Peptidyl nitrile compounds and uses thereof

Abstract

Provided are peptidyl nitrile compounds and uses thereof, and specifically disclosed are a compound of formula (I) and / or a pharma- ceutically acceptable salt thereof, a pharmaceutical composition comprising said compound and / or a pharma- ceutically acceptable salt thereof, a method for preparing said compound, and the use of said compound in the treatment of diseases caused by cathepsin C and downstream serine proteases.

Description

[Technical field]

[0001] The present invention relates to the technical field of medicine, in particular to novel peptidyl nitrile compounds and their uses. [Background technology]

[0002] Inflammatory diseases are currently an important area of ​​drug research and development. Interleukin antibody drugs have been applied in clinical practice, and small molecule drugs such as JAK inhibitors have also been applied in clinical practice, but they all have different degrees of deficiencies, for example, antibody drugs can only be administered by injection, with poor clinical acceptance, and JAK inhibitors are used in inflammatory diseases, with potential cardiovascular adverse events due to the target mechanism (Norman P, Expert Opinion on Investigational Drugs. 2014, 23 (8): 1067-77). Therefore, the search for new anti-inflammatory drugs is highly needed.

[0003] Cathepsin C (CTSC), also known as dipeptidyl peptidase I (DPP-1), is a lysosomal cysteine ​​protease with a molecular weight of 200 KDa that belongs to the papain family. Cathepsin C is one of four serine peptidases in inflammatory cells, including neutrophils and mast cell granules, elastase (NE), cathepsin G (CatG), and protease 3 (PR). 3) and neutrophil serine protease (NSP4), as well as mast cell-associated chymase, tryptase and serine proteases (Guay, D. et al, Curr. Top. Med. Chem. 2010, 10, 708-716; Korkmaz, B. et al, Pharmacol. Ther. 2018, 190, 202-236). Activation of these proteases by cathepsin C leads to tissue damage and chronic inflammation by degrading various extracellular matrix components. Therefore, cathepsin C inhibitors can be potential therapeutic agents for the treatment of neutrophil-dominant inflammatory diseases, including chronic obstructive pulmonary disease (COPD), emphysema, asthma, multiple sclerosis, idiopathic pneumonia, cystic fibrosis, etc. (Laine et al, Expert Opin. Ther. Patents 2010, 20, 497).

[0004] The pathogenesis of other immune diseases, such as inflammatory bowel disease, rheumatoid arthritis, antineutrophil cytoplasmic antibody-associated necrotizing crescent glomerulonephritis, ANCA-mediated vasculitis, and severe systemic inflammatory diseases, such as sepsis, acute lung injury (acute respiratory distress syndrome), and acute pancreatitis, is mostly caused by increased activity of specific inflammatory proteases, so cathepsin C inhibitors can also be potential drugs for treating these diseases. In addition, since elastase, a serine protease downstream of cathepsin, plays a very important role in the development and metastasis of cancer and cardiovascular diseases such as myocardial infarction, theoretically, cathepsin inhibitors also have a pharmacological effect of inhibiting elastase by inhibiting cathepsin. Therefore, theoretically, cathepsin inhibitors can also be used to treat cancer and cardiovascular diseases (Pharmacol Ther. 2018 Oct; 190: 202-236; Int J Mol Sci. 2021 Jan 13; 22 (2): 722.).

[0005] Although cathepsin C has been discovered for over 70 years, clinical cathepsin C inhibitors remain very limited (Korkmaz B.et al,J.Med.Chem.,2020,63,13258;Shen,XB et al,EJMed.Chem.,2021,225-113818). As recently as June 2020, the US Food and Drug Administration granted breakthrough drug status to the cathepsin C inhibitor Brenosocatib, which has just completed a Phase II clinical trial, for use in treating non-cystic fibrosis bronchiectasis (NCFBE) in adults (Doyle K.et al,J.Med.Chem.,2016,59,9457). There remains a large unmet need for cathepsin C inhibitors. Because conventional compounds are poor at inhibiting the activity of cathepsin C and downstream serine proteases, there is a need to provide novel peptidyl nitrile compounds and uses thereof. Summary of the Invention

[0006] The object of the present invention is to provide compounds of general formula (I) or their pharma- ceutically acceptable salts, [ka] and / or a pharma- ceutically acceptable salt thereof or a prodrug thereof, and / or a solvate, hydrate, metabolite, oxynitride, racemic mixture, enantiomer, diastereomer and tautomer thereof or a mixture in any ratio thereof (including a racemic mixture), In the formula, Cy is [ka] and p is 0 to 6; W is selected from CH2-CH2-O-, -O-, -S-, -SO2-, -CH2-, -OCH2-, -CH2O-, -CH2S-, -SCH2-, -CH2SO2-, -SO2CH2-, -CH2-CH2-, -(CH2)3-, -CH2-CH2-S-, -CH2-CH2-SO2-, -CH2-O-CH2-, -CH2-S-CH2-, -CH2-SO2-CH2-; R a are each independently deuterium, halogen, hydroxy, cyano, sulfhydryl, 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)2N-, C 1-6 Alkyl-C(O)HN-, -C(O)NHC 1-6 alkyl, oxo, and thio, each of which may be optionally substituted with halogen and deuterium; a may be linked to the same carbon atom or to different carbon atoms, R a Or two R's a Let's go together 1-4 forming an alkylene or an ether chain containing 1 to 4 carbon atoms, such as -CH2-O-CH2-CH2-CH2-, -CH2-O-CH2-, the alkylene or ether chain can form, together with the original ring, a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, a bridged ring, a fused ring, and a spiro ring, with or without a heteroatom, the heteroatom including N, S, O, the cycloalkyl, the cycloalkenyl, the heterocycloalkyl, the heterocycloalkenyl, the bridged ring, the fused ring, and the spiro ring can be optionally substituted with deuterium, hydroxy, halogen, alkyl, and alkoxy, C, S can be optionally oxidized to -C=O, -S=O, -S(O)2-, or two R aform, together with the carbon atom to which each is attached, a 6-membered aryl, a 5-membered heteroaryl, or a 6-membered heteroaryl, which also forms a fused ring with the original ring, said fused ring being optionally substituted with hydroxy, halogen, cyano, alkyl, or alkoxy, each of which is optionally substituted with halogen and deuterium; A and B are each independently selected from hydrogen, deuterium, and fluorine, or A and B together with the carbon atom to which they are attached form a cyclopropane; X, Y, and Z are each independently selected from CH, N, S, O, and Se; or one of X, Y, and Z is a bond in a ring, i.e., the atoms on either side of X, Y, or Z are directly connected, and the connected bond may be a single bond or a double bond; R 2 is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 cycloalkoxy, wherein any of said alkyl, alkoxy, cycloalkyl and cycloalkoxy may be optionally substituted with halogen and deuterium; q is 0 to 3; 1) Cy [ka] If not, 2) If X, Y, and Z are not simultaneously CH, 3) R 2 If is not hydrogen and q is not 0, then 4) If A and B are not hydrogen at the same time (there are four cases in an and / or relationship), R 1is selected from a cyclic group, specifically, an aryl, a heteroaryl, a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, the cyclic group may be a monocyclic or bicyclic ring, and may optionally contain one or more heteroatoms of N, O, S, and Se, and C and S in the ring may be optionally oxidized or sulfurized to -CO-, -CS-, -CO--SO-, and -SO2-, the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl may optionally be selected from one or more R 1a may be optionally substituted with R 1a is hydrogen, deuterium, halogen, cyano, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR 3 R 4 , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR 3 , -S(O)2R 3 , -S(O)(NH)R 3 , -S(O)(NR 4 )R 3 , -S(O)NR 3 R 4 , -OS(O)2R 3 , -NR 3 R 4 , -NR 3 (CO)R 4 , -NR 3 (SO2)R 4 , -NR 3 R 4 Alkyl substituted with -CR 3 R4 , -SR 3 , aryl, and 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R 3 and two R 1a may be linked to the same carbon atom or nitrogen atom or to different carbon atoms or nitrogen atoms, and two R 1a can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R 3 C and S in the ring may be selectively oxidized or sulfurized to -CO-, -CS-, -SO-, or -SO2-; R 3 , R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, alkylcarbonyl, alkylsulfone, alkylC(O)NH-, alkylS(O)NH-, carboxy, and alkylcarbonyl, where amino, hydroxy, carboxy, alkyl, cycloalkyl, cycloalkoxy, heterocycloalkoxy, and heterocycloalkyl are optionally further substituted with alkyl, halogen, cyano, hydroxy, hydroxyalkyl, and alkoxy; and two R 3 may be attached to the same atom or to different atoms, or two R 3 , or R 3 and R 4can selectively form a 3- to 10-membered cycloalkyl, heterocycloalkyl, spiro ring, bridged ring, or fused ring, including, but not limited to, an oxetane, azetidine, morpholine ring, piperidine ring, piperazine ring, azaoxetane, furan ring, or pyrrolidine, together with the same carbon atom or nitrogen atom to which each is bonded, and C and S in the cycloalkyl, heterocycloalkyl, spiro ring, bridged ring, or fused ring may be selectively oxidized to -CO-, -SO-, or -SO2-, and one or more halogens, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, C 3-8 optionally substituted with heterocyclyl; Cy [ka] X, Y, and Z are all CH, and R 2 is hydrogen and A / B are both H, R 1 is selected from pyrimidine, pyrazine, pyridazine, pyrazole, furan, imidazole, thiazole, oxazole, isoxazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, and pyrimidine, pyrazine, pyridazine, triazinyl, pyrazole, furan, imidazole, thiazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl are selected from one or more R 1a may be substituted with (R 1a is defined as above), or S or 1-2 carbon atoms may be selectively oxidized, and / or R 1 teeth, [ka] is selected from f is 0 to 2; g is 0 to 3; h is 0 to 5; k is 0 to 2; R 1a is defined as above, and R 1a The same substituents may be selected at the same time, or different substituents may be selected. 1a can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-. R 3 and R 4 is as defined above unless otherwise stated. f and g are not 0, R 1a If is not hydrogen, then R 1b =H, R 1a and R 1b and R 1a , or two R 1a can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-. If f and g are 0, or if f and g are not 0, then R 1a is hydrogen, then R 1bis hydrogen, deuterium, halogen, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR 3 R 4 , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR 3 , -S(O)2R 3 , -S(O)(NH)R 3 , -S(O)(NR 4 )R 3 , -S(O)NR 3 R 4 , -OS(O)2R 3 , -NR 3 R 4 , -NR 3 (CO)R 4 , -NR 3 (SO2)R 4 , -NR 3 R 4 Alkyl substituted with -CR 3 R 4 , -SR 3 , aryl, and 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R 3 and R 1b and R 1a , or two R 1acan alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-. k is not 0, R 1a If is not hydrogen, then R 5a , R 5 and R 6 =R 1a or R 5a , R 5 , R 6 , 1 to 2 R 1a Two of the R may alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, the 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 formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-. k is 0 or k is not 0 and R 1a If is hydrogen, then R 5a Deuterium, bromine, cyano, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, cyano, C 2-8Alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR 3 R 4 , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR 3 , -S(O)2R 3 , -S(O)(NH)R 3 , -S(O)(NR 4 )R 3 , -S(O)NR 3 R 4 , -OS(O)2R 3 , -NR 3 R 4 , -NR 3 (CO)R 4 , -NR 3 (SO2)R 4 , -NR 3 R 4 Alkyl substituted with -CR 3 R 4 , -SR 3 , aryl, or 5- to 6-membered heteroaryl, and the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, or heteroaralkyloxy is selected from one or more of R 3 may be selectively substituted with R 5 and R 6 =R 1a or R 5 , R 6 , R 5a and 1 to 2 R 1aTwo of the R may alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, the 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 formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-. R 5a When is chlorine, fluorine, or CH3, R 5 , R 6 =R 1a and R 5a When is H, R 6 =R 1a and R 5 is an alkyl group selected from the group consisting of deuterium, hydroxy, amino, sulfhydryl, carboxy, sulfone, sulfoxide, oxo, thio, nitro, cyano, alkyl, alkyl substituted with 1 to 2 fluorines, alkyl substituted with 1 to 3 bromines, alkyl substituted with 1 to 3 chlorines, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR 3 R 4 (However, R 3 and R 4 cannot be H at the same time), alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR 3 , -S(O)C 4-8 Alkyl, -OS(O)2C 4-8 Cycloalkyl, -OS(O)2C 4-8 Heterocycloalkyl, -S(O)(NH)R 3 , -S(O)(NR4 )R 3 , S(O)NR 3 R 4 (However, R 3 and R 4 can form together with the N atom to which it is attached a heteroalkenyl, piperazinyl, a 5- to 7-membered azaalkyl containing at least one O atom, morpholinyl, or a bridged ring morpholinyl; or R 3 and R 4 is singly substituted and does not form a ring), -S(O)2NH2, -OS(O)2R 3 , -NR 3 R 4 , -NR 3 (CO)R 4 , -NR 3 (SO2)R 4 , -NR 3 R 4 Alkyl substituted with -CR 3 R 4 , -SR 3 , aryl, and 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R 3 may be optionally substituted with Or, R 5a When is H, chlorine, fluorine, or CH3, R 1 teeth, [ka] is selected from however, V is -O-, -S-, -Se-, -CH2-, -CF2-, -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 -O-, -S-, -Se-, -CO-, -SO-, -S(O)2, -NR 7 -, -CR 8 R 9 - selected from When V is -O-, -S-, -CF2- and U is -CO-, T is -O-, -S-, -Se-, -CO, -SO-, -S(O)2, -CR 8 R 9 -, -NH-, -N(CHF)-, -N(CF2)-, -N(CH2-CH(OH)-CH3)-, -N(CH2-CH(OCH3)-CH3)-, -N(CH2-CH2-OCH3)-, -N(C 4-8 alkyl)-, -N(cycloalkyl)-, -N(cycloalkoxy)-, -N(oxetane)-, -N(tetrahydrofuran)-, -N(tetrahydropyran)-, wherein the -N(C 4-8 -N(alkyl)-, -N(cycloalkyl)-, -N(cycloalkoxy)-, -N(oxetane)-, -N(tetrahydrofuran)-, and -N(tetrahydropyran) are C 1-3 Alkoxy, C 1-3 Alkyl, C 3-6 Cycloalkyl, NH(C 1-3 alkyl), N(C 1-3 T is optionally substituted with -O-, -S-, -Se-, -CO-, -SO-, -SO2-, -C(R 8 R 9 )-, -N(R 7 )-and X1, Y1, and Z1 may be independently selected from CH and N; R 7 =R 1a and R 8 , R 9 =R 1a or R 8 , R 9can alternatively form a saturated or unsaturated cyclic group together with the atoms to which they are originally attached, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, and heteroaryl, and the cyclic group can be formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-. and / or its pharma- ceutically acceptable salts or prodrugs thereof, and / or its solvates, hydrates, metabolites, oxynitrides, racemic mixtures, enantiomers, diastereomers and tautomers or mixtures thereof in any ratio (including racemic mixtures), In the formula, Cy is [ka] and p is 0 to 6; W is selected from CH2-CH2-O-, -O-, -S-, -SO2-, -CH2-, -OCH2-, -CH2O-, -CH2S-, -SCH2-, -CH2SO2-, -SO2CH2-, -CH2-CH2-, -(CH2)3-, -CH2-CH2-S-, -CH2-CH2-SO2-, -CH2-O-CH2-, -CH2-S-CH2-, -CH2-SO2-CH2-; R a are each independently deuterium, halogen, hydroxy, cyano, sulfhydryl, 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)2N-, C 1-6 Alkyl-C(O)HN-, -C(O)NHC 1-6alkyl, oxo, and thio, each of which may be optionally substituted with halogen and deuterium; a may be linked to the same carbon atom or to different carbon atoms, R a Or two R's a The common one is C. 1-4 forming an alkylene or an ether chain containing 1 to 4 carbon atoms, such as -CH2-O-CH2-CH2-CH2-, -CH2-O-CH2-, the alkylene or ether chain can form, together with the original ring, a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, a bridged ring, a fused ring, and a spiro ring, with or without a heteroatom, the heteroatom including N, S, O, the cycloalkyl, the cycloalkenyl, the heterocycloalkyl, the heterocycloalkenyl, the bridged ring, the fused ring, and the spiro ring can be optionally substituted with deuterium, hydroxy, halogen, alkyl, and alkoxy, C, S can be optionally oxidized to -C=O, -S=O, -S(O)2-, or two R a form, together with the carbon atom to which each is attached, a 6-membered aryl, a 5-membered heteroaryl, or a 6-membered heteroaryl, which also forms a fused ring with the original ring, said fused ring being optionally substituted with hydroxy, halogen, cyano, alkyl, or alkoxy, each of which is optionally substituted with halogen and deuterium; A and B are each independently selected from hydrogen, deuterium, and fluorine, or A and B together with the carbon atom to which they are attached form a cyclopropane; X, Y, and Z are each independently selected from CH, N, S, O, and Se; or one of X, Y, and Z is a bond in a ring, i.e., the atoms on either side of X, Y, or Z are directly connected, and the connected bond may be a single bond or a double bond; R 2 is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl, C 3-6 cycloalkoxy, wherein any of said alkyl, alkoxy, cycloalkyl and cycloalkoxy may be optionally substituted with halogen and deuterium; q is 0 to 3; 1) Cy [ka] If not, 2) If X, Y, and Z are not simultaneously CH, 3) R 2 If is not hydrogen and q is not 0, then 4) If A and B are not hydrogen at the same time (there are four cases in an and / or relationship), R 1 is selected from a cyclic group, specifically, an aryl, a heteroaryl, a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, the cyclic group may be a monocyclic or bicyclic ring, and may optionally contain one or more heteroatoms of N, O, S, and Se, and C and S in the ring may be optionally oxidized or sulfurized to -CO-, -CS-, -CO--SO-, and -SO2-, the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl may optionally be selected from one or more R 1a may be optionally substituted with R 1a is hydrogen, deuterium, halogen, cyano, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR 3R 4 , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR 3 , -S(O)2R 3 , -S(O)(NH)R 3 , -S(O)(NR 4 )R 3 , -S(O)NR 3 R 4 , -OS(O)2R 3 , -NR 3 R 4 , -NR 3 (CO)R 4 , -NR 3 (SO2)R 4 , -NR 3 R 4 Alkyl substituted with -CR 3 R 4 , -SR 3 , aryl, and 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R 3 and two R 1a may be linked to the same carbon atom or nitrogen atom or to different carbon atoms or nitrogen atoms, and two R 1a can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R 3 C and S in the ring may be selectively oxidized or sulfurized to -CO-, -CS-, -SO-, or -SO2-; R 3 , R 4are each independently selected from hydrogen, deuterium, halogen, cyano, halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, alkylcarbonyl, alkylsulfone, alkylC(O)NH-, alkylS(O)NH-, carboxy, and alkylcarbonyl, where amino, hydroxy, carboxy, alkyl, cycloalkyl, cycloalkoxy, heterocycloalkoxy, and heterocycloalkyl are optionally further substituted with alkyl, halogen, cyano, hydroxy, hydroxyalkyl, and alkoxy; and two R 3 may be attached to the same atom or to different atoms, or two R 3 , or R 3 and R 4 can selectively form a 3- to 10-membered cycloalkyl, heterocycloalkyl, spiro ring, bridged ring, or fused ring, including, but not limited to, an oxetane, azetidine, morpholine ring, piperidine ring, piperazine ring, azaoxetane, furan ring, or pyrrolidine, together with the same carbon atom or nitrogen atom to which each is bonded, and C and S in the cycloalkyl, heterocycloalkyl, spiro ring, bridged ring, or fused ring may be selectively oxidized to -CO-, -SO-, or -SO2-, and one or more halogens, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, C 3-8 optionally substituted with heterocyclyl; Cy [ka] X, Y, and Z are all CH, and R 2 is hydrogen and A / B are both H, R 1is selected from pyrimidine, pyrazine, pyridazine, pyrazole, furan, imidazole, thiazole, oxazole, isoxazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, and pyrimidine, pyrazine, pyridazine, triazinyl, pyrazole, furan, imidazole, thiazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl are selected from one or more R 1a may be substituted with (R 1a is defined as above), or S or 1-2 carbon atoms may be selectively oxidized, and / or R 1 teeth, [ka] is selected from f is 0 to 2; g is 0 to 3; h is 0 to 5; k is 0 to 2; R 1a is defined as above, and R 1a The same substituents may be selected at the same time, or different substituents may be selected. 1a can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-. R 3 and R 4 is as defined above unless otherwise stated. f and g are not 0, R 1a If is not hydrogen, then R 1b =H, R 1a and R1b and R 1a , or two R 1a can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-. If f and g are 0, or if f and g are not 0, then R 1a is hydrogen, then R 1b is hydrogen, deuterium, halogen, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR 3 R 4 , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR 3 , -S(O)2R 3 , -S(O)(NH)R 3 , -S(O)(NR 4 )R 3 , -S(O)NR 3 R 4 , -OS(O)2R 3 , -NR 3 R 4 , -NR 3 (CO)R 4 , -NR 3 (SO2)R 4 , -NR 3 R4 Alkyl substituted with -CR 3 R 4 , -SR 3 , aryl, and 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R 3 and R 1b and R 1a , or two R 1a can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-. k is not 0, R 1a If is not hydrogen, then R 5a , R 5 and R 6 =R 1a or R 5a , R 5 , R 6 , 1 to 2 R 1a Two of the R may alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, the 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 formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-. k is 0 or k is not 0 and R 1a If is hydrogen, then R5a Deuterium, bromine, cyano, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, cyano, C 2-8 Alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR 3 R 4 , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR 3 , -S(O)2R 3 , -S(O)(NH)R 3 , -S(O)(NR 4 )R 3 , -S(O)NR 3 R 4 , -OS(O)2R 3 , -NR 3 R 4 , -NR 3 (CO)R 4 , -NR 3 (SO2)R 4 , -NR 3 R 4 Alkyl substituted with -CR 3 R 4 , -SR 3 , aryl, or 5- to 6-membered heteroaryl, and the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, or heteroaralkyloxy is selected from one or more of R 3 When it may be optionally substituted with R 5 and R 6 =R1a or R 5 , R 6 , R 5a and 1 to 2 R 1a Two of the R may alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, the 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 formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-. R 5a When is chlorine, fluorine, or CH3, R 5 , R 6 =R 1a and R 5a When is H, R 6 =R 1a and R 5 is an alkyl group selected from the group consisting of deuterium, hydroxy, amino, sulfhydryl, carboxy, sulfone, sulfoxide, oxo, thio, nitro, cyano, alkyl, alkyl substituted with 1 to 2 fluorines, alkyl substituted with 1 to 3 bromines, alkyl substituted with 1 to 3 chlorines, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR 3 R 4 (However, R 3 and R 4 cannot be H at the same time), alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR 3 , -S(O)C 4-8 Alkyl, -OS(O)2C4-8 Cycloalkyl, -OS(O)2C 4-8 Heterocycloalkyl, -S(O)(NH)R 3 , -S(O)(NR 4 )R 3 , S(O)NR 3 R 4 (However, R 3 and R 4 can form together with the N atom to which it is attached a heteroalkenyl, piperazinyl, a 5- to 7-membered azaalkyl containing at least one O atom, morpholinyl, or a bridged ring morpholinyl; or R 3 and R 4 is singly substituted and does not form a ring), -S(O)2NH2, -OS(O)2R 3 , -NR 3 R 4 , -NR 3 (CO)R 4 , -NR 3 (SO2)R 4 , -NR 3 R 4 Alkyl substituted with -CR 3 R 4 , -SR 3 , aryl, and 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R 3 may be optionally substituted with Or, R 5a When is H, chlorine, fluorine, or CH3, R 1 teeth, [ka] is selected from however, V is -O-, -S-, -Se-, -CH2-, -CF2-, -CO-, -SO-, -SO2-, -N(R 7 )-, -C(R 8 R9 )-, -O-CH(alkyl)-, -O-CH(cycloalkyl)-, -S-CH(cycloalkyl)-, -CH=C(alkyl)-, -N=C(alkyl)-, -CH=C(cycloalkyl)-, -N=C(cycloalkyl)-; U is -O-, -S-, -Se-, -CO-, -SO-, -S(O)2, -NR 7 -, -CR 8 R 9 - selected from When V is -O-, -S-, -CF2- and U is -CO-, T is -O-, -S-, -Se-, -CO, -SO-, -S(O)2, -CR 8 R 9 -, -NH-, -N(CHF)-, -N(CF2)-, -N(CH2-CH(OH)-CH3)-, -N(CH2-CH(OCH3)-CH3)-, -N(CH2-CH2-OCH3)-, -N(C 4-8 alkyl)-, -N(cycloalkyl)-, -N(cycloalkoxy)-, -N(oxetane)-, -N(tetrahydrofuran)-, -N(tetrahydropyran)-, wherein the -N(C 4-8 -N(alkyl)-, -N(cycloalkyl)-, -N(cycloalkoxy)-, -N(oxetane)-, -N(tetrahydrofuran)-, and -N(tetrahydropyran) are C 1-3 Alkoxy, C 1-3 Alkyl, C 3-6 Cycloalkyl, NH(C 1-3 alkyl), N(C 1-3 T is optionally substituted with -O-, -S-, -Se-, -CO-, -SO-, -SO2-, -C(R 8 R 9 )-, -N(R 7 )-and X1, Y1, and Z1 may be independently selected from CH and N; R 7 =R 1a and R 8 , R 9 =R 1a or R 8 , R9 can alternatively form a saturated or unsaturated cyclic group together with the atoms to which they are originally attached, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, and heteroaryl, and the cyclic group can be formed by one or more R 3 and C and S in the ring may be selectively oxidized to -CO-, -SO-, or -SO2-, or a pharma- ceutically acceptable salt thereof.

[0007] In a preferred embodiment of the present invention, Cy is [ka] is selected from Ar is a pyridine and benzene ring; R b is chlorine, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, trifluoromethoxy, or a pharma- ceutically acceptable salt thereof.

[0008] A preferred embodiment of the invention is a compound according to formula (I) or a pharma- ceutically acceptable salt thereof, wherein A and B are both selected from H or from F.

[0009] A preferred embodiment of the present invention is a compound according to formula (I) or a pharma- ceutically acceptable salt thereof, wherein X and Y are each independently selected from CH and N, and Z is selected from CH.

[0010] A preferred embodiment of the present invention is 2 is selected from hydrogen, fluorine, methyl, and said q is selected from 1; or a pharma- ceutically acceptable salt thereof.

[0011] A preferred embodiment of the present invention is 1 teeth, [ka] is selected from however, X1, Y1, and Z1 are independently selected from CH and N; m, n, and o are 0 to 3; U is -C(=O)-, -S(O)2-, -O-, -NR 7 -, -CR 8 R 9 may be selected from V is -C(=O)-, -S(O)2-, -O-, -S-, -Se-, -NR 7 -, -CR 8 R 9 may be selected from R 7 is hydrogen, CH3OCH2CH2-, oxetanyl, azetidine, tetrahydrofuryl, tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine, -C 1-3 Alkyl, C 3-6 cycloalkyl, 1-3 Alkyl, C 3-6 Cycloalkyl, azetidine, tetrahydrofuryl, tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine are optionally substituted with 1, 2 or 3 fluorines and / or C 1-3 Alkyl, hydroxy, -OC 1-3 Alkyl, -N(C 1-3 R 7 may be the same or different substituents; R 8 , R 9 is hydrogen, fluorine, -C 1-6 Alkyl, -C 1-6 haloalkyl, or R 8 and R 9 together with the nitrogen or carbon atom to which they are attached, C 3-6cycloalkyl, oxetane, azetidine, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuryl, tetrahydropyranyl, and the cyclopropane, oxetane, azetidine, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuryl, tetrahydropyranyl are each independently selected from the group consisting of C 1-3 may be optionally substituted with alkyl, cyclopropane, oxetane, azetidine, cyclopropyloxy; C and D are independently -NR 7 C(O)-, -C(O)NR 7 -, -CH2-CH2-, -C(O)-O-, -OC(O)-, -CH2-O-, -O-CH2-, -CH2-NR 7 -, -NR 7 -CH2-, -CH2-, or one of C and D is a bond (a single or double bond in a ring, with both ends directly connected); Cy [ka] and R 2 is H, X, Y, Z are all selected from CH, and V, if present in the structure, is -O-, -S-, or -CF2-; R 5 is -S(O)C 1-3 Alkyl, -CONH2, -SO2NHC 1-3 Alkyl, -SO2NR 3 R 4 (However, R 3 and R 4 together with the N atom to which they are attached form a heterocyclyl, said heterocyclyl is selected from piperazinyl, morpholinyl, said piperazinyl and morpholinyl being C 1-3 alkyl, cyclopropyl; R 6 is selected from hydrogen, fluorine, chlorine, bromine, and methyl; R 7a is H, -CHF, -CF2, -CH2-CH(OH)-CH3, -CH2-CH(OCH3)-CH3, -C 4-8alkyl, -cycloalkyl, -cycloalkoxy, -CH2-CH2-OCH3, -oxetane, -tetrahydrofuran, -tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine; 4-8 Alkyl, tetrahydrofuran, pyrrolidine, piperazine, morpholine, piperidine are optionally substituted with 1, 2 or 3 fluorines and / or hydroxy, -OC 1-3 Alkyl, -N(C 1-3 alkyl), cyclopropyl, Otherwise, R 5 is cyano, -SO2C 1-3 Alkyl, -CONH2, -SO2NR 3 R 4 Selected from R 3 , R 4 is hydrogen, -C 1-6 alkyl, or R 3 and R 4 form an azetidine, oxetane, pyrrolidine, piperidine ring, piperazine ring, or morpholine ring together with the nitrogen atom to which they are bonded, and the azetidine, oxetane, pyrrolidine, piperidine ring, piperazine ring, or morpholine ring is C 1-3 may be optionally substituted with alkyl, cyclopropyl, R 6 is selected from hydrogen, fluorine, chlorine, bromine, and methyl; R 7a =R 7 or a pharma- ceutically acceptable salt thereof.

[0012] A preferred embodiment of the present invention is 1 teeth, [ka] is selected from R 7 is hydrogen, -CF2, -CHF, CH3OCH2CH2-, oxetanyl, tetrahydrofuryl, tetrahydropyran, -C 1-3 Alkyl, -C 3-6cycloalkoxy, wherein C 1-3 Alkyl, oxetanyl, tetrahydrofuryl, tetrahydropyran may be optionally substituted with 1, 2 or 3 fluorines and / or hydroxy, -OC 1-3 Alkyl, -N(C 1-3 alkyl), cyclopropyl, or cyclopropyl; R 7 may be the same or different substituents; Cy [ka] and R 2 is H, X, Y, and Z are all selected from CH, and A and B are both H, then R 7a is H, -CHF, -CF2, -CH2-CH(OH)-CH3, -CH2-CH(OCH3)-CH3, -C 4-8 Alkyl, -C 3-6 Cycloalkyl, -C 3-6 cycloalkoxy, -CH2-CH2-OCH3, -oxetane, -tetrahydrofuran, -tetrahydropyran, wherein the oxetane, tetrahydrofuran, and tetrahydropyran are selected from C 1-3 Alternatively, R 7a =R 7 or a pharma- ceutically acceptable salt thereof.

[0013] Exemplary compounds of the present invention include, but are not limited to, the following: or a pharma- ceutically acceptable salt thereof.

[0014] [ka]

[0015] [ka]

[0016] [ka]

[0017] [ka]

[0018] [ka]

[0019] [ka]

[0020] The beneficial effect of the present invention relates to the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for the treatment and prevention of diseases caused by cathepsin C and its downstream serine proteases NE, PR3, CaTG, NSP4.

[0021] Furthermore, the compound of formula (I) or a pharma- ceutically acceptable salt thereof can be used in the treatment of respiratory diseases, metabolic diseases, cardiovascular diseases, autoimmune diseases, cancer, infectious diseases, and other inflammation-related diseases such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, pulmonary arterial hypertension, non-cystic fibrosis, cystic fibrosis, bronchiectasis, bronchitis, pneumonia, emphysema, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, allergic diseases, immune-mediated inflammatory bowel diseases, rheumatoid arthritis, glomerulonephritis, eosinophilic disease, and the like. and / or in the preparation of a medicament for the treatment of chronic inflammatory bowel disease, neutrophil disorders, ANCA associated inflammation, antineutrophil cytoplasmic antibody associated necrotizing crescent glomerulonephritis, acute brain injury, acute myocarditis, acute kidney injury, a-1-antitrypsin deficiency (AATD) and associated inflammation, liver fibrosis, fatty liver and hepatic steatosis, obesity, insulin resistance, diabetes, pathogenic microbial infections, infectious gastroenteritis diseases, lung cancer and / or radiation injury syndrome in a patient suffering from or at risk of said diseases.

[0022] The beneficial effects of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharmaceutical carrier or excipient.

[0023] Further, the pharmaceutical composition comprises one or more compounds of formula (I) and a pharma- ceutical active compound selected from the group consisting of other compounds, including, but not limited to, b-mimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists and SYK inhibitors, NE inhibitors, MMP9 inhibitors, MMP12 inhibitors, and combinations of two or three active substances.

[0024] Further, the pharmaceutical compositions further include those used in combination with small molecule compounds and / or polymeric antibodies to treat cancer, inflammation, bone marrow-related diseases and autoimmune diseases, and the small molecule compounds and / or polymeric antibodies include, but are not limited to, glucocorticoids, adrenergic agonists, cholinergic receptor antagonists, theophylline drugs, 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 and IL-23 antibodies, targeted anti-thymic stromal lymphopoietin (TSLP) antibodies such as tezepelumab, and complement inhibitors.

[0025] The beneficial effect of the present invention relates to the use of a composition of the compound of formula (I) in a medicament for treating and preventing diseases caused by cathepsin C and its downstream serine proteases NE, PR3, CaTG, NSP4, said diseases being selected from respiratory diseases, metabolic diseases, cardiovascular diseases, autoimmune diseases, cancer, infectious diseases or inflammatory infectious diseases.

[0026] The beneficial effect of the present invention is 1 , R 2wherein, Cy, A, B, X, Y, Z and q each carry a substituent; and the solvates, racemic mixtures, enantiomers, diastereomers, tautomers, or mixtures thereof in any ratio, including racemic mixtures, of compounds of formula (I). [ka]

[0027] The compounds of the present invention may be asymmetric, for example, having one or more stereocenters. Unless otherwise limited, all stereoisomers are, for example, enantiomers and diastereomers. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be prepared by resolution of racemates or by using chiral synthons or chiral reagents.

[0028] The compounds of the present invention may include tautomeric forms, which are produced when a single bond and an adjacent double bond swap together with the migration of a proton.

[0029] Compounds of the invention may include all isotopic forms of atoms occurring in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

[0030] The present invention further includes pharma- ceutically acceptable salts of the compounds of formula (I). Pharmaceutically acceptable salts refer to derivatives of the compounds of formula (I) in which the parent compound is modified by converting basic moieties present, or acid moieties present, into their salt forms.

[0031] Specifically, examples of pharma- ceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups (e.g., amines) or inorganic or organic base salts of acidic groups (e.g., carboxylic acids).The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compounds of formula (I) by reacting the free base forms of these compounds with 1 to 4 equivalents of an appropriate acid in a solvent system.Suitable salts are listed in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).

[0032] The compounds of the present invention and their pharma- ceutically acceptable salts further include solvate or hydrate forms.In general, solvate or hydrate forms are equivalent to non-solvate or non-hydrate forms, and both are included within the scope of the present invention.Some compounds of the present invention may exist in multiple crystalline or amorphous forms.In summary, all physical forms of compounds are included within the scope of the present invention.

[0033] The present invention further includes prodrugs of the compounds of formula (I). Prodrugs are pharmacological substances (i.e. drugs) derived from a parent drug, which, when administered, are metabolized in the body to become the parent drug. Prodrugs can be prepared by replacing one or more functional groups present in the compound, where the substituents in the prodrug are thus removed in vivo and converted to the parent compound. The preparation and use of prodrugs are described, for example, in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems" Vol. 14 of the ACS Symposium Series and Bioreversible. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The present invention will now be further described with reference to specific examples.

[0035] The present invention will be further described below by examples, which are merely for the purpose of more specifically illustrating the preferred embodiments of the present invention, and are not intended to limit the technical solutions of the present invention. The above-mentioned solutions of the present invention are all technical solutions that can achieve the objectives of the present invention. The temperatures and reagents employed in the following examples can all be replaced with the corresponding temperatures and reagents described above to achieve the objectives of the present invention.

[0036] Unless the context indicates otherwise, the following terms, phrases and symbols used in the present invention have the meanings set forth below.

[0037] A short dash ("-") between two letters or symbols indicates the point of attachment of a substituent. For example, -O(C 1-4 Alkyl) is a C linked to the rest of the molecule through an oxygen atom. 1-4 However, when the attachment site of the substituent is clear to one of ordinary skill in the art, for example in the case of a halogen substituent, the "-" may be omitted.

[0038] Unless expressly stated otherwise, terms such as "a" and "an" as used herein refer to one or more.

[0039] The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group containing 1 to 18 carbon atoms, for example 1 to 12 carbon atoms, also 1 to 6 carbon atoms, and further 1 to 4 carbon atoms. For example, "C1-6 alkyl" refers to an alkyl group within the scope of "alkyl" having 1 to 6 carbon atoms as described above. Examples of alkyl include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("n-Pr"), isopropyl ("i-Pr"), n-butyl ("n-Bu"), isobutyl ("i-Bu"), s-butyl ("sBu"), and t-butyl ("t-Bu").

[0040] The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon group containing one or more, for example 1, 2 or 3, carbon-carbon double bonds (C=C) and containing 2 to 10 carbon atoms, for example 2 to 6 carbon atoms, also 2 to 4 carbon atoms. For example, "C2-6 alkenyl" is within the scope of "alkenyl" and represents an alkenyl having 2 to 6 carbon atoms as described above. Examples of alkenyl include, but are not limited to, vinyl, 2-propenyl and 2-butenyl.

[0041] The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon group containing one or more, for example, one, two or three carbon-carbon triple bonds (C≡C) and containing 2 to 10 carbon atoms, for example, 2 to 6 carbon atoms, and also 2 to 4 carbon atoms. For example, "C 2-6 "Alkynyl" refers to an alkynyl group containing one carbon-carbon triple bond (C≡C) as defined above and having 2 to 6 carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.

[0042] As used herein, the term "halo" refers to fluoro, chloro, bromo and iodo, and "halogen" refers to fluorine, chlorine, bromine and iodine.

[0043] The term "haloalkyl" as used herein refers to an alkyl as defined herein having one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, replaced by halogen atoms, and when more than one hydrogen atom is replaced by halogen atoms, the halogen atoms may be the same or different. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl as defined herein having two or more hydrogen atoms, for example 2, 3, 4 or 5 hydrogen atoms, replaced by halogen atoms, and the halogen atoms are the same. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl as defined herein having two or more hydrogen atoms, for example 2, 3, 4 or 5 hydrogen atoms, replaced by halogen atoms, and the halogen atoms are different. Examples of haloalkyl include, but are not limited to, -CF3, -CHF2, -CH2CF3, and the like.

[0044] The term "alkoxy" as used herein refers to an -O-alkyl group, where alkyl is as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, pentyloxy and hexyloxy, and their isomers.

[0045] 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, alternatively 3 to 6 ring carbon atoms, and may have one or more rings, for example 1 or 2 rings. For example, "C3-8 cycloalkyl" refers to a cycloalkyl having 3 to 8 ring carbon atoms as described above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and similar groups.

[0046] The term "heterocyclyl" or "heterocyclic" as used herein means a ring selected from 4-12 membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings, comprising at least one heteroatom, for example selected from O, S and N, for example 1-4 heteroatoms, further for example 1-3, or further for example 1 or 2 heteroatoms plus at least one carbon atom. The attachment point of the heterocyclyl can be on a heteroatom or on a carbon. "Heterocyclyl" or "heterocyclic" also means a monocyclic ring containing at least one heteroatom selected from O, S and N, or, in the case of fused rings, fused rings in which at least one ring contains at least one heteroatom selected from O, S and N, and in which none of the other rings are heteroaryl or aryl, and in which the attachment point can be on the heterocycle or on the other ring.

[0047] The term "cycloalkoxy" as used herein refers to an -O-cycloalkyl group, where cycloalkyl is defined above. Examples of cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, and isomers thereof.

[0048] The term "heterocycloalkoxy" as used herein refers to an -O-heterocycloalkyl group, where heterocycloalkyl is as defined above. Examples of cycloalkoxy include, but are not limited to, azelidyloxy, epoxypropanoxy, azetidinyloxy, oxetanyloxy, and the isomers thereof.

[0049] According to the present invention, "cycloalkenyl" refers to a non-aromatic cyclic hydroxyl containing one or more, for example, one, two or three carbon-carbon double bonds, and containing 3 to 12 ring carbon atoms, preferably 3 to 8 ring carbon atoms, more preferably 3 to 6 ring carbon atoms, and may have one or more, preferably one or two rings. For example, C 3-8 cycloalkenyl having 10 ring carbon atoms, preferably "C 3-6"Cycloalkenyl", i.e., cycloalkenyl having 3 to 6 ring carbon atoms as described above. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0050] The "heterocycloalkenyl" according to the present invention refers to the above "cycloalkenyl" in which one or more carbon atoms are replaced with N, O, or S. For example, C 3-8 is a heterocycloalkenyl of 1 to 4 ring atoms, preferably "C 3-6 Heterocycloalkenyl" is a heterocycloalkenyl having 3 to 6 ring atoms as described above. Examples of heterocycloalkenyl include, but are not limited to, azetidinyl, oxetenyl, azetanyl, oxolinyl, and oxetenyl.

[0051] The term "aryl" as used herein, unless expressly defined otherwise, refers to a carbocyclic hydrocarbon group containing 6-14 ring carbon atoms, e.g., 6-12 ring carbon atoms, to which one or more rings are fused, where at least one ring is an aromatic ring and the other ring is not a heteroaryl as defined below, and the attachment point may be to the aromatic ring or to another ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetralinyl, indenyl, indanyl, azulenyl, with phenyl and naphthyl being preferred. As used herein, "aryl" or "aromatic" refers to Huckel's rule, where the number of pi electrons is equal to 4n+2, where n is 0 or any positive integer up to 6.

[0052] The term "heterocyclyl" or "heterocyclic" as used herein means a ring selected from 4-12 membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings, comprising at least one heteroatom, for example selected from O, S and N, for example 1-4 heteroatoms, further for example 1-3, or further for example 1 or 2 heteroatoms plus at least one carbon atom. The attachment point of the heterocyclyl can be on a heteroatom or on a carbon. "Heterocyclyl" or "heterocyclic" also means a monocyclic ring containing at least one heteroatom selected from O, S and N, or, in the case of fused rings, fused rings in which at least one ring contains at least one heteroatom selected from O, S and N, and in which none of the other rings are heteroaryl or aryl, and in which the attachment point can be on the heterocycle or on the other ring.

[0053] The term "heteroaryl" as used in the present invention, unless otherwise clearly defined, refers to monocyclic aromatic hydrocarbon groups having 5, 6 or 7, for example 6, ring atoms and containing 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, for example 9 or 10 ring atoms and containing 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, and at least one ring being an aromatic ring. For example, bicyclic heteroaryl includes a 5-6 membered heteroaryl ring fused with a 5-6 membered cycloalkyl ring, heterocyclyl ring or aryl ring, where the point of attachment can be on the heteroaryl ring or the cycloalkyl ring / heterocyclyl ring / aryl ring. When the total number of S and O atoms in a heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other. Heteroaryl also includes heteroaryls in which the N ring heteroatom is in N-oxide form, such as N-pyrimidinyl oxide. In some embodiments, the ring heteroatom in the above heteroaryl is an N atom, and such heteroaryls are referred to as "nitrogen-containing heteroaryls". Nitrogen-containing heteroaryl also includes heteroaryls in which the N ring heteroatom is in N-oxide form, such as N-pyridyl oxide.

[0054] Examples of heteroaryl are pyridyl, N-pyridyloxide, pyrazolyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazoyl, tetrazolyl, triazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl, benzo[d]thiazolyl, benzo m-dioxolinyl, e.g. benzo[d][1,3]m-dioxolinyl, benzoxazolyl, e.g. benzo[d]oxazolyl, imidazopyridyl, e.g. imidazo[1,2-a]pyridyl, triazolopyridyl, e.g. [1,2, These include, but are not limited to, 4]triazolo[4,3-a]pyridyl and [1,2,4]triazolo[1,5-a]pyridyl, indazolyl, 2H-indazolyl, pyrrolopyrimidinyl such as pyrrolo[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrazolopyrimidinyl such as pyrazolo[1,5-a]pyrimidinyl, tetrazolopyridyl such as tetrazolo[1,5-a]pyridyl, benzothienyl, benzofuryl, benzimidazolinyl, indolyl, indolinyl, purinyl such as 9H-purinyl and 7H-purinyl.

[0055] Examples of nitrogen-containing heteroaryls include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazolyl, pyrimidinyl, N-pyrimidinyloxide, pyridazinyl, pyrrolopyrimidinyl, such as pyrrolo[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, purinyl, such as 9H-purinyl and 7H-purinyl, quinolinyl, indolyl, and indazolyl.

[0056] The term "hydroxy" according to the present invention refers to an --OH group.

[0057] As used herein, the term "sulfhydryl" refers to a --SH group.

[0058] As used herein, the term "oxo" refers to the group ═O.

[0059] As used herein, the term "carboxy" refers to the group -C(O)-OH.

[0060] As used herein, the term "cyano" refers to a -CN group.

[0061] As used herein, the term "amino" refers to the group --NH.

[0062] As used herein, "group" and "-yl" are synonymous and are used to describe a functional group or molecular fragment capable of linking to another molecular fragment.

[0063] The numerical ranges of p, q, f, g, h, k, m, n, and o described in the present invention refer to any integer included in the range. For example, 0 to 6 refers to any integer of 0, 1, 2, 3, 4, 5, and 6.

[0064] When a certain structural formula of the present invention contains an asterisk "*", the compound represented by the structural formula is a chiral compound, i.e., the compound is an R or S configuration. The configuration of a compound can be determined by a person skilled in the art based on a general method using various analytical techniques such as single crystal X-ray crystallography and / or optical rotation measurement.

[0065] The term "optionally" as used in the present invention means that the following substitution, event or situation may occur one or more times, or may not occur, and the description includes the cases where the substitution occurs and does not occur. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined in the present invention. Those skilled in the art should understand that for any group that contains one or more substituents, the group does not include substitutions that are spatially impractical, chemically imprecise, synthetically impossible, and / or inherently unstable.

[0066] As used herein, the term "including but not limited to" means that the selection gives preference to the groups listed, but groups not listed can also be used.

[0067] The term "substituted" or "substituted with" as used herein means that one or more hydrogen atoms on the indicated atom or group are replaced with one or more substituents selected from the group consisting of the indicated substituents, provided that the replacement does not exceed the normal valence of the indicated atom. When the substituent is oxo (i.e. =O), two hydrogen atoms on a single atom are replaced with oxygen. Such combinations are permissible only if the combination of substituents and / or variables results in a chemically precise and stable compound. A chemically precise and stable compound means that the compound is sufficiently stable that it can be isolated from a reaction mixture, the chemical structure of the compound can be determined, and it can be formulated into a preparation having at least practical utility.

[0068] Unless otherwise noted, substituents are named relative to the core structure, for example, when (cycloalkyl)alkyl is listed as a possible substituent, it is to be understood that the point of attachment of the substituent to the core structure is at the alkyl portion.

[0069] As used herein, the term "substituted with one or more substituents" means that one or more hydrogen atoms of the indicated atom or group are independently replaced with one or more substituents selected from the indicated group. In some embodiments, "substituted with one or more substituents" means that the indicated atom or group is replaced with 1, 2, 3, or 4 substituents independently selected from the indicated group.

[0070] Those skilled in the art should understand that some of the compounds of formula (I) may contain one or more chiral centers, and therefore exist in two or more stereoisomeric forms.The racemic mixtures of these isomers, mixtures enriched in individual isomers and in certain enantiomers, as well as diastereomers in which two chiral centers exist, and mixtures partially enriched in certain diastereomers are within the scope of the present invention.Furthermore, those skilled in the art should understand that the present invention includes all individual stereoisomers (e.g., enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formula (I), and, where applicable, their individual tautomers.

[0071] In other words, in some embodiments, the present invention provides compounds of various stereoisomeric purity, i.e., diastereomeric purity or enantiomeric purity, expressed as various "ee" or "de" values. In some embodiments, the compound of formula (I) (e.g., as described in the present invention) 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 those recited values). In some embodiments, the compound of formula (I) (e.g., as described in the present invention) has an enantiomeric purity of greater than 99.9% ee, ranging up to 100% ee. In some embodiments, the compound of formula (I) (e.g., as described in the present invention) 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 in the present invention) has a diastereomeric purity of more than 99.9% de.

[0072] The term "enantiomeric excess" or "ee" indicates how much of one enantiomer is present relative to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |RS|*100, where R and S are the moles or weight fractions of each enantiomer in the mixture such that R+S=1. Using knowledge of the optical rotation of chiral substances, the percent enantiomeric excess is defined as ([a]obs / [a]max)*100, where [a]obs is the optical rotation of the mixture of enantiomers and [a]max is the optical rotation of the pure enantiomer.

[0073] The term "diastereomeric excess" or "de" refers to how much of one diastereomer is present relative to the other and is defined similarly to 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 respective moles or weight fractions of diastereomers in the mixture such that D1+D2=1.

[0074] Determination of diastereomeric and / or enantiomeric excess can use a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography and / or optical rotation measurements, and is accomplished following routine protocols well known to those skilled in the art.

[0075] Racemic mixtures can be used as is or resolved into their individual isomers. Resolution provides stereochemically pure compounds or mixtures 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 can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming 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 the salts, and then liberating one or both of the resolved bases and optionally repeating the process to obtain one or both in a form substantially free of the other, i.e., the desired stereoisomer is, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% optically pure by weight. Alternatively, as known to those skilled in the art, the racemic mixture can be covalently linked with a chiral compound (auxiliary group) to obtain the diastereomers, which can be separated by chromatography or fractional crystallization, followed by chemical removal of the chiral auxiliary group to obtain the pure enantiomers.

[0076] According to the present invention, a "pharmaceutically acceptable salt" means an acid or base salt of the free form of a compound of formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject.

[0077] "Pharmaceutically acceptable salt" refers to acid addition salts of compounds of formula (I) with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, and the like, and acid addition salts of compounds of formula (I) with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, mesylate, paratoluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts of the formula HOOC-(CH2) nThe "pharmaceutically acceptable salt" includes, but is not limited to, salts of -COOH (wherein n is 0-4) with alkanedicarboxylic acids, etc. The "pharmaceutically acceptable salt" also includes base addition salts of the compound of formula (I) having 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 obtained pharmaceutically acceptable salt includes, but is not limited to, 1:1, 1:2, 1:3 and 1:4.

[0078] "Prodrugs" according to the present invention refer to pharmacological substances (i.e. drugs) derived from a parent drug, which, when administered, are metabolized in the body to become the parent drug. Prodrugs can be prepared by replacing one or more functional groups present in a compound, where the substituents in the prodrug are thus removed in vivo and converted to the parent compound. The preparation and use of prodrugs are described in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series and Bioreversible. "Prodrugs" include, but are not limited to, esters, such as phosphate esters, formates, carbamates, and amides, such as formamides, acetamides, of the compounds of formula (I).

[0079] Also, when the compound described in the present invention is obtained as an acid addition salt, the free base can be obtained by basifying the solution of the acid addition salt. Conversely, when the product is a free base, an acid addition salt, particularly a pharma- ceutically acceptable acid addition salt, can be prepared 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. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharma-ceutically acceptable acid addition salts without undue experimentation.

[0080] The term "solvate" refers to a solvent addition form that contains a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a certain molar ratio of solvent molecules in the solid state, thereby forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by combining one or more molecules of water with one molecule of the substance, where the water maintains its molecular state as H2O, and such combination can form one or more hydrates, such as hemihydrate, monohydrate, and dihydrate, as well as various hydrates.

[0081] As used herein, "group" and "-yl" are synonymous and are used to describe a functional group or molecular fragment capable of linking to another molecular fragment.

[0082] The term "active ingredient" is used to indicate a chemical entity having biological activity. In some embodiments, an "active ingredient" is a chemical entity having pharmaceutical utility. In the United States, practical drug activity may be established by suitable preclinical assays, whether in vitro or in vivo. Drug activity sufficient to be approved by a regulatory agency (e.g., the FDA in the United States) is of a higher standard than preclinical assays. For such higher standard drug activity, the success of which is generally not reasonably predictable from preclinical results, may be established by suitable and successful randomized double-blind controlled clinical trials in humans.

[0083] The term "treatment" or "therapy" of a disease or disorder refers to the administration of one or more pharmaceutical agents, particularly the compounds of formula (I) according to the present invention and / or pharma- ceutically acceptable salts thereof, to a subject (e.g., a human) having said disease or disorder, or having symptoms of said disease or disorder, or having a predisposition to said disease or disorder, with the intent to cure, ameliorate, alleviate, relieve, alter, remedy, modify, ameliorate, or affect said disease or disorder, symptoms of said disease or disorder, or predisposition to said disease or disorder, in a situation that achieves a beneficial therapeutic effect. In some embodiments, said disease or disorder is cancer.

[0084] With respect to chemical reactions, the terms "treating," "contacting," and "reacting" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. It will be appreciated that the reaction that produces the indicated and / or desired product does not necessarily result directly from the combination of the two reagents initially added, i.e., there may be one or more intermediates produced in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0085] The term "effective amount" as used in the present invention refers to an amount or dosage of a cathepsin C inhibitor sufficient to generally provide therapeutic benefit to 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 in the present invention can be determined by common methods (e.g., modeling, dose escalation studies or clinical trials) and by taking into account common considerations (e.g., mode or route of administration or drug delivery, pharmacokinetics of the drug, severity and course of the disease or disorder, previous or ongoing therapy of the subject, health status and response to the drug of the subject, and the judgment of the attending physician). In the United States, the determination of effective dosage is generally difficult to predict from preclinical studies. In practice, dosage is not completely predictable, and dosage will evolve into new and unpredictable dosing regimens after initial use in randomized double-blind controlled clinical trials.

[0086] Exemplary doses are from about 0.0001 to about 200 mg of active agent per kg of subject body weight per day, e.g., from about 0.001 to 100 mg / kg / day, or from about 0.01 to 35 mg / kg / day, or from about 0.1 to 10 mg / kg, administered once daily or in divided dose units (e.g., twice per day, three times per day, four times per day). For a 70 kg human, a suitable dose range is from about 0.05 to about 7 g / day, or from about 0.2 to about 5 g / day. Once improvement of the patient's disease or disorder is observed, the dose can be adjusted to maintain treatment. For example, the dose or frequency of administration, or both, can be reduced to a level at which the desired therapeutic effect is maintained, depending on the changing symptoms. Of course, once the symptoms have been alleviated to an appropriate level, treatment may be stopped. However, the patient may require intermittent treatment for an extended period of time upon recurrence of symptoms.

[0087] The term "inhibit" refers to a decrease in the basal activity of a biological activity or process. The term "inhibit cathepsin C activity" is used for the purposes of the present invention for the actual drug activity and refers to a decrease in cathepsin C activity in direct or indirect response to the presence of the compound of formula (I) and / or its pharmaceutically acceptable salts according to the present invention, compared to the cathepsin C activity in the absence of the compound of formula (I) and / or its pharmaceutically acceptable salts. The decrease in activity may be caused by the direct interaction of the compound of formula (I) and / or its pharmaceutically acceptable salts according to the present invention with cathepsin C, or may be caused by the interaction of the compound of formula (I) and / or its pharmaceutically acceptable salts according to the present invention with one or more other factors that affect cathepsin C activity. For example, the presence of a compound of formula (I) according to the present invention and / or a pharma- ceutically acceptable salt thereof can reduce the activity of cathepsin C by directly binding to cathepsin C, or by directly or indirectly influencing another factor, or by directly or indirectly reducing the amount of cathepsin C present in a cell or organism.

[0088] The term "subject" as used herein refers to mammals and non-mammals. Mammals refer to any member of the class Mammalia, including, but not limited to, humans, non-human primates such as chimpanzees, other apes and monkeys, farm animals such as cows, horses, sheep, goats, pigs, livestock such as rabbits, dogs, cats, laboratory animals including rodents such as rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" is not limited to a particular age or sex. In some embodiments, the subject is a human.

[0089] In general, the term "about" is used in the present invention to adjust a numerical value above and below the stated value by 20%.

[0090] A general method for the synthesis of compounds of formula (I) is as follows. [ka]

[0091] In scheme 1, in the compound of formula II, PG represents a protecting group such as t-butoxycarbonyl. As shown in scheme 1, the compound of formula II is activated by 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU) under basic conditions (e.g., using N,N-diisopropylethylamine as base) and reacted with aqueous ammonia to obtain the compound of formula III. The deprotected product of the compound of formula III, the compound of formula IV and the acid of the compound of formula V are reacted with the acid of formula V to obtain the amide compound of formula VI by general literature reported methods, for example, using N,N-diisopropylethylamine as base and HATU or HBTU as activation reagent.

[0092] Suzuki coupling reaction of a compound of formula VI with a borate compound of formula VIII utilizes a palladium catalyst such as dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium to give a compound of formula IX using a suitable base such as potassium acetate in a suitable solvent such as dioxane.

[0093] Another scheme converts a compound of formula VI to a borate compound of formula VII. The compound of formula VI is reacted with bis-pinacolatodiboron under the catalysis of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium using potassium acetate as a base in dimethylsulfoxide to give the borate compound of formula VII. The compound of formula XI is subjected to Suzuki coupling reaction with the borate compound of formula VII to give the compound of formula IX using a palladium catalyst such as dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium using a suitable base such as potassium acetate in a suitable solvent such as dioxane.

[0094] The amide of the compound of formula IX can be dehydrated with N-(triethylammoniumsulfonyl)methylcarbamate in dichloromethane to give the compound of formula X. Deprotection of the compound of formula X gives the final product, the compound of formula I.

[0095] The compound of formula (I) according to the present invention (e.g., any compound in the present invention) and / or a pharma- ceutically acceptable salt thereof, alone or in combination with one or more other active ingredients, can be prepared into a pharmaceutical composition comprising (a) an effective amount of a compound of formula (I) according to the present invention and / or a pharma- ceutically acceptable salt thereof, and (b) a pharma- ceutically acceptable excipient (e.g., a pharma- ceutically acceptable carrier).

[0096] Pharmaceutically acceptable carrier refers to a carrier that is compatible with the active ingredient in the composition (in some embodiments, can stabilize the active ingredient) and is not harmful to the subject being treated. For example, solubilizers such as cyclodextrins (which form a specific more soluble complex with the compound of formula (I) and / or its pharma-ceutically acceptable salts described in the present invention) can be used as pharmaceutical excipients for the delivery of active ingredients. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and dyes such as D&C Yellow#10. Suitable pharma-ceutically acceptable carriers are disclosed in standard reference texts in the field (Remington's Pharmaceutical Sciences, A. Osol).

[0097] Pharmaceutical compositions comprising the compounds of formula (I) according to the present invention (e.g., any compound according to the present invention) and / or pharma- ceutically acceptable salts thereof can be administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation or by implantation. The term "parenteral" as used in the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intraspinal, intralesional and intracranial injection or infusion.

[0098] The pharmaceutical compositions according to the present invention can be prepared in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. In some embodiments, the pharmaceutical compositions comprising the compound of formula (I) and / or its pharma- ceutically acceptable salts are formulated for intravenous infusion, topical administration, or oral administration.

[0099] Oral compositions may be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions and solutions. Commonly used carriers for tablets include lactose and cornstarch. Lubricants such as magnesium stearate are also generally included in tablets. For oral administration in capsule form, useful diluents include lactose and dry cornstarch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oil phase together with an emulsifying or suspending agent. If desired, certain sweetening, flavoring or coloring agents can be added.

[0100] In some embodiments, the compound of formula (I) and / or pharma- ceutically acceptable salts thereof may be present in tablets in amounts of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg. In some embodiments, the compound of formula (I) and / or pharma- ceutically acceptable salts thereof may be present in capsules in amounts of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg.

[0101] Sterile injectable compositions (e.g., aqueous or oily suspensions) can be prepared using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable intermediates can be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Pharmaceutically acceptable carriers and solvents that can be used include, inter alia, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils (e.g., synthetic mono- or diglycerides) are also conventionally used as solvents or suspending media. Fatty acids, such as oleic acid and its glyceride derivatives, and natural pharma-ceutically acceptable oils, such as olive oil or castor oil (especially their polyoxyethylated versions), are useful for injectable intermediates. These oily solutions or suspensions can also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants.

[0102] Inhalation compositions can be prepared according to techniques well known in the art of pharmaceutical formulation using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art, and can also be prepared as a solution in saline.

[0103] Topical compositions can be formulated in the form of oils, creams, lotions, ointments, and the like. Suitable carriers for this composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain oils and fats, animal fats, and high molecular weight alcohols (i.e., alcohols with 12 or more carbon atoms). In some embodiments, pharma- ceutically acceptable carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants, and antioxidants may also be included, along with agents that impart color or fragrance, if desired. In addition, transdermal penetration enhancers may also be used in these topical formulations. Examples of such enhancers can be found in U.S. Patents U.S. Nos. 3,989,816 and 4,444,762.

[0104] Creams may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water into which is mixed the active ingredient dissolved in a small amount of oil, such as almond oil. An example of such a cream contains about 40 parts by weight of water, about 20 parts by weight of beeswax, about 40 parts by weight of mineral oil and about 1 part by weight of 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 allowing the mixture to cool. An example of such an ointment contains about 30% by weight of almond oil and about 70% by weight of white soft paraffin.

[0105] Suitable in vitro assays can be used to evaluate the substantial usefulness of the compound of formula (I) and / or its pharma- ceutically acceptable salts described in the present invention in inhibiting the activity of cathepsin C. The compound of formula (I) and / or its pharma- ceutically acceptable salts described in the present invention can also be further evaluated by in vivo assays for further substantial usefulness in treating pulmonary disease, inflammatory disease, metabolic disease, infectious disease, cardiovascular disease, or autoimmune disease. For example, the compound of formula (I) and / or its pharma- ceutically acceptable salts described in the present invention can be administered to animals (e.g., mouse models) with pulmonary disease, inflammatory disease, metabolic disease, infectious disease, cardiovascular disease, cancer, or autoimmune disease, and its therapeutic effect can be evaluated, and if preclinical results are favorable, the dose range and administration route for animals such as humans can be further planned, or it can be administered to non-disease model animals (e.g., rats) to evaluate the inhibitory effect on serine proteases downstream of cathepsin C, thereby predicting the effect in pulmonary disease without a validated disease model, such as bronchiectasis.

[0106] The compounds of formula (I) and / or pharma- ceutically acceptable salts thereof according to the present invention may be shown to have substantial preclinical utility sufficient to warrant clinical trials as desired to demonstrate beneficial therapeutic or prophylactic effects in subjects with, for example, pulmonary and inflammatory diseases.

[0107] The term "pulmonary disease" refers to a pathological condition associated with the lungs. Non-limiting examples of such diseases include bronchiectasis, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, asthma, chronic obstructive pulmonary disease, pneumonia, acute lung injury, and acute respiratory distress syndrome.

[0108] The term "inflammatory disease" refers to pathological conditions resulting in inflammation, particularly caused by neutrophil chemotaxis. Non-limiting examples of such diseases include inflammatory skin diseases (psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; responses associated with inflammatory bowel disease (IBD) (e.g., Crohn's disease and ulcerative colitis); ischemia-reperfusion injury, including surgical tissue reperfusion injury, and myocardial ischemia, such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery, and abnormal contractile responses of coronary vessels after percutaneous transluminal coronary angioplasty, stroke, and tissue reperfusion injury during abdominal aortic aneurysm surgery; cerebral edema secondary to stroke. These include: tumors; cranial trauma; hypovolemic shock; asphyxiation; adult respiratory distress syndrome; acute lung injury; Behcet's disease; dermatomyositis; polymyositis; autoimmune diseases such as rheumatoid arthritis (RA); pulmonary inflammation including pleuritis, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonia, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis; and other inflammations such as ANCA-associated inflammation and antineutrophil cytoplasmic antibody-associated necrotizing crescent glomerulonephritis.

[0109] The compounds of formula (I) and / or pharma- ceutically acceptable salts according to the present invention can be used to achieve beneficial therapeutic or prophylactic effects in subjects with, for example, metabolic diseases, infectious diseases, cardiovascular diseases, infectious diseases, cancer, autoimmune diseases.

[0110] The term "autoimmune disease" refers to a disease or condition caused by the body's own immune response to its own antigens, resulting in damage to its own 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, as well as myeloid proliferative disorders such as myelofibrosis, postpolycythemia vera / essential thrombocytosis myelofibrosis (PV / ET).

[0111] The term "metabolic disease" refers to a disease caused by or related to metabolic disorders, and non-limiting examples include non-alcoholic fatty liver, non-alcoholic steatohepatitis, AATD, obesity, diabetes, and the like.

[0112] The term "infectious disease" refers to a pathological condition caused by infection with a virus, bacteria, parasite, etc. Non-limiting examples of such diseases include leishmaniasis, novel coronavirus pneumonia, and sepsis.

[0113] The term "cardiovascular disease" 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, etc.

[0114] The term "cancer" as used herein refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, the ability to invade inappropriate surrounding tissues, and / or the ability to establish new growth at ectopic 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, bone, cartilage, blood, and blood vessels. The term "cancer" includes primary and metastatic cancers. Non-limiting examples of solid tumors include lung cancers, such as non-small cell lung cancer (NSCLC).

[0115] In some embodiments, inflammatory and autoimmune diseases include rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, lupus erythematosus, systemic lupus erythematosus, psoriasis, and multiple sclerosis.

[0116] In addition, the compounds of formula (I) described in the present invention (e.g., any compound in the present invention) and / or pharma- ceutically acceptable salts thereof may be combined with additional active ingredients in the treatment of respiratory diseases, inflammatory or autoimmune diseases, and cancer. The additional active ingredients may be co-administered separately with the compounds of formula (I) described in the present invention and / or pharma-ceutically acceptable salts thereof, or may be included with such ingredients in a drug composition according to the present disclosure, such as a fixed-dose combination drug product. In an exemplary embodiment, the additional active ingredient is one that is known or found to be effective in the treatment of diseases mediated by cathepsin C and its downstream serine protease activity, such as another cathepsin C modulator or a compound that effectively antagonizes another target associated with a particular disease. The combination may serve to enhance the efficacy (e.g., by including in the combination a compound that enhances the potency or efficacy of the compound of formula (I) according to the present invention and / or a pharma- ceutically acceptable salt thereof), reduce one or more side effects, or reduce the required dose of the compound of formula (I) according to the present invention and / or a pharma- ceutically acceptable salt thereof. EXAMPLES

[0117] The following examples are intended to be illustrative of the present invention and should not be considered as limiting in any way. Unless otherwise stated, parts are parts by weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. All data were measured by Agilent (Agilent 6120 and / or 1100). All reagents used in the present invention, except for the synthesized intermediates, are commercially available. All compound names, except for the reagents, were generated by ChemDraw 20.0.

[0118] The following abbreviations are used:

[0119] ACN Acetonitrile Boc t-Butoxycarbonyl (Boc)2O Di-t-butylpyrocarbonate BH3 Borane DAST Diethylaminosulfur trifluoride DCM Dichloromethane DEA Diethylamine DMF N,N-Dimethylformamide DMA Dimethylacetamide DIBAL-H Hydrogenated diisobutylaluminum DIEPA N,N-Diisopropylethylamine EDCI 1-(3-Dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride EA Ethyl acetate Et3N Triethylamine HATU 2-(7-azabenzotriazole)-N,N, N',N'-Tetramethyluronium hexafluoro Orophosphate HBTU O-benzotriazole-tetramethyluronium Hexafluorophosphate HOAc Acetic acid HOBt 1-Hydroxybenzotriazole eee Enantiomeric excess mL Milliliters g Grams mg Milligrams ng Nanogram Mol Mole mmol Millimole h time MeOH methanol NaH Sodium Hydrogen NCS N-Chlorosuccinimide NMP N-Methyl-2-pyrrolidone PE Petroleum Ether Pd(dppf)2Cl2 dichloro[1,1'-bis(diphenylphos fin)ferrocene]palladium Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium PMB p-Methoxybenzyl PPh3 Triphenylphosphine Pin2B2 Bis(pinacolato)diboron THF Tetrahydrofuran TFA Trifluoroacetic acid TsOH 4-Methylbenzenesulfonic acid Xphos 2-Dicyclohexylphosphino-2',4', 6'-Triisopropylbiphenyl Burgess Reagent N-(Triethylammonium Sulfonyl) Methyl carbamate

[0120] 1. Intermediate 1 [ka]

[0121] a) At room temperature under the protection of nitrogen, CDI (20.7 g, 127.7 mmol) was added to a solution of compound 2-amino-4-bromophenol (20.0 g, 106.4 mmol) in 2-MeTHF (300 mL), refluxed for 1 h, cooled to room temperature, washed successively with 2 M HCl (aq) (300 mL), 8% NaHCO3 (aq) (300 mL), and saturated brine (150 mL), dried over Na2SO4, and concentrated to obtain a light brown solid product 1a (21.9 g, 96%). MS (ESI): m / z = 215.9 [M + H] + . 1 HNMR (400MHz, DMSO-d6): δ11.85 (s, 1H), 7.26-7.23 (m, 3H).

[0122] b) At room temperature under nitrogen protection, sodium chlorodifluoroacetate (3.6 g, 23.5 mmol), S8 (6.0 g, 23.5 mmol), sodium-t-butoxide (1.8 g, 18.8 mmol), and 4A molecular sieves (200 mg, dry powder) were added to a solution of compound 1a (1.0 g, 4.7 mmol) in DMF (15.0 mL) in sequence, and the mixture was heated to 70° C. and stirred for 6 hours. After cooling to room temperature, the molecular sieves were filtered off, washed with EA (50 mL), diluted with EA (100 mL), washed with saturated brine (50 mL×5), dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (TFA was used as buffer, A was 0.05% TFA in water, B was 0.05% TFA in acetonitrile, and the chromatographic column was Waters XBridgePeptideBEHC18, 19×250 mm, 10 μm, 130A) to give a white solid product 1 (660 mg, 53%). MS (ESI): m / z=266.0 [M+H] + . 1 HNMR (400MHz, DMSO-d6): 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).

[0123] 2. Intermediate 2 [ka]

[0124] a) 1a (1.0 g, 4.7 mmol) and formaldehyde (37% aqueous solution, 610 μL) were added to water (5 mL) at room temperature. The reaction mixture was stirred at 80° C. overnight, cooled to room temperature, filtered, washed with water (3×10 mL), and the crude product was dried in vacuum to give a light brown solid 2a (960 mg, 84%). MS (ESI): m / z=228.1 [M+H] + . 1 HNMR (400MHz, DMSO-d6): δ7.60 (t, J=1.2Hz, 1H); 7.33 (br, 3H); 5.21 (s, 2H).

[0125] b) DAST (265 μL, 2.0 mmol) was added dropwise to a dichloromethane solution (5 mL) of 2a (312 mg, 1.3 mmol) at -50°C under nitrogen protection. After the addition was completed, the reaction was gradually warmed to room temperature and stirred overnight, then quenched with saturated NaHCO3 (10 mL), extracted with dichloromethane, washed with saturated brine (10 mL), dried over Na2SO4, and concentrated to give a light brown solid 2 (306 mg, 95%). MS (ESI): m / z = 246.1 [M+H] + . 1 HNMR (400MHz, DMSO-d6): δ7.86 (brs, 1H); 7.41-7.39 (m, 2H); 6.02 (d, J = 52Hz, 2H).

[0126] 3. Intermediate 3 [ka]

[0127] a) At room temperature, 2-amino-4-bromophenol (1.0 g, 5.3 mmol) and 3-oxetanone (764 mg, 10.6 mmol) were dissolved in dry THF (15.0 mL). BH3·THF (1 M, 5.3 mL) was slowly added dropwise under ice cooling. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 6 h. Then, 3-oxetanone (764 mg, 10.6 mmol) and BH3·THF (1 M, 5.3 mL) were added and stirred overnight. The reaction solution was ice-cooled, and excess BH3 was quenched by slowly adding aqueous NaOH (1 M, 20 mL), the organic phase was separated, dried over Na2SO4, and concentrated to obtain the crude product. Column chromatography purification (eluent DCM / MeOH=50 / 1) gave a light brown solid product 3a (640 mg, 50%). MS (ESI): m / z=246.2 [M+H] + . 1HNMR (400MHz, DMSO-d6): 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).

[0128] b) At room temperature, under the protection of nitrogen, CDI (535 mg, 3.3 mmol) was added to a solution of compound 3a (603 mg, 2.5 mmol) in 2-MeTHF (10 mL). After heating to reflux for 1 h, the reaction solution was cooled to room temperature and washed successively with 2M HCl (aq) (15 mL), 8% NaHCO3 (aq) (15 mL) and saturated brine (8 mL). The organic phase was separated, dried over Na2SO4 and concentrated to obtain the crude product. Column chromatography purification (eluent PE / EA = 10:1 to 2:1, V / V) gave the light brown solid product 3 (230 mg, 35%). MS (ESI): m / z = 270.0 [M+H] + . 1 HNMR (400MHz, DMSO-d6): 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).

[0129] 4. Intermediates 4 and 5 [ka]

[0130] a) At 0° C. under nitrogen protection, to a solution of 1a (1.1 g, 5.1 mmol) in DMF (15 mL) was added Cs2CO3 (1.6 g, 5.1 mmol) and MeI (658 μL, 10.2 mmol) in DMF (15 mL) successively. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0° C. and water (15 mL) was added dropwise. The mixture was filtered, washed with water, and dried under vacuum at 55° C. to give a light brown solid 4 (826 mg, 71%). MS (ESI): m / z=230.3 [M+H] + . 1HNMR (400MHz, DMSO-d6): δ7.55-7.54 (m, 1H), 7.29-7.28 (m, 2H), 3.32 (s, 3H).

[0131] b) Under the protection of argon, 4 (228 mg, 1.0 mmol), Pin2B2 (305 mg, 1.2 mmol), Pd(OAc)2 (7 mg, 0.03 mmol), XPhos (29 mg, 0.06 mmol) and KOAc (294 mg, 3.0 mmol) were added to dioxane (5 mL) and heated to 75 °C, followed by stirring for 1 h. The mixture was cooled to room temperature, filtered and the solid was washed 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 grey solid product 5 (232 mg, 84.4%). MS (ESI): m / z = 276.4 [M+H] + . 1 HNMR (400MHz, DMSO-d6): δ7.47(dd,J=8.0,1.2Hz,1H),7.44(s,1H),7.33(d,J=8.0Hz,1H),3.35(s,3H),1.30(s,12H).

[0132] 5. Intermediates 6 and 7 [ka]

[0133] a) At 70°C, AIBN (524 mg, 3.2 mmol) was added to a suspension of 3-methylthiophene-2-carboxylic acid methyl ester (5 g, 32.05 mmol) and NBS (5.7 g, 32.02 mmol) in CCl4 (80 mL). Stirring continued for 3 h, cooled to 40°C, and NBS (2.85 g, 16 mmol) was added. The temperature was then raised to 70°C and stirring continued for 1 h. Cooled to room temperature, the solid was filtered off, the filtrate was spin-dried, and the resulting residue was dissolved in EA (100 mL), washed successively with saturated NaHCO3 (30 mL) and water (30 mL), dried over Na2SO4, and concentrated to give oily product 6a (10 g). The crude product was used directly in the next reaction. MS (ESI): m / z = 155.4 [M-Br]+ .

[0134] b) At room temperature, 7N NH3 in MeOH (100 mL) was added dropwise to a solution of 6a (crude product 10 g, ca. 32.05 mmol) in DMF (50 mL), followed by stirring for 2 h. Then, H2O (200 mL) and EA (3 x 150 mL) were added to the reaction solution, and the pH was adjusted to 8 with solid NaHCO3. Then, dioxane (50 mL) and Boc2O (5 g, 22.9 mmol) were added successively, followed by stirring at room temperature for 3 h. The mixture was concentrated under reduced pressure to evaporate dioxane, extracted with EA (3 x 100 mL), dried over Na2SO4, and concentrated to obtain the crude product. Column chromatography purification (eluent PE:EA = 6:1 to 5:1 to 4:1, product Rf = 0.7 for PE / EA 4 / 1) gave oily product 6b (4 g, containing some Boc2O). MS(ESI): m / z=294.3[M+Na] + .

[0135] c) TFA (20 mL) was added to a dichloromethane solution (60 mL) of 6b (crude product 4 g, ca. 14 mmol) at room temperature, followed by stirring for 1 h. The solvent and TFA were removed by concentration under reduced pressure. The resulting residue was dissolved in dichloromethane (100 mL) and spun dry again. The crude product was dissolved in MeOH (10 mL), and then 7N NH3 / MeOH was added to adjust the pH to 10. The liquid was purified by preparative HPLC (C18, CH3CN, 10 mM NH4HCO3 in water) to give pale white solid 6c (1.75 g, 31% yield for 4 steps). MS (ESI): m / z=171.9 [M+H] + . 1 HNMR (400MHz, CDCl3): 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).

[0136] d) Compound 6c (1.55 g, 9.06 mmol) and K2CO3 (1.25 g, 9.06 mmol) were mixed in MeOH (120 mL) and EtOH (120 mL) and refluxed overnight. After cooling to room temperature, the mixture was spin-dried to obtain the crude product. Column chromatography purification (eluent DCM:MeOH = 20:1 to 15:1, Rf = 0.2 for DCM / MeOH 20 / 1 solution) gave the light brown solid product 6d (680 mg, 53%). MS (ESI): m / z = 140.1 [M+H] + .

[0137] e) At 0°C, Br2 (300uL, 5.85mmol) was slowly added dropwise to a solution of 6d (745mg, 5.36mmol) in AcOH (10mL) / H2O (10mL), followed by stirring for 2h. Then, 10% Na2SO3 (20mL) and saturated NaHCO3 were added successively to adjust the pH to 7. Extraction with EA (3x50ml), drying and concentration gave pale white solid 6 (1.09g, 93%). MS (ESI): m / z=218.2[M+H] + . 1 HNMR (400MHz, CD3OD): δ7.29 (s, 1H), 4.39 (s, 2H).

[0138] f) At 0°C, NaH (60% in oil, 122 mg, 3.05 mmol) was added to a solution of 6 (600 mg, 2.75 mmol) in DMF (10 mL). After stirring for 30 min, MeI (205 uL, 3.29 mmol) was added dropwise, followed by stirring at room temperature for 2 h. The reaction was quenched with H2O (100 mL), neutralized to pH 7 with saturated NH4Cl solution, extracted with EA (50 mL*3), dried over Na2SO4, and concentrated to give the crude product. Column chromatography purification (EA:PE=2:1 to EA, Rf=0.5 for EA) gave a light brown solid 7 (400 mg, 62%). MS(ESI): m / z=232.1[M+H] + .

[0139] 6. Intermediates 8 and 9 [ka]

[0140] a) At 0°C, methyl 2-amino-4-bromobenzoate (20 g, 87 mmol) was added to a flask containing 10% H2SO4 (500 mL), followed by dropwise addition of 70 mL aqueous NaNO2 (12 g, 173.9 mmol). After stirring for 40 min, dropwise addition of 70 mL aqueous KI (57.73 g, 347.8 mmol) was continued for 1 h. The reaction was quenched with saturated Na2SO3 (200 mL) and extracted with EA (3 x 500 mL). Drying over Na2SO4 and concentration gave the crude product. Column chromatography purification (eluent PE / EA = 10:1, V / V) gave oily product 8a (25 g, 84%). MS (ESI): m / z = 342.8 [M + H] + . 1 HNMR (400MHz, CDCl3): δ8.19(d,J=1.6Hz,1H),7.71(d,J=8.4Hz,1H),7.57-7.54(m,1H),3.94(s,3H).

[0141] 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 -70 °C, i PrMgCl-LiCl (27.3 ml, 35.5 mmol, 1.3 mol / L in THF) was slowly added dropwise and stirred for 30 min. The dry ice bath was removed, and the mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO3 (200 mL) and extracted with EA (3 x 500 mL). The mixture was dried over Na2SO4 and concentrated to give the crude product. Column chromatography purification (eluent PE / EA = 10:1, V / V) gave yellow solid product 8b (6 g, 53%). MS (ESI): m / z = 298.1 [M-55] + . 1 HNMR (400MHz, CDCl3): 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).

[0142] 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 h, the mixture was concentrated under reduced pressure to give a brown oily product 8c (1 g, 91%). MS (ESI): m / z = 256.0 [M+H] + .

[0143] d) At room temperature, 8c (1 g, 2.82 mmol) and paraformaldehyde (1.69 g, 56.3 mmol) were added to MeOH (40 mL) and AcOH (5 mL), and stirred for 1 h. NaBH(OAc)3 (600 mg, 2.82 mmol) was added, and stirred for 30 min. This step was repeated 9 times, and then stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was added with saturated NaHCO3 (150 mL), extracted with EA (3 x 200 mL), dried over Na2SO4, and concentrated to obtain the crude product. Column chromatography purification (eluent PE / EA = 3:1 to 1:1, V / V) gave the white solid product 8 (400 mg, 66.7%). MS (ESI): m / z = 270.0 [M + H] + . 1 HNMR (400MHz, CDCl3): 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).

[0144] e) To a solution of 8b (6 g, 16.9 mmol) in THF (100 mL) was added LiBH4 (1.49 g, 67.8 mmol) in THF (100 mL) at room temperature. After stirring for 24 h, the reaction was quenched with water (200 mL), extracted with EA (3 x 500 mL), dried over Na2SO4, and concentrated to give crude product 9a. Purification by preparative HPLC (NH4HCO3 aqueous solution was used as buffer, A was 10 mM NH4HCO3 aqueous solution, B was acetonitrile, column was Waters XBridge Peptide BEH C18, 19 x 250 mm, 10 μm, 130A) gave white solid product 9a (4.5 g, 75%). MS (ESI): m / z = 380.2 [M + Na] + .

[0145] f) At 0°C, p-toluenesulfonic anhydride (2.73 g, 8.4 mmol) was added in portions to a solution of 9a (2.5 g, 7.0 mmol) and TEA (3.53 g, 35 mmol) in THF (100 mL). After stirring for 30 min, the mixture was warmed to room temperature and stirred for 48 h. The mixture was concentrated under reduced pressure, water (200 mL) was added, extracted with EA (3 x 200 mL), dried over Na2SO4, and concentrated to give the crude product. Column chromatography purification (eluent PE / EA = 5:1, V / V) gave the white solid product 9b (1.9 g, 80%). MS (ESI): m / z = 284.2 [M-55] + . 1 HNMR(400MHz, CDCl3): δ7.62(d,J=1.6Hz,1H),7.48-7.46(m,1H),7.10(d,J=8.0H z,1H),5.07(s,2H),4.32(d,J=10.0Hz,2H),4.13(d,J=10.0Hz,2H),1.50(s,9H).

[0146] 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 3 h, the mixture was concentrated under reduced pressure to give a brown oil 9c (1.05 g, 99%). MS (ESI): m / z = 242.1 [M+H] + .

[0147] h) At room temperature, 9c (1.05 g, 2.97 mmol) and paraformaldehyde (1.78 g) were added to a flask containing MeOH (60 mL) and AcOH (10 mL), and stirred for 1 h. After that, NaBH(OAc)3 (629 mg, 2.97 mmol) was added and stirred for 30 min. This step was repeated 9 times, and the reaction was stirred overnight. Concentrated under reduced pressure, saturated NaHCO3 (200 mL) was added, extracted with EA (3 x 200 mL), dried over Na2SO4, and concentrated to obtain the crude product. Column chromatography purification (eluent PE / EA = 2:1 to 1:1, V / V) gave colorless oily product 9 (650 mg, 86%). MS (ESI): m / z = 256.0 [M+H] + . 1HNMR(400MHz, CDCl3): 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).

[0148] 7. Intermediate 10 [ka]

[0149] a) AIBN (840 mg, 5.1 mmol) was added to a suspension of 2-methylthiophene-3-carboxylic acid methyl ester (8 g, 51.3 mmol) / NBS (9.1 g, 51.1 mmol) in carbon tetrachloride (120 mL) at 70° C. The reaction mixture was stirred at 70° C. for 4 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with saturated NaHCO3 (50 mL) / water (50 mL). The organic layer was separated, dried over Na2SO4, filtered and evaporated to give the light brown oily crude product 10a (13 g). The crude product was used directly in the next step. MS (ESI): m / z=155.4 [M-Br] + .

[0150] b) A solution of 7N NH3 (30 mL, 210 mmol) in MeOH was added to a solution of 10a (crude product 13 g, ca. 51.3 mmol) in THF (100 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated and 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, CD3OD): δ7.59-7.55 (m, 2H), 4.61 (s, 2H), 3.94 (s, 3H).

[0151] c) After refluxing a mixture of 10b (3.3 g, 19.3 mmol) / K2CO3 (2.66 g, 19.3 mmol) in MeOH (120 mL) for 24 h, the reaction mixture was cooled to room temperature and evaporated. The residue was purified by silica gel chromatography (DCM:MeOH=20:1, Rf=0.5 for DCM / MeOH 20 / 1) to give a white solid 10c (890 mg, 33%). MS(ESI): m / z=140.4[M+H] + . 1 HNMR (400MHz, MeOD): δ7.56 (d, J = 5.2 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 4.53 (s, 2H).

[0152] d) At 0° C., Br2 (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° C. for 1 h. Br2 (40 uL, 0.78 mmol) was added again to the reaction mixture and stirred at 0° C. for 1 h again. The reaction mixture was added with 10% Na2SO3 (20 mL) until it became colorless, followed by saturated NaHCO3 until pH 7, and extracted with EA (3×50 mL). The EA layers were combined, dried over Na2SO4, filtered and evaporated. The residue was washed with EA (10 mL) / PE (5 mL) to give a white solid 10 (1.22 g, 90% yield). MS (ESI): m / z=218.2 [M+H] + . 1 HNMR (400MHz, CD3OD): δ7.27 (s, 1H), 4.49 (s, 2H).

[0153] 8. Intermediate 11 [ka]

[0154] a) CH3NH2 (2N, in THF, 20 mL, 40 mmol) was added to a solution of 10a (crude product 3 g, ca. 11.54 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel chromatography (EA:PE=1:1-2:1-100% EA, Rf=0.1 for EA) to give 11a (1.4 g, 66% yield for two steps) as a brown oil. MS(ESI): m / z=186.4[M+H] + .

[0155] b) A mixture of 11a (1.4 g, 7.57 mmol) in K2CO3 (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. The residue was added with water (10 mL) and extracted with EA (3 x 20 mL). All EA layers were combined, dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel chromatography (EA:PE = 1:1 to 2:1 to 100% EA, Rf = 0.5 for EA / PE 2 / 1) to give a white solid 11b (500 mg, 43%). MS (ESI): m / z = 154.3 [M+H] + . 1 HNMR (400MHz, MeOD): δ7.55 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 4.8 Hz, 1H), 4.56 (s, 2H), 3.17 (s, 3H).

[0156] c) At 0°C, Br2 (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°C for 1 h. Br2 (35 uL, 0.68 mmol) was added to the reaction mixture and stirred again at 0°C for 2 h. 10% Na2SO3 (10 mL) was added to the reaction mixture until it became colorless, followed by saturated solution of NaHCO3 until pH 7, and extracted with EA (3 x 30 mL). The EA layers were combined, dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel chromatography (EA:PE = 1:1 to 2:1, Rf = 0.4 for EA / PE 2 / 1) to give a light solid 11 (400 mg, 52%).

[0157] 9. Intermediates 12 and 13 [ka]

[0158] a) At -70°C, iPrMgCl-LiCl (2.5ml, 3.2mmol, 1.3mol / L in THF) was added dropwise to a solution of compound 8a (1g, 2.9mmol) and 3-oxetanone (232mg, 3.2mmol) in THF (25mL). After stirring for 30min, the mixture was warmed to room temperature, saturated NaHCO3 (40mL) was added, extracted with EA (3x100mL), dried over Na2SO4, and concentrated to give the crude product. Purification by preparative HPLC (TFA as buffer, A is 0.05% TFA aqueous solution, B is acetonitrile, column is Waters XBridge Peptide BEH C18, 19x250mm, 10μm, 130A) gave the white solid product 12 (300mg, 40%). MS(ESI):m / z=257.0[M+H] + . 1 HNMR (400MHz, CDCl3): δ8.12(s,1H),7.77-7.73(m,2H),5.24(d,J=8.0Hz,2H),4.91(d,J=7.6Hz,1H).

[0159] b) LiBH4 (621 mg, 28.2 mmol) was added to a solution of compound 12 in THF (70 mL) at room temperature. After stirring for 24 h, water (200 mL) was added, extracted with EA (3 x 300 mL), dried over Na2SO4, and concentrated to give the crude product. Column chromatography purification (eluent PE / EA = 2:1, V / V) gave the white solid product 13a (1.6 g, 89%). MS (ESI): m / z = 281.0 [M + Na] + .

[0160] c) At 0°C, p-toluenesulfonic anhydride (1.51 g, 4.6 mmol) was added in portions to a solution of 13a (1 g, 3.9 mmol) and TEA (19.5 g, 19.3 mmol) in THF (50 mL). After stirring for 30 min, the mixture was warmed to room temperature and stirred for 48 h. The mixture was concentrated under reduced pressure, water (100 mL) was added, extracted with EA (3 x 300 mL), dried over Na2SO4, and concentrated to give the crude product. Column chromatography purification (eluent PE / EA = 10:1, V / V) gave the white solid product 13 (440 mg, 47%). MS (ESI): m / z = 243.1 [M+H] + . 1 HNMR (400MHz, DMSO-d6): 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).

[0161] 10. Intermediate D54-m [ka]

[0162] 1) Preparation of dibenzyl-D-serine methyl ester (D54-b) [ka]

[0163] Anhydrous K2CO3 (31.0 g, 224.1 mmol), D-serine methyl ester hydrochloride (D54-a, 23.25 g, 149.4 mmol), KI (12.4 g, 74.7 mol), and benzyl bromide (44.4 mL, 373.6 mol) were added to DMF (250 mL) at room temperature. After stirring overnight at room temperature, the reaction solution was poured into water (1 L). Extraction with ethyl acetate (500 mL x 3), washing with water (300 mL) and saturated saline (300 mL) in turn, drying over anhydrous Na2SO4, concentration, and column chromatography purification (PE / EA = 9 / 1 to 8 / 2) afforded a colorless oily liquid product (D54-b, 42.3 g, 88%). MS (ESI): m / z = 300.2 [M + H] + .

[0164] 2) Preparation of (S)-methyl 3-(dibenzylamino)-2-fluoropropionate (D54-c) [ka]

[0165] To a solution of diethylaminosulfur trifluoride (18.23 mL, 138 mmol) in THF (500 mL) was added 54-b (41.3 g, 138 mmol) over 3 h at room temperature. After stirring at room temperature for 1 h, ethyl acetate (500 mL) was added and neutralized to pH 7 with saturated NaHCO3 solution. The mixture was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (PE / EA=9 / 1-8 / 2) to give the colorless oily liquid product (D54-c, 38.1 g, 92%).

[0166] 3) Preparation of (S)-3-(dibenzylamino)-2-fluoropropanol (D54-d) [ka]

[0167] To a solution of 54-c (37.8 g, 125 mmol) in THF (500 mL) at 0° C., LAH (60 mL, 2.5 M in THF, 150 mmol) was added dropwise. After 1 h reaction, 5.7 mL of water was carefully added. After 30 min reaction, 5.7 mL of 15% NaOH was added. After 10 min stirring, 17 mL of water was added. Anhydrous Na2SO4 was added, the solid was filtered off, and concentrated to give a colorless oily liquid product (D54-d, 34.2 g, 99%). MS (ESI): m / z=274.1 [M+H] + .

[0168] 4) Preparation of (S)-benzyl (2-fluoro-3-hydroxypropyl)carbamic acid t-butyl ester (D54-e) [ka]

[0169] A mixture of 54-d (33.9 g, 124 mmol) and 10% Pd / C (2.4 g) in ethanol (500 mL) was placed under 1 atm of hydrogen at room temperature. After overnight reaction, the solid was filtered off and concentrated to give a colorless oily liquid product. Purification by column chromatography gave (D54-e, 33.6 g, 95%). MS (ESI): m / z=306.2 [M+Na] + .

[0170] 5) Preparation of (S)-3-(benzylamino)-2-fluoro-1-propanol (D54-f) [ka]

[0171] D54-e (10 g, 35.3 mmol) was added to DCM (120 mL) at room temperature (20 mL). After reacting for 3 h, it was concentrated, dissolved in DCM, and 30 g K2CO3 was added. After stirring for 20 min, the solid was filtered off, concentrated, and purified by reverse phase column (C18, buffer 10 nm NH4HCO3) to give (D54-f, 6.5 g, 91%). MS (ESI): m / z = 184.1 [M+H] +.

[0172] 6) Preparation of (S)-3-(benzyl((S)-3-(benzyloxy)-2-hydroxypropyl)amino)-2-fluoro-1-propanol (D54-h) [ka]

[0173] 54-f (6.3 g, 34.4 mmol) and (S)-2-((benzyloxy)methyl)oxirane (D54-g, 6.77 g, 41.3 mmol) were mixed in iPrOH (500 mL) at room temperature. The mixture was stirred at 55° C. overnight. The mixture was cooled to room temperature, concentrated, and purified by column chromatography to give a colorless oily product (D54-h, 4.5 g, 38%). MS (ESI): m / z=348.2 [M+H] + .

[0174] 7) Preparation of (S)-3-(benzyl((S)-3-(benzyloxy)-2-hydroxypropyl)amino)-2-fluoropropyl methanesulfonate (D54-i) [ka]

[0175] At -10°C, a solution of MsCl (346 mg, 3.02 mmol) in DCM (3 mL) was added dropwise to a solution of 54-h (1.0 g, 2.88 mmol) and DIPEA (447 mg, 3.46 mmol) in DCM (12 mL). The reaction was allowed to proceed for 1 h at -2°C, water (5 mL) was added, and the mixture was extracted with DCM (10 mL x 3). The mixture was dried over anhydrous Na2SO4 and concentrated to give a colorless oily liquid product (D54-i, 1.2 g). MS (ESI): m / z = 348.2 [M + H] + .

[0176] 8) Preparation of (2S,6S)-4-benzyl-2-((benzyloxy)methyl)-6-fluoro-1,4-oxazepane (D54-j) [ka]

[0177] At 0°C, NaH (60% in oil, 276 mg, 6.91 mmol) was added in portions to a solution of D54-h (1.2 g, 2.88 mmol) in THF (15 mL). The mixture was allowed to warm to room temperature and stirred overnight. Saturated NaHCO3 (5 mL) solution was added and concentrated to remove THF. The residue was extracted with ethyl acetate (50 mL x 3), washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to give a colorless oily liquid product (54-j, 350 mg, 37%). MS (ESI): m / z = 330.2 [M + H] + .

[0178] 9) Preparation of ((2S,6S)-6-fluoro-1,4-oxazepanyl-2-yl)methanol (D54-k) [ka]

[0179] A mixture of D54-i (680 mg, 2.06 mmol), 10% Pd / C (100 mg) and 4M HCl in dioxane (1.03 mL, 4.12 mmol) in ethanol (20 mL) was placed in a hydrogenation apparatus at room temperature. After hydrogenation for 4 hours, the solid was filtered off and the filtrate was concentrated to give a colorless oily liquid product (54-k, 0.4 g). MS (ESI): m / z = 150.1 [M+H] + .

[0180] 10) Preparation of (2S,6S)-6-fluoro-2-(hydroxymethyl)-1,4-oxazepanyl-4-carboxylate t-butyl ester (D54-l) [ka]

[0181] To a solution of D54-k (382 mg, 2.0 mmol) in DCM (20 mL) at room temperature, (Boc)2O (919 μL, 4.0 mmol) and TEA (1.4 mL, 10.0 mmol) were added successively. After stirring for 4 h, water (50 mL) was added, extracted with DCM (3×20 mL), washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated to give a colorless oily liquid product (D54-l, 0.50 g, 100%). MS (ESI): m / z=194.1 [M-tBu+H] + .

[0182] 11) Preparation of (2S,6S)-4-(t-butoxycarbonyl)-6-fluoro-1,4-oxazepanyl-2-carboxylic acid (D54-m) [ka]

[0183] Water (3 mL), TEMPO (5.9 mg, 0.038 mmol) and Bu4NHSO4 (45 mg, 0.133 mmol) were added successively to a solution of D54-l (475 mg, 1.9 mmol) in DCM (13 mL) at room temperature. 6.8 mL NaClO solution (10-15%) was adjusted to pH 8-9 with saturated NaHCO3. An aqueous solution (1.2 mL) of NaBr (60 mg, 5.8 mmol) was added to the prepared buffer solution. 10 mL of the buffer solution was taken and added dropwise to the reaction system at 0 °C. The mixture was stirred at room temperature for 3 h and adjusted to pH 2-3 with KHSO4 (2N) solution. Extraction with DCM (3 × 20 mL), drying over anhydrous Na2SO4, concentration and purification by reverse phase column chromatography gave a white solid product (D54-m, 385 mg, 68% overall yield for three steps). MS(ESI): m / z=208.3[M-tBu+H] + .

[0184] The intermediate (2S,6R)-4-(t-butoxycarbonyl)-6-fluoro-1,4-oxazepanyl-2-carboxylic acid was synthesized in a similar manner. [ka]

[0185] 11.Intermediate D62-f [ka]

[0186] 1) Preparation of 1-methyl-1H-imidazol-4-amine hydrochloride (D62-b) [ka]

[0187] To a solution of D62-a (530 mg, 4.17 mmol) in EtOH (20 mL) was added Pd(OH)2 / C (65 mg) at room temperature. The reaction was placed under hydrogen overnight, the solid was filtered off, and the filtrate was added with HCl (4 M in dioxane, 2 mL) and concentrated to give a yellow solid product (D62-b, 575 mg). MS (ESI): m / z=98.2 [M+H] + .

[0188] 2) Preparation of N-(5-chloro-2-methoxyphenyl)-1-methyl-1H-imidazol-4-amine (D62-d) [ka]

[0189] 4-Chloro-2-iodo-1-methoxybenzene (D62-c, 1.07 g, 3.99 mmol), D62-b (280 mg, 2.1 mmol), Pd2(dba)3 (261 mg, 0.285 mmol), XPhos (272 mg, 0.571 mmol) and NaOtBu (549 mg, 5.7 mmol) were added to dioxane (15 ml) at room temperature under argon. The reaction was stirred at 110 °C for 4 h, cooled to room temperature, concentrated and directly purified by column chromatography to give a brown solid product (D62-d, 235 mg, 47%). MS (ESI): m / z = 238.2 [M + H] + .

[0190] 3) Preparation of 4-chloro-2-((1-methyl-1H-imidazol-4-yl)amino)phenol (D62-e) [ka]

[0191] To a solution of D62-d (130 mg, 0.55 mmol) in DCM (4 mL) at 0° C., BBr3 (2 mL, 17% Wt in DCM) was added, followed by reaction at room temperature overnight. Saturated aqueous NaHCO3 (20 mL) was added, extracted with DCM (3×10 mL), dried over anhydrous Na2SO4, concentrated, and purified by reverse phase column chromatography to give the product (D62-e, 165 mg). MS (ESI): m / z=224.1 [M+H] + .

[0192] 4) Preparation of 5-chloro-3-(1-methyl-1H-imidazol-4-yl)benzo[d]oxazol-2(3H)-one (D62-f) [ka]

[0193] To a solution of D62-e (165 mg crude, 0.55 mmol) in DCM (3 mL) at 0° C., Et3N (206 μL, 1.48 mmol) and triphosgene (109 mg, 0.37 mmol) were added successively. Stirred overnight at room temperature, saturated aqueous NH4Cl (20 mL) was added, and extracted with DCM (20 mL×3). Drying over anhydrous Na2SO4, concentration, and purification by reverse phase column chromatography (C18, TFA buffer) gave a brown solid product (D62-f, 21 mg, 15% overall yield for two steps). MS (ESI): m / z=250.3 [M+H] + .

[0194] 12. Intermediate D63-e [ka]

[0195] 1) Preparation of N-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine (D63-c) [ka]

[0196] A mixture of D63-a (473 mg, 3.0 mmol), D63-b (483 mg, 3.0 mmol), XPhos Pd G3 (51.0 mg, 0.06 mmol) and NaOtBu (576 mg, 6.0 mmol) in dioxane (10 ml) was stirred under argon at 110° C. for 7 h. The mixture was cooled to room temperature, concentrated and purified by column chromatography to give a brown solid product (D63-c, 546 mg, 77%). MS (ESI): m / z=238.1 [M+H] + .

[0197] 2) Preparation of 4-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)phenol (D63-d) [ka]

[0198] To a solution of D63-c (546 mg, 2.3 mmol) in DCM (20 mL) was added BBr3 (5 mL, 17% Wt in DCM) dropwise at 0°C. Stirred overnight at room temperature and added saturated NaHCO3 (20 mL). Extracted with DCM (20 mL x 3). Dried over anhydrous Na2SO4 and concentrated to give the product (D63-d, 450 mg crude). MS (ESI): m / z = 224.0 [M + H] + .

[0199] 3) Preparation of 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazol-2(3H)-one (D63-e) [ka]

[0200] To a solution of D63-d (450 mg crude, 2.0 mmol) in DCM (5 mL) at 0° C., Et3N (840 uL, 6 mmol) and triphosgene (297 mg, 1.0 mmol) were added successively. After stirring at room temperature overnight, saturated aqueous NH4Cl (20 mL) was added. Extraction was performed with DCM (20 mL×3). The mixture was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to give a yellow solid (D63-e, 194 mg). MS (ESI): m / z=250.1 [M+H] + .

[0201] 13. Intermediate D64-e [ka]

[0202] 1) Preparation of N-(5-chloro-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-3-amine (D64-c) [ka]

[0203] A mixture of D64-a (486 mg, 3.1 mmol, 1 equiv), D64-b (500 mg, 3.1 mmol, 1 equiv), Pd2(dba)3 (283 mg, 0.3 mmol, 0.1 equiv), XPhos (294 mg, 0.6 mmol, 0.2 equiv) and NaOtBu (593 mg, 6.2 mmol, 2 equiv) in dioxane (20 mL) was stirred at 110 °C under argon for 4 h. It was cooled to room temperature, concentrated and purified by column chromatography to give a brown solid product (D64-c, 340 mg, 46% yield). MS (ESI): m / z = 239.2 [M+H] + .

[0204] 2) Preparation of 4-chloro-2-((1-methyl-1H-1,2,4-triazol-3-yl)amino)phenol (D64-d) [ka]

[0205] To a solution of D64-c (340 mg, 1.42 mmol, 1 equiv) in DCM (5 mL) at 0° C., BBr3 (2.5 mL, 17% Wt in DCM) was added dropwise. Stirred at room temperature overnight and saturated NaHCO3 (20 mL) was added. Extracted with DCM (20 mL×3). Drying over anhydrous Na2SO4 and concentration gave the product (D64-d, 340 mg crude). MS (ESI): m / z=225.1 [M+H] + .

[0206] 3) Preparation of 5-chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzo[d]oxazol-2(3H)-one (D64-e) [ka]

[0207] To a solution of D64-d (340 mg crude, 1.4 mmol, 1.0 equiv) in DCM (20 mL) at 0° C., Et3N (418 μL, 3.0 mmol, 2.0 equiv) and triphosgene (222 mg, 0.75 mmol, 0.5 equiv) were added successively. Stirred overnight at room temperature and added saturated NH4Cl (20 mL). Extracted with DCM (20 mL×3). Dried over anhydrous Na2SO4, concentrated and purified by column chromatography to give a yellow solid product (D64-e, 234 mg, 42%).

[0208] 14. Intermediate D68-b [ka]

[0209] Preparation of 5-bromo-3-(3-oxocyclobutyl)benzo[d]oxazol-2(3H)-one (D68-b) [ka]

[0210] At room temperature, NaH (376 mg, 9.4 mmol, 60% in oil) was added to a solution of 1-a (1.0 g, 4.7 mmol) in DMF (15 mL). After stirring for 30 min, D68-a (1.4 g, 9.4 mmol) was added. After stirring for 3 h, it was cooled to 0° C. and water (20 mL, 1 / 1, v / v) was added. Extraction was performed with DCM (20 mL×3). It was dried over anhydrous Na2SO4, concentrated, and purified by reverse phase column chromatography to give a yellow solid product (D68-b, 550 mg, 42%). MS (ESI): m / z=284.0 [M+H] + .

[0211] 15. Intermediate D73-b [ka]

[0212] Preparation of 5-bromo-3-methylisobenzofuran-1(3H)-one (D73-b) [ka]

[0213] To a solution of D73-a (1.5 g, 7 mmol) in THF (40 mL) at -78°C, LDA (8.8 mL, 17.6 mmol, 2 mol / L) was added dropwise over 15 min. After stirring for 15 min, MeI (10 g, 70.4 mmol) was added. The reaction was warmed to 0°C and stirred for 6 h. Water (100 mL) was added, extracted with ethyl acetate (250 mL x 3), dried over Na2SO4, concentrated, and purified by column chromatography to give a white solid product (D73-b, 528 mg). MS (ESI): m / z = 227.1 [M + H] + . 1 HNMR (400MHz, CDCl3): δ7.77(s,1H),7.70-7.67(m,1H),7.63(d,J=0.8Hz,1H),5.58-5.53(m,1H),1.65(d,J=6.4Hz,3H).

[0214] 16. Intermediate D75-c [ka]

[0215] 1) Preparation of (R)-1-(2-bromo-5-chlorophenyl)ethanol (D75-b) [ka]

[0216] Trimethyl borate (161 mg, 1.5 mmol) was added to a solution of (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol (297 mg, 1.3 mmol) in tetrahydrofuran (35 mL) at room temperature. After stirring for 1.25 hours, borane-methyl sulfide complex (7.1 mL of a 2 M solution in tetrahydrofuran, 14.2 mmol) was slowly added dropwise. The reaction was cooled to 0°C and a solution of D122-a (3 g, 12.8 mmol) in tetrahydrofuran (15 mL) was added dropwise over 1 hour. The mixture was allowed to warm to room temperature and stirred overnight. It was concentrated to remove most of the THF and taken up in 1N HCl solution. It was extracted with ethyl acetate (200 ml x 3), washed with saturated brine (200 ml), dried over Na2SO4, concentrated and purified by column chromatography to give a white solid product (D122-b, 2.9 g, 97%). MS(ESI): m / z=217.1[M-17] + .

[0217] 2) Preparation of (R)-5-chloro-3-methylisobenzofuran-1(3H)-one (D75-c) [ka]

[0218] To a solution of D122-b (200 mg, 0.85 mmol) in DMF (10 mL) at room temperature, Pd(dppf)Cl2 (62 mg, 0.09 mmol) and TEA (171 mg, 1.7 mmol) were added in sequence. The reaction system was filled with nitrogen three times, and then filled with carbon monoxide. The mixture was stirred at 130 °C for 16 h. The mixture was cooled to room temperature, concentrated, and purified by column chromatography to give a white solid product (D122-c, 80 mg, 52%). MS (ESI): m / z = 183.1 [M + H] + .

[0219] The intermediate (S)-5-chloro-3-methylisobenzofuran-1(3H)-one was synthesized in a similar manner. [ka]

[0220] 17. Intermediate D76-b [ka]

[0221] Preparation of 5-bromo-3-((dimethylamino)methyl)isobenzofuran-1(3H)-one (D76-b) [ka]

[0222] LiHMDS (4.8 mL, 4.8 mmol, 1 M in THF / hexane) was added dropwise to a solution of D73-a (1.035 g, 4.86 mmol) in THF (20 mL) at -78 °C. After stirring for 1 h, D76-b (900 mg, 4.86 mmol) was added in one portion. Stirring continued for 2 h at -78 °C. Saturated aqueous NH4Cl (100 mL) was added and extracted with DCM / MeOH (9:1) (3 * 20 mL). Dried over Na2SO4, concentrated and purified by reverse phase column chromatography to give a white solid product (D76-b, 0.6 g, 47%). MS (ESI): m / z = 272.1 [M + H] + .

[0223] 18. Intermediate D77-a [ka]

[0224] Preparation of 5-bromo-3-(methoxymethyl)isobenzofuran-1(3H)-one (D77-a) [ka]

[0225] LiHMDS (5.6 mL, 5.63 mmol, 1 M in THF / hexane) was added dropwise to a solution of D73-a (1.0 g, 4.69 mmol) in THF (20 mL) at -78 °C. After stirring for 15 min, bromo(methoxy)methane (417.88 μL, 5.15 mmol) was added dropwise. After continued stirring at -78 °C for 1 h, saturated aqueous NH4Cl (100 mL) was added and extracted with DCM / MeOH (9:1) (3 x 20 mL). Dried over Na2SO4, concentrated, and purified by reverse phase column chromatography to give a white solid product (D77-a, 0.6 g, 50%). MS (ESI): m / z = 257.0 [M + H] + .

[0226] 19. Intermediate D81-c [ka]

[0227] 1) Preparation of ethyl 2-(5-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (D81-a) [ka]

[0228] To a solution of 1-a (5 g, 23.48 mmol) in DMF (40 mL) at 0° C. was added NaH (1.03 g, 25.83 mmol). After stirring for 30 min, BrCH2CO2Et (3.9 g, 23.48 mmol) was added dropwise. After stirring at room temperature for 3 h, water was added, extracted with ethyl acetate, dried over Na2SO4, concentrated, and purified by reverse phase column chromatography to give a yellow solid product (D81-a, 4.8 g, 68.47%).

[0229] 2) Preparation of 1-(5-bromo-2-hydroxyphenyl)imidazoline-2,4-dione (D81-b) [ka]

[0230] To a solution of D81-a (4.8 g, 16.05 mmol) in EtOH (30 mL) was added NH4OH (300 ml) at room temperature. The mixture was stirred at room temperature for 24 hours, and the ethanol was removed under reduced pressure. Ice water was added, and the mixture was filtered to obtain a yellow solid product (D81-b, 2.4 g, 55.42%).

[0231] 3) Preparation of 6-bromobenzo[d]imidazol[2,1-b]oxazol-2(3H)-one (D81-c) [ka]

[0232] To a solution of D81-b (2.4 g, 8.89 mmol) in toluene (25 mL) was added POCl3 (25 ml) at 0° C. The mixture was stirred at 110° C. for 1 h, cooled to room temperature, added with ice water, extracted with ethyl acetate, dried over Na2SO4, concentrated, and purified by reverse phase column chromatography to give a yellow solid product (D81-c, 1.4 g, 5.56 mmol, 62.5%). 1 HNMR (400MHz, DMSO-d6) δ7.75 (s, 1H), 7.44-7.31 (m, 2H), 5.13 (s, 2H).

[0233] 20. Intermediate D84-n [ka]

[0234] 1) Preparation of 2-hydroxy-3-methoxybenzaldehyde (D84-b) [ka]

[0235] To a solution of D84-b (10 g, 65.77 mmol) in DCM (100 mL) at room temperature, Ac2O (10.07 g, 98.65 mmol), TEA (6.92 g, 68.40 mmol) and DMAP (0.8 g, 6.58 mmol) were added in sequence. After stirring for 30 min, water was added, extracted with dichloromethane, washed with dilute hydrochloric acid HCl (4.0 M) and saturated brine in sequence, dried over Na2SO4 and concentrated to give a white solid product (D84-b, 12 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 7.51-7.42 (m, 3H), 3.84 (s, 3H), 2.34 (s, 3H).

[0236] 2) Preparation of 6-formyl-2-methoxy-3-nitrophenyl acetate (D84-c) [ka]

[0237] To a mixture of D84-b (10 g, 51.50 mmol), KNO3 (5.31 g, 52.53 mmol) in DCM (40 mL) at -40 °C, TFAA:TFA (3:1, 37.5 mL) was added dropwise. The reaction was gradually warmed to room temperature and stirred overnight. Ice water was added and extracted with dichloromethane. It was dried over Na2SO4, concentrated and purified by column chromatography to give a red solid product (D84-c, 10.3 g, 83.6%).

[0238] 3) Preparation of 2-hydroxy-3-methoxy-4-nitrobenzoic acid (D84-d) [ka]

[0239] To a solution of D84-c (10 g, 41.81 mmol) in MeOH (150 mL) was added NaOH (6.8 g, 171.42 mmol) and water (800 mL) successively at room temperature. After stirring for 5 min, AgNO3 (8.5 g, 50.17 mmol) was added and stirred at 85 °C overnight. The solid was filtered off and the filtrate was adjusted to pH 2. Extraction with ethyl acetate, washing with saturated brine, drying over Na2SO4, and concentration gave a yellow solid product (D84-d, 7 g, 78.5%) (RT = 0.483 min, m / z = 211.9). LCMS: 211.9 [MH] + .

[0240] 4) Preparation of 2,3-dihydroxy-4-nitrobenzoic acid (D84-e) [ka]

[0241] To a solution of D84-d (13.45 g, 63.10 mmol) in HOAc (158 mL) was added 47% HBr aqueous solution (79 mL) at room temperature. The reaction was refluxed for 16 hours and cooled to room temperature. The mixture was extracted with ethyl acetate, washed with water, dried over Na2SO4, and concentrated to give a yellow solid product (D84-e, 9 g, 71.6%).

[0242] 5) Preparation of 4-amino-2,3-dihydroxybenzoic acid (D84-f) [ka]

[0243] D84-d (7.2 g, 36.16 mmol) was dissolved in MeOH (120 mL) at room temperature, and 10% Pd / C (0.6 g) was added, followed by placing in 40 Psi of hydrogen. When the hydrogen pressure did not continue to decrease, the solid was filtered off, and the filtrate was concentrated to give a yellow solid product (D84-f, 3.6 g, 58.9%). LCMS: 170.2 [M+H] + .

[0244] 6) Preparation of 4-bromo-2,3-dihydroxybenzoic acid (D84-g) [ka]

[0245] To a suspension of D84-f (3.9 g, 23.06 mmol) in H2O (8 mL) at 0°C, 48% aqueous HBr (6 mL) was added, followed by a solution of NaNO2 (1.2 g, 17.29 mmol) in water (8 mL). After stirring for 2 h at 0°C, a solution of CuBr (2.5 g, 17.29 mmol) in HBr (6 mL) was added. After stirring for 1 h at 0°C, the mixture was stirred at room temperature overnight. Extraction with ethyl acetate, washing with water, drying over Na2SO4, and concentration gave a black solid product (D84-g, 2.5 g, 46.5%). LCMS: 231.0 [MH] + .

[0246] 7) Preparation of ethyl 4-bromo-2,3-dihydroxybenzoate (D84-h) [ka]

[0247] To a solution of (D84-g, 1.2 g, 5.15 mmol) in EtOH (38 mL) was added concentrated H2SO4 (2 mL) at room temperature, followed by stirring at reflux overnight. Cooled to room temperature and removed EtOH under reduced pressure. Ethyl acetate was added and washed with saturated NaHCO3 and brine successively. Dried over Na2SO4, concentrated, and purified by column chromatography to give a white solid product (D84-h, 0.537 g, 39.9%). LCMS: 261.0 [M+H]+ .

[0248] 8) Preparation of ethyl 7-bromobenzo[d][1,3]dioxolaryl-4-carboxylate (D84-i) [ka]

[0249] Cs2CO3 (2.7 g, 8.43 mmol) was added to a solution of D84-h (1.0 g, 3.83 mmol) in DMF (8 mL) at room temperature, and the mixture was stirred for 1 hour, and then CH2I2 (1.7 g, 6.21 mmol) was added and reacted at 75° C. for 12 hours. The mixture was cooled to room temperature, and ethyl acetate and water were added. The mixture was dried over Na2SO4, concentrated, and purified by column chromatography to obtain a white solid product (D84-i, 598 mg, 57.2%). LCMS: 275.0 [M+H] + .

[0250] 9) Preparation of ethyl (7-bromobenzo[d][1,3]-dioxolaryl-4-yl)methanol (D84-j) [ka]

[0251] LiAlH4 (35.89 mL, 35.89 mmol) was added dropwise to a solution of D84-i (4.9 g, 17.94 mmol) in THF (80 mL) at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water was added, and the mixture was extracted with ethyl acetate, dried over Na2SO4, and concentrated to give the product (D84-j, 3.8 g, 92%). GCMS: 230.0 [M] + .

[0252] 10) Preparation of 4-bromo-7-(bromomethyl)benzo[d][1,3]dioxin (D84-k) [ka]

[0253] At 0°C, a solution of D84-j (3800 mg, 16.45 mmol) in THF (40 mL) was added with a solution of PBr3 (4897.14 mg, 18.09 mmol) in THF (20 mL). Stirred at 0°C for 2 hours, added saturated NH4Cl, extracted with ethyl acetate (300 mL x 4), dried over Na2SO4, concentrated, and purified by column chromatography to give a white solid product (D84-k, 2.6 g, 54%). GCMS: 294 [M] + .

[0254] 11) Preparation of (5R)-2-((7-bromobenzo[d][1,3]dioxolaryl-4-yl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (D84-m) [ka]

[0255] At -78°C, n-butyllithium (2.5M hexane, 6.29mL, 15.72mmol) was added dropwise to a solution of D84-l (2895.79mg, 15.72mmol) in tetrahydrofuran (dry, 60mL). After stirring for 30 minutes, a solution of D84-j (4200mg, 14.29mmol) in THF (dry, 20mL) was added dropwise, and the mixture was stirred for 1 hour, followed by addition of saturated NH4Cl solution, extraction with ethyl acetate, drying over Na2SO4, concentration, and purification by column chromatography to give a white solid product (D84-m, 1800mg, 32%). LCMS: [M+H] + :397.1

[0256] 12) Preparation of (S)-2-amino-3-(7-bromobenzo[d][1,3]dioxapentyl-4-yl)propionate methyl ester (D84-n) [ka]

[0257] To a solution of D84-m (1800 mg, 4.53 mmol) in acetonitrile (60 mL) was added 0.2 M HCl aqueous solution (47.57 mL, 9.51 mmol) at room temperature. After stirring for 12 h, the mixture was adjusted to pH 8 with saturated NaHCO3 solution, extracted with ethyl acetate, dried over Na2SO4, concentrated, and purified by column chromatography to give a white solid product (D84-n 1300.0 mg, 95%). 1HNMR(400MHz,CDCl3)δ6.87(d,J=8.4Hz,1H),6.54(d,J=8.4Hz,1H),6.01-5.94(m,2H),3.74( dd,J=7.5,5.6Hz,1H),3.68(s,3H),2.99(dd,J=13.8,5.3Hz,1H),2.77(dd,J=13.8,8.0Hz,1H).

[0258] 21. Intermediate D98-k [ka]

[0259] 1) Preparation of (3-(bromomethyl)oxetan-3-yl)methoxy)(t-butyl)diphenylsilane (D98-b) [ka]

[0260] To a solution of D98-b (25 g, 138.1 mmol) in DCM (600 mL) was added TBDPSCl (45.6 g, 165.7 mmol) and imidazole (37.6 g, 552.5 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours and concentrated to remove dichloromethane. EtOAc (1000 mL) was added, washed with water (250 mL x 3) and brine (250 mL), dried over Na2SO4, concentrated, and purified by column chromatography to give a colorless oily product (D98-b, 60.1 g, 96%). MS (ESI): m / z = 441.1 [M + Na] + .

[0261] 2) Preparation of N-benzyl-1-(3-(((t-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)formamide (D98-c) [ka]

[0262] A mixture of D98-b (70 g, 143.2 mmol), BnNH2 (38.3 g, 358 mmol), K2CO3 (39.8 g, 286.4 mmol) and KI (23.8 g, 143.2 mmol) in DMF (600 mL) was stirred at 70 °C for 24 h under nitrogen. It was cooled to room temperature, added with EtOAc (1500 mL), washed with saturated brine (350 mL x 4), dried over Na2SO4, concentrated and purified by column chromatography to give a colorless oily product (D98-c, 41.5 g, 65%). MS (ESI): m / z = 446.3 [M + H] + .

[0263] 3) Preparation of (S)-1-(benzyl((3-(((t-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)methyl)amino)-3-(benzyloxy)propan-2-ol (D98-e) [ka]

[0264] D98-c (40 g, 89.9 mmol) and D98-D (29.5 g, 179.8 mmol) were mixed under nitrogen. i The mixture was added to PrOH (200 mL) and stirred at 75° C. for 72 h. It was cooled to room temperature, concentrated, and purified by column chromatography to give a colorless oily product (D98-e, 58.4 g, 95%). MS (ESI): m / z=610.2 [M+H] + .

[0265] 4) Preparation of (S)-1-(benzyl((3-(hydroxymethyl)oxetan-3-yl)methyl)amino)-3-(benzyloxy)propan-2-ol (D98-f) [ka]

[0266] Under nitrogen, a mixture of D98-e (58.4 g, 95.9 mmol), KF (55.6 g, 959 mmol) and TBAF (4 mL, 1 mol / l) in THF (1000 mL) was stirred at room temperature for 48 h. It was concentrated and water (300 mL) was added. It was extracted with ethyl acetate (500 mL x 3), dried over Na2SO4, concentrated and purified by column chromatography to give a white solid product (D98-f, 18 g, 50.6%). MS (ESI): m / z = 372.3 [M + H] + .

[0267] 5) Preparation of (S)-(3-((benzyl(3-(benzyloxy)-2-hydroxypropyl)amino)methyl)oxetan-3-yl)methyl methanesulfonate (D98-g) [ka]

[0268] At -8°C, a solution of D98-f (15.3 g, 41.2 mmol) in DCM (250 mL) was added dropwise in sequence over 10 min. The mixture was stirred at -8°C for 2 h, and then ice water (150 mL) was added, extracted with DCM (200 mL x 3), dried over Na2SO4, filtered, and concentrated to give a colorless oily crude product (D98-g, 18.5 g, 99%). MS (ESI): m / z = 450.1 [M + H] + .

[0269] 6) Preparation of (S)-9-benzyl-7-((benzyloxy)methyl)-2,6-dioxa-9-azaspiro[3.6]decane (D98-h) [ka]

[0270] A suspension of NaH (8.24 g, 206 mmol, 60% purity) in THF (200 mL) was added dropwise to D98-g (18.5 g, 41.2 mmol) in THF (100 mL) at -0°C. The mixture was stirred at 50°C for 16 hours. The mixture was cooled to 0°C, saturated NaHCO3 (500 ml) solution was added, extracted with ethyl acetate (500 mL x 3), dried over Na2SO4, concentrated, and purified by column chromatography to give a colorless oily product (D98-h, 12.5 g, 86%). MS (ESI): m / z = 354.2 [M + H] + .

[0271] 7) Preparation of (S)-(2,6-dioxa-9-azaspiro[3.6]decan-7-yl)methanol TFA salt (D98-i) [ka]

[0272] D98-h (5 g, 14.2 mmol), Pd / C (2 g, C 10%), TFA (1.61 g, 14.2 mmol) and AcOH (10 mL) were added at room temperature. i The mixture was added to PrOH (200 mL) and placed in a hydrogenation apparatus. After stirring at room temperature and absorbing hydrogen for 16 h, the solid was filtered off and the filtrate was concentrated to give a brown oily crude product (D98-i, 4.5 g, 95%). MS (ESI): m / z=174.2 [M+H] + .

[0273] 8) Preparation of (S)-7-(hydroxymethyl)-2,6-dioxa-9-azaspiro[3.6]decane-9-carboxylate t-butyl ester (D98-j) [ka]

[0274] A mixture of D98-i (crude product 4.5 g, 14.2 mmol), (Boc)2O (6.18 g, 28.3 mmol) and saturated NaHCO3 (150 ml) in dioxane (150 mL) was stirred at room temperature for 4 h. Extraction with ethyl acetate (3 x 200 mL), drying over Na2SO4, concentration and purification by column chromatography gave a brown oily product (D98-j, 3.5 g, 90%). MS (ESI): m / z = 274.2 [M+H] + .

[0275] 9) Preparation of (S)-9-(t-butoxycarbonyl)-2,6-dioxa-9-azaspiro[3.6]decane-7-carboxylic acid (D98-k) [ka]

[0276] D98-j (1g, 3.7mmol), TEMPO (11mg, 0.07mmol), and Bu4NHSO4 (87mg, 0.3mmol) were added sequentially to DCM (20mL) and water (9mL) at room temperature. At the same time, 7.4mL NaClO solution (10-15%) was adjusted to pH 8-9 with saturated NaHCO3 (liquid + solid) (about 15mL), and an aqueous solution (1mL) of NaBr (64mg, 0.6mmol) was added to the buffer solution. At 0°C, the freshly prepared buffer solution was added dropwise to the reaction solution. After stirring at room temperature for 3 hours, KHSO4 (2N) solution was added to adjust the pH to 2-3. Extraction with DCM (100mLx3), drying with Na2SO4, and concentration gave a white solid product (D98-k, 850mg, 81%). MS(ESI): m / z=310.2[M+Na] + .

[0277] 22. Intermediate D100-f [ka]

[0278] 1) Preparation of t-butyl 4-((5-bromo-2-hydroxyphenyl)amino)-3,3-difluoropiperidine-1-carboxylate (D100-c) [ka]

[0279] To a solution of D100-b (1.0 g, 4.0 mmol, 4 equiv.) and D100-a (376 mg, 2.0 mmol, 1 equiv.) in DMF (10 mL) at 0° C., TMSCl (1.0 mL, 8.0 mmol, 4.0 equiv.) was added. After stirring at 0° C. for 2 h, BH3·THF (1 M, 10 mL, 5 equiv.) was added dropwise. After stirring at room temperature for 3 h, saturated Na2CO3 (200 mL) and water (10 mL) were added. Extraction with ethyl acetate (100 mL×2), washing with water, drying over Na2SO4, concentration, and purification by column chromatography gave an orange oily product (D100-c, 730 mg, 90%). MS (ESI): m / z=353.0 [M-tBu+H] + .

[0280] 2) Preparation of t-butyl 4-(5-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)-3,3-difluoropiperidine-1-carboxylate (D100-d) [ka]

[0281] A mixture of D100-c (690 mg, 1.69 mmol), CDI (330 mg, 2.03 mmol) in dioxane (20 mL) was stirred at 110° C. for 6 h under argon. It was cooled to room temperature, concentrated, and purified by column chromatography to give a yellow solid product (D100-d, 586 mg, 76% yield). MS (ESI): m / z=455.0 [M+Na] + .

[0282] 3) Preparation of 5-bromo-3-(3,3-difluoropiperidin-4-yl)benzo[d]oxazol-2(3H)-one (D100-e) [ka]

[0283] A mixture of D100-d (566 mg, 1.3 mmol) in TFA / DCM (1:6, 7 mL) under argon is stirred at room temperature for 2 h and concentrated to give the product which is used directly in the next reaction. MS (ESI): m / z=334.9 [M+H] + .

[0284] 4) Preparation of 5-bromo-3-(3,3-difluoro-1-methylpiperidin-4-yl)benzo[d]oxazol-2(3H)-one (D100-f) [ka]

[0285] To a mixture of D100-e (490 mg crude, TFA salt, 1.1 mmol) in MeOH / HCHO aqueous solution (10 mL, 1:1) was added 250 μL HCOOH at room temperature. The reaction was stirred at 65° C. for 24 h. It was cooled to room temperature, concentrated, and lyophilized to give a yellow solid product (D100-f, 390 mg, 99% yield). MS (ESI): m / z=347.1 [M+H] + .

[0286] 23. Intermediate D115-j [ka]

[0287] 1) Preparation of (5-chloro-2-iodophenyl)methanol (D115-b) [ka]

[0288] To a solution of D115-a (2.0 g, 7.1 mmol, 1.0 equiv.) in THF (20 mL) at 0°C, BH3·THF (1 M in THF, 17.8 mL, 2.5 equiv.) was added dropwise, and the mixture was stirred at room temperature overnight. MeOH (25 mL) was added to the reaction mixture, which was then concentrated to give a white solid product (D115-b, 1.9 g, 99%). MS (ESI): m / z = 251.0 [M-OH] + .

[0289] 2) Preparation of 2-(bromomethyl)-4-chloro-1-iodobenzene (D115-c) [ka]

[0290] To a solution of D115-b (1.34 g, 5.0 mmol, 1.0 equiv) in DCM (50 mL) at 0° C., PBr3 (522 μL, 5.5 mmol, 1.1 equiv) was added dropwise. After stirring at 0° C. for 1 h and at room temperature for 2 h, saturated aqueous NaHCO3 (100 mL) was added. Extraction with dichloromethane (20 mL×2), drying over Na2SO4, concentration, and purification by column chromatography gave a white solid product (D115-c, 0.92 g, 56%).

[0291] 3) Preparation of 5'-chloro-1'-oxygen-1',3'-dihydrospiro[azetidine-3,2'-indene]-1-carboxylate t-butyl ester (D115-f) [ka]

[0292] At -78°C, LiHMDS (1M in hexane, 2.3mL) was added dropwise to a solution of D115-d (420mg, 2.3mmol) in THF (40ml). After stirring at -78°C for 30 minutes, D115-c (713mg, 2.15mmol) was added in one portion. The reaction solution was gradually warmed to room temperature and stirred for 3 hours. The reaction solution was cooled again to -78°C, and n-butyllithium (2.5M in hexane, 1.9mL) was added dropwise. The reaction solution was gradually warmed to room temperature and stirred overnight. Water H2O (100mLL) was then added, and the mixture was extracted with ethyl acetate EtOAc (30mLx3), dried over Na2SO4, concentrated, and purified by reverse phase column chromatography to obtain a pale yellow oily product (D115-f, 570mg, 86%). MS(ESI):m / z=252.2,330.1[M-tBu+H] + ,[M+Na] + .

[0293] 4) Preparation of 5'-chlorospiro[azetidin-3,2'-inden]-1'(3'H)-one (D115-g) [ka]

[0294] D115-f (570 mg, 1.85 mmol) was dissolved in TFA / DCM (1:10, 5.5 mL) at room temperature, stirred for 2 hours, and then concentrated to give the product (D115-g, 0.6 g, TFA salt). MS (ESI): m / z = 208.1 [M + H] + .

[0295] 5) Preparation of 5'-chloro-1-methyl-1',3'-dihydrospiro[azetidin-3,2'-inden]-1'-ol (D115-h) [ka]

[0296] To a solution of D115-g (0.6g crude, 1.85mmol, 1.0eq) in MeOH / AcOH (5:1, 24mL) was added paraformaldehyde (555mg, 18.5mmol, 10.0eq) at room temperature. After stirring for 5 hours, NaBH3CN (465mg, 7.4mmol, 4.0eq) was added. After stirring overnight at room temperature, the solid was filtered off and concentrated. The residue was added with saturated aqueous NaHCO3 (50mL) and extracted with a mixed solvent of dichloromethane / methanol (9 / 1, 20mLx6). It was dried over Na2SO4 and concentrated to give a pale yellow oily product (D115-h, 330mg). MS(ESI):m / z=224.2[M+H] + .

[0297] 6) Preparation of 5'-chloro-1-methylspiro[azetidin-3,2'-inden]-1'(3'H)-one (D115-i) [ka]

[0298] Dess-Martin periodinane (642 mg, 1.51 mmol, 1.1 equiv) was added to a solution of D115-h (308 mg, 1.38 mmol, 1.0 equiv) in DCM (20 mL) at room temperature. After stirring for 1 h, saturated aqueous NaHCO3 (30 mL) was added and extracted with DCM (20 mL x 3). The mixture was dried over Na2SO4, concentrated, and purified by reverse phase column chromatography to give a white solid product (D115-i, 280 mg). MS (ESI): m / z = 222.1 [M + H] + . 24. Intermediate D121-f [ka]

[0299] 1) Preparation of 2-bromoselenophene (D121-b) [ka]

[0300] To a solution of D121-a (5000 mg, 38.15 mmol) in DCM (60 mL) and CH3COOH (60 mL) was added NBS (6791 mg, 38.15 mmol) at 0° C. Stirred at 0° C. for 2 h, added water, extracted with dichloromethane, dried over Na2SO4, concentrated and purified by column chromatography to give a white oily product (D121-b, 5100 mgl, 63.7%).

[0301] 2) Preparation of 5-bromoselenophene-2-formaldehyde (D121-c) Page:IDSU22-32-060 [ka]

[0302] At -78°C, LDA (43.6mL, 43.58mmol) was added dropwise to a solution of D121-b (6100mg, 29.06mmol) in THF (60mL). After stirring for 30 minutes, DMF (2mL) was added dropwise. The mixture was then stirred at -78°C for 4 hours, water was added, extracted with dichloromethane, dried over Na2SO4, concentrated, and purified by column chromatography to obtain a brown oily product (D121-c, 2100mg, 30.4%). GCMS: 237[M]

[0303] 3) Preparation of (5-bromoselenophen-2-yl)methanol (D121-c) [ka]

[0304] To a solution of D121-b (2600 mg, 10.93 mmol) in MeOH (50 mL) was added NaBH4 (827 mg, 21.85 mmol) at 0° C. After stirring at 0° C. for 2 h, water was added, extracted with dichloromethane, dried over Na2SO4, and concentrated to give brown oily product YD02-I46-4 (D121-c, 2100 mg).

[0305] 4) Preparation of 2-bromo-5-(bromomethyl)selenophene (D121-d) [ka]

[0306] To a solution of D121-c (2100 mg, 8.75 mmol) in diethyl ether (20 mL) was added PBr3 (3079 mg, 11.37 mmol) dropwise at 0° C. After stirring at 0° C. for 2 h, water was added, extracted with dichloromethane, dried over Na2SO4, and concentrated to give a brown oily product (D121-d, 2500 mg).

[0307] 5) Preparation of (5R)-2-((5-bromoselenophen-2-yl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (D121-e) [ka]

[0308] At -78°C, n-butyllithium (4.95mL, 12.38mmol) was added dropwise to a solution of D84-l (1825mg, 9.91mmol) in THF (50mL). After stirring for 1 hour, D121-f (2500mg, 8.25mmol) in THF (10mL) was added dropwise. After reacting at -78°C for 2 hours, saturated aqueous NH4Cl was added, extracted with ethyl acetate, dried over Na2SO4, concentrated, and purified by column chromatography to obtain a white solid product (D121-e, 2000mg, 59.7%). LCMS: 407.0 [M+H] + .

[0309] 6) Preparation of methyl 2-amino-3-(5-bromoselenophen-2-yl)propionate (D121-f) [ka]

[0310] To a solution of D121-e (2000 mg, 4.92 mmol) in CH3CN (20 mL) was added HCl (52 mL, 0.2 mol / L) at room temperature. After stirring for 30 min, it was concentrated and purified by HPLC to give a white solid product (D121-f, 1002 mg, 65.4%). LCMS: 312.0 [M+H] + .

[0311] Example 1 Synthesis of Compound D01 [ka]

[0312] 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. The mixture was stirred for 2 h and spin-dried to obtain brown solid product D01b (1 g, 96.5%). MS (ESI): m / z = 291.0 [M + H] + .

[0313] b) (S)-4-(t-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid: Under ice cooling, the compound (S)-4-(t-butoxycarbonyl)-1,4-oxazepane-2-methanol (7.9 g, 34.2 mmol) was dissolved in dichloromethane (134 mL) and water (28 mL). (S)-4-(t-butoxycarbonyl)-1,4-oxazepane-2-methanol was synthesized by the scheme reported in the patent (WO2015110826). Then, TEMPO (107 mg, 0.68 mmol) and Bu4NHSO4 (812 mg, 2.4 mmol) were added sequentially. At the same time, a buffer solution was prepared. 68 mL NaClO solution (10-15%) was added with saturated NaHCO3 solution (about 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 gradually dripped into the reaction solution. Note that the reaction is exothermic, so the temperature in the flask should be kept below 10°C for 1 h. Stir overnight at room temperature, adjust pH to 2-3 with KHSO4 (2N), extract the reaction solution with dichloromethane (3 x 500 mL), dry, and concentrate to obtain the crude product. Column chromatography purification (eluent PE / EA = 2:1 to 1:1, V / V) gave the white solid product (S)-4-(t-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (30.9 g, 65%). MS (ESI): m / z = 268.1 [M + Na] + . 1 HNMR (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).

[0314] c) At room temperature, compound D01b (10.16 g, 25 mmol) and (S)-4-(t-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (5.56 g, 22.7 mmol) were dissolved in DCM (300 mL), and DIPEA (11.71 g, 90.8 mmol), HOBt (3.06 g, 22.7 mmol) and HBTU (9.46 g, 25 mmol) were added in sequence and stirred overnight. Water (200 mL) was added to the reaction solution, which was then extracted with dichloromethane (3 x 400 mL), dried, and concentrated to obtain a crude product. Column chromatography purification (eluent PE / EA = 1:1 to 1:4, V / V) gave white solid product D01c (10.6 g, 91%). MS (ESI): m / z = 540.1 [M + Na] + . 1 HNMR(400MHz,CDCl3):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).

[0315] d) Compound D01c (9.7 g, 18.8 mmol) and Pin2B2 (9.53 g, 37.5 mmol) were dissolved in DMSO (250 mL) at room temperature under argon, followed by the addition of Pd(dppf)Cl2 (960 mg, 1.3 mmol) and KOAc (5.52 g, 56.3 mmol). The reaction was heated to 85 °C and stirred for 8 h. The mixture was cooled to room temperature, diluted with EA (1000 mL), washed with saturated brine (5 × 200 mL), dried over Na2SO4, and concentrated to give the crude product. Column chromatography purification (eluent PE / EA = 1:1 to 1:6, V / V) gave the white solid product D01d (8.5 g, 87.6%). MS (ESI): m / z = 540.3 [M + Na] + . 1HNMR(400MHz,CDCl3):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).

[0316] e) At room temperature under argon, compound D01d (200 mg, 0.39 mmol), 6-bromoimidazo[1,2-a]pyridine (115 mg, 0.58 mmol) were dissolved in dioxane (8 mL) and water (0.8 mL), and then PdCl2dppf (30 mg, 0.04 mmol) and KOAc (115 mg, 1.17 mmol) were added, and the mixture was heated to 85°C and stirred for 4 h. The reaction mixture was cooled to room temperature, EA (50 mL) was added, extracted, washed with saturated brine (10 mL), dried over Na2SO4, and concentrated to obtain a crude product. Column chromatography purification (eluent EA to EA:MeOH = 10:1, Rf = 0.3 for EA / MeOH 10 / 1) gave brown oily product D01e (120 mg, 60%). MS(ESI): m / z=508.3[M+H] + . 1 HNMR (400MHz, CDCl3): 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),3.8 0-3.76 (m, 0.5H), 3.52-3.02 (m, 5.5H), 1.92-1.90 (m, 2H), 1.47 (s, 9H).

[0317] f) Burgess reagent (338 mg, 1.42 mmol) was added to a solution of D01e (120 mg, 0.237 mmol) in dichloromethane (10 mL) at room temperature. After continued stirring at room temperature for 4 h, the reaction solution was diluted with dichloromethane (20 mL), washed with water (10 mL), dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by HPLC (TFA as buffer, A is 0.05% TFA aqueous solution, B is 0.05% TFA acetonitrile solution, column is Waters XBridge Peptide BEH C18, 19×250 mm, 10 μm, 130A) and lyophilized. The product obtained was neutralized to pH 7 with saturated NaHCO3, and the solution obtained was extracted with EA (3×50 mL), dried over Na2SO4, and concentrated to obtain brown solid product D01f (15 mg, 12% yield). MS(ESI): m / z=490.3[M+H] + .

[0318] g) At room temperature, HCOOH (3 mL) was added to compound D01f (10 mg, 0.02 mmol), and the mixture was heated to 50° C. and stirred for 10 min. The reaction mixture was concentrated to obtain a crude product, which was purified by HPLC (HCOOH was used as a buffer, A was a 0.1% HCOOH aqueous solution, B was acetonitrile, and the column was Waters XBridge Peptide BEH C18, 19×250 mm, 10 μm, 130A) to obtain a white solid product D01 (1.5 mg, 17% yield). 1 HNMR(400MHz,DMSO-d6):δ8.91(s,1H),8.71(d,J=8.4Hz,1H),8.20(s,1H),7.9 5(s,1H),7.68-7.55(m,5H),7.41(d,J=8Hz,2H),5.07-5.01(m,1H),4.09-4.06( m,1H),3.88-3.83(m,1H),3.79-3.70(m,1H),3.26-3.18(m,2H),3.12-3.08(m,1 H),2.88-2.82(m,1H),2.72-2.66(m,1H),2.63-2.57(m,1H),1.80-1.73(m,2H).

[0319] [Table 1]

[0320] Following the method of Example 1, the following compounds were prepared by substituting and reacting 6-bromoimidazo[1,2-a]pyridine with different bromides.

[0321] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0322] Additionally, the following compounds could be prepared by substituting and reacting 6-bromoimidazo[1,2-a]pyridine with different bromides following the procedure of Example 1:

[0323] [Table 3-1] [Table 3-2] [Table 3-3]

[0324] Further, following the method of Example 1, the following compounds were prepared from different fluorine-substituted L-phenylalanine (L-2-Fluoro-Phenylalanine) analogs by similar methods.

[0325] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] [Table 4-15] [Table 4-16] [Table 4-17] [Table 4-18] [Table 4-19] [Table 4-20] [Table 4-21]

[0326] Example 2 Synthesis of Compound D11 [ka]

[0327] a) At room temperature under argon, D01d (200 mg, 0.387 mmol), 2-bromo-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one (170 mg, 0.78 mmol), PdCl2dppf (60 mg, 0.08 mmol) and KOAc (114 mg, 1.16 mmol) were added to dioxane (8 mL) and H2O (0.8 mL). Stirred at 90 °C overnight. The reaction was cooled to room temperature and EA (50 mL) and saturated brine (10 mL) were added. Extraction with EA (3 x 300 mL), drying over Na2SO4 and concentration gave the crude product. A relatively pure product was obtained by column chromatography purification (eluent EA, EA:MeOH=20:1 to 10:1, Rf=0.5 for EA / MeOH 10 / 1), which was further purified by preparative HPLC (C18, CH3CN, 10 mM NH4HCO3 in water) to give the white solid product D11a (120 mg, 58% yield). MS (ESI): m / z=551.2 [M+Na] + . 1 HNMR (400MHz, CDCl3): 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).

[0328] 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 4 h, diluted with dichloromethane DCM (20 mL), washed with water (10 mL), dried over Na2SO4, and concentrated to give the crude product. Column chromatography purification (eluent EA to EA:MeOH = 20:1, Rf = 0.1 for EA) gave the white solid product D11b (130 mg, 88% yield). MS (ESI): m / z = 548.2 [M-Boc] + . 1HNMR(400MHz,DMSO-d6):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,2) H),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).

[0329] c) At room temperature, 4N HCl (0.2 mL) methanol solution (0.5 mL) was added dropwise to a solution of D11b (50 mg, 0.077 mmol) in MeOH (0.5 mL) and CH3CN (3 mL). After stirring for 2 h, 4N HCl (0.2 mL) was added and stirred for another 2 h. Then, Et2O (40 mL) was added to the reaction solution, and a small amount of white precipitate was precipitated. After centrifugation for 2 min, the liquid was removed, and the residue was purified by preparative HPLC (NH4HCO3 aqueous solution was used as the buffer, A was 10 mM NH4HCO3 aqueous solution, B was acetonitrile, and the column was Waters XBridge Peptide BEH C18, 19 × 250 mm, 10 μm, 130A) to obtain the white solid product D11, a white solid (20 mg, 47% yield). MS (ESI): m / z = 548.1 [M + H] + . 1 HNMR(400MHz,DMSO-d6):δ8.96(d,J=8.4Hz,1H),8.2(brs,1H),7.67(d,J=8.4Hz ,2H),7.56(s,1H),7.36(d,J=8.4Hz,2H),5.09-5.03(m,1H),4.82(s,2H),4.37- 4.34(m,1H),3.92-3.86(m,1H),3.79-3.73(m,1H),3.40-3.38(m,1H),3.31(s,3 H),3.26-3.19(m,3H),3.09-3.03(m,1H),2.82-2.76(m,1H),1.96-1.93(m,2H).

[0330] Example 3 Synthesis of Compound D15 [ka]

[0331] a) Compounds ethyl cyanoacetate (20 g, 177 mmol), 1,2-dibromoethane (66.5 g, 354 mmol) and K2CO3 (73.3 g, 531 mmol) were added sequentially to acetone (300 mL) at room temperature. After heating under reflux overnight, the mixture was cooled to room temperature and the solid was filtered off. The filtrate was concentrated to obtain yellow oily product D15a (22 g, 89%). MS (ESI): m / z = 140.4 [M + H] + .

[0332] b) At 0° C., D15a (22 g, 158.3 mmol) was dissolved in dry THF (150 mL) and slowly added dropwise to LiAlH4 (24.06 g, 633.1 mmol) in THF (250 mL). After stirring overnight, the reaction was cooled to 0° C., diluted with Et2O (250 mL), carefully quenched with water (22.06 mL), 15% aqueous NaOH (22.06 mL), and additional water (22.06 mL), the solid was filtered off, and washed with MeOH (400 mL). The filtrate was dried over Na2SO4, the solid was filtered off, HCl (100 ml, 4 mol / L in dioxane) was added, and concentrated to give the crude product D15b (22 g, 80%) as a brown oil. 1 HNMR (400MHz, DMSO-d6): 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).

[0333] c) At room temperature, D15b (5 g, 80% purity, 29.1 mmol), benzaldehyde (4.63 g, 43.6 mmol) and TEA (2.94 g, 29.1 mmol) were added to MeOH (100 mL) and stirred for 2 h, followed by the addition of NaBH4 (2.21 g, 58.2 mmol) in multiple portions. After stirring for 2 h, the solid was filtered off, the filtrate was concentrated and purified by column chromatography (eluent MeOH / DCM=1:15, V / V) to give brown oily product D15c (4.8 g, 87%). MS (ESI): m / z=192.4 [M+H]+ . 1 HNMR (400MHz, CDCl3): 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).

[0334] d) Compound D15c (9.3 g, 48.7 mmol) and (S)-benzyl glycidyl ether (8.38 g, 51.1 mmol) were mixed at room temperature. i The mixture was added to PrOH (100 mL) and stirred at 50° C. for 16 h. The mixture was cooled to room temperature, concentrated, and purified by column chromatography (eluent PE / EA=1:1 to 1:2, V / V) to give brown oily product D15d (14 g, 81%). MS (ESI): m / z=356.2 [M+H] + . 1 HNMR(400MHz,CDCl3):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=1 3.2Hz,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).

[0335] e) In an ice bath, DIPEA (5.6 g, 43.4 mmol) was added to a solution of D15d (11 g, 31 mmol) in dichloromethane (100 mL), followed by slow dropwise addition of MsCl (3.9 g, 34.1 mmol) over 1 h. After stirring for 1 h, ice water (100 mL) was added and extracted with dichloromethane (3 x 200 mL). Drying over Na2SO4 and concentration gave the crude product D15e as a brown oil. MS (ESI): m / z = 434.2 [M+H] + .

[0336] f) At 0°C, a solution of D15e (14 g, 32.3 mmol) dissolved in THF (100 mL) was slowly added dropwise to a suspension of NaH (3.88 g, 97 mmol, purity: 60% in oil) in THF (300 mL). Stirred at 50°C for 16 h, cooled to 0°C, added saturated NaHCO3 (200 ml), and extracted with EA (3 x 400 mL). Dried over Na2SO4 and concentrated to give the crude product. Column chromatography purification (eluent PE / EA = 6:1 to 5:1, V / V) gave brown oily product D15f (8 g, 73%). MS (ESI): m / z = 338.2 [M+H] + . 1 HNMR(400MHz,CDCl3):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).

[0337] g) At room temperature, D15f (4 g, 11.9 mmol) was dissolved in a hydrogenation apparatus containing methanol (100 mL), and then Pd / C (800 mg, C 10%) and AcOH (4 mL) were added. After the air in the hydrogenation apparatus was replaced with hydrogen four times, hydrogen was added and the mixture was shaken for 7 h. Then, HCl (1 ml, 12 mol / L, 12 mmol) was added and hydrogenation was continued for 16 h. Pd / C was filtered off and concentrated to obtain brown oily product D15g (2.4 g, 90%). MS (ESI): m / z = 158.2 [M + H] + .

[0338] h) At room temperature, D15h (4.8 g, 24.8 mmol) was dissolved in dioxane (150 mL) and water (150 mL), followed by the addition of (Boc)2O (10.82 g, 49.6 mmol) and NaHCO3 (10.42 g, 124 mmol). After stirring for 16 h, it was extracted with EA (3 x 500 mL). It was dried over Na2SO4 and concentrated to give the crude product. Column chromatography purification (eluent PE / EA = 2:1 to 1:1, V / V) gave the colorless oily product D15h (5.7 g, 90%). MS (ESI): m / z = 280.0 [M + Na] + . 1 HNMR (400MHz, CDCl3): δ3.85-2.92(m,9H); 1.58-1.40(m,9H); 0.66-0.45(m,4H).

[0339] i) At room temperature, D15h (2 g, 7.78 mmol) was dissolved in dichloromethane (35 mL), and water, TEMPO (24 mg, 0.16 mmol), and Bu4NHSO4 (185 mg, 0.54 mmol) were added in sequence. At the same time, 15.5 mL NaClO solution (10-15%) was adjusted to pH 8-9 with saturated NaHCO3 (liquid + solid) (about 30 mL). An aqueous solution (1 mL) of NaBr (136 mg, 1.32 mmol) was added to the buffer solution. The resulting solution was cooled to 0 °C and slowly added dropwise to the reaction solution. After reacting at 0 °C for 1 h, it was stirred overnight. The reaction solution was adjusted to pH 2-3 with KHSO4 (2N). It was extracted with dichloromethane, dried over Na2SO4, and concentrated to obtain the crude product. Column chromatography purification (eluent PE / EA = 2:1 to 1:1, V / V) gave a white solid product D15i (1.08 g, 40%). MS (ESI): m / z = 294.2 [M+Na] + .

[0340] j) At room temperature, 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) were added in sequence to a solution of (S)-2-amino-3-(4-iodophenyl)propanamide trifluoroacetate (1.79 g, 4.4 mmol) in dichloromethane (40 mL). After stirring for 5 h, water (50 mL) was added and extracted with dichloromethane (3 x 150 mL). The crude product was obtained by drying over Na2SO4 and concentration. After purification by column chromatography (eluent PE / EA = 1:1 to 1:5, V / V), the crude product was obtained by flash column chromatography purification (C18, CH3CN, 10 mM NH4HCO3 aqueous solution) to obtain a white solid product D15j (1 g, 50%). MS(ESI): m / z=566.0[M+Na] + . 1 HNMR(400MHz,CDCl3):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=1 2.8Hz,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).

[0341] k) At room temperature, Pin2B2 (936 mg, 3.68 mmol), Pd(dppf)Cl2 (269 mg, 0.37 mmol) and KOAc (541 mg, 5.52 mmol) were added to a solution of D15j (1 g, 1.84 mmol) in DMSO (30 mL). The reaction flask was evacuated under reduced pressure and then charged with argon. After repeating three times, the mixture was stirred at 85 °C and reacted for 5 h. The mixture was cooled to room temperature, diluted with EA (500 mL) and washed with saturated brine (5 × 100 mL). The mixture was dried over Na2SO4 and concentrated to obtain the crude product. Column chromatography purification (eluent PE / EA = 1:2 to 1:6, V / V) gave the brown solid product D15k (900 mg, 90%). MS (ESI): m / z = 566.3 [M + Na] + . 1 HNMR(400MHz,CDCl3):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).

[0342] l) At room temperature, D15k (200 mg, 0.37 mmol) was dissolved in dioxane (10 mL), and then 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (126 mg, 0.55 mmol), Pd(dppf)Cl2 (54 mg, 0.07 mmol), KOAc (108 mg, 1.1 mmol) and water (1 mL) were added in sequence. The reaction flask was purged with argon after removing air under reduced pressure. The reaction mixture was stirred at 85 °C for 6 h. It was cooled to room temperature, concentrated, and purified by column chromatography (eluent PE / EA = 1:1 to 1:6 MeOH / DCM = 1:10, V / V) to obtain a relatively pure product. Further purification by column (C18, CH3CN, 10 mM NH4HCO3 aqueous solution) gave brown solid product D15l (150 mg, 72%). MS(ESI): m / z=587.3[M+Na] + .

[0343] m) At room temperature, D15l (140 mg, 0.25 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of Burgess reagent (354 mg, 1.49 mmol). After stirring at room temperature for 3 h, it was concentrated and purified by preparative HPLC (NH4HCO3 was used as buffer, A was 10 mM NH4HCO3 aqueous solution, B was acetonitrile, and the column was Waters XBridge Peptide BEH C18, 19×250 mm, 10 μm, 130A) to give the brown solid product D15m (80 mg, 59%). MS (ESI): m / z=569.3 [M+Na] + .

[0344] n) HCl-dioxane (1.172 mmol, 4 mol / 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 1.5 h, cold Et2O (45 mL) was added, centrifuged, and the liquid phase was removed. The residue was washed twice with Et2O (15 mL). Purification by preparative HPLC (A is 0.8% NH4HCO3 aqueous solution, B is CH3CN, column is Xbridge BEH peptide C18, 19 mm × 250 mm) gave the white solid product D15 (35 mg, 53%). The HPLC purity is 99.46%.

[0345] [Table 5]

[0346] The following compounds were prepared from different analogues of L-Phenylalanine by a similar method:

[0347] [Table 6]

[0348] The following compounds were prepared in a similar manner from different 6- and 7-membered ring amino acids:

[0349] [Table 7]

[0350] Example 4 Inhibition test of DPP1 activity in U937 cells The measurement of intracellular enzyme activity was performed in a 384-well plate, and the cell culture medium was 1640, 10% FBS, 1*PS. 30 μL of cell suspension in cell culture medium containing U937 cells was added to the 384-well plate, and 2 × 10 4Each well contained 100 cells, and 30nL AZD7986, vehicle control (100% DMSO) or serial dilutions of test compounds were added to the wells by Echo, and incubated at 37℃ for 1h. Then, h-Gly-phe-AFC (10μL) was added to each well, reacted, and incubated at 37℃ for another 1h. Then, the fluorescence absorption value was read by EXλ400nm and EMλ505nm. The above detection results were used to calculate IC50 values ​​using Graphpad8.0, and the results are shown in the table below.

[0351] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0352] Example 5: Inhibitory effect test of DPP1 enzyme activity The experimental materials were: Recombinant human cathepsin rhCathepsin C / DPP1, purchased from R&D systems; Recombinant human cathepsin rhCathepsin L purchased from R&D systems; AZD7986 purchased from MCE, Gly-Arg-AMC (hydrogen chloride) purchased from Cayman Chemical; DMSO purchased from Sigma-Aldrich.

[0353] Experimental Method 1) Compound preparation and treatment: The exact amount of compound was weighed and dissolved in 10 mL DMSO to prepare 10 mL stock solution, which was further diluted as required.

[0354] 2) Screening measurement: Recombinant human cathepsin rhCathepsin C / DPP1 and recombinant human cathepsin rhCathepsin L were diluted using activation buffer and incubated at 37°C for 60 minutes. 4uL of the test compound was added to the white microwells of a plate equipped with 384 wells. After the incubation, 4uL of the enzyme mixture was taken and added to the white microwells. The 384 well plate was closed, left at room temperature for 30 minutes, and 8uL of 2-fold diluted Gly-Arg-AMC (hydrogen chloride) was added. The 384 well plate was closed and left at room temperature for 2 hours. A 4x stop solution was prepared and 4uL of the stop solution was added to the white microwells. Fluorescence data was read using a Victor Nivo35 fluorometer.

[0355] 3) Data Analysis All IC50 values ​​were converted to percentage inhibition using Prism Graphpad 8.0. The results are shown in the table below.

[0356] [Table 9]

[0357] The examples in this patent are provided only as illustrative rather than limiting, and those skilled in the art will readily appreciate that non-key parameters can be changed or modified to produce substantially similar results.

[0358] Although the technical solutions of the present invention have been described and enumerated in detail, it is obvious to those skilled in the art to modify the above embodiments or adopt equivalent alternative means, and it should be understood that all such modifications or improvements made without departing from the spirit of the present invention are within the scope of the protection claimed by the present invention.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 and / or a pharma- ceutically acceptable prodrug thereof, and / or a solvate, hydrate, metabolite, oxynitride, racemic mixture, enantiomer, diastereomer and tautomer thereof or a mixture thereof in any ratio (including a racemic mixture), In the formula, Cy is 【Chemistry 2】 and p is 0 to 6; W is 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 selected from R ａ are each independently deuterium, halogen, hydroxy, cyano, sulfhydryl, 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) ２ N-, C １－６ Alkyl-C(O)HN-, -C(O)NHC １－６ alkyl, oxo, and thio, each of which may be optionally substituted with halogen and deuterium; ａ may be linked to the same carbon atom or different carbon atoms; R ａ Or two R's ａ Let's go together １－４ Alkylene, or -CH ２ -O-CH ２ -CH ２ -CH ２ --, --CH ２ -O-CH ２ -, said alkylene or ether chain together with the original ring can form cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged, fused and spiro rings with or without heteroatoms, said heteroatoms include N, S, O, said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged, fused and spiro rings can be optionally substituted with deuterium, hydroxy, halogen, alkyl and alkoxy, C, S can be -C=O, -S=O, -S(O), ２ -, or two R ａ form, together with the carbon atom to which each is attached, a 6-membered aryl, a 5-membered heteroaryl, or a 6-membered heteroaryl, and form a fused ring with the original ring, said fused ring being optionally substituted with hydroxy, halogen, cyano, alkyl, alkoxy, and said alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy being optionally substituted with halogen and deuterium; A and B are each independently selected from hydrogen, deuterium, and fluorine, or A and B together with the carbon atom to which they are attached form a cyclopropane; X, Y, and Z are each independently selected from CH, N, S, O, and Se; or one of X, Y, and Z is a bond in a ring, i.e., the atoms on either side of X, Y, or Z are directly connected, and the connecting bond may be a single bond or a double bond; R ２ is hydrogen, deuterium, halogen, cyano, C １－６ Alkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl, C ３－６ cycloalkoxy, wherein any of said alkyl, alkoxy, cycloalkyl and cycloalkoxy may be optionally substituted with halogen and deuterium; q is 0 to 3; 1) Cy 【Chemistry 3】 If not, 2) X, Y, and Z are not simultaneously CH, 3) R ２ When is not hydrogen and q is not 0, 4) If A and B are not hydrogen at the same time (there are four cases in an and / or relationship), R １ is a cyclic group, specifically selected from aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl, the cyclic group may be monocyclic or bicyclic and may optionally contain one or more heteroatoms of N, O, S and Se, and C and S in the ring are -CO-, -CS-, -SO-, -SO ２ -, wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl are optionally oxidized or sulfurized to one or more R １ａ may be optionally substituted with R １ａ is hydrogen, deuterium, halogen, cyano, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ３ R ４ , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ３ , -S(O) ２ R ３ , -S(O)(NH)R ３ , -S(O)(NR ４ ) R ３ , -S(O) ２ N.R. ３ R ４ , -OS(O) ２ R ３ , -NR ３ R ４ , -NR ３ (CO)R ４ , -NR ３ (SO ２ ) R ４ , -NR ３ R ４ alkyl substituted with -CR ３ R ４ , -SR ３ , aryl, and 5- to 6-membered heteroaryl, wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R ３ and two R １ａ may be linked to the same carbon atom or nitrogen atom or to different carbon atoms or nitrogen atoms, and two R １ａ can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further optionally substituted with -CO-, -CS-, -SO-, -SO ２ may be selectively oxidized or sulfurized to -, R ３ , R ４ are each independently hydrogen, deuterium, halogen, cyano, halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, alkylcarbonyl, alkylsulfone group, alkylC(O)NH-, alkylS(O) ２ NH-, carboxy, alkylcarbonyl, wherein amino, hydroxy, carboxy, alkyl, cycloalkyl, cycloalkoxy, heterocycloalkoxy, heterocycloalkyl may be further substituted with alkyl, halogen, cyano, hydroxy, hydroxyalkyl, alkoxy, and two R ３ may be attached to the same atom or to different atoms, or two R ３ , or R ３ and R ４ can selectively form a 3- to 10-membered cycloalkyl, heterocycloalkyl, spiro ring, bridged ring, or fused ring, including, but not limited to, an oxetane, azetidine, morpholine ring, piperidine ring, piperazine ring, azaoxetane, furan ring, or pyrrolidine, together with the same carbon atom or nitrogen atom to which each is bonded, and C and S in the cycloalkyl, heterocycloalkyl, spiro ring, bridged ring, or fused ring can each be -CO-, -SO-, -SO ２ -, and one or more halogens, C １－３ Alkyl, halogenated C １－３ Alkyl, C １－３ Alkoxy, C ３－８ optionally substituted with heterocyclyl; Cy 【Chemistry 4】 X, Y, and Z are all CH; R ２ is hydrogen and A / B are both H, R １ is selected from pyrimidine, pyrazine, pyridazine, pyrazole, furan, imidazole, thiazole, oxazole, isoxazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, and pyrimidine, pyrazine, pyridazine, triazinyl, pyrazole, furan, imidazole, thiazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl are selected from one or more of R １ａ (R １ａ is defined above), or S or 1-2 carbon atoms may be selectively oxidized; and / or R １ teeth, 【Chemistry 5】 is selected from f is 0 to 2; g is 0 to 3; h is 0 to 5; k is 0 to 2; R １ａ is defined as above, and R １ａ The same substituents may be selected at the same time, or different substituents may be selected. １ａ can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ - may be selectively oxidized to R ３ and R ４ is as defined above unless otherwise stated. f and g are not 0, R １ａ When is not hydrogen, R １ｂ = H, R １ａ and R １ｂ and R １ａ , or two R １ａ can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ - may be selectively oxidized to When f and g are 0, or when f and g are not 0, R １ａ is hydrogen, then R １ｂ is hydrogen, deuterium, halogen, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ３ R ４ , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ３ , -S(O) ２ R ３ , -S(O)(NH)R ３ , -S(O)(NR ４ ) R ３ , -S(O) ２ N.R. ３ R ４ , -OS(O) ２ R ３ , -NR ３ R ４ , -NR ３ (CO)R ４ , -NR ３ (SO ２ ) R ４ , -NR ３ R ４ alkyl substituted with -CR ３ R ４ , -SR ３ , aryl, and 5- to 6-membered heteroaryl, wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R ３ and R １ｂ and R １ａ , or two R １ａ can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ - may be selectively oxidized to k is not 0, R １ａ When is not hydrogen, R ５ａ , R ５ and R ６ = R １ａ or R ５ａ , R ５ , R ６ , 1 to 2 R １ａ Two of the R can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic group including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, fused ring, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ - may be selectively oxidized to k is 0 or k is not 0 and R １ａ If is hydrogen, then R ５ａ Deuterium, bromine, cyano, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, cyano, C ２－８ Alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ３ R ４ , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ３ , -S(O) ２ R ３ , -S(O)(NH)R ３ , -S(O)(NR ４ ) R ３ , -S(O) ２ N.R. ３ R ４ , -OS(O) ２ R ３ , -NR ３ R ４ , -NR ３ (CO)R ４ , -NR ３ (SO ２ ) R ４ , -NR ３ R ４ alkyl substituted with -CR ３ R ４ , -SR ３ , aryl, or 5- to 6-membered heteroaryl, and the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, or heteroaralkyloxy is selected from one or more of R ３ may be selectively substituted with R ５ and R ６ = R １ａ or R ５ , R ６ , R ５ａ and 1 to 2 R １ａ Two of the R can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic group including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, fused ring, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ - may be selectively oxidized to R ５ａ is chlorine, fluorine, CH ３ When R ５ , R ６ = R １ａ and R ５ａ is H, then R ６ = R １ａ and R ５ is deuterium, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, cyano, alkyl, alkyl substituted with 1 to 2 fluorines, alkyl substituted with 1 to 3 bromines, alkyl substituted with 1 to 3 chlorines, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ３ R ４ (However, R ３ and R ４ cannot be H at the same time), alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ３ , -S(O) ２ C ４－８ Alkyl, -OS(O) ２ C ４－８ Cycloalkyl, -OS(O) ２ C ４－８ Heterocycloalkyl, -S(O)(NH)R ３ , -S(O)(NR ４ ) R ３ , S(O)NR ３ R ４ (However, R ３ and R ４ can form together with the N atom to which it is attached a heteroalkenyl, piperazinyl, a 5- to 7-membered azaalkyl containing at least one O atom, morpholinyl, a bridged ring morpholinyl, or R ３ and R ４ is singly substituted and does not form a ring), -S(O) ２ N.H. ２ , -OS(O) ２ R ３ , -NR ３ R ４ , -NR ３ (CO)R ４ , -NR ３ (SO ２ ) R ４ , -NR ３ R ４ alkyl substituted with -CR ３ R ４ , -SR ３ , aryl, and 5- to 6-membered heteroaryl, wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R ３ may be optionally substituted with Or, R ５ａ is H, chlorine, fluorine, CH ３ If R １ teeth, 【Chemistry 6】 is selected from however, V is -O-, -S-, -Se-, -CH ２ -, -CF ２ -, -CO-, -SO-, -SO ２ -, -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 -O-, -S-, -Se-, -CO-, -SO-, -S(O) ２ , -NR ７ -, -CR ８ R ９ - selected from V is -O-, -S-, -CF ２ When 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)-, ４－８ -N(alkyl)-, -N(cycloalkyl)-, -N(cycloalkoxy)-, -N(oxetane)-, -N(tetrahydrofuran)-, and -N(tetrahydropyran) are C １－３ Alkoxy, C １－３ Alkyl, C ３－６ Cycloalkyl, NH(C １－３ Alkyl), N(C １－３ Alkyl) ２ or optionally substituted with 1 to 3 halogens, otherwise T is -O-, -S-, -Se-, -CO-, -SO-, -SO ２ -, -C(R ８ R ９ ) -, -N(R ７ ) - and X １ , Y １ , Z １ may be independently selected from CH and N; R ７ = R １ａ and R ８ , R ９ = R １ａ or R ８ , R ９ can alternatively form a saturated or unsaturated cyclic group together with the atoms to which they are originally attached, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, and heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ - may be selectively oxidized to and / or a pharma- ceutically acceptable salt thereof or a prodrug thereof, and / or a solvate, hydrate, metabolite, oxynitride, racemic mixture, enantiomer, diastereomer and tautomer thereof or a mixture in any ratio thereof (including a racemic mixture), In the formula, Cy is 【Chemistry 7】 and p is 0 to 6; W is 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 selected from R ａ are each independently deuterium, halogen, hydroxy, cyano, sulfhydryl, 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) ２ N-, C １－６ Alkyl-C(O)HN-, -C(O)NHC １－６ alkyl, oxo, and thio, each of which may be optionally substituted with halogen and deuterium; ａ may be linked to the same carbon atom or different carbon atoms; R ａ Or two R's ａ The common one is C. １－４ Alkylene, or -CH ２ -O-CH ２ -CH ２ -CH ２ --, --CH ２ -O-CH ２ -, said alkylene or ether chain together with the original ring can form cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged, fused and spiro rings with or without heteroatoms, said heteroatoms include N, S, O, said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged, fused and spiro rings can be optionally substituted with deuterium, hydroxy, halogen, alkyl and alkoxy, C, S can be -C=O, -S=O, -S(O), ２ -, or two R ａ form, together with the carbon atom to which each is attached, a 6-membered aryl, a 5-membered heteroaryl, or a 6-membered heteroaryl, and form a fused ring with the original ring, said fused ring being optionally substituted with hydroxy, halogen, cyano, alkyl, alkoxy, and said alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy being optionally substituted with halogen and deuterium; A and B are each independently selected from hydrogen, deuterium, and fluorine, or A and B together with the carbon atom to which they are attached form a cyclopropane; X, Y, and Z are each independently selected from CH, N, S, O, and Se; or one of X, Y, and Z is a bond in a ring, i.e., the atoms on either side of X, Y, or Z are directly connected, and the connecting bond may be a single bond or a double bond; R ２ is hydrogen, deuterium, halogen, cyano, C １－６ Alkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl, C ３－６ cycloalkoxy, wherein any of said alkyl, alkoxy, cycloalkyl and cycloalkoxy may be optionally substituted with halogen and deuterium; q is 0 to 3; 1) Cy 【Chemistry 8】 If not, 2) X, Y, and Z are not simultaneously CH, 3) R ２ When is not hydrogen and q is not 0, 4) If A and B are not hydrogen at the same time (there are four cases in an and / or relationship), R １ is a cyclic group, specifically selected from aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl, the cyclic group may be monocyclic or bicyclic and may optionally contain one or more heteroatoms of N, O, S, Se, and C and S in the ring are -CO-, -CS-, -CO-SO-, -SO ２ -, wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl are optionally oxidized or sulfurized to one or more R １ａ may be optionally substituted with R １ａ is hydrogen, deuterium, halogen, cyano, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ３ R ４ , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ３ , -S(O) ２ R ３ , -S(O)(NH)R ３ , -S(O)(NR ４ ) R ３ , -S(O) ２ N.R. ３ R ４ , -OS(O) ２ R ３ , -NR ３ R ４ , -NR ３ (CO)R ４ , -NR ３ (SO ２ ) R ４ , -NR ３ R ４ alkyl substituted with -CR ３ R ４ , -SR ３ , aryl, and 5- to 6-membered heteroaryl, wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R ３ and two R １ａ may be linked to the same carbon atom or nitrogen atom or to different carbon atoms or nitrogen atoms, and two R １ａ can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further optionally substituted with -CO-, -CS-, -SO-, -SO ２ may be selectively oxidized or sulfurized to -, R ３ , R ４ are each independently selected from hydrogen, deuterium, halogen, cyano, halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, alkylcarbonyl, alkylsulfone, alkylC(O)NH-, alkylS(O)2NH-, carboxy, and alkylcarbonyl, where amino, hydroxy, carboxy, alkyl, cycloalkyl, cycloalkoxy, heterocycloalkoxy, and heterocycloalkyl are optionally further substituted with alkyl, halogen, cyano, hydroxy, hydroxyalkyl, and alkoxy; ３ may be attached to the same atom or to different atoms, or two R ３ , or R ３ and R ４ can selectively form a 3- to 10-membered cycloalkyl, heterocycloalkyl, spiro ring, bridged ring, or fused ring, including, but not limited to, an oxetane, azetidine, morpholine ring, piperidine ring, piperazine ring, azaoxetane, furan ring, or pyrrolidine, together with the same carbon atom or nitrogen atom to which each is bonded, and C and S in the cycloalkyl, heterocycloalkyl, spiro ring, bridged ring, or fused ring can each be -CO-, -SO-, -SO ２ -, and one or more halogens, C １－３ Alkyl, halogenated C １－３ Alkyl, C １－３ Alkoxy, C ３－８ optionally substituted with heterocyclyl; Cy 【Chemistry 9】 X, Y, and Z are all CH; R ２ is hydrogen and A / B are both H, R １ is selected from pyrimidine, pyrazine, pyridazine, pyrazole, furan, imidazole, thiazole, oxazole, isoxazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, and pyrimidine, pyrazine, pyridazine, triazinyl, pyrazole, furan, imidazole, thiazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl are selected from one or more of R １ａ (R １ａ is as defined above), or, with the proviso that S or 1-2 carbon atoms may be selectively oxidized; and / or R １ teeth, 【Chemistry 10】 is selected from f is 0 to 2; g is 0 to 3; h is 0 to 5; k is 0 to 2; R １ａ is defined as above, and R １ａ The same substituents may be selected at the same time, or different substituents may be selected. １ａ can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ - may be selectively oxidized to R ３ and R ４ is as defined above unless otherwise stated. f and g are not 0, R １ａ When is not hydrogen, R １ｂ = H, R １ａ and R １ｂ and R １ａ , or two R １ａ can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ - may be selectively oxidized to When f and g are 0, or when f and g are not 0, R １ａ is hydrogen, then R １ｂ is hydrogen, deuterium, halogen, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ３ R ４ , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ３ , -S(O) ２ R ３ , -S(O)(NH)R ３ , -S(O)(NR ４ ) R ３ , -S(O) ２ N.R. ３ R ４ , -OS(O) ２ R ３ , -NR ３ R ４ , -NR ３ (CO)R ４ , -NR ３ (SO ２ ) R ４ , -NR ３ R ４ alkyl substituted with -CR ３ R ４ , -SR ３ , aryl, and 5- to 6-membered heteroaryl, wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R ３ and R １ｂ and R １ａ , or two R １ａ can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ - may be selectively oxidized to k is not 0, R １ａ When is not hydrogen, R ５ａ , R ５ and R ６ = R １ａ or R ５ａ , R ５ , R ６ , 1 to 2 R １ａ Two of the R can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic group including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, fused ring, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ - may be selectively oxidized to k is 0 or k is not 0 and R １ａ If is hydrogen, then R ５ａ Deuterium, bromine, cyano, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, cyano, C ２－８ Alkyl, haloalkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ３ R ４ , alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ３ , -S(O) ２ R ３ , -S(O)(NH)R ３ , -S(O)(NR ４ ) R ３ , -S(O) ２ N.R. ３ R ４ , -OS(O) ２ R ３ , -NR ３ R ４ , -NR ３ (CO)R ４ , -NR ３ (SO ２ ) R ４ , -NR ３ R ４ alkyl substituted with -CR ３ R ４ , -SR ３ , aryl, or 5- to 6-membered heteroaryl, and the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, or heteroaralkyloxy is selected from one or more of R ３ When it may be optionally substituted with R ５ and R ６ = R １ａ or R ５ , R ６ , R ５ａ and 1 to 2 R １ａ Two of the R can alternatively form a saturated or unsaturated cyclic group together with a carbon or nitrogen atom in the original ring, said cyclic group including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, fused ring, aryl, heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ - may be selectively oxidized to R ５ａ is chlorine, fluorine, CH ３ When R ５ , R ６ = R １ａ and R ５ａ is H, then R ６ = R １ａ and R ５ is deuterium, hydroxy, amino, sulfhydryl, carboxy, sulfone group, sulfoxide group, oxo, thio, nitro, cyano, alkyl, alkyl substituted with 1 to 2 fluorines, alkyl substituted with 1 to 3 bromines, alkyl substituted with 1 to 3 chlorines, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, -CONR ３ R ４ (However, R ３ and R ４ cannot be H at the same time), alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR ３ , -S(O) ２ C ４－８ Alkyl, -OS(O) ２ C ４－８ Cycloalkyl, -OS(O) ２ C ４－８ Heterocycloalkyl, -S(O)(NH)R ３ , -S(O)(NR ４ ) R ３ , S(O)NR ３ R ４ (However, R ３ and R ４ can form together with the N atom to which it is attached a heteroalkenyl, piperazinyl, a 5- to 7-membered azaalkyl containing at least one O atom, morpholinyl, a bridged ring morpholinyl, or R ３ and R ４ is singly substituted and does not form a ring), -S(O) ２ N.H. ２ , -OS(O) ２ R ３ , -NR ３ R ４ , -NR ３ (CO)R ４ , -NR ３ (SO ２ ) R ４ , -NR ３ R ４ alkyl substituted with -CR ３ R ４ , -SR ３ , aryl, and 5- to 6-membered heteroaryl, wherein said alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, and heteroaralkyloxy are each selected from one or more R ３ may be optionally substituted with Or, R ５ａ is H, chlorine, fluorine, CH ３ If R １ teeth, 【Chemistry 11】 is selected from however, V is -O-, -S-, -Se-, -CH ２ -, -CF ２ -, -CO-, -SO-, -SO ２ -, -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 -O-, -S-, -Se-, -CO-, -SO-, -S(O) ２ , -NR ７ -, -CR ８ R ９ - selected from V is -O-, -S-, -CF ２ When 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)-, ４－８ -N(alkyl)-, -N(cycloalkyl)-, -N(cycloalkoxy)-, -N(oxetane)-, -N(tetrahydrofuran)-, and -N(tetrahydropyran) are C １－３ Alkoxy, C １－３ Alkyl, C ３－６ Cycloalkyl, NH(C １－３ Alkyl), N(C １－３ Alkyl) ２ or optionally substituted with 1 to 3 halogens, otherwise T is -O-, -S-, -Se-, -CO-, -SO-, -SO ２ -, -C(R ８ R ９ ) -, -N(R ７ ) - and X １ , Y １ , Z １ may be independently selected from CH and N; R ７ = R １ａ and R ８ , R ９ = R １ａ or R ８ , R ９ can alternatively form a saturated or unsaturated cyclic group together with the atoms to which they are originally attached, said cyclic groups including, but not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged rings, spiro rings, fused rings, aryl, and heteroaryl, and the cyclic group can be formed by one or more R ３ C and S in the ring may be further selectively substituted with -CO-, -SO-, -SO ２ A compound of formula (I) or a pharma- ceutically acceptable salt thereof, which may be selectively oxidized to -.

2. The Cy is 【Chemistry 12】 is selected from Ar is a pyridine and benzene ring; R ｂ 2. The compound of formula (I) according to claim 1, wherein is chlorine, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, trifluoromethoxy, or a pharma- ceutically acceptable salt thereof.

3. 2. The compound of formula (I) according to claim 1, wherein A and B are both selected from H or F, or a pharma- ceutically acceptable salt thereof.

4. 2. The compound of formula (I) according to claim 1, wherein X and Y are each independently selected from CH and N, and Z is selected from CH, or a pharma- ceutically acceptable salt thereof.

5. The R ２ 2. The compound of formula (I) according to claim 1, wherein is selected from hydrogen, fluorine, methyl, and said q is selected from 1, or a pharma- ceutically acceptable salt thereof.

6. The R １ teeth, 【Chemistry 13】 is selected from however, X １ , Y １ , Z １ is independently selected from CH and N; m, n, and o are each 0 to 3; U is -C(=O)-, -S(O) ２ -, -O-, -NR ７ -, -CR ８ R ９ - may be selected from V is -C(=O)-, -S(O) ２ -, -O-, -S-, -Se-, -NR ７ -, -CR ８ R ９ - may be selected from R ７ is hydrogen, CH ３ OCH ２ CH ２ -, oxetanyl, azetidine, tetrahydrofuryl, tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine, -C １－３ Alkyl, C ３－６ cycloalkyl, wherein C １－３ Alkyl, C ３－６ Cycloalkyl, azetidine, tetrahydrofuryl, tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine are optionally substituted with 1, 2 or 3 fluorines and / or C １－３ Alkyl, hydroxy, -OC １－３ Alkyl, -N(C １－３ Alkyl) ２ , cyclopropyl, and R ７ may be the same or different substituents; R ８ , R ９ is hydrogen, fluorine, -C １－６ Alkyl, -C １－６ haloalkyl, or R ８ and R ９ together with the nitrogen or carbon atom to which they are attached, ３－６ cycloalkyl, oxetane, azetidine, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuryl, tetrahydropyranyl, and the cyclopropane, oxetane, azetidine, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuryl, tetrahydropyranyl are each independently selected from the group consisting of C １－３ may be optionally substituted with alkyl, cyclopropane, oxetane, azetidine, cyclopropyloxy; C and D are independently -NR ７ C(O)-, -C(O)NR ７ --, --CH ２ -CH ２ -, -C(O)-O-, -OC(O)-, -CH ２ -O-, -O-CH ２ --, --CH ２ -NR ７ --, --NR ７ -CH ２ --, --CH ２ -, or one of C and D is a bond (a single or double bond in a ring, with both ends directly connected); Cy 【Chemistry 14】 and R ２ is H, X, Y, and Z are all selected from CH, and V is present in the structure, then -O-, -S-, or -CF ２ - if R ５ is -S(O) ２ C １－３ Alkyl, -CONH ２ , -SO ２ N.H.C. １－３ Alkyl, -SO ２ N.R. ３ R ４ (However, R ３ and R ４ together with the N atom to which they are attached form a heterocyclyl, said heterocyclyl is selected from piperazinyl, morpholinyl, and said piperazinyl and morpholinyl are C １－３ alkyl, cyclopropyl; R ６ is selected from hydrogen, fluorine, chlorine, bromine, and methyl; R ７ａ is 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, ４－８ Alkyl, tetrahydrofuran, pyrrolidine, piperazine, morpholine, piperidine are optionally substituted with 1, 2 or 3 fluorines and / or hydroxy, -OC １－３ Alkyl, -N(C １－３ Alkyl) ２ , cyclopropyl, Otherwise, R ５ is cyano, -SO ２ C １－３ Alkyl, -CONH ２ , -SO ２ N.R. ３ R ４ is selected from R ３ , R ４ is hydrogen, -C １－６ alkyl, or R ３ and R ４ form an azetidine, oxetane, pyrrolidine, piperidine ring, piperazine ring, or morpholine ring together with the nitrogen atom to which they are bonded, and the azetidine, oxetane, pyrrolidine, piperidine ring, piperazine ring, or morpholine ring is C １－３ may be optionally substituted with alkyl, cyclopropyl, R ６ is selected from hydrogen, fluorine, chlorine, bromine, and methyl; R ７ａ = R ７ 2. The compound of formula (I) according to claim 1, characterized in that it is: or a pharma- ceutically acceptable salt thereof.

7. The R １ teeth, 【Chemistry 15】 is selected from R ７ is hydrogen, -CF ２ , -CHF, CH ３ OCH ２ CH ２ -, oxetanyl, tetrahydrofuryl, tetrahydropyran, -C １－３ Alkyl, -C ３－６ cycloalkoxy, wherein C １－３ The alkyl, oxetanyl, tetrahydrofuryl, tetrahydropyran may be optionally substituted with one, two or three fluorines and / or hydroxy, -OC １－３ Alkyl, -N(C １－３ Alkyl) ２ , cyclopropyl, and R ７ may be the same or different substituents; Cy 【Chemistry 16】 and R ２ is H, X, Y, and Z are all selected from CH, and A and B are all H, then R ７ａ is 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, wherein the oxetane, tetrahydrofuran, and tetrahydropyran are selected from C １－３ Alternatively, R ７ａ = R ７ 2. The compound of formula (I) according to claim 1, characterized in that it is: or a pharma- ceutically acceptable salt thereof.

8. A compound of formula (I) below or a pharma- ceutically acceptable salt thereof: 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】

9. Use of the compound of formula (I) according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for the treatment and prevention of diseases caused by cathepsin C and its downstream serine proteases NE, PR3, CaTG, and NSP4.

10. The compound of formula (I) according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof is useful for the treatment of respiratory diseases, metabolic diseases, cardiovascular diseases, autoimmune diseases, cancer, infectious diseases and other inflammation-related diseases such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, pulmonary arterial hypertension, non-cystic fibrosis, cystic fibrosis, bronchiectasis, bronchitis, pneumonia, emphysema, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, allergic diseases, immune inflammatory bowel diseases, rheumatoid arthritis, glomerulonephritis, and the like.

5. Use of the compound of claim 1 in the preparation of a medicament for the treatment of glomerulonephritis, eosinophilic diseases, neutrophilic diseases, ANCA associated inflammation, antineutrophil cytoplasmic antibody associated necrotizing crescent glomerulonephritis, acute brain injury, acute myocarditis, acute kidney injury, a-1-antitrypsin deficiency (AATD) and associated inflammation, liver fibrosis, fatty liver and hepatic steatosis, obesity, insulin resistance, diabetes, pathogenic microbial infections, infectious gastroenteritis diseases, lung cancer and / or radiation injury syndrome in a patient suffering from or at risk of said diseases.

11. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof and at least one pharmaceutical carrier or excipient.

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

13. The pharmaceutical composition according to any one of claims 11 to 12, further comprising a combination of a small molecule compound and / or a polymeric antibody to treat cancer, inflammation, bone marrow-related disease and autoimmune disease, wherein the small molecule compound and / or polymeric antibody includes, but is not limited to, glucocorticoids, adrenergic agonists, cholinergic receptor antagonists, theophylline drugs, 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 antibody and IL-23 antibody, targeted anti-thymic stromal lymphopoietin (TSLP) antibodies such as tezeplumab, and complement inhibitors.

14. Use of the pharmaceutical composition according to claim 13 in the treatment and prevention of diseases caused by cathepsin C and its downstream serine proteases NE, PR3, CaTG and NSP4, characterized in that the diseases are selected from respiratory diseases, metabolic diseases, cardiovascular diseases, autoimmune diseases, cancer, infectious diseases or inflammatory infectious diseases.

15. The R １ , R ２ A solvate, racemic mixture, enantiomer, diastereomer, tautomer, or mixture in any ratio thereof, including a racemic mixture, of a compound of formula (I) according to any one of claims 1 to 8, characterized in that: , Cy, A, B, X, Y, Z and q each have a substituent. 【Chemistry 23】

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