyl, 3 -6 membered heterocycloalkyl, C _3-6 cycloalkoxy or

Substituted, and/or the C _6-10 aryl or 5-10 membered heteroaryl is fused with a C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl to form a fused ring, the C _{1 -6} alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 heterocycloalkoxy or condensed The closed ring is optionally substituted by one or more R _5c ;

R ₂ is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _3-6 cycloalkoxy; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 deuterium, Halogen, cyano, nitro, C _3-6 cycloalkyl, C _1-6 alkyl substituted;

R _is independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl.

所取代，所述C_1-6烷基、C_1-6烷氧基、C_3-6环烷基、3-6元杂环烷基、C_3-6环烷氧基、3-6元杂环烷氧基任选被一个或多个R_5c所取代；In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, said C _6-10 aryl or 5-10 membered heteroaryl Heteroaryl is optionally replaced by 1-3 members selected from deuterium, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, amino, C _1-6 alkoxy, C _3-6 cycloalkyl, 3 -6 membered heterocycloalkyl, C _3-6 cycloalkoxy or

Substituted, the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 Heterocycloalkoxy is optionally substituted by one or more R _5c ;

R _is independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl.

In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, said C _6-10 aryl or 5-10 membered heteroaryl Heteroaryl is fused with C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl to form a fused ring, which is optionally substituted by one or more R _5c .

In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, said C _6-10 aryl or 5-10 membered heteroaryl Heteroaryl is fused with C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl to form a 6-10 membered fused ring, and the 6-10 membered fused ring is optionally surrounded by one or more R _5c replaced.

In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R ₃ is selected from C _6-10 aryl, and the C _6-10 aryl is combined with 3-6 membered The heterocycloalkyl is fused to form a 6-10 membered fused ring optionally substituted with one or more R _5c .

In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R ₃ is selected from C _6-10 aryl, and the C _6-10 aryl is combined with 3-6 membered Heterocycloalkyl is fused to form a condensed ring of 6-10 members, and the condensed ring of 6-10 members is optionally substituted by one or more R _5c ; the heteroatoms are independently selected from nitrogen atoms, oxygen atom.

The present disclosure also provides a compound represented by formula II or a pharmaceutically acceptable salt thereof

Wherein A, B, R ₁ , n, R _5c are as defined in formula I;

R ₂ is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _3-6 cycloalkoxy;

X ₁ and X ₂ are independently selected from nitrogen atom, oxygen atom and sulfur atom; preferably X ₁ and X ₂ are independently selected from nitrogen atom and oxygen atom; more preferably X ₁ is an oxygen atom and X ₂ is a nitrogen atom.

In some embodiments, in the compound shown in formula I or formula II or its pharmaceutically acceptable salt, R ₂ is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _{3- 6} cycloalkyl, amino, the C _1-6 alkyl, C _3-6 cycloalkyl optionally replaced by 1-3 deuterium, halogen, cyano, nitro, C _3-6 cycloalkyl, C _{1 -6} alkyl substituted;

Preferably _R is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, said C _1-6 alkyl, C _3-6 Cycloalkyl is optionally substituted by 1-3 deuterium, halogen, cyano, nitro;

More preferably R _is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino.

In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R ₃ and R ₂ form a 5-10 membered cycloalkyl group or a 5-10 membered heterocycloalkyl group, and the 5-10 membered cycloalkyl group Or 5-10 membered heterocycloalkyl is optionally replaced by 1-3 deuterium, C _1-6 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido , acyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy substituted.

In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R ₃ and R ₂ form a 5-8 membered cycloalkyl group or a 5-8 membered heterocycloalkyl group, and the 5-8 membered cycloalkyl group Or 5-8 membered heterocycloalkyl is optionally replaced by 1-3 deuterium, C _1-6 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido , acyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy substituted.

In some embodiments, in the compound shown in formula I or its pharmaceutically acceptable salt, R ₃ and R ₂ form a 5-10 membered cycloalkyl group or a 5-10 membered heterocycloalkyl group, and the 5-10 membered cycloalkyl group Or a 5-10 membered heterocycloalkyl group is fused with a C _6-10 membered aryl group or a 5-10 membered heteroaryl group to form a fused ring, and the fused ring is optionally substituted by 1-3 R _5d .

The present disclosure also provides a compound represented by formula III or a pharmaceutically acceptable salt thereof

Wherein A, B, R ₁ , n, R _5d are as defined in right 1;

X ₃ and X ₄ are independently selected from nitrogen atom, oxygen atom, sulfur atom and carbon atom; preferably X ₃ and X ₄ are independently selected from nitrogen atom, oxygen atom and carbon atom; preferably X ₃ and X ₄ are independently selected from Oxygen atom, carbon atom; more preferably X ₃ is an oxygen atom, X ₄ is a carbon atom.

In some embodiments, the configuration of the carbon atom marked with * in formula I, formula II, and formula III is S, specifically the structure of the compound shown in formula IV, V, VI:

In some embodiments, R in the compound shown in formula I, II, III, IV, V or VI or its pharmaceutically acceptable salt is _{independently} selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, C _1-6 alkoxy; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy are optional Replaced by 1-3 R _5e ;

Preferably R ₁ is independently selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl,; said C _1-6 alkyl, C _{3- 6} cycloalkyl, C _1-6 alkoxy are optionally substituted by 1-3 R _5e .

In some embodiments, in the compound shown in formula I, II, III, IV, V or VI or its pharmaceutically acceptable salt, R _5a is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino , acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 members Heterocycloalkoxy, C _3-8 cycloalkenyloxy, methylsulfonyl.

In some embodiments, R _5a in the compound shown in formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof is independently selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C _{1 -6} alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl.

In some embodiments, R in the compound shown in formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof is _{independently} selected from halogen, deuterium, nitro, cyano, C _1-6 alkyl , C _3-6 cycloalkyl.

In some embodiments, in the compound shown in formula I, II, III, IV, V or VI or its pharmaceutically acceptable salt, R _5a is independently selected from halogen, deuterium, nitro, cyano, methyl, ethyl, Propyl, Cyclopropyl.

In some embodiments, R in the compound shown in formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof is _{independently} selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino , acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 membered heterocycle alkyl.

In some embodiments, R in the compound shown in formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof is _{independently} selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl.

In some embodiments, R in the compound shown in formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof is _{independently} selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino , C _1-6 alkyl, C _3-6 cycloalkyl.

In some embodiments, R in the compound shown in formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof is _{independently} selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino , methyl, ethyl, n-propyl, cyclopropyl.

In some embodiments, R in the compound shown in formula I, II, IV or V or a pharmaceutically acceptable salt thereof is _{independently} selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy group, methylsulfonyl group.

In some embodiments, in the compound shown in formula I, II, IV or V or its pharmaceutically acceptable salt, R _5c is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C _{1- 6} alkyl, C _3-6 cycloalkyl, methylsulfonyl.

In some embodiments, in the compound shown in formula I, II, IV or V or its pharmaceutically acceptable salt, R _5c is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, methyl, Ethyl, cyclopropyl, methylcyclopropyl, methylsulfonyl.

所述C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6环烷基、3-6元杂环烷基、C_3-6环烷氧基、3-6元杂环烷氧基、C_3-8环烯氧基任选被1-3选自卤素、氘、羟基、氧代、硝基、氰基取代。In some embodiments, R in the compound shown in formula I, III, V or VI or its pharmaceutically acceptable salt is _selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _{3- 6} cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, methylsulfonyl,

The C _1-6 alkyl, C _1-6 alkoxy _{, C 2-6 alkenyloxy, C 2-6 alkynyloxy} , C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy are optionally substituted by 1-3 selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano .

所述C_1-6烷基、C_1-6烷氧基、C_3-6环烷基、3-6元杂环烷基、C_3-6环烷氧基、3-6元杂环烷氧基任选被1-3选自卤素、氘、羟基、氧代、硝基、氰基取代。In some embodiments, in the compound shown in formula I, III, V or VI or its pharmaceutically acceptable salt, R _5d is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkane group, C _1-6 alkoxy group, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkoxy group, 3 to 6 membered heterocycloalkoxy group, methylsulfonyl group,

The C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 heterocycloalkane Oxy group is optionally substituted with 1-3 selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

In some embodiments, in the compound shown in formula I, III, V or VI or its pharmaceutically acceptable salt, R _5d is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkane Base, C _3-6 cycloalkyl, said C _1-6 alkyl, C _3-6 cycloalkyl are optionally substituted by 1-3 selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

In some embodiments, in the compound shown in formula I, III, V or VI or its pharmaceutically acceptable salt, R _5d is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkane Base, C _3-6 cycloalkyl.

In some embodiments, R in the compound shown in formula I, III, V or VI or its pharmaceutically acceptable salt is _selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, methyl, ethyl , cyclopropyl, propyl, the methyl, ethyl, cyclopropyl, propyl are optionally substituted by 1-3 selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

In some embodiments, R in the compound shown in formula I, III, V or VI or its pharmaceutically acceptable salt is _{independently} selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy Base, C _3-8 cycloalkenyloxy, methylsulfonyl.

In some embodiments, R in the compound shown in formula I, III, V or VI or a pharmaceutically acceptable salt thereof is _{independently} selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C _1-6 alkyl , C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl.

In some embodiments, in the compound shown in formula I, III, V or VI or its pharmaceutically acceptable salt, R _5e is independently selected from halogen, deuterium, nitro, cyano, C _1-6 alkyl, C _{3- 6} cycloalkyl.

In some embodiments, R in the compound shown in formula I, III, V or VI or its pharmaceutically acceptable salt is _{independently} selected from halogen, deuterium, nitro, cyano, methyl, ethyl, propyl, ring Propyl.

Typical compounds shown in formula I or pharmaceutically acceptable salts thereof include but are not limited to:

The present disclosure also provides a pharmaceutical composition, comprising at least one therapeutically effective amount of the aforementioned formula I, or a pharmaceutically acceptable salt thereof, or a compound prepared by the aforementioned method or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Accepted excipients.

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

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

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

The present disclosure also provides a method for preventing and/or treating a patient with a cathepsin C-related disorder by administering a therapeutically effective amount of a compound as shown in formula I, II, III, IV, V or VI to the patient or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

In some embodiments, the diseases related to cathepsin C include but are not limited to respiratory diseases such as asthma, obstructive pulmonary disease, bronchiectasis, etc., and autoimmune diseases such as ANCA-associated vasculitis, psoriasis, nail antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, or rheumatoid arthritis.

The present disclosure also provides a method for preventing and/or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha-1 antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease or A method for a patient with rheumatoid arthritis, by administering to the patient a therapeutically effective amount of the compound shown in formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

The present disclosure also provides a compound as shown in formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition used in the preparation for preventing and/or treating diseases related to cathepsin C Uses in medicine.

The present disclosure also provides compounds or pharmaceutically acceptable salts thereof as shown in formula I, II, III, IV, V or VI, or the aforementioned pharmaceutical composition used for preventing and/or treating asthma, obstructive pulmonary disease, bronchial Dilatation, ANCA-associated vasculitis, psoriasis, type 1 antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease or rheumatoid arthritis.

Pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic or organic salts.

Compounds of the present disclosure may exist in particular 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 their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. 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 reagents.

Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).

表示未指定构型，即如果化学结构中存在手性异构体，键

可以为

或

或者同时包含

和

两种构型。本公开所述化合物的化学结构中，键

并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。In the chemical structure of the compound of the present invention, the bond

Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond

can be

or

or both

and

Two configurations. In the chemical structures of the compounds described in this disclosure, the bond

If the configuration is not specified, it can be the Z configuration or the E configuration, or both configurations.

Although all of the above formulas are drawn as certain isomeric forms for simplicity, the present invention may include all isomers such as tautomers, rotamers, geometric isomers, diastereoisomers body, racemate and enantiomer.

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

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

Any isotopically labeled derivatives of the compounds described in the present disclosure, or pharmaceutically acceptable salts thereof, or isomers thereof are covered by the present disclosure. Atoms capable of being isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, and the like. They can be replaced by isotopes ² H(D), ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and 125I, respectively. Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to mean deuterium having an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (ie, at least 45 % deuterium incorporation).

The present disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound of formula (I). 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 ethyl iodide and deuterated methyl iodide, etc.

Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes occasions where the event or circumstance occurs or does not occur. For example, "optionally substituted by halogen or cyano The C ₁ -C ₆ alkyl" means that halogen or cyano may but not necessarily exist, and this description includes the situation where the alkyl is substituted by halogen or cyano and the situation where the alkyl is not substituted by halogen or cyano.

Explanation of terms:

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. Forming agent. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.

"Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, agent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.

An "effective amount" or "therapeutically effective amount" as used in the present 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. Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

"Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxygen Generation, nitro, cyano, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, ₃ to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl Oxygen, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl any substituted by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

"Alkenyl" includes branched and straight chain alkenes or alkenes containing aliphatic hydrocarbon groups having 2 to 12 carbon atoms. For example "C _2-6 alkenyl" means alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Alkenyl 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 halogen, deuterium, hydroxyl, oxygen Generation, nitro, cyano, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, ₃ to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl Oxygen, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl any substituted by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

"Alkynyl" includes branched and straight chain alkynyl groups or alkene containing aliphatic hydrocarbon groups having 2 to 12 carbon atoms, or if specified to specify the number of carbon atoms, means that specific number. For example ethynyl, propynyl (eg 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl. Alkynyl 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 halogen, deuterium, hydroxyl, oxygen Generation, nitro, cyano, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, ₃ to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl Oxygen, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl any substituted by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

The term "cycloalkyl" or "carbocycle" 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 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; multicyclic cycloalkyls include spiro Cycloalkyl rings, fused rings and bridged rings. Cycloalkyl 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 halogen, deuterium, hydroxyl, Oxo _, nitro, cyano, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 Alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl Optionally substituted by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

The cycloalkyl ring may be fused to an aryl or heteroaryl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzo Heptyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano , C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy , C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 Alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. Cycloalkenyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano , C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy , C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 Alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

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

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

等。

wait.

Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano radical, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, _3-6 membered heterocycloalkoxy group, C _3-8 cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _{2- 6} -alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally replaced by one or more Substituted by halogen, deuterium, hydroxyl, oxo, nitro, cyano.

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

Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, _{C -6} alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _{3 -8} cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy , C _3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl are optionally selected from one or more halogen, Deuterium, hydroxyl, oxo, nitro, cyano are substituted.

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 membered, more preferably 5 or 6 membered. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,

etc.

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

Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano , C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy , C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 Alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano , C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy , C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 Alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, oxo, nitro, cyano. Similarly, the definitions of "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy", and "cycloalkenyloxy" are as defined above for "alkoxy".

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

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

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

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

"Monovalent group" means that a compound is "formally" eliminated from a monovalent atom or group. "Subunit" refers to a compound formed by "formally" eliminating two monovalent or one divalent atoms or atomic groups. Exemplary "alkyl" refers to the part remaining after removing 1 hydrogen atom from an alkane molecule, including linear and branched monovalent groups of 1 to 20 carbon atoms. "Alkylene (-CH ₂ -)" refers to the remaining part of an alkane molecule after removing 2 hydrogen atoms, including straight-chain and branched-chain subgroups of 1 to 20 carbon atoms. Alkylene groups containing 1 to 6 carbon atoms, non-limiting examples include methylene (-CH ₂ -), ethylene (such as -CH ₂ CH ₂ - or -CH(CH ₃ )-), ethylene Propyl (eg -CH ₂ CH ₂ CH ₂ - or -CH(CH ₂ CH ₃ )-), butylene (eg -CH ₂ CH ₂ CH ₂ CH ₂ -). The alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, Oxo _, nitro, cyano, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 Alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl Optionally substituted by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano.

Detailed ways

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

The experimental methods in the examples of the present disclosure that do not indicate specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the raw material or commodity manufacturers. Reagents without specific sources indicated are conventional reagents purchased in the market.

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is to use Bruker AVANCE-400 nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (Methanol-d ₄ ), internal standard is Tetramethylsilane (TMS).

The determination of HPLC uses Agilent1100 high pressure liquid chromatography, GAS15B DAD ultraviolet detector, WaterVbridge C18 150*4.6mm 5um chromatographic column.

MS was determined with Agilent6120 triple quadrupole mass spectrometer, G1315D DAD detector, Waters XbridgeC184.6*50mm, 5um chromatographic column, scanning in positive/negative ion mode, and the mass scanning range was 80-1200.

The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 silica gel plate, the specification of the thin-layer chromatography (TLC) silica gel plate is 0.2mm±0.03mm, and the specification of the thin-layer chromatography separation and purification product is 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 this disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Beide Pharmaceutical and other companies.

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

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

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

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

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

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

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

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

Example 1

Synthesis of compound 2

At 15°C, (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (62mg, 0.27mmol), N,N-diisopropylethyl Amine (143 mg, 1.10 mmol) and solvent N,N-dimethylformamide (3 mL). At 15°C, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (124mg, 0.327mmol) was continuously added. After stirring for 5 minutes, a solution of compound 1 (80 mg, 0.273 mmol) in N,N-dimethylformamide (0.5 mL) was added. React at 15°C for 5 hours, add water (20 mL), and extract with ethyl acetate (3×10 mL). Wash with saturated brine (15 mL×1), and dry over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 50% ethyl acetate/petroleum ether) to obtain compound 2 (90 mg). MS (ESI): m/z = 449.4 (M+H-56) ⁺ .

Synthesis of Example 1

At 15°C, compound 2 (80mg, 0.16mmol) and formic acid (1.5mL) were added into a 10ml three-neck flask. Stir at 30°C for 0.5 hours. After concentration, the residue was purified by C18 reverse phase column (30-80%, acetonitrile/water (0.1% ammonium bicarbonate) system) to obtain Example 1 (25 mg). MS (ESI): m/z = 405.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.66(d, J=8.0Hz, 2H), 7.57(s, 1H), 7.42-7.38(m, 4H), 4.99(t, J=8.0Hz ,1H),3.40(s,3H),3.22-3.06(m,4H),2.81-2.75(m,1H),2.71-2.63(m,1H),2.25-2.11(m,2H),1.71-1.48 (m,3H),1.16-1.04(m,1H).

biological evaluation

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

Test example 1 In vitro CatC enzyme activity detection experiment

1. Experimental materials

Control drug AZD7986

The specific synthesis method can be prepared with reference to the preparation method in CN105980367:

2. Experimental steps

AMC fluorescence assay was used to evaluate the inhibitory effect of compounds and positive controls on rhCatC enzyme activity in vitro. rhCatC can catalyze the reaction of substrate peptide H-Gly-Arg-AMC, and release AMC to generate fluorescence. The assay is carried out in a black-bottom 384-well plate, the initial maximum concentration is usually 30uM, and the enzyme activity test is performed by an 8.5 logarithmic dilution. 1) Preparation of test compound plate: the test compound and positive control AZD7986 were dissolved in 100% DMSO to prepare a compound stock solution with a final concentration of 10 mM. Compounds were diluted with DMSO to a 384-well Echo plate at a concentration 100X of the highest concentration at the beginning of the experiment. Pipette 0.2ul of the diluted compound to a black-bottomed 384-well reaction plate for use. Negative control wells were DMSO.

2) Activation of rhCatC: rhCatC and rhCatL were added to the activation buffer to make the final concentration of rhCatC 100ug/ml and the final concentration of rhCatL 20ug/ml, and incubate at room temperature for 1 hour. 3) Enzyme activity reaction: Dilute activated rhCatC to 0.4ug/ml with reaction buffer. Add to black bottom 384-well reaction plate, 10ul per well. 10ul of buffer was added to the blank control group. Incubate with compounds in the wells for 30 minutes at room temperature. Dilute H-Gly-Arg-AMC to 97uM with reaction buffer and add 10ul to each well. 4) Fluorescence detection: Envision measures the fluorescence intensity, Ex355 nM, Em460nM. 5) Inhibition rate and IC50 calculation: Inhibition rate: formula (1): Inh%=(Max-Signal)/(Max-Min)*100; IC50 value: formula (2): Y=Bottom+(Top-Bottom)/ (1+(IC50/X)*HillSlope), where Y is % inhibition and X is compound concentration.

RLU data and calculate the inhibition rate, and calculate the IC50 value according to the concentration and inhibition rate fitting curve, where the maximum value refers to the reading value of the DMSO control, and the minimum value refers to the reading value of the no enzyme activity control.

The embodiments of the present disclosure can be used to determine the inhibition of CatC enzyme activity in vitro by the above test, and the measured IC ₅₀ values are shown in Table 1.

Table 1

compound Bioactivity IC50(nM) Example 1 88 AZD7986 7.4

.

Claims (54)

1. The compound shown in formula I or its pharmaceutically acceptable salt

in A is a C _1-6 alkylene group, and the C _1-6 alkylene group is optionally replaced by one or more deuterium, C _1-6 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy; C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy are optional Replaced by 1-3 R _5a ; B is selected from 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C _6-10 aryl, the 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C _{6- 10} Aryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amido, oxo, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy or C _1-6 alkoxy; said C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy or C _1-6 alkoxy optionally substituted by 1-3 R _5b ; _R is independently selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy , C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy , C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy are optionally substituted by 1-3 R _5e ; n is an integer selected from 0-3; R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, and the C _6-10 aryl or 5-10 membered heteroaryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl, Cyano, nitro, C _1-6 alkyl, amino, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 Member heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 heterocycloalkoxy, cycloalkenyloxy or

Substituted, and/or the C _6-10 aryl or 5-10 membered heteroaryl is fused with a C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl to form a fused ring, the C _{1 -6} alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, cycloalkenyloxy or fused rings are optionally substituted by one or more R _5c ; _R is selected from deuterium, halogen, hydroxyl, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 Alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy; said C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 Alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 deuterium, halogen, cyano, nitro, C _3-6 cycloalkyl, C _1-6 alkane base replaced; Or R ₃ and R ₂ form 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl, described 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl is optionally replaced by one or more deuterium , C _1-6 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 alkenyloxy Base, C _2-6 alkynyloxy, C _3-6 cycloalkoxy substituted; Or R ₃ and R ₂ form 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl, described 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl and C _6-10 aryl or 5-10 membered heteroaryls are fused to form a fused ring, which is optionally substituted by 1-3 R _5d ; R _5d is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _{2 -6} alkynyloxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy , 6-10 membered aryl or 5-10 membered heteroaryl, methanesulfonyl,

The C _1-6 alkyl, C _1-6 alkoxy _{, C 2-6 alkenyloxy, C 2-6 alkynyloxy} , C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 heterocycloalkoxy, C _3-8 cycloalkenyloxy, 6-10 aryl or 5-10 heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, oxo, nitro, cyano; R _is independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl; R _5a is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 heterocycloalkoxy, C _3-8 cycloalkene Oxygen, 6-10 membered aryl, 5-10 membered heteroaryl or methylsulfonyl; R _5b is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 heterocycloalkoxy, C _3-8 cycloalkene Oxygen, 6-10 membered aryl or 5-10 membered heteroaryl, methylsulfonyl; R _5c is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 heterocycloalkoxy, C _3-8 cycloalkene Oxygen, 6-10 membered aryl or 5-10 membered heteroaryl, methylsulfonyl; R _is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 heterocycloalkoxy, C _3-8 cycloalkene Oxygen, 6-10 membered aryl or 5-10 membered heteroaryl, methylsulfonyl; *The configuration of the marked carbon atoms is S or R. 2. A compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein A is a C _1-6 alkylene group, and the C _1-6 alkylene group is optionally replaced by one or more deuterium, C _1-4 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy; C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy are optional Substituted by 1-3 R _5a . 3. A compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein A is a C _1-4 alkylene group, and the C _1-4 alkylene group is optionally replaced by one or more deuterium, C _1-4 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _3-6 cycloalkoxy; the C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy and C _3-6 cycloalkoxy are optionally substituted by 1-3 R _5a . 4. A compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein A is a C _1-4 alkylene group, and the C _1-4 alkylene group is optionally replaced by one or more deuterium, C _1-4 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, C _1-4 alkoxy, C _3-6 cycloalkoxy; said C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkane Oxygen, C _3-6 cycloalkoxy is optionally substituted by 1-3 R _5a . 5. A compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein A is a methylene group, and the methylene group is optionally replaced by one or more deuterium, C _1-4 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, C _1-4 alkoxy, C _3-6 cycloalkoxy; said C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _3-6 cycloalkoxy The group is optionally substituted by 1-3 R _5a . 6. A compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein A is a C _1-4 alkylene group, and the C _1-4 alkylene group is optionally replaced by one or more deuterium, methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl Base, halogen, hydroxyl, oxo, nitro, cyano, amino; the methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl are optionally 1-3 R _5a replace. 7. A compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein A is methylene, which is optionally replaced by one or more deuterium, methyl, ethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, halogen, hydroxyl, oxo, nitro Substituted by group, cyano group, amino group; said methyl group, ethyl group, cyclopropyl group, methyl cyclopropyl group, ethyl cyclopropyl group are optionally substituted by 1-3 R _5a . 8. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1-7, wherein B is selected from 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C _6-10 aryl, the 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C _{6- 10} Aryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amido, oxo, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy or C _1-6 alkoxy; said C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy or C _1-6 alkoxy Optionally substituted with 1-3 R _5b . 9. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1-7, wherein B is selected from 3-15 membered heterocycloalkyl groups, and the 3-15 membered heterocycloalkyl groups are optionally replaced by 1-3 members selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amido , oxo, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy or C _1-6 alkoxy; said C _1-6 alkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkoxy or C _1-6 alkoxy is optionally substituted by 1-3 R _5b . 10. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1-7, wherein B is selected from 3-15 membered heterocycloalkyl groups, and the 3-15 membered heterocycloalkyl groups are optionally replaced by 1-3 members selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _1-6 alkyl, C _3-6 cycloalkyl substituted; said C _1-6 alkyl, C _3-6 cycloalkyl is optionally substituted by 1-3 R _5b . 11. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1-7, wherein B is selected from a 3-15 membered heterocycloalkyl group containing 1-3 heteroatoms, and the 3-15 membered heterocycloalkyl group is optionally replaced by 1-3 members selected from deuterium, halogen, hydroxyl, cyano, nitro Base, amino, oxo, C _1-6 alkyl, C _3-6 cycloalkyl; said C _1-6 alkyl, C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b ; The heteroatoms are selected from nitrogen atoms or oxygen atoms. 12. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-7, wherein B is selected from a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms, and the 5-10 membered heterocycloalkyl group is optionally replaced by 1-3 members selected from deuterium, halogen, hydroxyl, cyano, nitrate Base, amino, oxo, C _1-6 alkyl, C _3-6 cycloalkyl; said C _1-6 alkyl, C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b ; The heteroatoms are selected from nitrogen atoms or oxygen atoms. 13. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-7, wherein B is selected from optionally substituted by 1-3 selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _1-6 alkyl, C _3-6 cycloalkyl

The C _1-6 alkyl and C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b . 14. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-7, wherein B is selected from optionally substituted by 1-3 selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _1-6 alkyl, C _3-6 cycloalkyl

The C _1-6 alkyl and C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b . 15. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1-7, wherein B is selected from optionally substituted by 1-3 selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _1-6 alkyl, C _3-6 cycloalkyl

The C _1-6 alkyl and C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b . 16. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1-7, wherein B is selected from optionally substituted by 1-3 selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _1-6 alkyl, C _3-6 cycloalkyl

The C _1-6 alkyl and C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b . 17. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-7, wherein B is selected from optionally substituted by 1-3 selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, oxo, C _1-6 alkyl, C _3-6 cycloalkyl

The C _1-6 alkyl and C _3-6 cycloalkyl are optionally substituted by 1-3 R _5b . 18. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-17, wherein R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, and the C _6-10 aryl or 5-10 membered heteroaryl is optionally replaced by 1-3 members selected from deuterium, halogen, hydroxyl, Cyano, nitro, C _1-6 alkyl, amino, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 Member heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 heterocycloalkoxy, cycloalkenyloxy or

Substituted, and/or the C _6-10 aryl or 5-10 membered heteroaryl is fused with a C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl to form a fused ring, the C _{1 -6} alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, cycloalkenyloxy or fused rings are optionally substituted by one or more R _5c ; R ₂ is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy; said C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 deuterium, halogen, cyano, nitro, C _3-6 cycloalkyl, C _{1 -6} alkyl substituted; R _is independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl. 19. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-17, wherein R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, and the C _6-10 aryl or 5-10 membered heteroaryl is optionally replaced by 1-3 members selected from deuterium, halogen, hydroxyl, Cyano, nitro, C _1-6 alkyl, amino, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy or

Substituted, and/or the C _6-10 aryl or 5-10 membered heteroaryl is fused with a C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl to form a fused ring, the C _{1 -6} alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 heterocycloalkoxy or condensed The closed ring is optionally substituted by one or more R _5c ; R ₂ is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _3-6 cycloalkoxy; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy are optionally replaced by 1-3 deuterium, Halogen, cyano, nitro, C _3-6 cycloalkyl, C _1-6 alkyl substituted; R _is independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl. 20. A compound or a pharmaceutically acceptable salt thereof as claimed in claim 18, wherein R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, and the C _6-10 aryl or 5-10 membered heteroaryl is optionally replaced by 1-3 members selected from deuterium, halogen, hydroxyl, Cyano, nitro, C _1-6 alkyl, amino, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy or

Substituted, the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 Heterocycloalkoxy is optionally substituted by one or more R _5c ; R _is independently selected from methyl, ethyl, cyclopropylmethyl, propyl, aryl, cyclopentyl, cyclohexyl. 21. The compound or pharmaceutically acceptable salt thereof as claimed in claim 18, wherein R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, the C _6-10 aryl or 5-10 membered heteroaryl and C _3-6 cycloalkyl or 3-6 membered heterocyclic The alkyl group is fused to form a fused ring optionally substituted with one or more R _5c . 22. A compound or a pharmaceutically acceptable salt thereof as claimed in claim 18, wherein R ₃ is selected from C _6-10 aryl or 5-10 membered heteroaryl, the C _6-10 aryl or 5-10 membered heteroaryl and C _3-6 cycloalkyl or 3-6 membered heterocyclic The alkyl group is fused to form a 6-10 membered fused ring, which is optionally substituted with one or more R _5c . 23. A compound or a pharmaceutically acceptable salt thereof as claimed in claim 18, wherein R ₃ is selected from C _6-10 aryl, said C _6-10 aryl is fused with a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms to form a fused ring of 6-10 members, said The 6-10 membered fused ring is optionally substituted by one or more R _5c ; the heteroatoms are independently selected from nitrogen atoms, oxygen atoms or sulfur atoms. 24. The compound or pharmaceutically acceptable salt thereof as claimed in claim 18, wherein R ₃ is selected from C _6-10 aryl, said C _6-10 aryl is fused with a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms to form a fused ring of _6-10 members, said _{The 6- to 10} -membered condensed ring is optionally substituted by one or more R _5c ; the heteroatoms are independently selected from nitrogen atoms and oxygen atoms. 25. A compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 , which is

Wherein A, B, R ₁ , n, R _5c , * are as defined in 1; R ₂ is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _3-6 cycloalkoxy; X ₁ and X ₂ are independently selected from nitrogen atom, oxygen atom and sulfur atom; preferably X ₁ and X ₂ are independently selected from nitrogen atom and oxygen atom; more preferably X ₁ is an oxygen atom and X ₂ is a nitrogen atom. 26. The compound of any one of claims 18-25, or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, the C _1-6 alkyl, C _3-6 ring Alkyl is optionally substituted by 1-3 deuterium, halogen, cyano, nitro, C _3-6 cycloalkyl, C _1-6 alkyl; Preferably _R is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino, said C _1-6 alkyl, C _3-6 Cycloalkyl is optionally substituted by 1-3 deuterium, halogen, cyano, nitro; More preferably R _is selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, amino. 27. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R ₃ and R ₂ form a 5-10 membered cycloalkyl group or a 5-10 membered heterocycloalkyl group, and the 5-10 membered cycloalkyl group or 5-10 membered heterocycloalkyl group is optionally replaced by 1-3 deuterium, C _1-6 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 alkenyl , C _2-6 alkynyloxy, C _3-6 cycloalkoxy substituted. 28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein R ₃ and R ₂ form a 5-8 membered cycloalkyl group or a 5-8 membered heterocycloalkyl group, and the 5-8 membered cycloalkyl group or 5-8 membered heterocycloalkyl group is optionally replaced by 1-3 deuterium, C _1-6 alkyl, halogen, hydroxyl, oxo, nitro, cyano, C _3-6 cycloalkyl, amino, amido, acyl, C _1-6 alkoxy, C _2-6 alkenyl , C _2-6 alkynyloxy, C _3-6 cycloalkoxy substituted. 29. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R ₃ and R ₂ form a 5-10 membered cycloalkyl group or a _5-10 membered heterocycloalkyl group. - 10 membered heteroaryl fused to form a fused ring optionally substituted with 1-3 R _5d . 30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

Wherein A, B, R ₁ , n, R _5d , * are as defined in 1; X ₃ and X ₄ are independently selected from nitrogen atom, oxygen atom, sulfur atom and carbon atom; preferably X ₃ and X ₄ are independently selected from nitrogen atom, oxygen atom and carbon atom; preferably X ₃ and X ₄ are independently selected from Oxygen atom, carbon atom; more preferably X ₃ is an oxygen atom, X ₄ is a carbon atom. 31. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1, 25, 30, wherein the configuration of the carbon atom marked with * in formula I, formula II, formula III is S. 32. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-13, wherein _R is independently selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _alkane base, C _3-6 cycloalkyl, amino, C _1-6 alkoxy; the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy are optionally replaced by 1-3 Each R _5e replaces; Preferably R ₁ is independently selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl,; said C _1-6 alkyl, C _{3- 6} cycloalkyl, C _1-6 alkoxy are optionally substituted by 1-3 R _5e . 33. The compound according to any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein R _{is independently} selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy Base, C _3-8 cycloalkenyloxy, methylsulfonyl. 34. The compound or pharmaceutically acceptable salt thereof as any one of claims 1-32, wherein R _5a is independently selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C _1-6 alkyl , C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl. 35. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-32, wherein R _5a is independently selected from halogen, deuterium, nitro, cyano, C _1-6 alkyl, C _{3- 6} cycloalkyl. 36. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein R _{is independently} selected from halogen, deuterium, nitro, cyano, methyl, ethyl, propyl, cyclo Propyl. 37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R _is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide _, C _1-6 alkyl, C _1-6 alkoxy, C 2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl. 38. The compound according to any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R _is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C _{1- 6} alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl. 39. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R _is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C _{1- 6} alkyl, C _3-6 cycloalkyl. 40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein R _{is independently} selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy group, methylsulfonyl group. 41. The compound or pharmaceutically acceptable salt thereof as any one of claims 1-39, wherein R _is independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C _{1- 6} alkyl, C _3-6 cycloalkyl, methylsulfonyl. 42. The compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein R _is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _{3- 6} cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, methylsulfonyl,

The C _1-6 alkyl, C _1-6 alkoxy _{, C 2-6 alkenyloxy, C 2-6 alkynyloxy} , C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy are optionally substituted by 1-3 selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano . 43. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-41, wherein _R is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkane group, C _1-6 alkoxy group, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkoxy group, 3 to 6 membered heterocycloalkoxy group, methylsulfonyl group,

The C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _3-6 cycloalkoxy, 3-6 heterocycloalkane Oxy group is optionally substituted with 1-3 selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano. 44. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-41, wherein _R is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkane Base, C _3-6 cycloalkyl, said C _1-6 alkyl, C _3-6 cycloalkyl are optionally substituted by 1-3 selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano. 45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein R _{is independently} selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy Base, C _3-8 cycloalkenyloxy, methylsulfonyl. 46. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-44, wherein R _is independently selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C _1-6 alkyl , C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl. 47. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-44, wherein R _is independently selected from halogen, deuterium, nitro, cyano, C _1-6 alkyl, C _{3- 6} cycloalkyl. 48. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein R _{is independently} selected from halogen, deuterium, nitro, cyano, methyl, ethyl, propyl, cyclo Propyl. 49. The structure of the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, selected from

50. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound of any one of claims 1-49 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 51. A method for preventing and/or treating patients with cathepsin C-related disorders, by administering to the patient a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-49, Or the pharmaceutical composition described in claim 50. 52. A method for preventing and/or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha-1 antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease or rheumatic A method for an arthritis patient, by administering a therapeutically effective amount of the compound of any one of claims 1-49 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 50 to said patient. 53. The compound of any one of claims 1-49 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 50 in the preparation of medicines for preventing and/or treating diseases related to cathepsin C use. 54. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-49, or the pharmaceutical composition described in claim 50 is used for preventing and/or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA Use in medicine for related vasculitis, psoriasis, type 1 antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease or rheumatoid arthritis.