CN116462672A

CN116462672A - Novel peptide-based nitrile compound and application thereof

Info

Publication number: CN116462672A
Application number: CN202210028063.2A
Authority: CN
Inventors: 叶斌; 郑鸣芳; 颜桃
Original assignee: Shanghai Yidian Medical Science And Technology Development Co ltd
Current assignee: Shanghai Yidian Medical Science And Technology Development Co ltd
Priority date: 2022-01-11
Filing date: 2022-01-11
Publication date: 2023-07-21

Abstract

The invention discloses a novel peptide nitrile compound and application thereof, in particular to a compound shown in a formula (I) and/or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and/or pharmaceutically acceptable salt thereof, a method for preparing the compound and application of the compound in treating diseases caused by cathepsin C and downstream serine protease thereof.

Description

Novel peptide-based nitrile compound and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a novel peptide nitrile compound and application thereof.

Background

Inflammatory diseases are an important field of drug development at present, and although interleukin antibody drugs are clinically applied and small molecule drugs such as JAK inhibitors and the like are clinically applied, the antibody drugs have defects of different degrees, such as only injection administration of the antibody drugs, low clinical compliance and JAK inhibitors are used for inflammatory diseases, and potential cardiovascular adverse reactions exist in a target mechanism (Norman P, expert Opinion on Investigational drugs.2014,23 (8): 1067-77), so that the research of novel anti-inflammatory drugs is also very necessary.

Cathepsin C (CTSC), also known as dipeptidyl peptidase I (DPP-1), is a lysosomal cysteine protease belonging to the papain family having a molecular weight of 200 KDa. Cathepsin C serves as a key enzyme for activating neutrophil and mast cell granule serine peptidases (e.g., four neutrophil proteases, elastase (NE), cathepsin G (CatG), proteinase 3 (PR 3) and neutrophil serine protease (NSP 4), and mast cell related chymase, tryptase and serine protease, etc.) in inflammatory cells (Guay, d.et al, curr.top.med.chem.2010,10,708-716;Korkmaz,B.et al,Pharmacol.Ther.2018,190,202-236). These proteases, once activated by cathepsin C, are capable of degrading various extracellular matrix components, which leads to tissue damage and chronic inflammation. Accordingly, inhibitors of cathepsin C are useful as potential therapeutic agents for the treatment of neutrophil-dominated inflammatory diseases, including Chronic Obstructive Pulmonary Disease (COPD), emphysema, asthma, multiple sclerosis, idiopathic pneumonia, cystic fibrosis, etc. (Laine et al, expert opin. Ter. Patents 2010,20,497).

Other immune disorders such as inflammatory bowel disease, rheumatoid arthritis, anti-neutrophil cytoplasmic antibody associated necrotizing crescentic glomerulonephritis, ANCA-mediated vasculitis, as well as more severe systemic inflammatory disorders such as sepsis, acute lung injury (acute respiratory distress syndrome), acute pancreatitis, etc., a significant portion of the pathogenesis of which is caused by increased activity of some of these inflammatory proteases, and therefore cathepsin C inhibitors are also potential drugs for the treatment of these disorders. In addition, the serine protease elastase downstream of cathepsin plays a very important role in the occurrence and metastasis of cancers and cardiovascular and cerebrovascular diseases such as myocardial infarction, so that theoretically inhibiting cathepsin also has the same pharmacological effect of inhibiting elastase, and thus theoretically cathepsin inhibitors can also be used for the treatment of cancerous diseases and cardiovascular and cerebrovascular diseases. (Pharmacol Ther.2018 Oct;190:202-236;Int J Mol Sci.2021 Jan 13;22 (2): 722.).

Cathepsin C has been found to date for over 70 years, but clinical drugs for cathepsin C inhibitors are still very limited (Korkmaz b.et al, J.Med.Chem.,2020,63,13258;Shen,XB et al,E.J.Med.Chem, 2021,225-113818). The U.S. food and drug administration did not qualify for the break-through drug of the cathepsin C inhibitor brenocatib, which was just completed in phase II clinical trials, until month 6 in 2020 for the treatment of adult non-cystic fibrosis bronchiectasis (NCFBE) (Doyle k.et al, j.med.chem.,2016,59,9457). There remains a great unmet need for cathepsin C inhibitors. The existing compounds have difficulty inhibiting the activities of cathepsin C and downstream serine proteases, and thus there is a need to provide novel peptide-based nitriles and uses thereof.

Disclosure of Invention

It is an object of the present invention to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof,

and/or pharmaceutically acceptable salts thereof or prodrugs thereof, and/or solvates, hydrates, metabolites, nitrogen oxides, racemic mixtures, enantiomers, diastereomers and tautomers thereof or mixtures thereof in any ratio, comprise racemic mixtures, wherein:

Cy is

p is 0-6;

w is selected from CH ₂ -CH ₂ -O-、-O-、-S-、-SO ₂ -、-CH ₂ -、-OCH ₂ -、-CH ₂ O-、-CH ₂ S-、-SCH ₂ -、-CH ₂ SO ₂ -、-SO ₂ CH ₂ -、-CH ₂ -CH ₂ -、-(CH ₂ ) ₃ -、-CH ₂ -CH ₂ -S-、-CH ₂ -CH ₂ -SO ₂ -、-CH ₂ -O-CH ₂ -、-CH ₂ -S-CH ₂ -、-CH ₂ -SO ₂ -CH ₂ -；

R ^a Each independently selected from deuterium, halogen, hydroxy, cyano, mercapto, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 Heterocycloalkyl, C _3-6 Cycloalkyloxy, heterocycloalkoxy, -SC _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, (C) _1-6 Alkyl group ₂ N-、C _1-6 alkyl-C (O) HN-, -C (O) NHC _1-6 Alkyl, oxo, thio, and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy groups are each optionally substituted with halogen and deuterium; two R ^a Can be connected with the same carbon atom or can be connected with different carbon atoms; r is R ^a Or two R ^a Together form C _1-4 Alkylene or ether chains containing 1 to 4 carbon atoms, e.g. -CH ₂ -O-CH ₂ -CH ₂ -CH ₂ -、-CH ₂ -O-CH ₂ -, the alkylene or ether chain may form with the original ring a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged, fused and spiro ring, with or without heteroatoms, including N, S, O, which cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged, fused and spiro rings may be optionally substituted with deuterium, hydroxy, halogen, alkyl and alkoxy, and wherein C, S may be optionally oxo-c=o, -s=o, -S (O) 2-; or two R ^a The carbon atoms to which each is attached constitute a 6 membered aryl, 5 membered heteroaryl, 6 membered heteroaryl, and forms a fused ring with the original ring, said fused ring being optionally substituted with hydroxy, halogen, cyano, alkyl, alkoxy; and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy groups are each optionally substituted with halogen and deuterium;

A and B are each independently selected from hydrogen, deuterium, fluorine, or a and B form cyclopropane with the carbon atom to which they are attached;

x, Y, Z are each independently selected from CH, N, S, O, or X, Y, Z wherein 1 is a bond in a ring, i.e. X, Y or an atom on either side of Z is directly attached, the attached bond may be a single bond or a double bond;

R ² selected from hydrogen, deuterium, halogen, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 A cycloalkoxy group, said alkyl, alkoxy, cycloalkyl and cycloalkoxy groups each optionally substituted with halogen and deuterium;

q is 0-3;

when in the following four cases (the four cases are and/or are related)

1) Cy is not

2) X, Y, Z are not simultaneously CH;

3)R ² is not hydrogen and q is not 0;

4) A and B are not hydrogen at the same time;

R ¹ selected from cyclic groups, in particular aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl; the cyclic group may be monocyclic or bicyclic, optionally containing one or more heteroatoms of N, O, S, se, and C, S of the ring may be optionally oxo or thiosubstituted with-CO-, -CS-, -CO-SO-, -SO2-; the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl groups can be substituted with one or more R ^1a Optionally substituted;

R ^1a Can be selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxyOptionally substituted with one or more R ₃ Substitution; two R ^1a Can be connected with the same carbon atom or nitrogen atom or can be connected with different carbon atoms or nitrogen atoms; two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aromatic, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, C, S in the ring may also be optionally oxo or thioxo-CO-, -CS-, -SO2-;

R ³ 、R ⁴ each independently selected from hydrogen, deuterium, halogen, cyano, halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, alkylcarbonyl, alkylsulfonyl, alkylcarbc (O) NH-, alkyl S (O) 2NH-, carboxyl, alkylcarbonyl; wherein amino, hydroxy, carboxyl, alkyl, cycloalkyl, cycloalkoxy, heterocycloalkoxy, heterocycloalkyl may be further substituted with alkyl, halogen, cyano, hydroxy, hydroxyalkyl, alkoxy; two R ³ May be attached to the same atom or to different atoms; or two R ³ Or R is ³ And R is ⁴ Optionally forming a 3-10 membered cycloalkyl, heterocycloalkyl, spiro, bridged, fused ring with the carbon or nitrogen atom to which each is commonly attached, including but not limited to oxetane, azetidine, morpholino, piperidino, piperazino, azetidine, furano, pyrrolidine, wherein C and S in the cycloalkyl, heterocycloalkyl, spiro, bridged, fused ring may be optionally oxo-CO-, -SO2-, and may be substituted with one or more halogens, C _1-3 Alkyl, halogenated C _1-3 Alkyl, C _1-3 Alkoxy, C _3-8 Optionally substituted with heterocyclyl;

when Cy isAnd X, Y, Z are CH and R ² Is hydrogen, and A/B are bothAnd H:

R ¹ selected from the group consisting of pyrimidine, pyrazine, pyridazine, pyrazole, furan, imidazole, thiazole, oxazole, isoxazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein pyrimidine, pyrazine, pyridazine, triazinyl, pyrazole, furan, imidazole, thiazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl can be substituted with one or more R ^1a Substitution (R) ^1a Definition as described above), or wherein S or 1-2 carbon atoms may be optionally oxo;

and/or R ¹ Selected from:

f is 0-2;

g is 0-3;

h is 0-5;

k is 0-2;

R ^1a r in the same ring as defined above ^1a The same substituent groups can be selected at the same time, and different substituent groups can also be selected; two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aromatic, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

R ³ and R is ⁴ Unless specifically stated otherwise, as defined above;

when f and g are not 0 and R ^1a When not hydrogen, R ^1b ＝H、R ^1a ；R ^1b And R is R ^1a Or two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aromatic ringA radical, heteroaryl, and a cyclic radical may be substituted by one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

when f and g are 0, or f and g are other than 0 and R ^1a When hydrogen, R ^1b Can be selected from hydrogen, deuterium, halogen, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocycloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ₃ Substitution; r is R ^1b And R is R ^1a Or two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

when k is not 0 and R ^1a When not hydrogen, R ^5a 、R ⁵ And R is ⁶ ＝R ^1a Or R is ^5a 、R ⁵ 、R ⁶ 1-2R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

when k is 0, or k is other than 0 and R ^1a When hydrogen:

if R is ^5a Deuterium, bromine, cyano, hydroxy, amino, mercapto, carboxyl, sulfonyl, sulfoxide, oxo, thio, nitro, cyano, C _2-8 Alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ³ Substitution;

then R is ⁵ And R is ⁶ ＝R ^1a Or R ⁵ 、R ⁶ 、R ^5a And 1 to 2R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

if R is ^5a Is chlorine, fluorine or CH ₃ When then R ⁵ 、R ⁶ ＝R ^1a ；

If R is ^5a Is H, then R ^6＝ R ^1a ，R ⁵ Can be selected from deuterium, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, cyano, alkyl, 1-2 fluoro substituted alkyl, 1-3 bromo substituted alkyl, 1-3 chloro substituted alkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ (wherein R is ³ And R is ⁴ Not simultaneously H), alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ³ 、-S(O)2C _4-8 Alkyl, -OS (O) 2C _4-8 Cycloalkyl, -OS (O) 2C _4-8 Heterocyclylalkyl, -S (O) (NH) R ³ 、-S(O)(NR ⁴ )R ³ 、S(O)2NR ³ R ⁴ (wherein R is ³ And R is ⁴ Can form, with the attached N atom, a heteroalkenyl group, a piperazinyl group, a 5-7 membered azaalkyl group containing at least 1O atom, a morpholinyl group, a bridged ring morpholinyl group, or R ³ And R is ⁴ Independently substituted with non-cyclic groups), -S (O) 2NH ₂ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ³ Substitution;

or R is ^5a Is H, chlorine, fluorine, CH ₃ When R is ¹ Selected from the group consisting of

Wherein the method comprises the steps of

V is selected from-O-, -S-, -Se-, -CH ₂ -、-CF ₂ -、-CO-、-SO-、-SO2-、-N(R ⁷ )-、-C(R ⁸ R ⁹ ) -O-CH (alkyl) -, -O-CH (cycloalkyl) -, -S-CH (cycloalkyl) -, -ch=c (alkyl) -, -n=c (alkyl) -, -ch=c (cycloalkyl) -, -n=c (cycloalkyl) -;

u is selected from-O-, -S-, -Se-, -CO-, -SO-, -S (O) 2, -NR ⁷ -、-CR ⁸ R ⁹ -；

When V is-O-, -S-, -CF ₂ When-and U is-CO-, T is-O-, -S-, -Se-, -CO, -SO-, -S (O) 2, -CR ⁸ R ⁹ -，-NH-、-N(CHF)-、-N(CF ₂ )-、-N(CH ₂ -CH(OH)-CH ₃ )-、-N(CH ₂ -CH(OCH ₃ )-CH ₃ )-、-N(CH ₂ -CH ₂ -OCH ₃ )-、-N(C _4-8 Alkyl) -, -N (cycloalkyl) -, -N (cycloalkoxy) -, -N (oxetane) -, -N (tetrahydrofuran) -, -N (tetrahydropyran) -, wherein the is-N (C) _4-8 Alkyl) -, -N (cycloalkyl) -, -N (cycloalkoxy) -, -N (oxetane) -, -N (tetrahydrofuran) -, -N (tetrahydropyran) is optionally C _1-3 Alkoxy, C _1-3 Alkyl, C _3-6 Cycloalkyl, NH (C) _1-3 Alkyl), N (C) _1-3 Alkyl group) ₂ Or 1 to 3 halogen substitutions; otherwise T is-O-, -S-, -Se-; -CO-, -SO2-, -C (R) ⁸ R ⁹ )-、-N(R ⁷ )-；

X ₁ 、Y ₁ 、Z ₁ May be independently selected from CH and N;

R ⁷ ＝R ^1a ；

R ⁸ 、R ⁹ ＝R ^1a or R ⁸ 、R ⁹ Can optionally form a saturated or unsaturated cyclic group with the atom to which they are originally attached, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group can be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-; and/or pharmaceutically acceptable salts thereof or prodrugs thereof, and/or solvates, hydrates, metabolites, nitrogen oxides, racemic mixtures, enantiomers, diastereomers and tautomers thereof or mixtures thereof in any ratio, comprise racemic mixtures, wherein:

Cy is

p is 0-6;

R ² selected from hydrogen, deuterium, halogen, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy groups, said alkyl, alkoxy, cycloalkyl and cycloalkoxy groups being all possibleOptionally substituted with halogen and deuterium;

q is 0-3;

when in the following four cases (the four cases are and/or are related)

1) Cy is not

2) X, Y, Z are not simultaneously CH;

3)R ² is not hydrogen and q is not 0;

4) A and B are not hydrogen at the same time;

R ^1a Can be selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ₃ Substitution; two R ^1a Can be connected with the same carbon atom or nitrogen atom or can be connected with different carbon atoms or nitrogen atoms; two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aromatic, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, C, S in the ring may also be optionally oxo or thioxo-CO-, -CS-, -SO2-;

when Cy isAnd X, Y, Z are CH and R ² When hydrogen is used and both A/B are H:

and/or R ¹ Selected from:

f is 0-2;

g is 0-3;

h is 0-5;

k is 0-2;

R ³ and R is ⁴ Unless specifically stated otherwise, as defined above;

when f and g are not 0 and R ^1a When not hydrogen, R ^1b ＝H、R ^1a ；R ^1b And R is R ^1a Or twoR ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

when f and g are 0, or f and g are other than 0 and R ^1a When hydrogen, R ^1b Can be selected from hydrogen, deuterium, halogen, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocycloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ₃ Substitution; r is R ^1b And R is R ^1a Or two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenylBridged, spiro, fused, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

when k is 0, or k is other than 0 and R ^1a When hydrogen:

if R is ^5a Deuterium, bromine, cyano, hydroxy, amino, mercapto, carboxyl, sulfonyl, sulfoxide, oxo, thio, nitro, cyano, C _2-8 Alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl,Heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy optionally substituted with one or more R ³ Substitution;

If R is ^5a Is H, then R ^6＝ R ^1a ，R ⁵ Can be selected from deuterium, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, cyano, alkyl, 1-2 fluoro substituted alkyl, 1-3 bromo substituted alkyl, 1-3 chloro substituted alkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ (wherein R is ³ And R is ⁴ Not simultaneously H), alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ³ 、-S(O)2C _4-8 Alkyl, -OS (O) 2C _4-8 Cycloalkyl, -OS (O) 2C _4-8 Heterocyclylalkyl, -S (O) (NH) R ³ 、-S(O)(NR ⁴ )R ³ 、S(O)2NR ³ R ⁴ (wherein R is ³ And R is ⁴ Can form with the attached N atomHeteroalkenyl, piperazinyl, 5-to 7-membered azaalkyl containing at least 1O atom, morpholinyl, endocyclic morpholinyl, or R ³ And R is ⁴ Independently substituted with non-cyclic groups), -S (O) 2NH ₂ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ³ Substitution;

Wherein the method comprises the steps of

When V is-O-, -S-, -CF ₂ When-and U is-CO-, T is-O-, -S-, -Se-, -CO, -SO-, -S (O) 2, -CR ⁸ R ⁹ -，-NH-、-N(CHF)-、-N(CF ₂ )-、-N(CH ₂ -CH(OH)-CH ₃ )-、-N(CH ₂ -CH(OCH ₃ )-CH ₃ )-、-N(CH ₂ -CH ₂ -OCH ₃ )-、-N(C _4-8 Alkyl) -, -N (cycloalkyl) -, -N (cycloalkoxy) -, -N (oxetane) -, -N (tetrahydrofuran) -, -N (tetrahydropyran) -, wherein the is-N (C) _4-8 Alkyl) -, N ]Cycloalkyl) -, -N (cycloalkoxy) -, -N (oxetane) -, -N (tetrahydrofuran) -, -N (tetrahydropyran) is optionally substituted by C _1-3 Alkoxy, C _1-3 Alkyl, C _3-6 Cycloalkyl, NH (C) _1-3 Alkyl), N (C) _1-3 Alkyl group ₂ Or 1 to 3 halogen substitutions; otherwise T is-O-, -S-, -Se-; -CO-, -SO2-, -C (R) ⁸ R ⁹ )-、-N(R ⁷ )-；

X ₁ 、Y ₁ 、Z ₁ May be independently selected from CH and N;

R ⁷ ＝R ^1a ；

R ⁸ 、R ⁹ ＝R ^1a or R ⁸ 、R ⁹ Can optionally form a saturated or unsaturated cyclic group with the atom to which they are originally attached, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group can be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-.

In a preferred embodiment of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Cy is selected from

Ar is pyridine and benzene ring;

R ^b is chloro, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, trifluoromethoxy

In a preferred embodiment of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A and B are both selected from H, or are both selected from F.

In a preferred embodiment of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X, Y are each independently selected from CH, N, and Z is selected from CH.

In a preferred embodiment of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereofSalts, wherein R is ² Selected from hydrogen, fluorine, methyl, q is selected from 1.

In a preferred embodiment of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from the group consisting of

Wherein the method comprises the steps of

X ₁ 、Y ₁ 、Z ₁ Independently selected from CH, N;

m, n and o are 0-3;

u may be selected from-C (=O) -, -S (O) 2-, -O-, -NR ⁷ -、-CR ⁸ R ⁹ -；

V may be selected from-C (=O) -, -S (O) 2-, -O-, -S-, -Se-, -NR ⁷ -、-CR ⁸ R ⁹ -；

R ⁷ Selected from hydrogen, CH ₃ OCH ₂ CH ₂ -, oxetanyl, azetidine, tetrahydrofuranyl, tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine, -C _1-3 Alkyl, C _3-6 Cycloalkyl, wherein said C _1-3 Alkyl, C _3-6 Cycloalkyl, azetidine, tetrahydrofuranyl, tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine, optionally substituted with 1, 2 or 3 fluoro, and/or optionally substituted with one substituent selected from the group consisting of: c (C) _1-3 Alkyl, hydroxy, -OC _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ Cyclopropyl; r in different positions in the same structure ⁷ The same substituent groups can be selected, and different substituent groups can also be selected;

R ⁸ 、R ⁹ is hydrogen, fluorine, -C _1-6 Alkyl, -C _1-6 Haloalkyl, or R ⁸ And R is ⁹ Together with the nitrogen or carbon atom to which it is attached form C _3-6 Cycloalkyl, oxetane, azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydropyranyl, said cyclopropane, oxetane, azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuranPyranyl and tetrahydropyranyl groups can be C _1-3 Optionally substituted with alkyl, cyclopropane, oxetane, azetidine, cyclopropyloxy;

C. d is independently selected from-NR ⁷ C(O)-、-C(O)NR ⁷ -、-CH ₂ -CH ₂ -、-C(O)-O-、-O-C(O)-、-CH ₂ -O-、-O-CH ₂ -、-CH ₂ -NR ⁷ -、-NR ⁷ -CH ₂ -、-CH ₂ -; or 1 of C and D is a bond (single bond or double bond in the ring, atoms at both ends being directly connected);

when Cy isAnd R is ² Is H and X, Y, Z are all selected from CH and are-O-, -S-or-CF if V is present in the structure ₂ -when:

R ⁵ selected from the group consisting of-S (O) 2C _1-3 Alkyl, -CONH ₂ 、-SO ₂ NHC _1-3 Alkyl, -SO ₂ NR ³ R ⁴ (wherein R is ³ And R is ⁴ If the N atom to which it is attached forms a heterocyclic group, the heterocyclic group is selected from piperazinyl, morpholinyl, which may optionally be C _1-3 Alkyl, cyclopropyl substitution);

R ⁶ Selected from hydrogen, fluorine, chlorine, bromine, methyl;

R ^7a selected from H, -CHF, -CF ₂ 、-CH ₂ -CH(OH)-CH ₃ 、-CH ₂ -CH(OCH ₃ )-CH ₃ 、-C _4-8 Alkyl, -cycloalkyl, -cycloalkoxy, -CH ₂ -CH ₂ -OCH ₃ -oxetane, -tetrahydrofuran, -tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine; wherein said C _4-8 Alkyl, tetrahydrofuran, pyrrolidine, piperazine, morpholine, piperidine optionally substituted with 1, 2 or 3 fluorine and/or optionally substituted with one substituent selected from the group consisting of: hydroxy, -OC _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ Cyclopropyl;

otherwise: r is R ⁵ Selected from cyano, -SO ₂ C _1-3 Alkyl, -CONH ₂ 、-SO ₂ NR ³ R ⁴ Wherein R is ³ 、R ⁴ Is hydrogen, -C _1-6 Alkyl, or R ³ And R is ⁴ Together with the nitrogen atom to which it is attached, form an azetidine, oxetane, pyrrolidine, piperidine, piperazine, morpholine ring, which azetidine, oxetane, pyrrolidine, piperidine, piperazine, morpholine ring can be substituted with C _1-3 Alkyl, cyclopropyl optionally substituted;

R ⁶ selected from hydrogen, fluorine, chlorine, bromine, methyl;

R ^7a ＝R ⁷ ；

in a preferred embodiment of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ Select to

R ⁷ Selected from hydrogen, -CF ₂ 、-CHF、CH ₃ OCH ₂ CH ₂ -, oxetanyl group tetrahydrofuranyl group tetrahydropyran, -C _1-3 Alkyl, -C _3-6 A cycloalkoxy group; wherein said C _1-3 Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyran may optionally be substituted with 1, 2 or 3 fluoro, and or optionally be substituted with one substituent selected from the group consisting of: hydroxy, -OC _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ Cyclopropyl; r in different positions in the same structure ⁷ The same substituent groups can be selected, and different substituent groups can also be selected;

when Cy isAnd R is ² When H and X, Y, Z are all CH and A and B are H: r is R ^7a Selected from H, -CHF, -CF ₂ 、-CH ₂ -CH(OH)-CH ₃ 、-CH ₂ -CH(OCH ₃ )-CH ₃ 、-C _4-8 Alkyl, -C _3-6 Cycloalkyl, -C _3-6 Cycloalkoxy, -CH ₂ -CH ₂ -OCH ₃ -oxetane, -tetrahydrofuran, -tetrahydropyran, which oxetane, tetrahydrofuran, tetrahydropyran may be substituted by C _1-3 Alkyl, cyclopropyl optionally substituted; otherwise R is ^7a ＝R ⁷ 。

Typical compounds of the present invention include, but are not limited to:

/>

or a pharmaceutically acceptable salt thereof.

The beneficial effects of the invention relate to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and prevention of diseases of cathepsin C and downstream serine proteases NE, PR3, caTG and NSP4 thereof.

Further relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of respiratory diseases, metabolic diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, cancer, infectious diseases and other inflammatory related diseases in a patient suffering from asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, pulmonary arterial hypertension, non-cystic fibrosis, bronchiectasis, bronchitis, pneumonia, emphysema, acute Lung Injury (ALI), acute Respiratory Distress Syndrome (ARDS), sepsis, allergic diseases, immune inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis, eosinophilic diseases, neutrophilic granulocyte diseases, ANCA-related inflammation, anti-neutrophil cytoplasmic antibody-related necrotic crescent glomerulonephritis, acute brain trauma, acute myocarditis, acute kidney injury, a-1-antitrypsin deficiency (AATD) and related inflammation, liver fibrosis, fatty liver and hepatic steatosis, obesity, insulin resistance, diabetes, pathogenic micro-organism infection, infectious gastroenteritis and radiation syndrome or a disease in a patient at risk of said injury.

The beneficial effects of the invention relate to a pharmaceutical composition comprising a compound of formula (I) a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

Further, the pharmaceutical composition contains one or more compounds of formula (I), and a pharmaceutically active compound selected from the group consisting of other compounds including, but not limited to: b mimetics, anticholinergic agents, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists, SYK inhibitors, NE inhibitors, MMP9 inhibitors, MMP12 inhibitors, and combinations of two or three active substances.

Further, the pharmaceutical compositions also include use in combination with small molecule compounds and/or large molecule antibodies, including but not limited to glucocorticoids, adrenergic agonists, cholinergic receptor antagonists, theophyllines, antioxidants, elastase inhibitors, metalloproteinase inhibitors, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists and SYK inhibitors, chemokine receptor inhibitors, interleukin antibodies such as IL-6 antibodies, IL-23 antibodies, targeted anti-Thymic Stromal Lymphopoietin (TSLP) antibodies such as tezepemab, complement inhibitors, for the treatment of cancer, inflammation, bone marrow-related diseases, and autoimmune diseases.

The beneficial effects of the present invention relate to the use of a composition of compounds of formula (I) in the treatment and prevention of diseases selected from respiratory diseases, metabolic diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, cancer, infectious diseases or inflammatory infectious diseases, by cathepsin C and its downstream serine proteases NE, PR3, caTG, NSP 4.

The beneficial effects of the present invention relate to solvates, racemic mixtures, enantiomers, diastereomers, tautomers of the compounds of formula (I) or mixtures thereof in any ratio including racemic mixtures, characterized in that R ¹ 、R ² Each substituent of Cy, A, B, X, Y, Z and q:

the compounds of the invention may be asymmetric, for example having one or more stereocenters. Unless otherwise defined, all stereoisomers, such as enantiomers and diastereomers. Containing asymmetrically substituted carbon atoms. The compounds of the invention may be isolated in optically pure or racemic forms. Optically pure forms can be prepared by resolution of racemates or by the use of chiral synthons or chiral reagents.

The compounds of the invention may also include tautomeric forms. The new form of the tautomer results from the exchange of single bonds and adjacent double bonds together with the migration of protons.

The compounds of the present invention may also include all isotopic forms of the atoms present in the intermediate or final compound. Isotopes include those atoms having the same atomic number but different mass numbers. Isotopes of hydrogen include deuterium and tritium, for example.

The invention also includes pharmaceutically acceptable salts of the compounds of formula (I). Pharmaceutically acceptable salts refer to derivatives of the compounds of formula (I) wherein the parent compound is modified by conversion of the existing base moiety to its salt form, or wherein the parent compound is modified by conversion of the existing acid moiety to its salt form.

Specifically, examples of pharmaceutically acceptable salts include, but are not limited to: salts of inorganic or organic acids of basic groups (e.g., amines) or salts of inorganic or organic bases of acidic groups (e.g., carboxylic acids). Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound of formula (I) by reacting the free base form of these compounds with 1 to 4 equivalents of the appropriate acid in a solvent system. Suitable salts are listed in Remington's PharmaceuticalSciences,17th ed., mack Publishing Company, easton, pa.,1985, p.1418 and Journal of Pharmaceutical Science,66,2 (1977).

The compounds of the present invention, and pharmaceutically acceptable salts thereof, also include solvate forms or hydrate forms. In general, solvate forms or hydrated forms are equivalent to non-solvate forms or non-hydrated forms and are included within the scope of the present invention. Some compounds of the invention may exist in a variety of crystalline or amorphous forms. In general, all physical forms of the compounds are included within the scope of the present invention.

The invention also includes prodrugs of the compounds of formula (I). A prodrug is a pharmacological substance (i.e., drug) derived from a parent drug that, once administered, is metabolized in the body to the parent drug. Prodrugs can be prepared by substituting one or more functional groups present in the compound, wherein the substituents of the prodrug are removed in vivo in such a way as to be converted to the parent compound. The preparation and use of prodrugs is described, for example, in T.Higuchi and V.stella, "Pro-drugs as Novel Delivery Systems" Vol.14 of the A.C.S. symposium Series and Bioreversible.

Detailed Description

The invention is further illustrated below in connection with specific examples:

the invention is further illustrated by the following examples, which are only intended to more particularly illustrate preferred embodiments of the invention and are not intended to limit the technical solutions of the invention. The above-mentioned solutions of the present invention are all technical solutions for achieving the objects of the present invention. The temperatures and reagents employed in the examples below may be replaced with the corresponding temperatures and reagents described above to achieve the objects of the present invention.

The following terms, phrases and symbols used in the present invention have the meanings as described below, unless the context indicates otherwise.

The short dash ("-") between two letters or symbols represents the attachment site for a substituent. For example，-O(C _1-4 Alkyl) means C linked to the remainder of the molecule through an oxygen atom _1-4 An alkyl group. However, "-" may be omitted when the attachment site for the substituent is apparent to those skilled in the art, for example, a halogen substituent.

Unless explicitly stated otherwise, the use of terms such as "a" or "an" refer to one or more.

The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group containing from 1 to 18 carbon atoms, for example from 1 to 12 carbon atoms, for example from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms. For example, "C1-6 alkyl" is within the scope of "alkyl" and refers to alkyl groups having 1 to 6 carbon atoms as described. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("n-Pr"), isopropyl ("i-Pr"), n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("sBu"), and tert-butyl ("t-Bu").

The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical containing 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms, further e.g. 2 to 4 carbon atoms, containing one or more, e.g. 1, 2 or 3, carbon-carbon double bonds (c=c). For example, "C2-6 alkenyl" is within the scope of "alkenyl" and means that the alkenyl group has 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl.

The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing 2 to 10 carbon atoms, for example 2 to 6 carbon atoms, and still more for example 2 to 4 carbon atoms, containing one or more, for example 1, 2 or 3 carbon-carbon triple bonds (c≡c). For example, "C _2-6 Alkynyl "means the alkynyl group described comprising 1 carbon-carbon triple bond (c≡c) and having 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.

The term "halo" as used herein refers to fluoro, chloro, bromo and iodo, and "halogen" refers to fluoro, chloro, bromo and iodo.

The term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein two or more hydrogen atoms, for example 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are identical to each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein two or more hydrogen atoms, for example 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2CF3, and the like.

The term "alkoxy" as used herein refers to the group-O-alkyl, wherein alkyl is as defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy and hexoxy, including isomers thereof.

The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated cyclic hydrocarbon group containing 3 to 12 ring carbon atoms, for example 3 to 8 ring carbon atoms, and still more for example 3 to 6 ring carbon atoms, which may have one or more rings, for example 1 or 2 rings. For example, "C3-8 cycloalkyl" means cycloalkyl having 3 to 8 ring carbon atoms as described. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.

The term "heterocyclyl" or "heterocyclic" as used herein refers to a ring selected from 4 to 12 membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated, which contains at least one carbon atom in addition to at least one, such as 1-4, still more such as 1-3 or still more such as 1 or 2 heteroatoms selected from O, S and N. The point of attachment of the heterocyclyl may be on a heteroatom or on a carbon. "heterocyclyl" or "heterocyclic" also refers to a single ring comprising at least one heteroatom selected from O, S and N; or fused rings wherein at least one ring contains at least one heteroatom selected from O, S and N and the other rings are not heteroaryl or aryl, the point of attachment of which may be on a heterocycle or on other rings.

The term "cycloalkoxy" as used herein refers to the group-O-cycloalkyl, wherein cycloalkyl is as defined above. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, including their isomers.

The term "heterocycloalkoxy" as used herein refers to the group-O-heterocycloalkyl, where heterocycloalkyl is as defined above. Examples of cycloalkoxy groups include, but are not limited to, aziridioxy, glycidoxyoxy, azetidinyloxy, oxetyloxy, including isomers thereof.

"cycloalkenyl" as used herein refers to a non-aromatic cyclic hydroxyl group containing one or more, e.g., 1, 2 or 3 carbon-carbon double bonds, containing 3 to 12 ring carbon atoms, preferably 3 to 8 ring carbon atoms, more preferably 3 to 6 ring carbon atoms, which may have one or more rings, preferably 1 or 2 rings. For example, C _3-8 Having ring carbon atoms and cycloalkenyl groups, preferably "C _3-6 Cycloalkenyl ", i.e. the cycloalkenyl group having 3 to 6 ring carbon atoms. Examples of cycloalkenyl groups include, but are not limited to, cyclopropene and, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

"heterocycloalkenyl" as used herein means that one or more of the carbon atoms in the "cycloalkenyl" are replaced by N, O, S. For example, C _3-8 Heterocycloalkenyl of ring atoms, preferably "C _3-6 Heterocycloalkenyl ", i.e., the heterocycloalkenyl group having 3-6 ring atoms. Examples of heterocycloalkenyl groups include, but are not limited to, azetidine, oxetenyl, azapentenyl, oxapentenyl, and oxahexenyl.

The term "aryl" as used herein, unless explicitly defined, refers to a carbocyclic hydrocarbon group of 6 to 14 ring carbon atoms, e.g., 6 to 12 ring carbon atoms, consisting of one ring or multiple rings fused together, wherein at least one ring is an aromatic ring and the other rings are not heteroaryl groups as defined below, the points of attachment of which may be on an aromatic ring or on other rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl. As used herein, "aryl" or "aromatic" follow the huckel's rule, where pi electrons number is equal to 4n+2, n being zero or any positive integer up to 6.

The term "heteroaryl" as used herein, unless explicitly defined, means: a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, for example having 6 ring atoms, which contains one or more, for example 1, 2 or 3, for example 1 or 2, ring heteroatoms independently selected from N, O and S (for example N) in the ring, the remaining ring atoms being carbon atoms; and bicyclic aromatic hydrocarbon groups having 8-12 ring atoms, for example 9 or 10 ring atoms, comprising one or more, for example 1, 2, 3 or 4, for example 1 or 2, ring heteroatoms independently selected from N, O and S (for example N) in the ring, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring. For example, bicyclic heteroaryl groups include 5-6 membered heteroaryl rings fused to a 5-6 membered cycloalkyl, heterocyclyl or aryl ring, where the point of attachment may be on the heteroaryl ring or on the cycloalkyl/heterocyclyl/aryl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other. Heteroaryl groups also include those in which the N-ring heteroatom is in the form of an N-oxide, such as an N-oxidized pyrimidinyl group. In some embodiments, the ring heteroatoms in the heteroaryl groups described above are N atoms, and such heteroaryl groups are referred to as "nitrogen-containing heteroaryl groups". Nitrogen-containing heteroaryl groups also include those heteroaryl groups in which the N-ring heteroatom is in the form of an N-oxide, such as a pyridyl N-oxide.

Examples of heteroaryl groups include, but are not limited to: pyridyl, N-pyridyl oxide; pyrazinyl; pyrimidinyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; tetrazolyl; triazolyl; thienyl; a furyl group; pyranyl; a pyrrole group; a pyridazinyl group; benzo [ d ] thiazolyl; benzodioxolyl groups, such as benzo [ d ] [1,3] dioxolyl; benzoxazolyl groups, such as benzo [ d ] oxazolyl; imidazopyridinyl, such as imidazo [1,2-a ] pyridinyl; triazolopyridinyl groups such as [1,2,4] triazolo [4,3-a ] pyridinyl and [1,2,4] triazolo [1,5-a ] pyridinyl; indazolyl; 2H-indazolyl; pyrrolo pyrimidinyl groups, such as pyrrolo [3,4-d ] pyrimidinyl, 7H-pyrrolo [2,3-d ] pyrimidinyl; pyrazolopyrimidinyl, such as pyrazolo [1,5-a ] pyrimidinyl; tetrazolopyridinyl, such as tetrazolo [1,5-a ] pyridinyl; benzothienyl; benzofuranyl; a benzimidazolinyl group; indolyl; indolinyl; purinyl groups, e.g. 9H-purinyl and 7H-purinyl

Examples of nitrogen-containing heteroaryl groups include, but are not limited to: a pyrrole group; pyrazolyl; imidazolyl; a pyridyl group; pyrazinyl; pyrimidinyl, N-oxidized pyrimidinyl; a pyridazinyl group; pyrrolo pyrimidinyl groups, such as pyrrolo [3,4-d ] pyrimidinyl, 7H-pyrrolo [2,3-d ] pyrimidinyl; purinyl groups such as 9H-purinyl and 7H-purinyl; quinolinyl; indolyl; indazolyl.

The term "hydroxy" as used herein refers to an-OH group.

The term "mercapto" as used herein refers to a-SH group.

The term "oxo" as used herein refers to an =o group.

The term "carboxyl" as used herein refers to a-C (O) -OH group.

The term "cyano" as used herein refers to a-CN group.

The term "amino" as used herein refers to a-NH 2 group.

As used herein, "group" and "group" are synonymous and are used to denote a functional group or molecular fragment that can be attached to other molecular fragments.

The numerical range p, q, f, g, h, k, m, n, o of the present invention is intended to include any integer within the range, and for example, 0 to 6 is any integer of 0, 1, 2, 3, 4, 5, 6.

If a formula of the present invention includes an asterisk "," the compound represented by the formula is a chiral compound, i.e., the compound is in the R-configuration or S-configuration. The configuration of the compounds can be determined by one skilled in the art using a variety of analytical techniques, such as single crystal X-ray crystallography and/or optical polarimetry, and according to conventional protocols.

The terms "selective", "selectively", "optional" or "optionally" as used herein mean that the subsequently described substitution pattern, event or circumstance may or may not occur, and that the description includes instances where said substitution pattern occurs and instances where said substitution pattern does not occur. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined herein. It will be appreciated by those skilled in the art that for any group containing one or more substituents, the group does not include any sterically impractical, chemically incorrect, synthetically infeasible and/or inherently unstable substitution patterns.

The term "including but not limited to" as used herein means that the selected range is preferably followed by the recited group, but that groups not recited may also be used.

The term "substituted" or "substituted with … …" as used herein means that one or more hydrogen atoms on a given atom or group is replaced with one or more substituents selected from a given set of substituents, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., =o), then two hydrogen atoms on a single atom are replaced with oxygen. Such combinations are permissible only if the combination of substituents and/or variables result in chemically correct and stable compounds. Chemically correct and stable compounds means that the compounds are stable enough to be separated from the reaction mixture and to determine the chemical structure of the compounds and can then be formulated into a formulation having at least practical utility.

Unless otherwise indicated, substituents are named into the core structure. For example, it is understood that when a (cycloalkyl) alkyl group is listed as one possible substituent, it means that the point of attachment of the substituent to the core structure is in the alkyl moiety.

The term "substituted with one or more substituents" as used herein means that one or more hydrogen atoms on a given atom or group are independently replaced with one or more substituents selected from the given group. In some embodiments, "substituted with one or more substituents" means that a given atom or group is substituted with 1, 2, 3, or 4 substituents independently selected from a given group.

It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and thus two or more stereoisomers may be present. Racemic mixtures of these isomers, single isomers and one enantiomerically enriched mixture, as well as diastereomeric and particular diastereomeric partially enriched mixtures when there are two chiral centers are all within the scope of the invention. It will also be understood by those skilled in the art that the present invention includes all individual stereoisomers (e.g. enantiomers), racemic mixtures or partially resolved mixtures of compounds of formula (I) and, where appropriate, individual tautomers thereof.

In other words, in some embodiments, the present invention provides compounds containing multiple stereoisomers in purity, i.e., diastereomeric or enantiomeric purity, expressed in terms of different "ee" or "de" values. In some embodiments, a compound of formula (I) (e.g., as described herein) has an enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee, or any value between these recited values). In some embodiments, the compound of formula (I) (e.g., as described herein) has an enantiomeric purity of greater than 99.9% ee, up to 100% ee. In some embodiments, a compound of formula (I) (e.g., as described herein) has a diastereomeric purity of at least 60% de (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% de, or any value between these recited values). In some embodiments, the compound of formula (I) (e.g., as described herein) has a diastereomeric purity of greater than 99.9% de.

The term "enantiomeric excess" or "ee" refers to how much one enantiomer is relative to another enantiomer. For mixtures of R and S enantiomers, the percent enantiomeric excess is defined as |r-s| 100, where R and S are the molar or weight fractions of the respective enantiomers in the mixture, r+s=1. If the optical rotation of a chiral species is known, the percent enantiomeric excess is defined as ([ a ] obs/[ a ] max) ×100, where [ a ] obs is the optical rotation of the enantiomeric mixture and [ a ] max is the optical rotation of the pure enantiomer.

The term "diastereomeric excess" or "de" refers to how much one diastereomer is relative to another diastereomer, and is defined by analogy in terms of enantiomeric excess. Thus, for a mixture of diastereomers D1 and D2, the percent diastereomeric excess is defined as |d1-d2| 100, where D1 and D2 are the molar or weight fraction of each diastereomer in the mixture, d1+d2=1.

Determination of diastereomer and/or enantiomeric excess can be accomplished using a variety of analytical techniques, including nuclear magnetic resonance spectroscopy, chiral column chromatography, and/or optical polarimetry, and according to conventional protocols familiar to those skilled in the art.

The racemic mixture may be used as such or resolved into individual isomers. The resolution can be carried out to obtain a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known and include physical methods such as chromatography using chiral adsorbents. Individual isomers of chiral form can be prepared from chiral precursors. Alternatively, one or both of the isomers substantially free of the other isomer, i.e., the desired stereoisomer having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight, can be obtained by chemical separation of the individual isomers from the mixture by formation of diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α -bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractional crystallization of said salts, and then liberating one or both of the resolved bases, optionally repeating this process. Alternatively, as is well known to those skilled in the art, the racemate may be covalently attached to a chiral compound (adjunct) to provide diastereomers, which may be separated by chromatography or fractional crystallization, followed by chemical removal of the chiral adjunct to provide the pure enantiomer.

The term "pharmaceutically acceptable salt" as used herein refers to salts of the free acid or base of a compound of formula (I) that are non-toxic, biologically tolerable or otherwise biologically suitable for administration to a subject being treated. .

"pharmaceutically acceptable salts" include, but are not limited to: acid addition salts of the compounds of formula (I) with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and acid addition salts of compounds of formula (I) with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate and salts with alkanedicarboxylic acids of formula HOOC- (CH 2) n-COOH (where n is 0-4), and the like. "pharmaceutically acceptable salts" also include base addition salts of compounds of formula (I) bearing an acidic group with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium. The molar ratio of the compound of formula (I) to the acid or cation in the resulting pharmaceutically acceptable salt includes, but is not limited to, 1:1, 1:2, 1:3, and 1:4.

The term "prodrug" as used herein refers to a pharmacological substance derived from a parent drug (i.e., drug) that, once administered, is metabolized in vivo to the parent drug. Prodrugs can be prepared by substituting one or more functional groups present in the compound, wherein the substituents of the prodrug are removed in vivo in such a way as to be converted to the parent compound. Preparation and use of prodrugs can be found in T.Higuchi and V.stilla, "Pro-drugs as Novel Delivery Systems," Vol.14of the A.C.S. symposium Series and Bioreversible. "prodrugs" include, but are not limited to: esters of the compounds of formula (I) such as phosphates, formates, carbamates; amides such as formamide, acetamide.

Furthermore, if the compounds according to the invention are obtained in the form of acid addition salts, the free base form thereof can be obtained by basifying a solution of the acid addition salts. Conversely, if the product is in the form of the free base, its acid addition salts, particularly the pharmaceutically acceptable acid addition salts, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. One skilled in the art can determine, without undue experimentation, various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts.

The term "solvate" means a solvent addition form comprising a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to cross a fixed molar ratio of solvent molecules in the solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more molecules of water with a molecule of the substance, wherein the water retains its molecular state of H2O, and such a combination is capable of forming one or more hydrates, such as hemihydrate, monohydrate, and dihydrate, as well as variable hydrates.

The terms "group" and "group" as used herein are synonymous and are used to denote a functional group or molecular fragment that can be attached to other molecular fragments.

The term "active ingredient" is used to denote a chemical substance having biological activity. In some embodiments, an "active ingredient" is a chemical substance that has pharmaceutical use. In the united states, the actual pharmaceutical activity can be determined by appropriate preclinical testing, whether in vitro or in vivo. But is sufficiently pharmaceutically active to be accepted by regulatory authorities (e.g., FDA in the united states) to have a higher standard than preclinical testing. Whether such a higher standard of pharmaceutical activity is successful or not is generally reasonably unexpected from preclinical test results, can be established by appropriate and effective randomized, double-blind, controlled clinical trials in humans.

The term "treating" or "treatment" of a disease or disorder, where a beneficial therapeutic effect is achieved, refers to the administration of one or more pharmaceutical substances, in particular a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, according to the present invention, to an individual, e.g. a human, suffering from, or having symptoms of, or predisposed to, the disease or disorder, for curing, healing, alleviating, altering, treating, improving, modifying or affecting the disease or disorder, the symptoms of, or the predisposition to the disease or disorder. In some embodiments, the disease or disorder is cancer.

When chemical reactions are involved, the terms "treat," "contacting," and "reacting" mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It will be appreciated that the reaction to produce the indicated and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e., there may be one or more intermediates formed in the mixture that ultimately lead to the formation of the indicated and/or desired product.

The term "effective amount" as used herein refers to an amount or dose of a cathepsin C inhibitor that is generally sufficient to produce a beneficial therapeutic effect in a patient in need of treatment for a disease or disorder mediated by cathepsin C and downstream serine protease activity. The effective amount or dosage of an active ingredient of the present invention can be determined by conventional means (e.g., modeling, dose escalation studies or clinical trials) in combination with conventional influencing factors (e.g., the manner or route of administration or administration, the pharmacokinetics of the pharmaceutical ingredient, the severity and course of the disease or disorder, the previous or ongoing treatment of the individual, the health condition and response of the individual to the drug, and the judgment of the attending physician). In the united states, determination of effective doses is generally difficult to predict from preclinical trials. In fact, dosages are completely unpredictable, and new unpredictable dosage regimens may develop after the initial use in randomized, double-blind, controlled clinical trials.

Typical dosages range from about 0.0001 to about 200 milligrams of active ingredient per kilogram of body weight of the subject per day, for example from about 0.001 to 100 milligrams per kilogram of body weight per day, or from about 0.01 to 35 milligrams per kilogram per day, or from about 0.1 to 10 milligrams per kilogram of body weight per day, once daily or in divided dosage units (e.g., twice daily, three times daily, four times daily). For a 70 kg person, a suitable dosage range may be about 0.05 to about 7 grams per day, or about 0.2 to about 5 grams per day. Once the patient's disease or disorder has improved, the dosage may be adjusted to maintain the treatment. For example, the amount or number of administrations, or the amount and number of administrations, may be reduced to a level that maintains the desired therapeutic effect, depending on the change in symptoms. Of course, if symptoms are reduced to appropriate levels, treatment may be stopped. However, for recurrence of symptoms, the patient may require intermittent long-term treatment.

The term "inhibition" refers to a decrease in baseline activity of a biological activity or process. The term "inhibiting cathepsin C activity" is the actual pharmaceutical activity for the purposes of the present invention and refers to a decrease in cathepsin C activity in the direct or indirect response to the presence of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein, relative to cathepsin C activity in the absence of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof. The reduction in activity may be caused by direct interaction of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof according to the invention with cathepsin C or by interaction of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof according to the invention with one or more other factors which in turn affect cathepsin C activity. For example, the presence of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof according to the present invention may reduce the activity of cathepsin C by binding directly to cathepsin C, may reduce the activity of cathepsin C by affecting another factor directly or indirectly, or may reduce the activity of cathepsin C by reducing the amount of cathepsin C present in a cell or body directly or indirectly.

The term "individual" as used herein refers to both mammalian and non-mammalian animals. By mammal is meant any member of the mammal, including but not limited to: a person; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds and the like. The term "individual" is not limited to a particular age or sex. In some embodiments, the individual is a human.

In general, the term "about" is used herein to adjust a given value to be above or below 20% of that value.

A compound of formula (I) or a pharmaceutically acceptable salt thereof,

and/or pharmaceutically acceptable prodrugs thereof, and/or solvates, hydrates, metabolites, nitrogen oxides, racemic mixtures, enantiomers, diastereomers and tautomers thereof, or mixtures thereof in any ratio, including racemic mixtures, wherein:

cy is

/>

p is 0-6;

R ^a Each independently selected from deuterium, halogen, hydroxy, cyano, mercapto, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 Heterocycloalkyl, C _3-6 Cycloalkyloxy, heterocycloalkoxy, -SC _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, (C) _1-6 Alkyl group ₂ N-、C _1-6 alkyl-C (O) HN-, -C (O) NHC _1-6 Alkyl, oxo, thio, and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy groups are each optionally substituted with halogen and deuterium; two R ^a Can be connected with the same carbon atom or can be connected with different carbon atoms; r is R ^a Or two R ^a Together form C _1-4 Alkylene or ether chains containing 1 to 4 carbon atoms, e.g. -CH ₂ -O-CH ₂ -CH ₂ -CH ₂ -、-CH ₂ -O-CH ₂ -, the alkylene or ether chain may form, with the original ring, a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged, fused and spiro ring, with or without heteroatoms, including N, S, O, which cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged, fused and spiro rings may be optionally substituted with deuterium, hydroxy, halogen, alkyl and alkoxy, and where C, S may be optionally substitutedOxo is-c=o, -s=o, -S (O) 2-; or two R ^a The carbon atoms to which each is attached constitute a 6 membered aryl, 5 membered heteroaryl, 6 membered heteroaryl, and forms a fused ring with the original ring, said fused ring being optionally substituted with hydroxy, halogen, cyano, alkyl, alkoxy; and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy groups are each optionally substituted with halogen and deuterium.

q is 0-3;

when in the following four cases (the four cases are and/or are related)

1) Cy is not

2) X, Y, Z are not simultaneously CH;

3)R ² is not hydrogen and q is not 0;

4) A and B are not hydrogen at the same time;

R ¹ selected from cyclic groups, in particular aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl; the cyclic group may be monocyclic or bicyclic, may optionally contain one or more heteroatoms of N, O, S, se, and C, S in the ring may be optionally oxo or thiosubstituted with-CO-, -CS-, -SO2-; the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl groups can be substituted with one or more R ^1a Optionally substituted;

R ^1a Can be selected from hydrogen,Deuterium, halogen, cyano, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocycloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ₃ Substitution; two R ^1a Can be connected with the same carbon atom or nitrogen atom or can be connected with different carbon atoms or nitrogen atoms; two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aromatic, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, C, S in the ring may also be optionally oxo or thioxo-CO-, -CS-, -SO2-;

R ³ 、R ⁴ each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, and,Alkylcarbonyl, alkylsulfonyl, alkyl C (O) NH-, alkyl S (O) 2NH-, carboxyl, alkylcarbonyl; wherein amino, hydroxy, carboxyl, alkyl, cycloalkyl, cycloalkoxy, heterocycloalkoxy, heterocycloalkyl may be further substituted with alkyl, halogen, cyano, hydroxy, hydroxyalkyl, alkoxy; two R ³ May be attached to the same atom or to different atoms; or two R ³ Or R is ³ And R is ⁴ Optionally forming a 3-10 membered cycloalkyl, heterocycloalkyl, spiro, bridged, fused ring with the carbon or nitrogen atom to which each is commonly attached, including but not limited to oxetane, azetidine, morpholino, piperidino, piperazino, azetidine, furano, pyrrolidine, wherein C and S in the cycloalkyl, heterocycloalkyl, spiro, bridged, fused ring may be optionally oxo-CO-, -SO2-, and may be substituted with one or more halogens, C _1-3 Alkyl, halogenated C _1-3 Alkyl, C _1-3 Alkoxy, C _3-8 Optionally substituted with heterocyclyl;

when Cy isAnd X, Y, Z are CH and R ² When hydrogen is used and both A/B are H:

and/or R ¹ Selected from:

f is 0-2;

g is 0-3;

h is 0-5;

k is 0-2;

R ³ and R is ⁴ Unless specifically stated otherwise, as defined above;

when f and g are not 0 and R ^1a When not hydrogen, R ^1b ＝H、R ^1a ；R ^1b And R is R ^1a Or two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

when f and g are 0, or f and g are other than 0 and R ^1a When hydrogen, R ^1b Can be selected from hydrogen, deuterium, halogen, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocycloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkylcarbonyloxy, cycloalkylcarbonyloxyHeterocyclylcarbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ₃ Substitution; r is R ^1b And R is R ^1a Or two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

when k is 0, or k is other than 0 and R ^1a When hydrogen:

if R is ^5a Deuterium, bromine, cyano, hydroxy, amino, mercapto, carboxyl, sulfonyl, sulfoxide, oxo, thio, nitro, cyano, C _2-8 Alkyl, halogenSubstituted alkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ³ Substitution;

If R is ^5a Is H, then R ^6＝ R ^1a ，R ⁵ Is selected from deuterium, hydroxy, amino, mercapto, carboxyl, sulfone group,Sulfoxy, oxo, thioxo, nitro, cyano, alkyl, 1 to 2 fluoro-substituted alkyl, 1 to 3 bromo-substituted alkyl, 1 to 3 chloro-substituted alkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocycloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ (wherein R is ³ And R is ⁴ Not simultaneously H), alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ³ 、-S(O)2C _4-8 Alkyl, -OS (O) 2C _4-8 Cycloalkyl, -OS (O) 2C _4-8 Heterocyclylalkyl, -S (O) (NH) R ³ 、-S(O)(NR ⁴ )R ³ 、S(O)2NR ³ R ⁴ (wherein R is ³ And R is ⁴ Can form, with the attached N atom, a heteroalkenyl group, a piperazinyl group, a 5-7 membered azaalkyl group containing at least 1O atom, a morpholinyl group, a bridged ring morpholinyl group, or R ³ And R is ⁴ Independently substituted with non-cyclic groups), -S (O) 2NH ₂ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ³ Substitution;

Wherein the method comprises the steps of

V is selected from-O-、-S-、-Se-、-CH ₂ -、-CF ₂ -、-CO-、-SO-、-SO2-、-N(R ⁷ )-、-C(R ⁸ R ⁹ ) -O-CH (alkyl) -, -O-CH (cycloalkyl) -, -S-CH (cycloalkyl) -, -ch=c (alkyl) -, -n=c (alkyl) -, -ch=c (cycloalkyl) -, -n=c (cycloalkyl) -;

When V is-O-, -S-, -CF ₂ When-and U is-CO-, T is-O-, -S-, -Se-, -CO, -SO-, -S (O) 2, -CR ⁸ R ⁹ -，-NH-、-N(CHF)-、-N(CF ₂ )-、-N(CH ₂ -CH(OH)-CH ₃ )-、-N(CH ₂ -CH(OCH ₃ )-CH ₃ )-、-N(CH ₂ -CH ₂ -OCH ₃ )-、-N(C _4-8 Alkyl) -, -N (cycloalkyl) -, -N (cycloalkoxy) -, -N (oxetane) -, -N (tetrahydrofuran) -, -N (tetrahydropyran) -, wherein the is-N (C) _4-8 Alkyl) -, -N (cycloalkyl) -, -N (cycloalkoxy) -, -N (oxetane) -, -N (tetrahydrofuran) -, -N (tetrahydropyran) is optionally C _1-3 Alkoxy, C _1-3 Alkyl, C _3-6 Cycloalkyl, NH (C) _1-3 Alkyl), N (C) _1-3 Alkyl group ₂ Or 1 to 3 halogen substitutions; otherwise T is-O-, -S-, -Se-; -CO-, -SO2-, -C (R) ⁸ R ⁹ )-、-N(R ⁷ )-；

X ₁ 、Y ₁ 、Z ₁ May be independently selected from CH and N;

R ⁷ ＝R ^1a ；

R ⁸ 、R ⁹ ＝R ^1a or R ⁸ 、R ⁹ Can optionally form a saturated or unsaturated cyclic group with the atom to which they are originally attached, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group can be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-; and/or a pharmaceutically acceptable salt thereof or a prodrug thereofAnd/or solvates, hydrates, metabolites, nitrogen oxides, racemic mixtures, enantiomers, diastereomers and tautomers thereof, or mixtures thereof in any ratio, including racemic mixtures, wherein:

Cy is

p is 0-6;

R ^a Each independently selected from deuterium, halogen, hydroxy, cyano, mercapto, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 Heterocycloalkyl, C _3-6 Cycloalkyloxy, heterocycloalkoxy, -SC _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylamino, (C) _1-6 Alkyl group ₂ N-、C _1-6 alkyl-C (O) HN-, -C (O) NHC _1-6 Alkyl, oxo, thio, and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy groups are each optionally substituted with halogen and deuterium; two R ^a Can be connected with the same carbon atom or can be connected with different carbon atoms; r is R ^a Or two R ^a Together form C _1-4 Alkylene or ether chains containing 1 to 4 carbon atoms, e.g. -CH ₂ -O-CH ₂ -CH ₂ -CH ₂ -、-CH ₂ -O-CH ₂ The alkylene or ether chain may form, with the original ring, a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, with or without heteroatoms,Fused rings and spiro rings, the heteroatoms including N, S, O, the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, fused rings and spiro rings being optionally substituted with deuterium, hydroxy, halogen, alkyl and alkoxy groups, and wherein C, S is optionally oxo-c=o, -s=o, -S (O) 2-; or two R ^a The carbon atoms to which each is attached constitute a 6 membered aryl, 5 membered heteroaryl, 6 membered heteroaryl, and forms a fused ring with the original ring, said fused ring being optionally substituted with hydroxy, halogen, cyano, alkyl, alkoxy; and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy groups are each optionally substituted with halogen and deuterium.

q is 0-3;

when in the following four cases (the four cases are and/or are related)

1) Cy is not

2) X, Y, Z are not simultaneously CH;

3)R ² is not hydrogen and q is not 0;

4) A and B are not hydrogen at the same time;

R ¹ selected from cyclic groups, in particular aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl; the cyclic group may be monocyclic or bicyclic, may optionally contain one or more N, O, S, se heteroatoms, and C, S of the ring may be optionally oxo or thioxois-CO-, -CS-, -CO-SO-, -SO2-; the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl groups can be substituted with one or more R ^1a Optionally substituted;

when Cy isAnd X, Y, Z are CH and R ² When hydrogen is used and both A/B are H:

and/or R ¹ Selected from:

f is 0-2;

g is 0-3;

h is 0-5;

k is 0-2;

R ³ and R is ⁴ Unless specifically stated otherwise, as defined above;

when f and g are 0, or f and g are other than 0 and R ^1a When hydrogen, R ^1b Can be selected from hydrogen, deuterium, halogen, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocycloxy, arylAcyloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ₃ Substitution; r is R ^1b And R is R ^1a Or two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

when k is 0, ork is not 0 and R ^1a When hydrogen:

if R is ^5a Is chlorine, fluorine or CH ₃ In the time-course of which the first and second contact surfaces,then R is ⁵ 、R ⁶ ＝R ^1a ；

Wherein the method comprises the steps of

X ₁ 、Y ₁ 、Z ₁ May be independently selected from CH and N;

R ⁷ ＝R ^1a ；

R ⁸ 、R ⁹ ＝R ^1a or R ⁸ 、R ⁹ Optionally forming a saturated or unsaturated cyclic group with the atom to which both are originally attached, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring,spiro, condensed ring, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-.

The Cy is selected from

Ar is pyridine and benzene ring;

A compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that: the A and B are both selected from H, or are both selected from F.

And each X and Y is independently selected from CH and N, and Z is selected from CH.

The R is ² Selected from hydrogen, fluorine, methyl, q is selected from 1.

The R is ¹ Selected from the group consisting of

Wherein the method comprises the steps of

X ₁ 、Y ₁ 、Z ₁ Independently selected from CH, N;

m, n and o are 0-3;

u may be selected from-C (=O) -, -S (O) 2-, -O-, -NR ⁷ -、-CR ⁸ R ⁹ -；

R ⁷ Selected from hydrogen, CH ₃ OCH ₂ CH ₂ -, oxetanyl, azetidine, tetrahydrofuranyl, tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine, -C _1-3 Alkyl, C _3-6 Cycloalkyl, wherein said C _1-3 Alkyl, C _3-6 Cycloalkyl, azetidine, tetrahydrofuranyl, tetrahydropyran, and pyriPyrrolidine, piperazine, morpholine, piperidine are optionally substituted with 1, 2 or 3 fluorine groups and/or optionally substituted with one substituent selected from the group consisting of: c (C) _1-3 Alkyl, hydroxy, -OC _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ Cyclopropyl; r in different positions in the same structure ⁷ The same substituent groups can be selected, and different substituent groups can also be selected;

R ⁸ 、R ⁹ is hydrogen, fluorine, -C _1-6 Alkyl, -C _1-6 Haloalkyl, or R ⁸ And R is ⁹ Together with the nitrogen or carbon atom to which it is attached form C _3-6 Cycloalkyl, oxetane, azetidine, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuranyl, tetrahydropyranyl, said cyclopropane, oxetane, azetidine, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted by C _1-3 Optionally substituted with alkyl, cyclopropane, oxetane, azetidine, cyclopropyloxy;

R ⁶ selected from hydrogen, fluorine, chlorine, bromine, methyl;

R ^7a ＝R ⁷ ；

the R is ¹ Select to

R ⁷ Selected from hydrogen, -CF ₂ 、-CHF、CH ₃ OCH ₂ CH ₂ -, oxetanyl group tetrahydrofuranyl group tetrahydropyran, -C _1-3 Alkyl, -C _3-6 A cycloalkoxy group; wherein said C _1-3 Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyran optionally substituted with 1, 2 or 3 fluoro, and or optionally substituted with one selected fromGroup substitution: hydroxy, -OC _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ Cyclopropyl; r in different positions in the same structure ⁷ The same substituent groups can be selected, and different substituent groups can also be selected;

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

/>

Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and prophylaxis of cathepsin C and downstream serine proteases NE, PR3, caTG, NSP 4.

The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a patient suffering from respiratory disease, metabolic disease, cardiovascular disease, autoimmune disease, cancer, infectious disease and other inflammatory related diseases are asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, pulmonary arterial hypertension, non-cystic fibrosis, bronchiectasis, bronchitis, pneumonia, emphysema, acute Lung Injury (ALI), acute Respiratory Distress Syndrome (ARDS), sepsis, allergic disease, immune inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis, eosinophilic disease, neutrophil disease, ANCA-related inflammation, anti-neutrophil cytoplasmic antibody-related necrotizing crescent glomerulonephritis, acute brain trauma, acute myocarditis, acute kidney injury, a-1-antitrypsin deficiency (AATD) and related inflammation, liver fibrosis, fatty liver and liver steatosis, obesity, insulin resistance, diabetes, pathogenic microorganism infection, infectious gastric cancer and/or radiation syndrome in a patient at risk of said disease.

A pharmaceutical composition comprising a compound of formula (I) a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

Which contains one or more compounds of formula (I), and a pharmaceutically active compound selected from the group consisting of other compounds including, but not limited to: b mimetics, anticholinergic agents, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists, SYK inhibitors, NE inhibitors, MMP9 inhibitors, MMP12 inhibitors, and combinations of two or three active substances.

The pharmaceutical compositions also include use in combination with small molecule compounds and/or large molecule antibodies, including but not limited to glucocorticoids, adrenergic agonists, cholinergic receptor antagonists, theophyllines, antioxidants, elastase inhibitors, metalloprotease inhibitors, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists and SYK inhibitors, chemokine receptor inhibitors, interleukin antibodies such as IL-6 antibodies, IL-23 antibodies, targeted anti-Thymic Stromal Lymphopoietin (TSLP) antibodies such as tezepelumab, complement inhibitors, for the treatment of cancer, inflammation, bone marrow related disorders, and autoimmune diseases.

Use of the composition in the manufacture of a medicament for the treatment and prophylaxis of a condition selected from the group consisting of respiratory, metabolic, cardiovascular and cerebrovascular, autoimmune, cancer, infectious or inflammatory diseases by cathepsin C and its downstream serine proteases NE, PR3, caTG, NSP 4.

Solvates, racemic mixtures, enantiomers, diastereomers, tautomers, or mixtures thereof in any ratio including racemic mixtures of the compounds of formula (I), said R ¹ 、R ² Each substituent of Cy, A, B, X, Y, Z and q:

general synthetic method for compounds of formula (I):

in scheme 1, PG in the compounds of formula II represents a protecting group, such as t-butoxycarbonyl. As shown in scheme 1, a compound of formula II is activated by 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) or O-benzotriazol-tetramethylurea Hexafluorophosphate (HBTU) under basic conditions (e.g., with N, N-diisopropylethylamine as a base) to react with aqueous ammonia to give a compound of formula III. Deprotection of a compound of formula III the compound of formula IV and the compound acid of formula V are reacted with conventional literature reporting methods such as using N, N-diisopropylethylamine as base, HATU or HBTU as activating reagent to give the compound of formula VI as amide.

The Suzuki coupling reaction of a compound of formula VI with a borate compound of formula VIII utilizes a palladium catalyst such as [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride in a suitable solvent such as dioxane and the use of a suitable base such as potassium acetate to give a compound of formula IX.

Another route is to convert the compound of formula VI to a borate compound of formula VII. The compound of the formula VI reacts with dipentaerythritol in dimethyl sulfoxide with the catalysis of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride by using potassium acetate as a base to obtain a borate compound of the formula VII. Suzuki coupling of the compound of formula XI with the borate compound of formula VII utilizes a palladium catalyst such as [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride in a suitable solvent such as dioxane and the use of a suitable base such as potassium acetate to give the compound of formula IX.

Amides of compounds of formula IX can be dehydrated in methylene chloride using methyl N- (triethylammonium sulfonyl) carbamate to give compounds of formula X. Deprotection of a compound of formula X affords the final product, a compound of formula I.

The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein (e.g., any of the compounds of the present invention) may be formulated as pharmaceutical compositions, either alone or in combination with one or more additional active ingredients. The pharmaceutical composition comprises: (a) An effective amount of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof according to the present invention; and (b) a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

Pharmaceutically acceptable carrier refers to a carrier that is compatible with the active ingredient of the composition (and, in some embodiments, stabilizes the active ingredient) and is not deleterious to the subject to be treated. For example, solubilizing agents such as cyclodextrins (which are capable of forming specific, more soluble complexes with the compounds of formula (I) and/or pharmaceutically acceptable salts thereof according to the present invention) can be used as pharmaceutical excipients to deliver the active ingredient. Examples of other carriers include colloidal silica, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D & C Yellow No. 10 (D & C Yellow # 10). Suitable pharmaceutically acceptable carriers are disclosed in a reference book (Remington's Pharmaceutical Sciences, a.osol) standard in the art.

Pharmaceutical compositions comprising a compound of formula (I) as described herein (e.g., any of the compounds of the present invention) and/or a pharmaceutically acceptable salt thereof may be administered in a variety of known ways, such as orally, topically, rectally, parenterally, inhaled or implanted. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intravertebral, intralesional and intracranial injection or infusion.

The pharmaceutical composition of the invention can be prepared into the forms of tablets, capsules, bagged electuaries, sugar-coated pills, powder, granules, buccal tablets, powder injection, liquid preparations or suppositories. In some embodiments, pharmaceutical compositions comprising a compound of formula (I) and/or a pharmaceutically acceptable salt thereof may be formulated for intravenous drip, topical administration, or oral administration.

The orally administered composition may be any orally acceptable dosage form including, but not limited to: tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. Common tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added to tablets. Useful diluents include lactose and dried cornstarch when administered orally in the form of capsules. When administered orally in the form of an aqueous suspension or emulsion, the active ingredient may be suspended or dissolved in the oil phase with emulsifying or suspending agents. If desired, certain sweeteners, flavoring agents or pigments may also be added.

In some embodiments, the amount of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof in the tablet may be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 milligrams. In some embodiments, the amount of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof in the capsule may be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 milligrams.

Sterile injectable compositions (e.g., aqueous or oleaginous suspensions) may be formulated according to the art-known techniques using suitable dispersing or wetting agents (e.g., tween 80) and suspending agents. The sterile injectable intermediate medium may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the pharmaceutically acceptable carriers and solvents that may be used are mannitol, water, ringer's solution and physiological saline. In addition, sterile, nonvolatile oils, such as synthetic mono-or diglycerides, are conventionally employed as a solvent or suspending medium. Fatty acids such as oleic acid and its glyceride derivatives, as well as natural pharmaceutically-acceptable oils such as olive oil or castor oil (especially in their polyoxyethylated versions) are commonly used as injectable intermediate media. These oil solutions or suspensions may also contain a long-chain alcoholic diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.

Inhalation compositions may be prepared according to techniques well known in the art of pharmaceutical formulation, or may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, using absorption promoters to enhance bioavailability, using fluorocarbons and/or other solubilizing or dispersing agents known in the art.

Topical compositions may be formulated as oils, creams, lotions, ointments and the like. Suitable carriers for the compositions include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (i.e., alcohols having more than 12 carbon atoms). In some embodiments, the pharmaceutically acceptable carrier is a carrier in which the active ingredient is soluble. The composition may further comprise emulsifiers, stabilizers, wetting agents and antioxidants, as well as substances imparting color or fragrance thereto, if desired. In addition, transdermal penetration enhancers may be added to the topical formulation. Examples of such accelerators can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762.

The cream may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which the active ingredient dissolved in a small amount of oil, such as almond oil, is mixed. One example of a cream comprises about 40 parts by weight water, about 20 parts beeswax, about 40 parts mineral oil, and about 1 part almond oil. Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and cooling the mixture. One example of an ointment comprises about 30% almond oil and about 70% white soft paraffin by weight.

Suitable in vitro experiments can be used to evaluate the practical use of the compounds of formula (I) and/or pharmaceutically acceptable salts thereof according to the invention in inhibiting cathepsin C activity. Further practical use of the compounds of formula (I) and/or pharmaceutically acceptable salts thereof according to the invention in the treatment of pulmonary diseases, inflammatory diseases, metabolic diseases, infectious diseases, cardiovascular and cerebrovascular diseases or autoimmune diseases can be detected by in vivo tests. For example, the compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein may be administered to an animal (e.g., a mouse model) suffering from a pulmonary disease, an inflammatory disease, a metabolic disease, an infectious disease, a cardiovascular disease, a cancer, an autoimmune disease, and then evaluated for their therapeutic effect and, if the result of a preclinical trial is successful, the dosage range and route of administration to the animal, e.g., a human, may be predicted; or to animals (e.g., rats) that have not yet been validated for disease model, are evaluated for their inhibitory effect on serine proteases downstream of cathepsin C to predict their benefit from pulmonary disease such as bronchodilation.

The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein may exhibit sufficient preclinical practical use to be worthy of clinical trials and are expected to exhibit beneficial therapeutic or prophylactic effects, for example, in individuals suffering from pulmonary and inflammatory diseases.

The term "pulmonary disease" refers to a pathological condition associated with a pulmonary organ. Non-limiting examples of such diseases include bronchiectasis, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, asthma, chronic obstructive pulmonary disease, pneumonia, acute lung injury, acute respiratory distress syndrome.

The term "inflammatory disease" or "inflammatory disease" refers to a pathological state that leads to an inflammatory response, in particular due to neutrophil chemotaxis. Non-limiting examples of such diseases include inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and scleroderma; responses associated with Inflammatory Bowel Disease (IBD) (e.g., crohn's disease and ulcerative colitis); ischemia reperfusion injury, including surgically induced tissue reperfusion injury, myocardial ischemia such as myocardial infarction, cardiac arrest, post-cardiac reperfusion and abnormal contractile response of coronary vessels following percutaneous transluminal coronary angioplasty, stroke and abdominal aortic aneurysm surgical tissue reperfusion injury; cerebral edema secondary to stroke; cranium trauma; hemorrhagic shock; suffocation; adult respiratory distress syndrome; acute lung injury; behcet's disease; dermatomyositis; polymyositis; autoimmune diseases such as Rheumatoid Arthritis (RA); pulmonary inflammation including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, allergic pneumonia, idiopathic Pulmonary Fibrosis (IPF), cystic fibrosis, and the like; other inflammatory ANCA-related inflammatory conditions, and necrotic crescentic glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies.

The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein may be used to achieve beneficial therapeutic or prophylactic effects, for example, in individuals suffering from metabolic disorders, infectious disorders, cardiovascular disorders, infectious disorders, cancer, autoimmune disorders.

The term "autoimmune disease" refers to a disease or condition caused by an immune response of an organism to an autoantigen resulting in damage to self tissues or organs. Examples of autoimmune diseases include, but are not limited to: chronic Obstructive Pulmonary Disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple Sclerosis (MS), rheumatoid Arthritis (RA), psoriasis, inflammatory Bowel Disease (IBD), asthma and idiopathic thrombocytopenic purpura (idiopathic thrombocytopenicpurpura) and myeloproliferative diseases (myeloid proliferative disorder), such as myelofibrosis (myelofilrosis), polycythemia vera/primary thrombocythemia myelofibrosis (postpolycythemia vera/essential thrombocytosis myelofibrosis, PV/ET).

The term "metabolic disease" refers to a disease caused by a metabolic disorder or a metabolic-related disease, non-limiting examples of which include non-alcoholic fatty liver, non-alcoholic steatohepatitis, AATD, obesity, diabetes, and the like.

The term "infectious disease" refers to a pathological condition caused by infection with a virus, bacterium, parasite, etc. Non-limiting examples of such diseases include leishmaniasis, novel coronavirus infection pneumonia, sepsis.

The term "cardiovascular and cerebrovascular diseases" refers to diseases related to the cardiovascular system and brain organs. Non-limiting examples of such diseases include ischemia reperfusion injury, acute brain injury, heart failure, myocarditis, myocardial infarction, and the like.

The term "cancer" as used herein refers to a cellular disorder characterized by uncontrolled or deregulated cell proliferation, reduced cell differentiation, improper ability to invade surrounding tissue, and/or the ability to establish new foci at other sites. The term "cancer" includes, but is not limited to: solid tumors and hematological malignancies. The term "cancer" includes cancers of the skin, tissues, organs, bones, cartilage, blood and blood vessels. The term "cancer" includes both primary and metastatic cancers. Non-limiting examples of solid tumors include lung cancer, such as non-small cell lung cancer (NSCLC).

In some embodiments, the inflammatory and autoimmune diseases include rheumatoid arthritis, chronic Obstructive Pulmonary Disease (COPD), allergic rhinitis, asthma, lupus erythematosus, systemic lupus erythematosus, psoriasis, and multiple sclerosis.

Furthermore, the compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein (e.g., any of the compounds of the present invention) may be used in combination with additional active ingredients for the treatment of respiratory diseases, inflammatory or autoimmune diseases and cancers. The additional active ingredient may be administered separately from the compound of formula (I) and/or a pharmaceutically acceptable salt thereof according to the present invention, or it may be included in a pharmaceutical composition according to the present disclosure, e.g. a fixed dose combination. In a typical embodiment, the additional active ingredient is one that is known or has been found to be effective in treating a disease mediated by cathepsin C and its downstream serine protease activity, e.g. another cathepsin C modulator or a compound that is effective in antagonizing another target associated with the particular disease. The combination may be used to increase the efficacy (e.g., by including in the combination a compound that enhances the efficacy or effectiveness of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein), reduce one or more side effects, or reduce the required dose of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein.

Examples

The following examples are illustrative of the invention and are not intended to limit the invention in any way. All fractions are weight fractions and temperatures are degrees celsius unless otherwise indicated. The pressure is at or near atmospheric pressure. All data were measured by Agilent 6120 and/or 1100. All reagents used in the present invention are commercially available except for synthetic intermediates. The names of all compounds except the reagent were generated by chemdrew 20.0.

The following abbreviations are used:

ACN acetonitrile

Boc t-Butoxycarbonyl group

(Boc) ₂ O-pyrocarbonic acid tert-butyl ester

BH ₃ Boranes

DAST diethylaminosulfur trifluoride

DCM dichloromethane

DEA diethylamino

DMF N, N-dimethylformamide

DMA dimethylacetamide

DIBAL-H diisobutylaluminum hydride

DIEPA N, N-diisopropylethylamine

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EA ethyl acetate

Et3N triethylamine

HATU 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HBTU O-benzotriazol-tetramethylurea hexafluorophosphate

HOAc acetic acid

HOBt 1-hydroxybenzotriazole

ee enantiomer excess

mL of

g

mg

ng Nake

mol

mmol millimoles

h hours

MeOH methanol

NaH sodium hydride

NCS N-chlorosuccinimide

NMP N-methyl-2-pyrrolidone

PE Petroleum ether

Pd(dppf) ₂ Cl ₂ [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride

Pd ₂ (dba) ₃ Tridibenzylidene acetone dipalladium

Pd(PPh ₃ ) ₄ Tetrakis (triphenylphosphine) palladium

PMB p-methoxycyanobenzyl group

PPh ₃ Triphenylphosphine and process for preparing same

Pin ₂ B ₂ Pinacol biboroate ester

THF tetrahydrofuran

TFA trifluoroacetic acid

TsOH 4-toluene sulfonic acid

Xphos 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl

Burgess reagent N- (triethylammonium sulfonyl) carbamic acid methyl ester

Intermediate 1:

a) CDI (20.7 g,127.7 mmol) was added to a solution of the compound 2-amino-4-bromophenol (20.0 g,106.4 mmol) in 2-MeTHF (300 mL) under nitrogen at room temperature, then refluxed for 1 hour, cooled to room temperature, and sequentially cooled to 2M HCl(aq.)(300mL),8％NaHCO ₃ (aq.) (300 mL), and saturated brine (150 mL), na ₂ SO ₄ Drying and concentration gave product 1a (21.9 g, 96%) as a light brown solid, MS (ESI) m/z=215.9 [ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.85(s,1H)；7.26-7.23(m,3H)。

b) To a solution of Compound 1a (1.0 g,4.7 mmol) in DMF (15.0 mL) at room temperature under nitrogen, sodium chlorodifluoroacetate (3.6 g,23.5 mmol) and S were added sequentially ₈ (6.0 g,23.5 mmol), sodium t-butoxide (1.8 g,18.8 mmol),molecular sieves (200 mg, dry powder) were then heated to 70 ℃ and stirring was continued for 6 hours. Cooled to room temperature, the molecular sieve was removed by filtration, washed with EA (50 mL), further diluted with EA (100 mL), washed with saturated brine (50 mL. Times.5), na ₂ SO ₄ Drying and concentrating to obtain crude product. The crude product was purified by preparative HPLC (using TFA buffer: A:0.05% aqueous TFA; B:0.05% acetonitrile in TFA; chromatographic column: waters XBridge Peptide BEH C, 19X 250mm,10 μm,)>) Product 1 (660 mg, 53%) as a white solid. MS (ESI) m/z=266.0 [ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.73(t,J＝57.4Hz,1H),7.58-7.57(m,1H),7.50(dd,J＝8.4,2.0Hz,1H),7.45(d,J＝8.4Hz,1H)。

Intermediate 2:

a) 1a (1.0 g,4.7 mmol) and formaldehyde (37% aqueous solution, 610. Mu.L) were added to water (5 mL) at room temperature. The reaction mixture was stirred overnight at 80 ℃, then cooled to room temperature, filtered, and washed with water (3×10 mL.) the crude product obtained was dried in vacuo to give light brown solid 2a (960 mg, 84%). MS (ESI): m/z=228.1 [ m+h] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.60(t,J＝1.2Hz,1H)；7.33(br,3H)；5.21(s,2H).

b) DAST (265. Mu.L, 2.0 mmol) was added dropwise to a solution of 2a (312 mg,1.3 mmol) in dichloromethane (5 mL) under nitrogen at-50 ℃. After the addition was completed, the reaction was allowed to slowly warm to room temperature and stirred overnight, then saturated NaHCO ₃ (10 mL) quenching, dichloromethane extraction, saturated brine washing (10 mL), na ₂ SO ₄ Drying and concentrating to give light brown solid 2 (306 mg, 95%). MS (ESI) m/z=246.1 [ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.86(brs,1H)；7.41-7.39(m,2H)；6.02(d,J＝52Hz,2H)。

Intermediate 3:

a) The compound 2-amino-4-bromophenol (1.0 g,5.3 mmol) and the compound 3-oxetanone (764 mg,10.6 mmol) were dissolved in dry THF (15.0 mL) at room temperature. Slowly drop BH under ice bath cooling ₃ THF (1M, 5.3 mL). After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirring was continued for 6 hours. Then, the compound 3-oxetanone (764 mg,10.6 mmol) and BH were further added ₃ THF (1M, 5.3 mL) and stirred overnight. The reaction solution was cooled in an ice bath, and an aqueous NaOH solution (1M, 20 mL) was slowly added dropwise to quench excess BH ₃ Separating out the organic phase, na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (purified with DCM/MeOH=50/1) afforded product 3a (640 mg, 50%) as a light brown solid, MS (ESI): m/z=246.2 [ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.64(s,1H),6.61-6.56(m,2H),6.32-6.28(m,1H),5.6(brs,1H),4.82-4.78(m,2H),4.53-4.45(m,3H)。

b) CDI (535 mg,3.3 mmol) was added to a solution of compound 3a (603 mg,2.5 mmol) in 2-MeTHF (10 mL) at room temperature under nitrogen. After refluxing under heating for one hour, the reaction mixture was cooled to room temperature, and was quenched with 2M HCl (aq.) (15 mL), 8% NaHCO ₃ (aq.) (15 mL) and saturated brine (8 mL). The organic phase was separated, na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE/ea=10:1 to 2:1, V/V) afforded product 3 (230 mg, 35%) as a pale brown solid. MS (ESI) m/z=270.0 [ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.68-7.66(m,1H),7.36-7.35(m,2H),5.42-5.37(m,1H),5.04-5.01(m,2H),4.93-4.88(m,2H)。

Intermediates 4 and 5:

a) Cs was added sequentially to a solution of 1a (1.1 g,5.1 mmol) in DMF (15 mL) at 0deg.C under nitrogen ₂ CO ₃ (1.6 g,5.1 mmol) in DMF (15 mL) and MeI (658. Mu.L, 10.2 mmol). Warmed to room temperature and stirred overnight. Cooled to 0℃and water (15 mL) was added dropwise. Filtration, washing with water and vacuum drying at 55deg.C gave 4 (826mg, 71%) as a pale brown solid MS (ESI) m/z=230.3 [ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.55-7.54(m,1H),7.29-7.28(m,2H),3.32(s,3H)。

b) Under the protection of argon, 4 (228 mg,1.0 mmol), pin ₂ B ₂ (305mg,1.2mmol)，Pd(OAc) ₂ (7 mg,0.03 mmol), XPhos (29 mg,0.06 mmol) and KOAc (254 mg,3.0 mmol) were added to dioxane (5 mL), heated to 75deg.C and stirring continued for 1 hour. Cool to room temperature, filter and wash the solid with EA (3×5 mL). The filtrate was concentrated and purified by column chromatography (eluent PE/dcm=0% to 100%, V/V) to give the product 5 (232 mg, 84.4%) as a grey solid MS (ESI) m/z=276.4 [ m+h] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ) Delta 7.47 (dd, J=8.0, 1.2Hz, 1H), 7.44 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 3.35 (s, 3H), 1.30 (s, 12H). Intermediates 6 and 7:

a) AIBN (524 mg,3.2 mmol) is added to a CCl containing methyl of 3-methylthiophene-2-carboxylate (5 g,32.05 mmol) and NBS (5.7 g,32.02 mmol) at 70 ℃ ₄ (80 mL) in suspension. Stirring was continued for 3 hours and NBS (2.85 g,16 mmol) was added cooled to 40 ℃. Then the temperature was raised to 70℃again and stirring was continued for 1 hour. Cooled to room temperature, the solids are removed by filtration, the filtrate is dried by spin-drying, the residue obtained is dissolved in EA (100 mL) and taken up in sequence with saturated NaHCO ₃ (30 mL), and water (30 mL), na ₂ SO ₄ Drying and concentrating to obtain oily product 6a (10 g), and the crude product is directly used in the next reaction. MS (ESI) m/z=155.4 [ M-Br ]] ⁺ 。

b) At room temperature, 7N NH ₃ in MeOH (100 mL) was added dropwise to a solution of 6a (crude 10g, ca. 32.05 mmol) in DMF (50 mL) and stirring was continued for 2 h. Then adding water H into the reaction solution ₂ O (200 mL) and EA (3X 150 mL), with solid NaHCO ₃ And regulating the pH value to be 8. Then adding dioxane (50 mL) and Boc in turn ₂ O (5 g,22.9 mmol) for 3 hours at room temperature. Concentrating under reduced pressure to evaporate dioxane, extracting with EA (3X 100 mL), na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE: ea=6:1 to 5:1 to 4:1, product rf=0.7 in PE/EA 4/1) gave product 6b (4 g, with some Boc ₂ O).MS(ESI):m/z＝294.3[M+Na] ⁺ 。

c) To a solution of 6b (crop 4g, about 14 mmol) in dichloromethane (60 mL) was added TFA (20 mL) at room temperature and stirring was continued for 1 hour. The solvent and TFA were removed by concentration under reduced pressure. The resulting residue was dissolved in dichloromethane (100 mL) and again dried by spin. The crude product was dissolved in MeOH (10 mL) and 7N NH3/MeOH was added to adjust pH to 10. The liquid was purified by preparative HPLC (C18, CH ₃ CN,10mM NH ₄ HCO ₃ Aqueous solution) to give off-white solid 6c (1.75 g, 31% yield over 4 steps.) MS (ESI) m/z=171.9 [ m+h] ⁺ . ¹ HNMR(400MHz,CDCl ₃ ):δ7.94(d,J＝4.8Hz,1H),7.5(brs,2H),7.32(d,J＝4.8Hz,1H),4.29(s,2H),3.83(s,3H)。

d) Let compound 6c (1.55 g,9.06 mmol) and K ₂ CO ₃ (1.25 g,9.06 mmol) was mixed in MeOH (120 mL) and EtOH (120 mL) and refluxed overnight. Cooling to room temperature, and spin-drying to obtain crude product. Column chromatography purification (eluent DCM: meoh=20:1 to 15:1, rf=0.2 in DCM/MeOH 20/1 solution) afforded product 6d (680 mg, 53%) as a light brown solid MS (ESI): m/z=140.1 [ m+h ] ⁺ 。

e) At 0 ℃, br ₂ (300 uL,5.85 mmol) AcOH (10 mL)/H of 6d (745 mg,5.36 mmol) was slowly added dropwise ₂ O (10 mL) and stirring was continued for 2 hours. Then, 10% ofNa ₂ SO ₃ (20 mL) and saturated NaHCO ₃ And adjusting the pH value to pH 7.EA (3X 50 ml) extraction, drying, concentrating off-white solid 6 (1.09 g, 93%). MS (ESI) m/z=218.2 [ M+H] ⁺ . ¹ HNMR(400MHz,CD3OD):δ7.29(s,1H),4.39(s,2H)。

f) NaH (60%in oil,122mg,3.05mmol) was added to a solution of 6 (600 mg,2.75 mmol) in DMF (10 mL) at 0deg.C. After stirring for half an hour, meI (205 uL,3.29 mmol) was added dropwise and then stirred at room temperature for 2 hours. Reaction liquid water H ₂ O (100 mL) quench, saturated NH ₄ Cl solution was neutralized to pH 7, EA (50 mL. Times.3) extracted, na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (EA: pe=2:1 to EA, rf=0.5 in EA) gave 7 (400 mg, 62%) as a light brown solid MS (ESI): m/z=232.1 [ m+h] ⁺ 。

Intermediate 8 and 9:

a) 2-amino-4-bromobenzoic acid methyl ester (20 g,87 mmol) was added at 0deg.C with 10% H ₂ SO ₄ In a flask (500 mL) was then added 70mLNaNO dropwise ₂ (12 g,173.9 mmol) in water. After stirring for 40 minutes, 70mL of an aqueous solution of KI (57.73 g,347.8 mmol) was added dropwise and stirring was continued for 1 hour. Saturated Na for reaction ₂ SO ₃ (200 mL) quenched, extracted with EA (3X 500 mL). Na (Na) ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE/EA=10:1, V/V) afforded product 8a (25 g, 84%) as an oil MS (ESI) m/z=342.8 [ M+H ] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ8.19(d,J＝1.6Hz,1H),7.71(d,J＝8.4Hz,1H),7.57-7.54(m,1H),3.94(s,3H)。

b) To a solution of 8a (11 g,32.3 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (6.08 g,35.5 mmol) in THF (230 mL) at-70deg.C was slowly added dropwise ⁱ PrMgCl-LiCl (27.3 ml,35.5mmol,1.3mol/L in THF) and stirring was continued for half an hour. The dry ice bath was removed, warmed to room temperature, and stirring was continued for 1 hour. Saturated NaHCO was used as the reaction solution ₃ (200 mL) of the aqueous solution was quenched and extracted with EA (3X 500 mL). Na (Na) ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE/EA=10:1, V/V) afforded yellow solid product 8b (6 g, 53%). MS (ESI): m/z=298.1 [ M-55 ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ7.93-7.91(m,1H),7.75(d,J＝1.2Hz,2H),4.55-4.52(m,2H),4.28-4.26(m,2H),1.51(s,9H)。

c) To a solution of 8b (0.8 g,2.35 mmol) in dichloromethane (20 mL) was added TFA (2 mL) at room temperature. After stirring for 7 hours, the product 8c (1 g, 91%) was concentrated under reduced pressure as a brown oil. MS (ESI) m/z=256.0 [ M+H ]] ⁺ 。

d) 8c (1 g,2.82 mmol) and paraformaldehyde (1.69 g,56.3 mmol) are added to MeOH (40 mL) and AcOH (5 mL) at room temperature, stirred for 1 hour, and then NaBH (OAc) is added ₃ (600 mg,2.82 mmol) and stirring was continued for half an hour. This step was repeated 9 times and then stirred overnight. The reaction solution was concentrated under reduced pressure, and saturated NaHCO was added to the residue ₃ (150 mL), EA (3X 200 mL) extraction, na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (fed with PE/ea=3:1 to 1:1, V/V) afforded product 8 (400 mg, 66.7%) as a white solid MS (ESI): m/z=270.0 [ m+h ] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ8.15-8.14(m,1H),7.70-7.69(m,2H),3.74-3.72(m,2H),3.67-3.65(m,2H),2.52(s,3H)。

e) To a solution of 8b (6 g,16.9 mmol) in THF (100 mL) at room temperature was added LiBH ₄ (1.49 g,67.8 mmol) in THF (100 mL). After stirring for 24h, the reaction was quenched with water (200 mL), extracted with EA (3X 500 mL), na ₂ SO ₄ Drying and concentrating to obtain crude product 9a. Purification by preparative HPLC (using NH ₄ HCO ₃ Aqueous solution A as buffer 10mM NH ₄ HCO ₃ An aqueous solution; acetonitrile; columb Waters XBridge Peptide BEH C, 19X 250mm,10 μm,) Product 9a (4.5 g, 75%) as a white solid was obtained as MS (ESI) m/z=380.2 [ M+Na ]] ⁺ 。

f) To a solution of 9a (2.5 g,7.0 mmol) and TEA (3.53 g,35 mmol) in THF (100 mL) at 0deg.C was added p-toluenesulfonic anhydride (2.73 g,8.4 mmol) in portions, stirred for 30 min, then warmed to room temperature and stirring continuedAnd stirring for 48 hours. Concentrating under reduced pressure, adding water (200 mL), extracting with EA (3X 200 mL), na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (fed with PE/ea=5:1, V/V) afforded product 9b (1.9 g, 80%) as a white solid MS (ESI): m/z=284.2 [ m-55 ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ7.62(d,J＝1.6Hz,1H),7.48-7.46(m,1H),7.10(d,J＝8.0Hz,1H),5.07(s,2H),4.32(d,J＝10.0Hz,2H),4.13(d,J＝10.0Hz,2H),1.50(s,9H)。

g) TFA (3 mL) was added dropwise to a solution of 9b (1 g,2.95 mmol) in dichloromethane (20 mL) at room temperature. After stirring for 3h, the mixture was concentrated under reduced pressure to give brown oil 9c (1.05 g, 99%) MS (ESI) m/z=242.1 [ M+H)] ⁺ 。

h) 9c (1.05 g,2.97 mmol) and paraformaldehyde (1.78 g) are added to a flask containing MeOH (60 mL) and AcOH (10 mL) at room temperature, stirred for 1h, and then NaBH (OAc) is added ₃ (629 mg,2.97 mmol) and stirring was continued for 30 min. This step was repeated 9 times and the reaction was stirred overnight. Concentrating under reduced pressure, adding saturated NaHCO ₃ (200 mL), EA (3X 200 mL) extraction, na ₂ SO ₄ Drying and concentrating to obtain crude product. Purification by column chromatography (eluent PE/EA=2:1 to 1:1, V/V) of the colourless oily product 9 (650 mg, 86%). MS (ESI) m/z=256.0 [ M+H] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ7.88(d,J＝1.6Hz,1H),7.45-7.42(m,1H),7.06(d,J＝8.0Hz,1H),5.02(s,2H),3.69-3.66(m,2H),3.43-3.40(m,2H),2.46(s,3H)。

Intermediate 10:

a) AIBN (840 mg,5.1 mmol) is added to a suspension of methyl 2-methylthiophene-3-carboxylate (8 g,51.3 mmol)/NBS (9.1 g,51.1 mmol) in carbon tetrachloride (120 mL) at 70 ℃. The reaction mixture was stirred at 70℃for 4h. The reaction mixture was cooled to room temperature and filtered. Saturated NaHCO was used for the filtrate ₃ (50 mL)/water (50 mL). The organic layer was separated with Na ₂ SO ₄ Dried, filtered and evaporated to give 10a as a light brown oil (13 g). The crude product was used directly in the next step. MS (ESI): m/z=155.4[M-Br]+。

b) 7N NH ₃ A solution of (30 mL,210 mmol) in MeOH was added to a solution of 10a (crude 13g, about 51.3 mmol) in THF (100 mL). The reaction mixture was stirred at room temperature for 1h. The reaction mixture was evaporated, the remaining light brown solid was washed with EA/MeOH 10/1 (50 mL) and filtered to give 10b (3.5 g, 39% yield) as a white solid. MS (ESI): m/z=172.0 [ m+h ] ]+。 ¹ HNMR(400MHz,MeOD):δ7.59-7.55(m,2H),4.61(s,2H),3.94(s,3H)

c) 10b (3.3 g,19.3 mmol)/K ₂ CO ₃ A solution of the mixture (2.66 g,19.3 mmol) in MeOH (120 mL) was refluxed for 24h, then the reaction mixture was cooled to room temperature and evaporated. The residue was purified by chromatography on silica gel (DCM: meoh=20:1, rf=0.5 in DCM/MeOH 20/1) to give 10c as a white solid (89mg, 33%). MS (ESI): m/z=140.4 [ m+h ]]+。 ¹ HNMR(400MHz,MeOD):δ7.56(d,J＝5.2Hz,1H),7.21(d,J＝5.2Hz,1H),4.53(s,2H)。

d) Br was taken up at 0 ℃ ₂ (320 uL,6.24 mmol) was added to a solution of 10c (0.86 g,6.19 mmol) in AcOH (10 mL)/H2O (10 mL). The reaction mixture was then stirred at 0℃for 1h. Further addition of Br to the reaction mixture ₂ (40 uL,0.78 mmol) and stirred at 0deg.C for a further 1h. 10% Na was added to the reaction mixture ₂ SO ₃ (20 mL) to colorless, then add saturated NaHCO ₃ To pH7 and extracted with EA (3X 50 mL). Combining EA layers with Na ₂ SO ₄ Dried, filtered and evaporated. The residue was washed with EA (10 mL)/PE (5 mL) to give 10 as a white solid (1.22 g, 90% yield). MS (ESI): m/z=218.2 [ m+h ]]+。 ¹ HNMR(400MHz,MeOD):δ7.27(s,1H),4.49(s,2H)。

Intermediate 11:

a) Will CH ₃ NH ₂ (2N in THF, 20mL,40 mmol) was added to a solution of 10a (crude 3g, about 11.54 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 2h. The reaction mixture was filtered and the filtrate evaporated. The residue was purified by silica gel chromatographyChemical (EA: pe=1:1-2:1-100% EA, rf=0.1 in EA) to give 11a (1.4 g, 66% yield in two steps) as a brown oil. MS (ESI) m/z=186.4 [ M+H ] ] ⁺ 。

b) 11a (1.4 g,7.57 mmol)/K ₂ CO ₃ (1.05 g,7.6 mmol) in MeOH (40 mL) was refluxed overnight. The reaction mixture was cooled to room temperature and evaporated to dryness. To the residue was added water (10 mL) and extracted with EA (3X 20 mL). Combining all EA layers with Na ₂ SO ₄ Dried, filtered and evaporated. Chromatography of the residue on silica gel (EA: pe=1:1-2:1-100% EA, rf=0.5 in EA/PE 2/1) gave 11b as a white solid (500 mg, 43%). MS (ESI) m/z=154.3 [ M+H ]] ⁺ . ¹ HNMR(400MHz,MeOD):δ7.55(d,J＝4.8Hz,1H),7.19(d,J＝4.8Hz,1H),4.56(s,2H),3.17(s,3H)。

c) Br was taken up at 0 ℃ ₂ (168 uL,3.27 mmol) was added to a solution of 11b (500 mg,3.27 mmol) in AcOH (5 mL)/H2O (5 mL). The reaction mixture was stirred at 0℃for 1h. Adding Br to the reaction mixture ₂ (35 uL,0.68 mmol) and stirred at 0deg.C for a further 2h. 10% Na was added to the reaction mixture ₂ SO ₃ (10 mL) to colorless, then add saturated solution. NaHCO (NaHCO) ₃ To pH7 and extracted with EA (3X 30 mL). The EA layers were combined, dried over Na 2 SO 4, filtered and evaporated. Purification of the residue by silica gel chromatography (EA: pe=1:1 to 2:1, rf=0.4 in EA/PE 2/1) afforded 11 as a pale solid (400 mg, 52%).

Intermediates 12 and 13:

a) To a solution of compound 8a (1 g,2.9 mmol) and 3-oxetanone (232 mg,3.2 mmol) in THF (25 mL) at-70deg.C was added drop wise iPrMgCl-LiCl (2.5 mL,3.2mmol,1.3mol/L in THF) after stirring for half an hour, warmed to room temperature, and saturated NaHCO was added ₃ (40 mL), EA (3X 100 mL) extraction, na ₂ SO ₄ Drying and concentrating to obtain crude product. Purification by preparative HPLC (using TFA as buffer: A:0.05% aqueous TFA; B: acetonitrile; column: waters XBridge Peptide BEH C, 19X 250mm,10μm,) 12 (300 mg, 40%) as a white solid MS (ESI): m/z=257.0 [ M+H ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ8.12(s,1H),7.77-7.73(m,2H),5.24(d,J＝8.0Hz,2H),4.91(d,J＝7.6Hz,1H).

b) LiBH was added to a solution of compound 12 in THF (70 mL) at room temperature ₄ (621 mg,28.2 mmol). After stirring for 24h, water (200 mL) was added, EA (3X 300 mL) was extracted, na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE/ea=2:1, V/V) afforded product 13a (1.6 g, 89%) as a white solid MS (ESI) m/z=281.0 [ m+na] ⁺ .

c) To a solution of 13a (1 g,3.9 mmol) and TEA (19.5 g,19.3 mmol) in THF (50 mL) at 0deg.C was added p-toluenesulfonic anhydride (1.51 g,4.6 mmol) in portions, stirred for half an hour, then warmed to room temperature and stirred for a further 48h. Concentrating under reduced pressure, adding water (100 mL), extracting with EA (3X 300 mL), na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE/EA=10:1, V/V) afforded product 13 (440 mg, 47%) as a white solid MS (ESI) m/z=243.1 [ M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.88(d,J＝1.6Hz,1H),7.56-7.54(m,1H),7.28(d,J＝8.0Hz,1H),5.00(s,2H),4.83-4.77(m,4H)。

Example 1: synthesis of Compound D01

a) Compound D01a (1 g,2.6 mmol) was dissolved in dichloromethane (30 mL) at room temperature, and trifluoroacetic acid (6 mL) was added dropwise. Stirring for 2h, spin-drying gave product D01b (1 g, 96.5%) as a brown solid. MS (ESI) m/z=291.0 [ M+H ] ] ⁺ .

b) (S) -4- (tert-butoxycarbonyl) -1, 4-oxazepan-2-carboxylic acid: the compound (S) -4- (tert-butoxycarbonyl) -1, 4-oxazepan-2-methanol (7.9 g,34.2 mmol) was dissolved in dichloromethane (134 mL) and water (28 mL) with ice-bath cooling. (S) -4- (tert-Butoxycarbonyl) -1, 4-oxazepan-2-oneAlcohols were synthesized according to the route reported in patent (WO 2015110826). TEMPO (107 mg,0.68 mmol) and Bu are then added sequentially ₄ NHSO ₄ (812 mg,2.4 mmol). At the same time, a buffer solution was prepared. To 68mL of NaClO solution (10-15%) was added saturated NaHCO3 solution (approximately 100 mL) to adjust the pH to 8-9. Then NaBr (599 mg,5.8 mmol) was dissolved in water (11.6 mL) and the above buffer solution was added. The buffer solution thus prepared was slowly dropped into the reaction solution. Note that the reaction was exothermic, please keep the temperature in the flask below 10 ℃ for 1h. Stirred overnight at room temperature and treated with KHSO ₄ (2N) adjusting pH to 2-3, extracting the reaction solution with dichloromethane (3X 500 mL), drying, and concentrating to obtain crude product. Column chromatography purification (fed with PE/ea=2:1 to 1:1, V/V) afforded the product (S) -4- (tert-butoxycarbonyl) -1, 4-oxazepan-2-carboxylic acid (30.9 g, 65%) as a white solid. MS (ESI) m/z=268.1 [ M+Na ] ] ⁺ . ¹ H NMR(400MHz,CDCl3):δ9.14(m,1H)；4.34-4.00(m,3H)；3.76-3.34(m,3H)；3.28-3.16(m,1H)；1.93-1.92(m,2H)；1.46(s,9H)。

c) Compound D01b (10.16 g,25 mmol) and (S) -4- (tert-butoxycarbonyl) -1, 4-oxazepan-2-carboxylic acid (5.56 g,22.7 mmol) were dissolved in DCM (300 mL) at room temperature, DIPEA (11.71 g,90.8 mmol), HOBt (3.06 g,22.7 mmol) and HBTU (9.46 g,25 mmol) were added sequentially and stirred overnight. To the reaction mixture was added water (200 mL), followed by extraction with methylene chloride (3X 400 mL), drying and concentration to obtain a crude product. Column chromatography purification (eluent PE/ea=1:1 to 1:4, V/V) afforded product D01c as a white solid (10.6 g, 91%). MS (ESI) m/z=540.1 [ M+Na ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ7.61(s,2H)；7.20-7.11(m,1H)；6.98(d,J＝8.4Hz,2H)；6.29(s,0.5H)；5.96(s,0.5H)；5.45(d,J＝8.0Hz,1H)；4.63-4.55(m,1H)；4.18-3.97(m,3H)；3.81-3.77(m,0.5H)；3.50-2.93(m,5.5H)；2.00-1.86(m,2H)；1.45(s,9H)。

d) Compounds D01c (9.7 g,18.8 mmol) and Pin were reacted under argon at room temperature ₂ B ₂ (9.53 g,37.5 mmol) in DMSO (250 mL) followed by Pd (dppf) Cl ₂ (960 mg,1.3 mmol) and KOAc (5.52 g,56.3 mmol). The reaction was heated to 85℃and stirring was continued for 8h. Cooled to room temperature, diluted with EA (1000 mL) and washed with saturated brine(5×200mL),Na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE/ea=1:1 to 1:6, V/V) afforded product D01D (8.5 g, 87.6%) as a white solid. MS (ESI) m/z=540.3 [ M+Na ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ7.76(d,J＝7.2Hz,2H)；7.25(d,J＝8.0Hz,2H)；7.18(d,J＝7.2Hz,1H)；6.15(s,0.5H)；5.88(s,0.5H)；5.48(d,J＝18Hz,1H)；4.67-4.61(m,1H)；4.20-3.99(m,3H)；3.85-3.80(m,0.5H)；3.54-3.11(m,5H)；2.96-2.90(m,0.5H)；2.02-1.96(m,2H)；1.46(s,9H),1.34(s,12H)。

e) Compound D01D (200 mg,0.39 mmol), 6-bromoimidazo [1,2-a, is reacted under argon at room temperature]Pyridine (115 mg,0.58 mmol) was dissolved in dioxane (8 mL) and water (0.8 mL) and then taken into PdCl ₂ dppf (30 mg,0.04 mmol) and KOAc (115 mg,1.17 mmol), heating to 85℃and stirring was continued for 4h. The reaction solution was cooled to room temperature, EA (50 mL) was added thereto, followed by extraction, washing with saturated brine (10 mL), na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent EA-EA: meoh=10:1, rf=0.3 in EA/MeOH 10/1) afforded product D01e (120 mg, 60%) as a brown oil, MS (ESI): m/z=508.3 [ m+h] ⁺ . ¹ HNMR(400MHz,CDCl ₃ ):δ8.35-8.31(m,1H),7.76-7.70(m,3H),7.66-7.41(m,3H),7.38-7.36(m,2H),7.26-7.19(m,1H),6.24(brs,0.5H),5.93(brs,0.5H),5.45(brs,1H),4.71-4.64(m,1H),4.22-4.02(m,3H),3.80-3.76(m,0.5H),3.52-3.02(m,5.5H),1.92-1.90(m,2H),1.47(s,9H)。

f) To a solution of D01e (120 mg,0.237 mmol) in methylene chloride (10 mL) was added Burgess reagent (338 mg,1.42 mmol) at room temperature. After stirring at room temperature for 4 hours, the reaction mixture was diluted with dichloromethane (20 mL), washed with water (10 mL), and then Na ₂ SO ₄ Drying and concentrating to obtain crude product. The crude product was purified by HPLC (with TFA buffer: A:0.05% aqueous TFA; B:0.05% acetonitrile TFA; column: waters XBridge Peptide BEH C, 19X 250mm,10 μm,) Purifying and freeze-drying. The obtained product is saturated NaHCO ₃ Neutralized to pH7, the resulting solution was extracted with EA (3X 50 mL), na ₂ SO ₄ Drying, concentrating the brown solid product D01f (15 mg,yield 12％).MS(ESI):m/z＝490.3[M+H] ⁺ 。

g) HCOOH (3 mL) was added to compound D01f (10 mg,0.02 mmol) at room temperature, followed by incubation to 50deg.C and stirring for an additional 10 min. The reaction mixture was concentrated to give a crude product, which was purified by-HPLC (using HCOOH buffer: A:0.1% HCOOH in water; B: acetonitrile; column: waters XBridge Peptide BEH C, 19X 250mm,10 μm,) White solid product D01 (1.5 mg, 17% yield). />

Following the procedure of example 1, substituting a different bromo compound for 6-bromoimidazo [1,2-a ] pyridine, the following compound is prepared:

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Further, following the procedure of example 1, substituting a different bromo compound for 6-bromoimidazo [1,2-a ] pyridine can also produce the following compound:

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example 2: synthesis of Compound D11

a) D01D (200 mg,0.387 mmol), 2-bromo-4, 5-dihydro-6H-thieno [2,3-c ] was treated under argon at room temperature]Pyrrole-6-one (170 mg,0.78 mmol), pdCl ₂ dppf (60 mg,0.08 mmol) and KOAc (114 mg,1.16 mmol) were added to dioxane (8 mL)/and H ₂ O (0.8 mL). Stirring was carried out overnight at 90 ℃. The reaction mixture was cooled to room temperature, and EA (50 mL) and saturated brine (10 mL) were added thereto, and EA (3X 300 mL) was added to extract, na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent EA, EA: meoh=20:1 to 10:1, rf=0.5 in EA/MeOH 10/1) afforded the relatively pure product, preparative HPLC (C18, CH ₃ CN,10mM NH ₄ HCO ₃ Aqueous) was further purified to give product D11a (120 mg, yield 58%) as a white solid, MS (ESI) m/z=551.2 [ m+na] ⁺ 。

¹ HNMR(400MHz,CDCl ₃ ):δ7.56-7.52(m,2H),7.32-7.20(m,3H),6.33-6.28(m,1.5H),5.97(brs,0.5H),5.46-5.35(m,1H),4.69-4.63(m,1H),4.40(s,2H),4.22-4.01(m,3H),3.81-3.76(m,0.5H),3.53-2.99(m,5.5H),2.03-1.82(m,2H),1.47(s,9H)。

b) Burgess reagent (325 mg,1.36 mmol) was added to a solution of D11a (120 mg,0.227 mmol) in dichloromethane (15 mL) and THF (5 mL) at room temperature, stirred for 4h, diluted with dichloromethane DCM (20 mL), washed with water (10 mL), na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent EA to EA: meoh=20:1, rf=0.1 in EA) of the white solid product D11b (130 mg, 88% yield.) MS (ESI): m/z=548.2 [ m-Boc ] ⁺ . ¹ HNMR(400MHz,DMSO-d ₆ ):δ8.78(d,J＝8Hz,1H),7.70(d,J＝8.4Hz,2H),7.62(s,1H),7.38(d,J＝8Hz,2H),5.05-4.99(m,1H),4.86(s,2H),4.12-4.08(m,1H),3.95-3.76(m,2H),3.57-3.47(m,2H),3.37(s,3H),3.26-2.95(m,4H),1.80-1.69(m,2H),1.39-1.34(m,9H)。

c) To D11b (50 mg,0.077 mmol) of MeOH (0.5 mL) and CH at room temperature ₃ To a solution of CN (3 mL), a solution of 4NHCl (0.2 mL) in methanol (0.5 mL) was added dropwise. After stirring for 2h, 4N HCl (0.2 mL) was added and stirring was continued for 2h. Then, et was added to the reaction solution ₂ O (40 mL), a portion of white precipitated out. After centrifugation for 2 min, the liquid was removed and the residue was purified by preparative HPLC (using NH ₄ HCO ₃ The aqueous solution is buffer solution: a10 mM NH ₄ HCO ₃ An aqueous solution; acetonitrile; column Waters XBridge Peptide BEH C18,19×250mm,10μm,) Product D11 was obtained as a white solid (20 mg, yield 47%) MS (ESI) with m/z=548.1 [ m+h ]] ⁺ 。

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Example 3: synthesis of Compound D15

a) The compound ethyl cyanoacetate (20 g,177 mmol), 1,2-dibromoethane (66.5 g,354 mmol) and K were combined at room temperature ₂ CO ₃ (73.3 g,531 mmol) was added sequentially to acetone (300 mL). Reflux was performed overnight, then cooled to room temperature, and the solid was filtered off. The filtrate was concentrated to give product D15a (22 g, 89%) as a yellow oil MS (ESI): m/z=140.4 [ m+h] ⁺ 。

b) D15a (22 g,158.3 mmol) was dissolved in dry THF (150 mL) at 0deg.C and added slowly dropwise to LiAlH containing solution ₄ (24.06 g,633.1 mmol) in THF (250 mL). The reaction was stirred overnight, then cooled to 0deg.C and quenched with Et ₂ O (250 mL) was diluted, carefully quenched with water (22.06 mL), 15% aq. NaOH (22.06 mL), and additional water (22.06 mL), the solids filtered off, and the droplets washed with MeOH (400 mL). The filtrate was treated with Na2SO ₄ Dried, the solid was filtered off, HCl (100 ml,4mol/L dioxane solution) was added and concentrated to give crude product D15b (22 g, 80%) as a brown oil. ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.09(s,3H)；3.32(s,2H)；2.79-2.75(m,2H)；0.58-0.55(m,2H)；0.45-0.42(m,2H)。

c) D15b (5 g, purity:80%,29.1 mmol), benzaldehyde (4.63 g,43.6 mmol) and TEA (2.94 g,29.1 mmol) were added to in MeOH (100 mL) at room temperature, and stirred for 2hAdding NaBH in portions ₄ (2.21 g,58.2 mmol). After stirring for 2h, the solid was filtered off, the filtrate was concentrated and the column chromatographed (eluent MeOH/DCM=1:15, V/V) as brown oily product D15c (4.8 g, 87%). MS (ESI): m/z=192.4 [ M+H] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ7.37-7.26(m,5H)；3.82(s,2H)；3.58(s,2H)；2.76(s,2H)；0.52-0.50(m,2H)；0..41-0.39(m,2H)。

d) Compound D15c (9.3 g,48.7 mmol) and (S) -benzyloxymethyloxirane (8.38 g,51.1 mmol) were added at room temperature ⁱ PrOH (100 mL) and stirred at 50deg.C for 16h. Cooled to room temperature, concentrated, and purified by column chromatography (eluent PE/ea=1:1 to 1:2, V/V) to give product D15D (14 g, 81%) as a brown oil. MS (ESI) m/z=356.2 [ M+H ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ7.38-7.26(m,10H)；4.52(s,2H)；4.09-4.03(m,1H)；3.86(d,J＝13.2Hz,1H)；3.59-3.36(m,5H)；2.87(d,J＝13.2Hz,1H)；2.77-2.71(m,1H)；2.52-2.48(m,1H)；2.35(d,J＝13.2Hz,1H)；0.60-0.56(m,1H)；0.47-0.40(m,2H)；0.35-0.31(m,1H)。

e) DIPEA (5.6 g,43.4 mmol) was added to a solution of D15D (11 g,31 mmol) in dichloromethane (100 mL) in ice bath, followed by MsCl (3.9 g,34.1 mmol) dropwise over 1 h. After stirring for 1h, ice water (100 mL) was added and extracted with dichloromethane (3X 200 mL). Na (Na) ₂ SO ₄ Drying and concentrating to obtain a brown oily crude product D15e. MS (ESI) m/z=434.2 [ M+H ]] ⁺ 。

f) To a suspension of NaH (3.88g,97mmol,purity:60%in oil) in THF (300 mL) at 0deg.C was slowly added dropwise a solution of D15e (14 g,32.3 mmol) in THF (100 mL). Stirring at 50deg.C for 16 hr, cooling to 0deg.C, adding sat NaHCO ₃ (200 mL), EA (3X 400 mL). Na (Na) ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE/EA=6:1 to 5:1, V/V) afforded product D15f (8 g, 73%) as a brown oil MS (ESI): m/z=338.2 [ M+H] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ7.36-7.23(m,10H)；4.57-4.49(m,2H)；4.15-4.08(m,1H)；3.75-3.62(m,3H)；3.56-3.49(m,2H)；3.40-3.36(m,1H)；2.97(d,J＝13.6Hz,1H)；2.70-2.60(m,2H)；2.34(d,J＝12.4Hz,1H)；0.58-0.44(m,3H)；0.35-0.30(m,1H)。

g) D15f (4 g,11.9 mmol) was dissolved in a hydrogenation apparatus containing methanol (100 mL) at room temperature, and then Pd/C (800 mg,10% on C) and AcOH (4 mL) were added. After the air of the hydrogenation apparatus was replaced by hydrogenation 4 times, hydrogenation was performed and the reaction mixture was shaken for 7 hours. HCl (1 ml,12mol/L,12 mmol) was then added and hydrogenation was continued for 16h. Pd/C was filtered off and the product D15g (2.4 g, 90%) was concentrated as a brown oil MS (ESI): m/z=158.2 [ M+H ]] ⁺ 。

h) D15g (4.8 g,24.8 mmol) was dissolved in dioxane (150 mL) and water (150 mL) at room temperature, then added (Boc) ₂ O (10.82 g,49.6 mmol) and NaHCO ₃ (10.42 g,124 mmol). After stirring for 16h, EA (3X 500 mL) was extracted, na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE/ea=2:1 to 1:1, V/V) afforded product D15h (5.7 g, 90%) as a colourless oil MS (ESI): m/z=280.0 [ m+na] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ3.85-2.92(m,9H)；1.58-1.40(m,9H)；0.66-0.45(m,4H)。

i) D15h (2 g,7.78 mmol) was dissolved in dichloromethane (35 mL) at room temperature, and water (7, TEMPO (24 mg,0.16 mmol), bu was added sequentially ₄ NHSO ₄ (185 mg,0.54 mmol) at the same time, 15.5. 15.5mL of NaClO solution (10-15%) was treated with sat. NaHCO ₃ (liquid+solid) (about 30 mL) was adjusted to a pH of 8-9, naBr (136 mg,1.32 mmol) in water (1 mL) was added to the buffer solution. The resulting solution was cooled to 0℃and slowly added dropwise to the reaction solution. After 1h reaction at 0 ℃, stirring overnight. KHSO reaction solution ₄ (2N) pH was adjusted to pH to 2-3. Dichloromethane extraction, na ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE/ea=2:1 to 1:1, V/V) afforded product D15i (1.08 g, 40%) as a white solid MS (ESI): m/z=294.2 [ m+na] ⁺ 。

j) To a solution of (S) -2-amino-3- (4-iodophenyl) propanamide trifluoroacetate (1.79 g,4.4 mmol) in dichloromethane (40 mL) was added D15i (1 g,3.7 mmol), DIPEA (1.9 g,14.8 mmol), HOBt (498 mg,3.7 mmol) and HBTU (1.68 g,4.4 mmol) in sequence at room temperature. After stirring for 5h, water (50 mL) was added and extracted with dichloromethane (3X 150 mL). Na (Na) ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE/ea=1:1 to 1:5, V/V) followed by flash columnPurifying by chromatography to obtain crude product, (C18, CH) ₃ CN,10mM NH ₄ HCO ₃ Aqueous solution), white solid product D15j (1 g, 50%). MS (ESI) m/z=566.0 [ m+na ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ7.66-7.64(m,2H)；7.19(d,J＝8.4Hz,0.5H)；7.10(d,J＝8.4Hz,0.5H)；7.00(d,J＝8.4Hz,2H)；6.23(s,0.5H)；5.89(s,0.5H)；5.37(s,1H)；4.66-4.59(m,1H)；4.30-4.06(m,2H)；3.88(d,J＝13.6Hz,0.5H)；3.76-3.71(m,1H)；3.51(d,J＝14Hz,0.5H)；3.38-3.34(m,0.5H)；3.30(d,J＝12.8Hz,1H)；3.14-3.00(m,3H)；2.84(d,J＝14Hz,0.5H)；1.49(s,5H)；1.47(s,4H)；0.66-0.47(m,4H)。

k) To a solution of D15j (1 g,1.84 mmol) in DMSO (30 mL) at room temperature was added Pin ₂ B ₂ (936mg,3.68mmol),Pd(dppf)Cl ₂ (267 mg,0.37 mmol) and KOAc (541 mg,5.52 mmol). The flask was depressurized to remove air and then refilled with argon. After repeating 3 times, the reaction was stirred at 85℃for 5 hours. Cooled to room temperature, diluted with EA (500 mL), and washed with saturated brine (5X 100 mL). Na (Na) ₂ SO ₄ Drying and concentrating to obtain crude product. Column chromatography purification (eluent PE/ea=1:2 to 1:6, V/V) afforded product D15k (900 mg, 90%) as a brown solid MS (ESI): m/z=566.3 [ m+na ] ⁺ . ¹ H NMR(400MHz,CDCl ₃ ):δ7.73-7.75(m,2H)；7.26(d,J＝7.6Hz,2H)；7.22-7.15(m,1H)；6.15(s,0.5H)；5.84(s,0.5H)；5.44(s,1H)；4.71-4.61(m,1H)；4.29-4.06(m,2H)；3.86(d,J＝13.6Hz,0.5H)；3.71-3.65(m,1H)；3.49(d,J＝14Hz,0.5H)；3.33-3.27(m,1.5H)；3.15-3.04(m,3H)；2.81(d,J＝13.6Hz,0.5H)；1.48(s,5H)；1.46(s,4H)；1.35(s,12H)；0.65-0.46(m,4H)。

l) dissolving D15k (200 mg,0.37 mmol) in dioxane (10 mL) at room temperature, followed by sequential addition of 5-bromo-3-methylbenzo [ D ]]Oxazol-2 (3H) -one (126 mg,0.55 mmol), pd (dppf) Cl ₂ (54 mg,0.07 mmol), KOAc (108 mg,1.1 mmol) and water (1 mL), the flask was depressurized to remove air and then argon was injected. The reaction mixture was stirred at 85℃for 6h. Cooled to room temperature, concentrated, and purified by column chromatography (eluent PE/ea= 1:1 to 1:6 to MeOH/dcm=1:10, V/V) to give a relatively pure product. Further column purification (C18, CH ₃ CN,10mM NH ₄ HCO ₃ Aqueous solution) to give brown solid product D15l (150 mg, 72%). MS (ESI): m/z=587.3 [ m+na] ⁺ 。

m) at room temperature, D15l (140 mg,0.25 mmol) was dissolved in dichloromethane (10 mL) and Burgess reagent (354 mg,1.49 mmol) was added. After stirring for 3h at room temperature, concentration and purification by preparative HPLC (Using NH) ₄ HCO ₃ buffer:A:10mM NH ₄ HCO ₃ An aqueous solution; b, acetonitrile; columb Waters XBridge Peptide BEH C, 19X 250mm,10 μm,) This gave product D15m (80 mg, 59%) as a brown solid, MS (ESI) m/z=569.3 [ M+Na ]] ⁺ 。

n) HCl-dioxane (1.172 mmol,4mol/L,0.293 mL) was added dropwise to a solution of D15m (80 mg,0.147 mmol) in MeCN (4.8 mL) at room temperature. After stirring at room temperature for 1.5h, cold Et was added ₂ O (45 mL), centrifuged to remove the liquid phase. The residue was taken up in Et ₂ O (15 mL) was washed twice. Purification by preparative HPLC (A: 0.8% NH) ₄ HCO ₃ Aqueous solution, B: CH ₃ A CN; columb Xbridge BEH peptide C, 19mm×250 mm) gave product D15 (35 mg, 53%) as a white solid with an HPLC purity of 99.46%.

The following compounds were prepared in a similar manner from different analogues of L-amphetamine (L-Phenylalanine):

the following compounds were prepared from different 6-membered and 7-membered cyclic amino acids in a similar manner:

example 4: evaluation of cathepsin C enzyme inhibition in vitro in cells (U937 cells)

Intracellular enzyme activity assays were performed in 384 well plates, cell culture medium: 1640 10% fbs,1 ps. mu.L of cell culture medium cell suspension containing U937 cells was added to 384-well plates so that each well contained 2X 10 ⁴ A cell; and 30nL of AZD7986, a vehicle control (100% DMSO) or serial dilutions of the test compound were added to the wells by Echo, after incubation at 37℃for 1h, h-Gly-phe-AFC (10. Mu.L) was added to each well and the reaction was started, further incubation was carried out at 37℃for 1h, and then fluorescence absorbance was read by EX. Lamda.400 nm and EM. Lamda.505 nm. The above test results were calculated as IC50 values using Graphpad 8.0, and the results are shown in the following Table:

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"++": the inhibition rate is more than or equal to 75 percent and less than 100 percent; "+": the inhibition rate is less than or equal to 30 percent and less than 75 percent; "-": inhibition rate <30%; "/": not tested.

The embodiments of this patent are provided by way of illustration only and not by way of limitation. Those skilled in the art will readily recognize that various non-critical parameters may be changed or modified to produce substantially similar results.

While the invention has been described and illustrated in considerable detail, it should be understood that modifications and equivalents to the above-described embodiments will become apparent to those skilled in the art, and that such modifications and improvements may be made without departing from the spirit of the invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that:

cy is

p is 0-6;

R ^a Each independently selected from deuterium, halogen, hydroxy, cyano, mercapto, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _3-6 Heterocycloalkyl, C _3-6 Cycloalkyloxy, heterocycloalkoxy, -SC _1-6 Alkyl group,C _1-6 Alkoxy, C _1-6 Alkylamino, (C) _1-6 Alkyl group ₂ N-、C _1-6 alkyl-C (O) HN-, -C (O) NHC _1-6 Alkyl, oxo, thio, and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy groups are each optionally substituted with halogen and deuterium; two R ^a Can be connected with the same carbon atom or can be connected with different carbon atoms; r is R ^a Or two R ^a Together form C _1-4 Alkylene or ether chains containing 1 to 4 carbon atoms, e.g. -CH ₂ -O-CH ₂ -CH ₂ -CH ₂ -、-CH ₂ -O-CH ₂ -, the alkylene or ether chain may form with the original ring a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged, fused and spiro ring, with or without heteroatoms, including N, S, O, which cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged, fused and spiro rings may be optionally substituted with deuterium, hydroxy, halogen, alkyl and alkoxy, and wherein C, S may be optionally oxo-c=o, -s=o, -S (O) 2-; or two R ^a The carbon atoms to which each is attached constitute a 6 membered aryl, 5 membered heteroaryl, 6 membered heteroaryl, and forms a fused ring with the original ring, said fused ring being optionally substituted with hydroxy, halogen, cyano, alkyl, alkoxy; and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy groups are each optionally substituted with halogen and deuterium;

q is 0-3;

when in the following four cases (the four cases are and/or are related)

1) Cy is not

2) X, Y, Z are not simultaneously CH;

3)R ² is not hydrogen and q is not 0;

4) A and B are not hydrogen at the same time;

R ^1a Can be selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, and ringAlkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy optionally substituted with one or more R ₃ Substitution; two R ^1a Can be connected with the same carbon atom or nitrogen atom or can be connected with different carbon atoms or nitrogen atoms; two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aromatic, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, C, S in the ring may also be optionally oxo or thioxo-CO-, -CS-, -SO2-;

when Cy isAnd X, Y, Z are CH and R ² When hydrogen is used and both A/B are H:

and/or R ¹ Selected from:

f is 0-2;

g is 0-3;

h is 0-5;

k is 0-2;

R ³ and R is ⁴ Unless specifically stated otherwise, as defined above;

when f and g are not 0 and R ^1a When not hydrogen, R ^1b ＝H、R ^1a ；R ^1b And R is R ^1a Or two R ^1a Optionally forming a saturated or unsaturated cyclic group with a carbon atom or a nitrogen atom in the original ring, said cyclic group comprisingIncluding but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

when f and g are 0, or f and g are other than 0 and R ^1a When hydrogen, R ^1b Can be selected from hydrogen, deuterium, halogen, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocycloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ₃ Substitution; r is R ^1b And R is R ^1a Or two R ^1a Optionally forming a saturated or unsaturated cyclic group with the carbon or nitrogen atom of the original ring, including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro, fused ring, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and the ringThe C, S groups of (C) can also be selectively oxo to-CO-, -SO2-;

when k is 0, or k is other than 0 and R ^1a When hydrogen:

if R is ^5a Deuterium, bromine, cyano, hydroxy, amino, mercapto, carboxyl, sulfonyl, sulfoxide, oxo, thio, nitro, cyano, C _2-8 Alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl,The heteroarylalkoxy groups may be optionally substituted with one or more R ³ Substitution;

If R is ^5a Is H, then R ^6＝ R ^1a ，R ⁵ Can be selected from deuterium, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, cyano, alkyl, 1-2 fluoro substituted alkyl, 1-3 bromo substituted alkyl, 1-3 chloro substituted alkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ (wherein R is ³ And R is ⁴ Not simultaneously H), alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ³ 、-S(O)2C _4-8 Alkyl, -OS (O) 2C _4-8 Cycloalkyl, -OS (O) 2C _4-8 Heterocyclylalkyl, -S (O) (NH) R ³ 、-S(O)(NR ⁴ )R ³ 、S(O)2NR ³ R ⁴ (wherein R is ³ And R is ⁴ Can form, with the attached N atom, a heteroalkenyl group, a piperazinyl group, a 5-7 membered azaalkyl group containing at least 1O atom, a morpholinyl group, a bridged ring morpholinyl group, or R ³ And R is ⁴ Singly substituted and unconfiguredRing formation), -S (O) 2NH ₂ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ³ Substitution;

Wherein the method comprises the steps of

X ₁ 、Y ₁ 、Z ₁ May be independently selected from CH and N;

R ⁷ ＝R ^1a ；

Cy is

p is 0-6;

R ² selected from hydrogen, deuterium, halogen, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl radicals、C _3-6 A cycloalkoxy group, said alkyl, alkoxy, cycloalkyl and cycloalkoxy groups each optionally substituted with halogen and deuterium;

q is 0-3;

when in the following four cases (the four cases are and/or are related)

1) Cy is not

2) X, Y, Z are not simultaneously CH;

3)R ² is not hydrogen and q is not 0;

4) A and B are not hydrogen at the same time;

when Cy isAnd X, Y, Z are CH and R ² When hydrogen is used and both A/B are H:

and/or R ¹ Selected from:

f is 0-2;

g is 0-3;

h is 0-5;

k is 0-2;

R ³ and R is ⁴ Unless specifically stated otherwise, as defined above;

when f and g are 0, or f and g are other than 0 and R ^1a When hydrogen, R ^1b Can be selected from hydrogen, deuterium, halogen, hydroxy, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocyclenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocycloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ³ R ⁴ Alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclyl carbonyloxy, -SOR ³ 、-S(O)2R ³ 、-S(O)(NH)R ³ 、-S(O)(NR ⁴ )R ³ 、-S(O)2NR ³ R ⁴ 、-OS(O)2R ³ 、-NR ³ R ⁴ 、-NR ³ (CO)R ⁴ 、-NR ³ (SO ₂ )R ⁴ 、-NR ³ R ⁴ Substituted alkyl, -CR ³ R ⁴ 、-SR ³ Aryl, 5-6 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaralkoxy is optionally substituted with one or more R ₃ Substitution; r is R ^1b And R is R ^1a Or two R ^1a Can be selectively formed into a saturated or unsaturated cyclic ring with the carbon atom or nitrogen atom in the original ringA cyclic group including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, fused ring, aryl, heteroaryl, and the cyclic group may be substituted with one or more R ³ Further optionally substituted, and C, S in the ring may also be optionally oxo-CO-, -SO2-;

when k is 0, or k is other than 0 and R ^1a When hydrogen:

Wherein the method comprises the steps of

When V is-O-, -S-, -CF ₂ When-and U is-CO-, T is-O-, -S-, -Se-, -CO, -SO-, -S (O) 2, -CR ⁸ R ⁹ -，-NH-、-N(CHF)-、-N(CF ₂ )-、-N(CH ₂ -CH(OH)-CH ₃ )-、-N(CH ₂ -CH(OCH ₃ )-CH ₃ )-、-N(CH ₂ -CH ₂ -OCH ₃ )-、-N(C _4-8 Alkyl) -, -N (cycloalkyl) -, -N (cycloalkoxy) -, -N (oxetane) -, -N (tetrahydrofuran) -, -N (tetrahydropyran) -, where the is-N (C) _4-8 Alkyl) -, -N (cycloalkyl) -, -N (cycloalkoxy) -, -N (oxetane) -, -N (tetrahydrofuran) -, -N (tetrahydropyran) is optionally C _1-3 Alkoxy, C _1-3 Alkyl, C _3-6 Cycloalkyl, NH (C) _1-3 Alkyl), N (C) _1-3 Alkyl group ₂ Or 1 to 3 halogen substitutions; otherwise T is-O-, -S-, -Se-; -CO-, -SO2-, -C (R) ⁸ R ⁹ )-、-N(R ⁷ )-；

X ₁ 、Y ₁ 、Z ₁ May be independently selected from CH and N;

R ⁷ ＝R ^1a ；

2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: the Cy is selected from

Ar is pyridine and benzene ring;

R ^b is chloro, fluoro, methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, trifluoromethoxy.

3. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: the A and B are both selected from H, or are both selected from F.

4. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: and each X and Y is independently selected from CH and N, and Z is selected from CH.

5. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: the R is ² Selected from hydrogen, fluorine, methyl, q is selected from 1.

6. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: the R is ¹ Selected from the group consisting of

Wherein the method comprises the steps of

X ₁ 、Y ₁ 、Z ₁ Independently selected from CH, N;

m, n and o are 0-3;

u may be selected from-C (=O) -, -S (O) 2-, -O-, -NR ⁷ -、-CR ⁸ R ⁹ -；

R ⁸ 、R ⁹ is hydrogen,Fluorine, -C _1-6 Alkyl, -C _1-6 Haloalkyl, or R ⁸ And R is ⁹ Together with the nitrogen or carbon atom to which it is attached form C _3-6 Cycloalkyl, oxetane, azetidine, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuranyl, tetrahydropyranyl, said cyclopropane, oxetane, azetidine, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted by C _1-3 Optionally substituted with alkyl, cyclopropane, oxetane, azetidine, cyclopropyloxy;

R ⁶ selected from hydrogen, fluorine, chlorine, bromine, methyl;

R ^7a selected from H, -CHF, -CF ₂ 、-CH ₂ -CH(OH)-CH ₃ 、-CH ₂ -CH(OCH ₃ )-CH ₃ 、-C _4-8 Alkyl, -cycloalkyl, -cycloalkoxy, -CH ₂ -CH ₂ -OCH ₃ -oxetane, -tetrahydrofuran, -tetrahydropyran, pyrrolidine, piperazine, morpholineA piperidine and a piperidine; wherein said C _4-8 Alkyl, tetrahydrofuran, pyrrolidine, piperazine, morpholine, piperidine optionally substituted with 1, 2 or 3 fluorine and/or optionally substituted with one substituent selected from the group consisting of: hydroxy, -OC _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ Cyclopropyl;

R ⁶ selected from hydrogen, fluorine, chlorine, bromine, methyl;

R ^7a ＝R ⁷ 。

7. a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: the R is ¹ Select to

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

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9. use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment and prophylaxis of diseases of cathepsin C and its downstream serine proteases NE, PR3, caTG, NSP 4.

10. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 in the manufacture of a medicament for the treatment of patients suffering from respiratory diseases, metabolic diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, cancer, infectious diseases and other inflammatory related diseases, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, pulmonary arterial hypertension, non-cystic fibrosis, bronchiectasis, bronchitis, pneumonia, emphysema, acute Lung Injury (ALI), acute Respiratory Distress Syndrome (ARDS), sepsis, allergic diseases, immune inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis, eosinophilic granulocyte diseases, neutrophil diseases, ANCA-related inflammation, anti-neutrophil cytoplasmic antibody-related necrotizing crescent glomerulonephritis, acute brain trauma, acute myocarditis, acute renal injury, a-1-antitrypsin deficiency (AATD) and related inflammation, hepatic fibrosis, fatty liver and liver steatosis, obesity, insulin resistance, diabetes, biological infections, infectious inflammation, and radiation-induced inflammatory bowel disease and radiation injury or the like.

11. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 8 in a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

12. A pharmaceutical composition according to claim 11, wherein: comprising one or more compounds of formula (I) as defined in any one of claims 1 to 8, and a pharmaceutically active compound selected from the group consisting of other compounds including, but not limited to: b mimetics, anticholinergic agents, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists, SYK inhibitors, NE inhibitors, MMP9 inhibitors, MMP12 inhibitors, and combinations of two or three active substances.

13. A pharmaceutical composition according to any one of claims 11-12, wherein: the pharmaceutical compositions also include use in combination with small molecule compounds and/or large molecule antibodies, including but not limited to glucocorticoids, adrenergic agonists, cholinergic receptor antagonists, theophyllines, antioxidants, elastase inhibitors, metalloprotease inhibitors, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists and SYK inhibitors, chemokine receptor inhibitors, interleukin antibodies such as IL-6 antibodies, IL-23 antibodies, targeted anti-Thymic Stromal Lymphopoietin (TSLP) antibodies such as tezepelumab, complement inhibitors, for the treatment of cancer, inflammation, bone marrow related disorders, and autoimmune diseases.

14. A pharmaceutical composition according to claim 13, wherein: use of the composition in the manufacture of a medicament for the treatment and prophylaxis of a condition selected from the group consisting of respiratory, metabolic, cardiovascular and cerebrovascular, autoimmune, cancer, infectious or inflammatory diseases by cathepsin C and its downstream serine proteases NE, PR3, caTG, NSP 4.

15. A solvate, racemic mixture, enantiomer, diastereomer, tautomer, or mixture comprising a racemic mixture of a compound of formula (I) according to any one of claims 1 to 8, wherein said R ¹ 、R ² Each substituent of Cy, A, B, X, Y, Z and q:

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