CN115974824A

CN115974824A - Cathepsin C small-molecule inhibitor

Info

Publication number: CN115974824A
Application number: CN202211691997.0A
Authority: CN
Inventors: 郝欣; 杜鑫明; 龚书逸
Original assignee: Ruishi Biomedical Co ltd
Current assignee: Ruishi Biomedical Co ltd
Priority date: 2022-12-27
Filing date: 2022-12-27
Publication date: 2023-04-18
Anticipated expiration: 2042-12-27

Abstract

The disclosure relates to a structure of a cathepsin C small-molecule inhibitor and a preparation method thereof, belongs to the field of medicines, and particularly provides amide nitrile compounds shown as a formula I, wherein the amide nitrile compounds have a certain cathepsin C inhibition effect.

Description

Cathepsin C small-molecule inhibitor

Technical Field

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

Background

Cathepsins are a class of proteolytic enzymes that are widely present in a variety of tissue cell lysosomes, and are classified according to their structure and catalytic type into serine proteases (cathepsins a and G), aspartic proteases (cathepsins D and E), and cysteine protease 3 classes. Among them, cysteine proteases are the largest family of cathepsins, including 11 proteases, cathepsins B, C, F, H, K, L, O, S, W, V and Z.

Cathepsin C (cathepsin C) is also known as dipeptidyl peptidase i or "DPPI", DPP1 is constitutively expressed in many tissues, with highest levels in the lung, kidney, liver and spleen. Some recently published studies have begun to describe the role cathepsin C plays in certain inflammatory processes. For example: j Clin invest.2002Feb, adkison et al; 109 363-71; 160-170, archives of Biochemistry and Biophysics, 2002, published by Tinh et al; from these studies, cathepsin C is co-expressed with certain serine proteases in granules and serves to process the precursor forms of these proteases into active forms, which are then released from the granules of inflammatory cells recruited to the site of inflammation. Once activated, these proteases have a number of functions, including degradation of various extracellular matrix components, which together can spread tissue damage and chronic inflammation.

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

WO 2009/074829 relates to peptidyl nitriles 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 inhibitor.

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

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

However, the amide nitrile compounds of formula I of this disclosure are not disclosed in any literature.

Disclosure of Invention

The disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof

Wherein:

a is selected from heterocycloalkyl, cycloalkyl, heteroaryl, aryl, said heterocycloalkyl, cycloalkyl, heteroaryl, aryl being optionally substituted by one or more R ₁ The substitution is carried out by the following steps,

R ₁ substituted by deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, alkyl or alkoxy; said alkyl, alkoxy being optionally substituted by one or more R _3a Substituted;

b is selected from the group consisting of spiroalkyl, spiroheterocyclyl, said spiroalkyl, spiroheterocyclyl optionally substituted with one or more R ₂ Substitution;

R ₂ selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, alkoxy, alkyl, alkenyloxy, alkynyloxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, aryl, fused rings of 3-20 membered cycloalkyl and aryl, fused rings of 3-20 membered heterocycloalkyl and aryl, aromatic fused rings, heteroaryl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, cycloalkenyloxy rings being optionally substituted with one or more R _3b Substituted;

R _3a independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkylOxy radical, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or 3-to 6-membered heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or 3-to 6-membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;

R _3b independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or 3-to 6-membered heteroaryl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or 3-to 6-membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

In some embodiments, A in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 3-10 heteroaryl, C _6-8 Aryl, said 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 3-10 heteroaryl, C _6-8 Aryl is optionally substituted by one or more R ₁ The substitution is carried out by the following steps,

R ₁ selected from deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, alkyl or alkoxy; said alkyl, alkoxy being optionally substituted by one or more R _3a And (4) substituting.

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 3-10 heteroaryl, C _6-8 Aryl, said 3-15 membered cycloalkyl, 3-15-membered heterocycloalkyl, 3-10 heteroaryl, C _6-8 Aryl is optionally substituted by one or more R ₁ The substitution is carried out by the following steps,

In some embodiments, A in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl containing 1-3 heteroatoms, 3-10 heteroaryl containing 1-3 heteroatoms, C _6-8 Aryl, said 3-to 15-membered cycloalkyl, 3-to 15-membered heterocycloalkyl containing 1-3 heteroatoms, 3-to 10-membered heteroaryl containing 1-3 heteroatoms, C _6-8 Aryl is optionally substituted by one or more R ₁ The substitution is carried out by the following steps,

R ₁ selected from deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy substituted; said C is _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted by one or more R _3a And (4) substituting.

In some embodiments, A in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing 1-3 heteroatoms, 3-10 heteroaryl containing 1-3 heteroatoms, C _6-8 Aryl, said 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl containing 1-3 heteroatoms, 3-to 10-membered heteroaryl containing 1-3 heteroatoms, C _6-8 Aryl is optionally substituted with one or more R ₁ The substitution is carried out by the following steps,

In some embodiments, a in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing 1-3 heteroatoms, said 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing 1-3 heteroatoms, optionally substituted with 1-3R ₁ The substitution is carried out by the following steps,

R ₁ selected from deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy substituted; said C is _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted with 1-3R _3a And (4) substituting.

R ₁ selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy substituted; said C is _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted with 1-3R _3a And (4) substituting.

In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is selected from 6-membered cycloalkyl, 5-10 membered heterocycloalkyl containing 1-2 heteroatoms, said 6-membered cycloalkyl, 3-10 membered heterocycloalkyl containing 1-3 heteroatoms, optionally substituted with 1-3R ₁ The substitution is carried out by the following steps,

R ₁ selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy substituted; said C is _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted with 1-3R _3a And (4) substitution.

The heteroatoms in the present disclosure are selected from one or more of nitrogen atoms, oxygen atoms, sulfur atoms, the same or different atoms.

In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereofIn the salt, A is selected from the group consisting of optionally substituted 1-3R ₁ Substituted by

In some embodiments, the R in the compound of formula I or a pharmaceutically acceptable salt thereof ₁ Selected from deuterium, halogen, amino substitution.

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

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In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, B is selected from spiro cyclic groups, spiro heterocyclyl groups, optionally substituted with one or more R ₂ Substitution;

R ₂ selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, alkenyloxy, alkynyloxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, C _6-8 Aryl, 3-20 membered heterocycloalkyl and C _6-8 Condensed rings of aryl, 3-20 membered cycloalkyl and C _6-8 Condensed ring of aryl, aromatic condensed ring, 3-20 membered heteroaryl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy substituted, said C _1-6 Alkyl radical, C _1-6 Alkoxy, alkenyloxy, alkynyloxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, C _6-8 Aryl, 3-20 membered heterocycloalkyl and C _6-8 Fused rings of aryl, 3-20 membered cycloalkyl and C _6-8 Fused rings of aryl, aromatic fused rings, heteroaryl, cycloalkoxy, cycloalkenyloxy rings optionally substituted with one or more R _3b And (4) substituting.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, B is selected from the group consisting of a spiroalkyl group containing 5-20 carbon atoms, a 5-20 membered spiroheterocyclyl group containing 1-3 heteroatoms, said spiroalkyl group containing 5-20 carbon atoms, 5-20 membered spiroheterocyclyl group containing 1-3 heteroatoms optionally substituted with one or more R ₂ Substitution;

R ₂ selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, alkenyloxy, alkynyloxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, C _6-8 Aryl, 3-20 membered heterocycloalkyl and C _6-8 Fused rings of aryl, 3-20 membered cycloalkyl and C _6-8 Condensed ring of aryl, aromatic condensed ring, 3-20 membered heteroaryl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy substituted, said C _1-6 Alkyl radical, C _1-6 Alkoxy, alkenyloxy, alkynyloxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, C _6-8 Aryl, 3-20 membered heterocycloalkyl and C _6-8 Fused rings of aryl, 3-20 membered cycloalkyl and C _6-8 Fused rings of aryl, aromatic fused rings, heteroaryl, cycloalkoxy, cycloalkenyloxy rings optionally substituted with one or more R _3b And (4) substitution.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, B is selected from the group consisting of a spiroalkyl group containing 5 to 20 carbon atoms, a 5-20 membered spiroheterocyclyl group containing 1 to 3 heteroatoms, said spiroalkyl group containing 5 to 20 carbon atoms, 5-20 membered spiroheterocyclyl group containing 1 to 3 heteroatoms optionally substituted with 1 to 3R ₂ Substitution;

R ₂ selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, alkenyloxy, alkynyloxy, 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, C _6-8 Aryl, 3-15 membered heterocycloalkyl and C _6-8 Aryl radicalsFused ring of (A), 3-15 membered cycloalkyl and C _6-8 Condensed ring of aryl, aromatic condensed ring, 3-10 membered heteroaryl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy substituted, said C _1-6 Alkyl radical, C _1-6 Alkoxy, alkenyloxy, alkynyloxy, 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Condensed rings of aryl, 3-15 membered cycloalkyl and C _6-8 Fused rings of aryl, aromatic fused rings, 3-10 membered heteroaryl, cycloalkoxy, cycloalkenyloxy rings optionally substituted with 1-3R _3b And (4) substitution.

In some embodiments, B in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a spiroalkyl group containing 5-20 carbon atoms, a 5-20 membered spiroheterocyclyl group containing 1-3 heteroatoms, said spiroalkyl group containing 5-20 carbon atoms, 5-20 membered spiroheterocyclyl group containing 1-3 heteroatoms optionally substituted with 1-3R ₂ Substitution;

R ₂ selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Fused rings of aryl, 3-10 membered cycloalkyl and C _6-8 Condensed ring of aryl, aromatic condensed ring, 3-10 membered heteroaryl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy substituted, said C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Fused rings of aryl, 3-10 membered cycloalkyl and C _6-8 Fused rings of aryl, aromatic fused rings, 3-10 membered heteroaryl, cycloalkoxy, cycloalkenyloxy rings optionally substituted with 1-3R _3b And (4) substituting.

R ₂ selected from hydrogen, deuterium, halogen, hydroxy,Cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Condensed ring of aryl, 3-to 10-membered heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Fused ring aryl, 3-10 membered heteroaryl optionally substituted with 1-3R _3b And (4) substitution.

In some embodiments, B in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a spiroalkyl group containing 5 to 15 carbon atoms, a 5-15 membered spiroheterocyclyl group containing 1 to 3 heteroatoms, said spiroalkyl group containing 5 to 15 carbon atoms, 5-15 membered spiroheterocyclyl group containing 1 to 3 heteroatoms optionally substituted with 1 to 3R ₂ Substitution;

R ₂ selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Condensed ring of aryl, 3-to 10-membered heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Fused ring, 3-10 membered heteroaryl of aryl optionally substituted with 1-3R _3b And (4) substituting.

In some embodiments, B in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a spiroalkyl group containing 5-12 carbon atoms, a 5-12 membered spiroheterocyclyl group containing 1-3 heteroatoms, said spiroalkyl group containing 5-12 carbon atoms, 5-12 membered spiroheterocyclyl group containing 1-3 heteroatoms optionally substituted with 1-3R ₂ Substitution;

R ₂ selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Condensed rings of aryl radicals, substituted by 3-to 10-membered heteroaryl radicals, orC is _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Fused ring aryl, 3-10 membered heteroaryl optionally substituted with 1-3R _3b And (4) substituting.

In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, B is selected from the group consisting of a spiroalkyl group containing 5 to 12 carbon atoms, a 5-12 membered spiroheterocyclyl group containing 1 to 3 heteroatoms, said spiroalkyl group containing 5 to 12 carbon atoms, 5-12 membered spiroheterocyclyl group containing 1 to 3 heteroatoms, optionally substituted with 1 to 3R ₂ Substitution;

R ₂ selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Condensed ring of aryl, 3-to 10-membered heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Fused ring aryl, 3-10 membered heteroaryl optionally substituted with 1-3R _3b And (4) substituting.

R ₂ selected from hydrogen, deuterium, halogen, cyano, amino, nitro, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 3-6 membered heterocycloalkyl and C _6-8 Condensed ring of aryl, 3-6 membered heteroaryl substituted, said C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 3-6 membered heterocycloalkyl and C _6-8 Fused ring aryl, 3-6 membered heteroaryl optionally substituted with 1-3R _3b And (4) substitution.

In some embodiments, formula (II) isIn the compound shown as the formula I or the pharmaceutically acceptable salt thereof, B is selected from spiro alkyl containing 5-12 carbon atoms, 5-12-membered spiro heterocyclic group containing 1-3 heteroatoms, spiro alkyl containing 5-12 carbon atoms, 5-12-membered spiro heterocyclic group containing 1-3 heteroatoms are optionally substituted by 1-3R ₂ Substitution;

R ₂ selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, oxo, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopentyl, phenyl, pyridyl, oxazolyl, thiazolyl, benzotetrahydrooxazolyl, said methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopentyl, phenyl, pyridyl, oxazolyl, thiazolyl, benzotetrahydrooxazolyl being optionally substituted with 1-3R _3b And (4) substitution.

In some embodiments, B is selected from the group consisting of spiroalkyl containing 5 to 12 carbon atoms, said spiroalkyl containing 5 to 12 carbon atoms optionally substituted with 1 to 3R ₂ Substitution;

R ₂ selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, oxo, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopentyl, phenyl, pyridyl, oxazolyl, thiazolyl, benzotetrahydrooxazolyl, said methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopentyl, phenyl, pyridyl, oxazolyl, thiazolyl, benzotetrahydrooxazolyl being optionally substituted with 1-3R _3b And (4) substituting.

In some embodiments, B is selected from the group consisting of optionally substituted with 1-3R in a compound of formula I or a pharmaceutically acceptable salt thereof ₂ Substituted by

R ₂ Selected from hydrogen, deuterium, halogen, cyano, amino, nitro, oxo, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopentyl, phenyl, pyridyl, oxazolyl, thiazolyl, and benztetrahydrooxazolyl, said methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopentyl, phenyl, and said substituted phenyl,Pyridyl, oxazolyl, thiazolyl, benzotetrahydrooxazolyl, optionally substituted with 1-3R _3b And (4) substitution.

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

R ₂ selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, oxo, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopentyl, phenyl, pyridyl, oxazolyl, thiazolyl, benzotetrahydrooxazolyl, said methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopentyl, phenyl, pyridyl, oxazolyl, thiazolyl, benzotetrahydrooxazolyl being optionally substituted with 1-3R _3b Substituted;

a is as defined in claim 1;

x is one selected from a nitrogen atom, an oxygen atom, a sulfur atom, and a carbon atom, preferably a nitrogen atom or a carbon atom, and more preferably a carbon atom.

In some embodiments, R in the compound of formula II or a pharmaceutically acceptable salt thereof ₂ Selected from cyclopropyl, phenyl, pyridyl, oxazolyl, thiazolyl, benzotetrahydrooxazolyl, said phenyl, pyridyl, oxazolyl, thiazolyl, benzotetrahydrooxazolyl optionally substituted with 1-3R _3b And (4) substituting.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof _3a Independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, said C _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof _3a Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, methyl, methoxy, nitro, cyano, amino, acylA group, an amide.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof _3a Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, methyl, methoxy, nitro, cyano and amino.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof _3b Independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, said C _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof _3b Independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, said C _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof _3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, methyl, ethyl and cyclopropyl, wherein the methyl, ethyl and cyclopropyl are optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro and cyano.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof _3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, methyl, ethyl, cyclopropyl.

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

The present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound represented by formula I, formula II, formula III, formula IV, formula V, formula VI, or formula VII, or a pharmaceutically acceptable salt thereof, or a compound prepared by the above method, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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

In certain embodiments, the pharmaceutical composition comprises from 0.01 to 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 comprises 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

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

The present disclosure also provides a method of preventing and/or treating a patient having a disorder associated with cathepsin C by administering to the patient a therapeutically effective amount of a compound according to formula I or formula II or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing.

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

The present disclosure also provides a method of preventing and/or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, type a antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease or rheumatoid arthritis in a patient by administering to the patient a therapeutically effective amount of a compound according to formula I or formula II or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

The present disclosure also provides the use of a compound as described in formula I or formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention and/or treatment of a disorder associated with cathepsin C.

The disclosure also provides a use of the compound as shown in formula I or formula II or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the compound and the pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-related vasculitis, psoriasis, type A antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease or rheumatoid arthritis.

The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

The disclosed compounds may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present 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. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

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

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

Denotes an unspecified configuration, i.e. if a chiral isomer is present in the chemical structure, the bond->

Can be based on->

Or both>

Two configurations.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactam isomerizations. An example of a lactam-lactam equilibrium is between A and B as shown below.

All compounds of the present invention can be drawn as form a or form B. All tautomeric forms are within the scope of the invention. The nomenclature of the compounds does not exclude any tautomers.

The disclosure also includes some isotopically-labeled compounds of the present disclosure that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as respectively 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, and the like.

Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The compound of examples can have a natural abundance of deuterium greater than that of deuterium of at least 1000 times the abundance of deuterium, deuterium of at least 2000 times the abundance of deuterium, deuterium of at least 3000 times the abundance of deuterium, deuterium of at least 4000 times the abundance of deuterium, deuterium of at least 5000 times the abundance of deuterium, deuterium of at least 6000 times the abundance of deuterium, or deuterium of greater abundance. The disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like.

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

Interpretation of terms:

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

"pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. food and drug administration for use in humans or livestock animals.

The "effective amount" or "therapeutically effective amount" as referred to in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage 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 having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, and various branched isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

"alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. E.g. "C _2-6 Alkenyl "denotes alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

"alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups, or if the specified number of carbon atoms is specified, that particular number is intended. For example, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl groups. Alkynyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "cycloalkyl" or "carbocyclic ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "spiroalkyl" refers to an aliphatic hydrocarbon group containing a spiro ring structure, non-limiting examples of which include:

wherein a, b, d, a, p, q, r, s are independently selected integers from 1 to 10, non-limiting examples of which include:

the spiroalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "spiroheterocyclyl" refers to heterocyclyl groups containing a spiro ring structure in which all ring atoms other than the spiro atom may be heteroatoms, non-limiting examples of which include:

the spiroheterocyclyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms,preferably containing 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. Cycloalkenyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms wherein one or more ring atoms is selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer of 0 to 2) but does not include a cyclic moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:

/>

and so on.

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

and the like.

The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached 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 groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

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,

and so on.

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

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, 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 groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano. Similarly, "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy", "cycloalkenyloxy" are as defined above for "alkoxy".

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

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

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

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

"monovalent group" means a compound that "formally" eliminates a monovalent atom or group. "subunit" means a compound that "formally" eliminates two monovalent or one divalent formed atoms or groups of atoms. Examples "alkyl" refers to the moiety remaining after removal of 1 hydrogen atom from an alkane molecule, and includes straight and branched chain monovalent groups of 1 to 20 carbon atoms. "alkylene (-CH) ₂ - "then denotes the remaining part of the alkane molecule after removal of 2 hydrogen atoms, including straight and branched chain subgroups of 1 to 20 carbon atoms.Alkylene having 1 to 6 carbon atoms, non-limiting examples of which include methylene (-CH) ₂ -), ethylene (e.g. -CH ₂ CH ₂ -or-CH (CH) ₃ ) -), propylene (e.g. -CH ₂ CH ₂ CH ₂ -or-CH (CH) ₂ CH ₃ ) -) butylene (e.g., -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 groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

Similarly, "alkyleneoxy", "alkenylene", "alkyleneoxy", "cycloalkylene", "heterocycloalkylene" are as defined for "alkylene".

Detailed Description

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

Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and are conventional reagents purchased in the market.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured by Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated Methanol (Methanol-d) ₄ ) Internal standard is Tetramethylsilane (TMS).

The HPLC assay used an Agilent1100 high pressure liquid chromatograph, GAS15B DAD uv detector, water Vbridge C18 x 4.6mm 5um column.

MS was measured using an Agilent6120 triple quadrupole mass spectrometer, G1315D DAD detector, waters Xbridge C18.6 x 50mm,5um chromatography column, scanning in positive/negative ion mode with a mass scan range of 80-1200.

The silica gel plate for thin layer chromatography is HSGF254 silica gel plate from yellow sea of cigarette platform, and the specification for Thin Layer Chromatography (TLC) is 0.2mm + -0.03 mm, and the specification for thin layer chromatography separation and purification product is 0.4mm-0.5mm.

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

The forward column chromatography generally uses 200-300 mesh or 300-400 mesh silica gel of Taiwan yellow sea as carrier, or uses the ultra-pure forward phase silica gel column (40-63 μm,60g,24g,40g,120g or other specifications) pre-filled by Santai in Changzhou.

Known starting materials in this disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as Shanghai Tantan technology, ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shao Yuan Chemical technology (Accela ChemBio Inc), biddy medicine, and the like.

In the examples, the reactions were all carried out under a nitrogen atmosphere without specific indication.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The hydrogen is prepared by QPH-1L type hydrogen generator of Shanghai Quanpu scientific instruments company.

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

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC).

Example 1

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Synthesis of Compound 4

Compound 1 (49.7 g, 303mmol), ethanol (500 mL) and 3- (benzylamino) propan-1-ol (50g, 303mmol) were added sequentially to a 1000mL single-neck flask at room temperature. The reaction mixture was stirred at 40 ℃ overnight. Concentration under reduced pressure and purification of the residue by column chromatography gave compound 2 (52 g). MS (ESI) M/z =330.2 (M + H) ⁺ 。

Compound 2 (52g, 158mmol), N, N-diisopropylethylamine (30.6 g,237 mmol) and methylene chloride (1000 mL) were added to a 2500 mL three-necked flask in an ice bath and stirred until dissolved. Methanesulfonyl chloride (18.1g, 158mmol) was added dropwise. The reaction mixture was stirred at 0 ℃ for 30 minutes. The reaction mixture was poured into a saturated sodium bicarbonate solution, extracted with dichloromethane (500 mL. Times.3), washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave compound 3 (64 g). The crude product was carried on to the next step without purification. MS (ESI) M/z =408.2 (M + H) ⁺ 。

To a 2500 mL three-necked flask, compound 3 (32g, 78.6 mmol) and tetrahydrofuran (500 mL) were added under ice-bath, and stirred until dissolved. Sodium hydride (9.4g, 235.9mmol) was added in portions. The reaction solution was stirred at room temperature for 16 hours. Sodium sulfate decahydrate was added to the reaction mixture, followed by stirring and filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 4 (11 g). MS (ESI) M/z =312.1 (M + H-56) ⁺ 。

Synthesis of Compound 7

Compound 4 (28g, 90.0 mmol) and methanol (200 mL) were added to a 500mL single-necked flask at room temperature, and stirred until dissolved. 10% Palladium hydroxide on carbon (2.8 g) was added. The reaction system is replaced by hydrogen for 3 times and stirred at room temperature 4For 8 hours. Filtration and concentration of the filtrate under reduced pressure gave compound 5 (14 g). The crude product was used in the next step without purification. Compound 5 (14g, 38.17mmol) and methanol (200 mL) were added to a 500mL single-neck flask at room temperature, stirred to dissolve, and di-tert-butyl dicarbonate (27.9g, 128mmol) was added. The reaction solution was stirred at room temperature for 16 hours. The residue was purified by column chromatography to give compound 6 (17 g). MS (ESI) M/z =176.1 (M + H-56) ⁺ 。

In a 2500 mL single-neck flask, compound 6 (17g, 73.6 mmol) and acetone (1000 mL) were added under ice-cooling and stirred until dissolved. Sodium bromide (2.3 g, 22.1mmol), 2, 6-tetramethylpiperidine oxide (1.2 g, 7.36mmol) and saturated sodium bicarbonate solution (280 mL) were added. The reaction mixture was stirred for 30 minutes, and 1,3, 5-trichloro-1, 3, 5-triazinan-2, 4, 6-trione (37.6 g, 162mmol) was added thereto. The reaction solution was stirred at room temperature for 16 hours. Isopropanol (50 mL) was added to the reaction solution, and the mixture was stirred for 30 minutes. Filter and wash the filter cake with ethyl acetate. Concentrated under reduced pressure, and the residue was added with water, extracted with methylene chloride (500 mL. Times.2), washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave compound 7 (7.5 g). MS (ESI) M/z =190.1 (M + H-56) ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.71(s,1H),4.20–4.17(m,1H),3.96–3.79(m,2H),3.65–3.54(m,2H),3.48–3.42(m,1H),3.18–3.07(m,1H),1.71(s,2H),1.40(s,9H)。

Synthesis of Compound 9

Under cooling in an ice bath, methyl triphenyl phosphonium bromide (37g, 102.7 mmol) and tetrahydrofuran (100 mL) were added to a 500-mL three-necked flask, nitrogen gas was replaced three times, a solution of bis (trimethylsilyl) amino potassium in tetrahydrofuran (103mL, 103mmol) was slowly added, and the mixture was stirred at 0 ℃ for 1 hour. Compound 8 (10g, 68.5mmol) was dissolved in tetrahydrofuran (20 mL) and slowly added dropwise to the reaction solution. After stirring at 0 ℃ for 1 hour, the reaction mixture was poured into a saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (100 mL. Times.3), washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification by column chromatography gave compound 9 (4 g). ¹ H NMR(400MHz,CDCl3)δ7.33–7.17(m,5H),4.85 -4.82(m,2H),3.57-3.48(m,1H),3.14–3.06(m,2H),2.90–2.82(m,2H).

Synthesis of Compound 10

Compound 9 (60mg, 0.42mmol), zinc copper powder (90mg, 1.25mmol) and diethyl ether (2 mL) were added sequentially to a 25mL three-necked flask at room temperature. The reaction system was replaced with nitrogen 3 times. Simultaneously, to another 25mL single-neck flask, phosphorus oxychloride (0.05mL, 0.46mmol), trichloroacetyl chloride (0.1mL, 0.84mmol) and diethyl ether (2 mL) were added in this order, and the mixture was stirred at room temperature for 0.5 hour, and the reaction mixture was slowly added to the above reaction mixture by means of a syringe and stirred at 45 ℃ overnight. Filtration, concentration of the filtrate under reduced pressure and purification of the residue by column chromatography gave compound 10 (100 mg). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.36–7.34(m,1H),7.30–7.18(m,4H),3.78(s,2H),3.49–3.40(m,2H),2.98–2.92(m,1H),2.55–2.49(m,2H).

Synthesis of Compound 12

Compound 10 (400mg, 1.57mmol) was added to a 25-mL single-neck flask at room temperature, acetic acid (5 mL) was added thereto, the mixture was stirred until dissolved, and zinc powder (510mg, 7.8mmol) was added thereto. The nitrogen was replaced 3 times, and the reaction solution was refluxed overnight. The reaction mixture was slowly poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (20 mL. Times.3), washed with saturated brine (20 mL. Times.3), and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification of the residue by column chromatography gave compound 11 (210 mg). MS (ESI) M/z =187.2 (M + H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ7.36–7.13(m,5H),3.54–3.43(m,1H),3.24(q,J＝3.0Hz,2H),3.04(q,J＝3.1Hz,2H),2.58–2.51(m,2H),2.39–2.30(m,2H).

Compound 11 (200mg, 1.1mmol), carbethoxymethylenetriphenylphosphine (570mg, 1.6 mmol) and toluene (5 ml) were sequentially added to a 25-ml single-neck flask at room temperature, and the reaction mixture was stirred under reflux overnight, while substituting with nitrogen three times. The reaction mixture was poured into 20mL of water, extracted with dichloromethane (10 mL. Times.2), washed with saturated brine (10 m), and dried over anhydrous sodium sulfate. Concentration under reduced pressure, and purification of the residue by column chromatography gave compound 12 (150 mg).

¹ H NMR(400MHz,DMSO)δ7.32–7.14(m,5H),5.70–5.58(m,1H),4.09-4.02(m,2H),3.43-3.37(m,1H),3.22(d,J＝2.5Hz,1H),3.00(s,2H),2.78(s,1H),2.47–2.38(m,2H),2.21–2.11(m,2H),1.24–1.14(m,3H).

Synthesis of Compound 15

Compound 12 (150mg, 0.59mmol) was added to a 25mL single-neck flask at room temperature, methanol (5 mL) was added, stirred until dissolved, and 10% palladium on carbon (50 mg) was added. The reaction system was replaced with hydrogen 3 times and stirred at room temperature overnight. Filtration and concentration of the filtrate under reduced pressure gave compound 13 (170 mg).

Compound 13 (170mg, 0.65mmol), lithium hydroxide (47mg, 1.98mmoL), tetrahydrofuran (3 mL) and water (1 mL) were added sequentially to a 25mL single-necked flask at room temperature, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was poured into an aqueous ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL. Times.2), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate to give compound 14 (140 mg).

Compound 14 (140mg, 0.61mmol) and dichloromethane (3 mL) were added to a 25mL single-neck flask at room temperature and stirred until dissolved. O-benzotriazole-tetramethyluronium Hexafluorophosphate (HBTU) (350mg, 0.92mmol), diisopropylethylamine (157mg, 1.22mmol) and dimethylhydroxylamine hydrochloride (71mg, 0.73mmol) were added in this order, and the reaction solution was stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (20 mL. Times.3). The extract was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification of the residue by column chromatography gave compound 15 (80 mg). MS (ESI) M/z =274.3 (M + H) ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.30–7.25(m,2H),7.19–7.13(m,3H),3.68(s,3H),3.44–3.33(m,1H),3.16(s,3H),2.67–2.59(m,1H),2.53–2.46(m,2H),2.44–2.38(m,1H),2.33–2.27(m,1H),2.16–2.06(m,3H),1.87–1.82(m,1H),1.73–1.64(m,2H).

Synthesis of Compound 17

Compound 15 (1.2 g,4.4 mmol) was added to a 50mL three-necked flask at room temperature, and diethyl ether (20 mL) was added and stirred until dissolved. At 0 deg.C, a tetrahydrofuran solution of lithium aluminum hydride (4.8mL, 4.8mmol) was slowly added dropwise thereto, and the reaction mixture was stirred in ice bath for 1 hour. Sodium sulfate decahydrate was added slowly to the reaction solution, filtered, and the filter cake was washed with dichloromethane (25 mL. Times.3). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 16 (800 mg). ¹ HNMR(400MHz,CDCl ₃ )δ9.70(t,J＝1.9Hz,1H),7.30–7.26(m,2H),7.18–7.14(m,3H),3.46(d,J＝1.2Hz,1H),3.42–3.35(m,1H),2.65–2.61(m,1H),2.56–2.55(m,1H),2.48–2.39(m,2H),2.37–2.27(m,1H),2.19–2.02(m,3H),1.87–1.83(m,1H),1.73–1.67(m,1H).

Compound 16 (200mg, 0.93mmol) and methanol (5 mL) were added sequentially to a 25mL three-necked flask at 0 ℃ under nitrogen substitution three times, and 7M ammonia methanol solution (0.4 mL,2.8 mmol) was slowly added and stirred at room temperature for 0.5 hour. Trimethylsilyl cyanide (184mg, 1.86mmol) was added, and the reaction solution was stirred at 65 ℃ for 6 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added an aqueous ammonium chloride solution, followed by extraction with methylene chloride (10 mL. Times.3), washing with saturated brine (10 mL), and drying over anhydrous sodium sulfate. Concentration under reduced pressure, and purification of the residue by column chromatography gave compound 17 (100 mg). MS (ESI) M/z =241.2 (M + H) ⁺ 。

Synthesis of example 1

Compound 17 (100mg, 0.42mmol), (S) -4- (tert-butoxycarbonyl) -1, 4-oxaheptane-2-carboxylic acid (123mg, 0.5 mmol), and N, N-dimethylformamide (3 mL) were added in this order to a 50-mL single-neck flask at room temperature, and stirred until dissolved. benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate (240mg, 0.63mmol) and N, N-diisopropylethylamine (0.15mL, 0.84mmol) were added. The reaction solution was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate (20 mL. Times.3), washed with saturated brine (20 mL. Times.3), and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification of the residue by column chromatography gave compound 18 (70 mg). MS (ESI) M/z =412.2 (M + H-56) ⁺ 。

Compound 18 (70mg, 0.15mmol) and acetonitrile (3 mL) were added to a 25mL three-necked flask at 0 ℃ and stirred until dissolved. Sodium iodide (48mg, 0.45mmol) and trimethylsilyl chloride (67mg, 0.45mmol) were slowly added, and the reaction solution was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (10 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (water (0.03% trifluoroacetic acid)/acetonitrile (0.03% trifluoroacetic acid)) to afford example 1 (16 mg). ¹ H NMR(400MHz,DMSO)δ8.90–8.80(m,3H),7.29-7.26(m,2H),7.21–7.11(m,3H),4.67-4.64(m,1H),4.49–4.38(m,1H),4.04–3.90(m,1H),3.85–3.70(m,1H),3.62-3.58(m,1H),3.38–3.29(m,2H),3.23-3.19(m,2H),2.46–2.38(m,1H),2.31-2.16(m,3H),2.08-1.90(m,7H),1.86–1.75(m,1H),1.72–1.59(m,1H).MS(ESI)：m/z＝368.3(M+H) ⁺ 。

Example 2

Synthesis of example 2

Compound 19 (160mg, 0.67mmol), 4- ((tert-butoxycarbonyl) amino) tetrahydro-2H-pyran-4-carboxylic acid (327mg, 1.34mmol) and N, N-dimethylformamide (1 mL) and dichloromethane (5 mL) were added to a 50mL single-neck flask at room temperature and stirred until dissolved. benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate (380mg, 1.00mmol) and N, N-diisopropylethylamine (173mg, 1.34mmol) were added. The reaction solution was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated sodium hydrogencarbonate solution, extracted with ethyl acetate (20 mL. Times.3), washed with saturated brine (20 mL. Times.1), and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification of the residue by column chromatography gave compound 20 (70 mg). MS (ESI): m/z =412.3 (M + H-56) ⁺ 。

Compound 20 (60mg, 0.13mmol) and acetonitrile (3 mL) were added to a 25mL three-necked flask at zero degrees and stirred until dissolved. Sodium iodide (77mg, 0.51mmol) and trimethylsilyl chloride (55.4 mg, 0.51mmol) were added, and the reaction solution was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL. Times.3), washed with saturated brine (10 mL), and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography to give example 2 (8 mg). ¹ H NMR(400MHz,DMSO)δ7.29-7.25(m,2H),7.19-7.13(m,3H),4.65-4.60(m,1H),3.70–3.55(m,4H),3.39–3.35(m,1H),2.45-2.39(m,1H),2.33–2.17(m,3H),2.08–1.87(m,7H),1.84-1.78(m,1H),1.70-1.62(m,1H),1.30-1.27(m,2H).MS(ESI):m/z:368.5(M+H) ⁺ 。

Example 3

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Synthesis of Compound 23

Compound 21 (4.0 g,19.0 mmol), carbethoxymethylenetriphenylphosphine (10.0 g,28.4 mmol) and toluene (20 mL) were added in this order to a 100mL single-neck flask at room temperature, and stirred until dissolved. The reaction system was purged with nitrogen three times, and stirred at 110 ℃ for 12 hours. Concentrating under reduced pressure. The residue was purified by column chromatography to give compound 22 (4.8 g). MS (ESI) M/z =226.2 (M + H-56) ⁺ 。

Compound 2 (4.6 g,16.4 mmol) was added to a 25-mL single-neck flask at room temperature, ethanol (40 mL) was added thereto, the mixture was stirred until dissolved, and 10% palladium on carbon (1.30 g) was added to the reaction mixture. The reaction system was replaced with hydrogen three times, and the reaction solution was stirred at room temperature for 12 hours. The filtrate was concentrated under reduced pressure to give compound 23 (4.4 g). MS (ESI) M/z =228.4 (M + H-56) ⁺ 。

Synthesis of Compound 25

Compound 23 (4.4 g,15.5 mmol) was added to a 100mL three-necked flask at 0 ℃ and dichloromethane (30 mL) was added and stirred until dissolved. Trifluoroacetic acid (10 mL) was added to the reaction mixture. The reaction solution was stirred at 25 ℃ for 3 hours. Concentration under reduced pressure gave compound 24 (6.0 g) as a colorless oily liquid. The crude product was used in the next reaction without purification. MS (ESI) M/z =184.2 (M + H) ⁺ 。

To a 250 mL single-necked flask, compound 24 (4.0g, 13.5mmol), iodobenzene (8.8g, 43.5mmol) and toluene (100 mL) were added in this order at room temperature, and stirred until dissolved. To the reaction mixture were added tris (dibenzylideneacetone) dipalladium (2g, 2.2mmol) and 2-dicyclohexylphosphonium-2 ',6' -diisopropoxy-1, 1' -biphenyl (2g, 4.4 mmol). The reaction system was purged with nitrogen three times and stirred at 110 ℃ for 12 hours. The reaction solution was cooled to 25 ℃ and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 25 (2.5 g). MS (ESI) M/z =260.2 (M + H) ⁺ 。

Synthesis of Compound 29

To a 100mL single-neck flask, compound 25 (2.5g, 9.6 mmol) was added at room temperature, and tetrahydrofuran (30 mL) and water (10 mL) were added and stirred until dissolved. Lithium hydroxide (0.7g, 28.8mmol) was added to the reaction solution. The reaction mixture was stirred at 40 ℃ for 12 hours. Water (100 mL) was added to the reaction mixture, and lemon was addedThe acid was adjusted to pH =6, extracted with dichloromethane (100 mL × 2), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give compound 26 (2.2 g). MS (ESI) M/z =232.2 (M + H) ⁺ 。

To a 50mL single-neck flask were added compound 26 (2.1g, 9.1mmol), N, O-dimethylhydroxylamine hydrochloride (1.3g, 13.6 mmol) and dichloromethane (10 mL) in this order at room temperature, and stirred until dissolved. benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate (6.2g, 16.4mol) and N, N-diisopropylethylamine (5mL, 27.3mmol) were added to the reaction solution. Stirred at room temperature for 12 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (100 mL. Times.3). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure, and purification of the residue by column chromatography gave compound 27 (1.4 g). MS (ESI) M/z =275.2 (M + H) ⁺ 。

Compound 27 (500mg, 1.82mmol) was added to a 25mL three-necked flask at 0 ℃ and tetrahydrofuran (2 mL) was added and stirred until dissolved. A tetrahydrofuran solution of lithium aluminum hydride (2mL, 2mmol) was slowly added dropwise to the reaction mixture at 0 ℃. Stirred at 0 ℃ for 2 hours. Sodium sulfate decahydrate was added slowly to the reaction, the paste was filtered, and the filter cake was washed with dichloromethane (25 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 28 (150 mg). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.61(s,1H),7.14(t,J＝7.9Hz,2H),6.64(t,J＝7.3Hz,1H),6.38(d,J＝7.7Hz,2H),3.81(s,2H),3.68(s,2H),2.61–2.52(m,3H),2.37–2.32(m,2H),1.91–1.87(m,2H).MS(ESI):m/z＝216.2(M+H) ⁺ 。

Compound 28 (150mg, 0.70mmol) and methanol (10 mL) were added to a 25mL three-necked flask at 0 ℃. The reaction system was purged with nitrogen three times and 7M ammonia in methanol (0.3 mL, 2.1mmol) was added slowly. Stirred at room temperature for half an hour. Trimethylsilane (140mg, 1.40mmol) was added to the reaction mixture. Stirred at 70 ℃ for 6 hours. Concentrated under reduced pressure, and the residue was added with saturated aqueous sodium bicarbonate (10 mL), extracted with dichloromethane (20 mL. Times.3), washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification of the residue by column chromatography gave compound 29 (140 mg). MS (ESI) M/z =242.2 (M + H) ⁺ 。

Synthesis of example 3

Compound 29 (140mg, 0.58mmol), 4- ((((tert-butoxycarbonyl) amino)) tetrahydro-2H-pyran-4-carboxylic acid (170mg, 0.70mmol) and methylene chloride (5 mL) were added sequentially to a 50mL single-neck flask at room temperature and stirred to dissolve. benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate (330mg, 0.87mmol) and N, N-diisopropylethylamine (0.40mL, 2.32mmol) were added to the reaction solution. The reaction solution was stirred for 12 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (20 mL. Times.3), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure, and purification of the residue by column chromatography gave compound 30 (260 mg). MS (ESI) M/z =469.3 (M + H) ⁺ 。

Compound 30 (280mg, 0.6 mmol) and acetonitrile (5 mL) were added to a 25mL three-necked flask at room temperature and stirred until dissolved. To the reaction solution were added sodium iodide (270mg, 1.80mmol) and chlorotrimethylsilane (194mg, 1.80mmol) in that order. The reaction solution was stirred for 30 minutes. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (10 mL), which was extracted with dichloromethane (20 mL. Times.3), washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification by preparative liquid chromatography after dissolution of the crude product in acetonitrile gave example 3 (22 mg). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.15–7.11(m,2H),6.64(t,J＝7.3Hz,1H),6.38(d,J＝7.6Hz,2H),4.66-4.62(m,1H),3.80–3.77(m,2H),3.73–3.55(m,6H),2.37–2.16(m,3H),2.00–1.84(m,6H),1.27–1.24(m,2H).MS(ESI):m/z＝369.2(M+H) ⁺ 。

Example 4

Synthesis of example 4

To a 50ml single-necked flask, compound 31 (120mg, 0.50mmol), (S) -4- (tert-butoxycarbonyl) -1, 4-oxaheptane was added in this order at room temperature2-carboxylic acid (147mg, 0.6 mmol) and dichloromethane (4 mL) were stirred until dissolved. benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate (284mg, 0.75mmol) and N, N-diisopropylethylamine (258mg, 2mmol) were added to the reaction solution. The reaction solution was stirred for 12 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL. Times.3), washed with brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification of the residue by column chromatography gave compound 32 (70 mg). MS (ESI) M/z =469.3 (M + H) ⁺ 。

Compound 32 (70mg, 0.15mmol) was added to a 25mL single-neck flask at room temperature, and acetonitrile (5 mL) was added and stirred until dissolved. To the reaction solution were added chlorotrimethylsilane (50mg, 0.45mmol) and sodium iodide (70mg, 0.45mmol) in this order. The reaction solution was stirred for 30 minutes. A saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture, which was extracted with dichloromethane (20 mL. Times.3), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure and dissolution of the crude in acetonitrile followed by purification by preparative liquid chromatography gave example 4 (11 mg). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.03-8.92(m,3H),7.16–7.12(m,2H),6.66(t,J＝7.3Hz,1H),6.39(d,J＝7.8Hz,2H),4.72-4.66(m,1H),4.49–4.42(m,1H),3.98–3.92(m,1H),3.83–3.74(m,3H),3.70-3.66(m,2H),3.62–3.59(m,1H),3.34–3.32(m,1H),3.27–3.10(m,2H),2.37–2.18(m,3H),2.08–1.84(m,6H).MS(ESI):m/z＝369.2(M+H) ⁺ 。

Biological evaluation

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

Test example 1In vitro CatC enzyme Activity detection assay

1. Experimental Material

2. Experimental procedure

The inhibition of rhCatC enzyme activity in vitro by the compound and positive control was evaluated by AMC fluorescence assay. The rhCatC can catalyze the reaction of a substrate peptide fragment H-Gly-Arg-AMC and release AMC to generate fluorescence. The assay was performed in 384 well plates with black matrix, starting at a maximum concentration of typically 30uM, and enzyme activity was tested at 8 point semilogarithmic dilution. 1) Preparation of test compound plates: test compounds and positive control AZD7986 were dissolved in 100% DMSO to make up a stock solution of compound at a final concentration of 10 mM. Compounds were diluted with DMSO into 384-well Echo plates at 100X of the highest concentration at the start of the experiment. 0.2ul of the diluted compound was transferred to a 384-well black-bottomed plate and prepared for use. Negative control wells were DMSO. 2) Activating rhCatC: rhCatC and rhCatL were added to the activation buffer to give a final rhCatC concentration of 100ug/ml and a final rhCatL concentration of 20ug/ml, and incubated at room temperature for 1 hour. 3) Enzyme activity reaction: activated rhCatC was diluted to 0.4ug/ml with reaction buffer. Add black-bottom 384-well plates, 10ul per well. The blank control group was added with 10ul of buffer. Incubate with the compounds in the wells for 30 min at room temperature. The H-Gly-Arg-AMC was diluted to 97uM with reaction buffer and 10ul was added per well. 4) Fluorescence detection: envision measured the fluorescence intensity, ex355 nM, em460nM. 5) Inhibition and IC50 calculation: inhibition rate: formula (1) Inh% = (Max-Signal)/(Max-Min) × 100; IC50 value: formula (2) Y = Bottom + (Top-Bottom)/(1 + (IC 50/X) — HillSlope), where Y is% inhibition and X is compound concentration.

RLU data and calculated inhibition, and IC50 values were calculated from concentration and inhibition fitted curves, where the maximum is the reading of the DMSO control and the minimum is the reading of the no enzyme active control.

Inhibition of rhCatC enzyme Activity in vitro by the examples of the present disclosure the IC determined by the above assay ₅₀ The values are shown in Table 1.

TABLE 1

Compound (I)	Biological activity IC50 (nM)
		Example 1	2641
Example 2	72
		Example 3	86
Example 4	3634

。

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof

Wherein:

R ₁ substituted by deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amido, oxo, alkyl or alkoxy; said alkyl, alkoxy being optionally substituted by one or more R _3a Substituted;

b is selected from the group consisting of spiroalkyl, spiroheterocyclyl, said spiroalkyl, spiroheterocyclyl being optionally substituted with one or more R ₂ Substitution;

R ₂ selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, alkoxy, alkyl, alkenyloxy, alkynyloxy3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, aryl, fused rings of 3-20 membered cycloalkyl and aryl, fused rings of 3-20 membered heterocycloalkyl and aryl, aromatic fused rings, heteroaryl, cycloalkoxy, heterocycloalkoxy or cycloalkenoxy, said alkyl, alkoxy, alkenyloxy, alkynoxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, cycloalkenoxy rings optionally being substituted with one or more R _3b Substituted;

R _3a independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or 3-to 6-membered heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or 3-to 6-membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;

R _3b independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or 3-to 6-membered heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _2-6 Alkynyloxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or 3-to 6-membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

A is selected from the group consisting of 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 3-10 heteroaryl, C _6-8 Aryl, said 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 3-10 heteroaryl, C _6-8 Aryl is optionally substituted by one or more R ₁ The substitution is carried out by the following steps,

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

A is selected from the group consisting of 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 3-10 heteroaryl, C _6-8 Aryl, said 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 3-10 heteroaryl, C _6-8 Aryl is optionally substituted with one or more R ₁ The substitution is carried out by the following steps,

4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

A is selected from 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl containing 1-3 heteroatoms, 3-10 heteroaryl containing 1-3 heteroatoms, C _6-8 Aryl, said 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl containing 1-3 heteroatoms, 3-10 heteroaryl containing 1-3 heteroatoms, C _6-8 Aryl is optionally substituted with one or more R ₁ The substitution is carried out by the following steps,

R ₁ selected from deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy substituted; said C is _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted by one or more R _3a And (4) substitution.

5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing 1-3 heteroatoms, 3-10 heteroaryl containing 1-3 heteroatoms, C _6-8 Aryl, said 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl containing 1-3 heteroatoms, 3-to 10-membered heteroaryl containing 1-3 heteroatoms, C _6-8 Aryl is optionally substituted by one or more R ₁ The substitution is carried out by the following steps,

6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing 1-3 heteroatoms, said 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl containing 1-3 heteroatoms optionally substituted with 1-3R ₁ The substitution is carried out by the following steps,

R ₁ selected from deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amido, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy substituted; said C is _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted with 1-3R _3a And (4) substitution.

7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

9. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

A is selected from 6-membered cycloalkyl, 5-10 membered heterocycloalkyl containing 1-2 heteroatoms, said 6-membered cycloalkyl, 3-10 membered heterocycloalkyl containing 1-3 heteroatoms optionally substituted with 1-3R ₁ The substitution is carried out by the following steps,

10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the heteroatoms are selected from one or more of nitrogen atoms, oxygen atoms, sulphur atoms, which may be the same or different.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein a is selected from optionally substituted with 1-3R ₁ Substituted by

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R is ₁ Selected from deuterium, halogen, amino substitution.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein a is selected from

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein a is selected from

15. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

B is selected from spiro cyclic groups, spiro heterocyclic groups, optionally substituted with one or more R ₂ Substitution;

R ₂ selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, alkenyloxy, alkynyloxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, C _6-8 Aryl, 3-20 membered heterocycloalkyl and C _6-8 Condensed rings of aryl, 3-20 membered cycloalkyl and C _6-8 Condensed ring of aryl, aromatic condensed ring, 3-20 membered heteroaryl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy substituted, said C _1-6 Alkyl radical, C _1-6 Alkoxy, alkenyloxy, alkynyloxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, C _6-8 Aryl, 3-20 membered heterocycloalkyl and C _6-8 Condensed rings of aryl, 3-20 membered cycloalkyl and C _6-8 Fused rings of aryl, aromatic fused rings, heteroaryl, cycloalkoxy, cycloalkenyloxy rings optionally substituted with one or more R _3b And (4) substituting.

16. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

B is selected from the group consisting of a spiroalkyl group containing 5 to 20 carbon atoms, a 5-20 membered spiroheterocyclyl group containing 1 to 3 heteroatoms, said spiroalkyl group containing 5 to 20 carbon atoms, 5-20 membered spiroheterocyclyl group containing 1 to 3 heteroatoms optionally substituted with one or more R ₂ Substitution;

17. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

B is selected from the group consisting of a spiroalkyl group containing 5 to 20 carbon atoms, a 5-20 membered spiroheterocyclyl group containing 1 to 3 heteroatoms, said spiroalkyl group containing 5 to 20 carbon atoms, a 5-20 membered spiroheterocyclyl group containing 1 to 3 heteroatoms optionally substituted with 1 to 3R ₂ Substitution;

R ₂ selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, alkenyloxy, alkynyloxy, 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, C _6-8 Aryl, 3-15 membered heterocycloalkyl and C _6-8 Fused rings of aryl, 3-15 membered cycloalkyl and C _6-8 Fused rings of aryl, fused aromatic rings, 3-to 10-membered heteroaryl, cycloalkoxy, heterocycloalkoxyOr cycloalkenyloxy, said C _1-6 Alkyl radical, C _1-6 Alkoxy, alkenyloxy, alkynyloxy, 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Fused rings of aryl, 3-15 membered cycloalkyl and C _6-8 Fused rings of aryl, aromatic fused rings, 3-10 membered heteroaryl, cycloalkoxy, cycloalkenyloxy rings optionally substituted with 1-3R _3b And (4) substituting.

18. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

B is selected from the group consisting of a spiroalkyl group containing 5 to 20 carbon atoms, a 5-20 membered spiroheterocyclyl group containing 1 to 3 heteroatoms, said spiroalkyl group containing 5 to 20 carbon atoms, 5-20 membered spiroheterocyclyl group containing 1 to 3 heteroatoms optionally substituted with 1 to 3R ₂ Substitution;

R ₂ selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Condensed rings of aryl, 3-to 10-membered cycloalkyl and C _6-8 Condensed ring of aryl, aromatic condensed ring, 3-10 membered heteroaryl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy substituted, said C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Fused rings of aryl, 3-10 membered cycloalkyl and C _6-8 Fused rings of aryl, aromatic fused rings, 3-10 membered heteroaryl, cycloalkoxy, cycloalkenyloxy rings optionally substituted with 1-3R _3b And (4) substituting.

19. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

R ₂ selected from hydrogen, deuteriumHalogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Condensed rings of aryl, substituted with 3-to 10-membered heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Fused ring aryl, 3-10 membered heteroaryl optionally substituted with 1-3R _3b And (4) substituting.

20. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

B is selected from the group consisting of a spiroalkyl group containing 5 to 15 carbon atoms, a 5-15 membered spiroheterocyclyl group containing 1 to 3 heteroatoms, said spiroalkyl group containing 5 to 15 carbon atoms, 5-15 membered spiroheterocyclyl group containing 1 to 3 heteroatoms optionally substituted with 1 to 3R ₂ Substitution;

21. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

B is selected from the group consisting of a spiroalkyl group containing 5 to 12 carbon atoms, a 5-12 membered spiroheterocyclyl group containing 1 to 3 heteroatoms, said spiroalkyl group containing 5 to 12 carbon atoms, 5-12 membered spiroheterocyclyl group containing 1 to 3 heteroatoms optionally substituted with 1 to 3R ₂ Substitution;

R ₂ selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amido, oxo, C _1-6 Alkoxy radical、C _1-6 Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Condensed ring of aryl, 3-to 10-membered heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl and C _6-8 Fused ring aryl, 3-10 membered heteroaryl optionally substituted with 1-3R _3b And (4) substitution.

22. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

23. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

R ₂ selected from hydrogen, deuterium, halogen, cyano, amino, nitro, oxo, C _1-6 Alkoxy radical, C _1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 3-6 membered heterocycloalkyl and C _6-8 Aryl radicalsSubstituted by fused ring, 3-6 membered heteroaryl, said C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 3-6 membered heterocycloalkyl and C _6-8 Fused ring aryl, 3-6 membered heteroaryl optionally substituted with 1-3R _3b And (4) substituting.

24. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

25. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

B is selected from the group consisting of spiroalkyl containing 5 to 12 carbon atoms, said spiroalkyl containing 5 to 12 carbon atoms optionally substituted with 1 to 3R ₂ Substitution;

26. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, wherein

B is selected from optionally substituted 1-3R ₂ Substituted by

27. A compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, which is

R ₂ Selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, oxo, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopentyl, phenyl, pyridyl, oxazolyl, thiazolyl, benzotetrahydrooxazolyl, said methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopentyl, phenyl, pyridyl, oxazolyl, thiazolyl, benzotetrahydrooxazolyl being optionally substituted with 1-3R _3b Substituted; a is as defined in claim 1;

28. The compound of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R ₂ Is selected from cyclopropyl, phenyl, pyridyl, oxazolyl, thiazolyl, and benztetrahydrooxazolyl, said phenyl, pyridyl, oxazolyl, thiazolyl, benztetrahydrooxazolyl being optionally substituted with 1-3R _3b And (4) substitution.

29. The compound of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein

R _3a Independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, said C _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

30. The compound of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein

R _3a Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, methyl, methoxy, nitro, cyano, amino, acyl, amide.

31. The compound of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein

R _3a Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, methyl, methoxy, nitro, cyano and amino.

32. A compound according to claims 1-28, or a pharmaceutically acceptable salt thereof, wherein

R _3b Independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, said C _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

33. The compound of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein

R _3b Independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, said C _1-6 Alkyl radical, C _1-6 Alkoxy is optionally substituted by one or moreSelected from halogen, deuterium, hydroxyl, oxo, nitro and cyano.

34. The compound of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein

R _3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, methyl, ethyl and cyclopropyl, wherein the methyl, ethyl and cyclopropyl are optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro and cyano.

35. The compound of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein

R _3b Independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, methyl, ethyl, cyclopropyl.

36. A compound structure as claimed in claim 1 selected from the group consisting of

37. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

38. A method of preventing and/or treating a patient having a cathepsin C-related disorder by administering to the patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1-36, or a pharmaceutical composition of claim 37.

39. A method of prophylactic and/or therapeutic treatment of a patient suffering from asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, type a antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease or rheumatoid arthritis by administering to said patient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 37.

40. Use of a compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 37, in the manufacture of a medicament for the prevention and/or treatment of a cathepsin C-related disorder.

41. Use of a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 37, in the manufacture of a medicament for the prevention and/or prophylaxis of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, type a antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease or rheumatoid arthritis.