Peptidylnitrile compounds and their use

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] This invention relates to the field of pharmaceutical technology, and more particularly to novel peptidylnitrile compounds and their uses. [Background technology]

[0002] Inflammatory diseases are currently a crucial area of ​​drug research and development. Interleukin antibody drugs are used clinically, as are small molecule drugs such as JAK inhibitors. However, each has different degrees of drawbacks. For example, antibody drugs can only be administered by injection and have low clinical acceptance, while JAK inhibitors are used for inflammatory diseases and can cause potential cardiovascular adverse events due to their targeting mechanism (Norman P, Expert Opinion on Investigational Drugs. 2014, 23(8):1067-77). Therefore, the search for novel anti-inflammatory drugs is extremely necessary.

[0003] Cathepsin C (CTSC), also known as dipeptidyl peptidase I (DPP-1), is a lysosomal cysteine ​​protease with a molecular weight of 200 kDa belonging to the papain family. Cathepsin C is a serine peptidase of neutrophils and mast cell granules in inflammatory cells (e.g., four neutrophil proteases: elastase (NE), cathepsin G (CatG), protease 3 (PR)). 3Cathepsin C acts as a key enzyme that activates neutrophil serine protease (NSP4), as well as mast cell-related chymases, tryptases, 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). When these proteases are activated by cathepsin C, they degrade various extracellular matrix components, leading to tissue damage and chronic inflammation. 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, and cystic fibrosis (Laine et al, Expert Opin.Ther.Patents 2010, 20, 497).

[0004] Since the pathogenesis of other immune diseases, such as inflammatory bowel disease, rheumatoid arthritis, anti-neutrophil 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 an increase in the activity of specific inflammatory proteases, cathepsin C inhibitors can be potential drugs to treat these diseases. Furthermore, since elastase, a serine protease downstream of cathepsin, plays a crucial role in cancer development and metastasis, and in cardiovascular diseases such as myocardial infarction, theoretically, inhibiting cathepsin also has a pharmacological effect of inhibiting elastase. 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] More than 70 years have passed since the discovery of cathepsin C, but clinical trials of cathepsin C inhibitors remain very limited (Korkmaz B. et al, J. Med. Chem., 2020, 63, 13258; Shen, XB et al, EJ Med. Chem., 2021, 225-113818). In June 2020, the U.S. Food and Drug Administration granted breakthrough drug status to the cathepsin C inhibitor Brensocatib immediately after it completed Phase II clinical trials, and Brensocatib is now used to treat non-cystic fibrotic bronchiectasis (NCFBE) in adults (Doyle K. et al, J. Med. Chem., 2016, 59, 9457). There is still a great need for cathepsin C inhibitors. Conventional compounds are less effective at inhibiting the activity of cathepsin C and downstream serine proteases; therefore, there is a need to provide novel peptidylnitrile compounds and their uses. [Overview of the project]

[0006] The object of the present invention is a compound of general formula (I) or a pharmaceutically acceptable salt thereof, [ka] and / or pharmaceutically acceptable salts thereof or prodrugs thereof, and / or solvates, hydrates, metabolites, oxidnitrides, racemic mixtures, enantiomers, diastereomers and tautomers thereof or mixtures thereof in any proportion (including racemic mixtures), In the formula, Cy is [ka] And, p is between 0 and 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 is, independently of each other, 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, thio, and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl and heterocycloalkoxy may each be optionally substituted with halogen and deuterium, and two R a may be linked to the same carbon atom or to different carbon atoms, and R a or two R a together may form C 1-4 alkylene, or an ether chain containing 1 to 4 carbon atoms such as -CH2-O-CH2-CH2-CH2-, -CH2-O-CH2-, and the alkylene or ether chain together with the original ring may form a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, fused ring and spiro ring which may or may not contain a hetero atom, the hetero atom including N, S, O, and the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, fused ring and spiro ring may be selectively substituted with deuterium, hydroxy, halogen, alkyl and alkoxy, and C, S may be selectively oxidized to -C=O, -S=O, -S(O)2-, or two R aEach of these, together with the bonded carbon atom, forms a 6-membered aryl, 5-membered heteroaryl, and 6-membered heteroaryl ring, and also forms a fused ring with the original ring, and the fused ring may be selectively substituted with hydroxyl, halogen, cyano, alkyl, or alkoxy, and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy may each be optionally substituted with halogen and deuterium. A and B are independently selected from hydrogen, deuterium, and fluorine, or A and B together with the carbon atom to which they are bonded form 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 both sides of X, Y, or Z are directly linked, and the linked bond may be a single bond or a double bond. R 2 These are hydrogen, deuterium, halogens, cyano, and C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Selected from cycloalkoxys, the alkyl, alkoxy, cycloalkyl and cycloalkoxy may all be optionally substituted with halogens and deuterium. q is between 0 and 3. 1) Cy is [ka] If not, 2) If X, Y, and Z are not simultaneously CH, 3) R 2 If it is not hydrogen and q is not 0, 4) If A and B cannot be hydrogen at the same time (in the case of four, there is an and / or relationship), R 1The cyclic group is selected from aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl, and the cyclic group may be monocyclic or bicyclic, and may selectively contain one or more heteroatoms of N, O, S, and Se, and the C and S in the ring may be selectively oxidized or sulfurized to -CO-, -CS-, -CO--SO-, and -SO2-, and the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl may contain one or more R 1a It may be selectively replaced by, R 1a This includes 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)2NR 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 The alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, heteroaralkyloxy are one or more R 3 It may be selectively substituted with two R 1a The two R atoms may be linked to the same carbon or nitrogen atom, or to different carbon or nitrogen atoms. 1a The ring can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 They may be further selectively substituted, and the C and S in the ring may be selectively oxidized or sulfurized to -CO-, -CS-, -SO-, and -SO2-. R 3 , R 4 Each of these is independently selected from hydrogen, deuterium, halogen, cyano, halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, alkylcarbonyl, alkylsulfone group, alkyl C(O)NH-, alkyl S(O)2NH-, carboxy, and alkylcarbonyl, where amino, hydroxy, carboxy, alkyl, cycloalkyl, cycloalkoxy, heterocycloalkoxy, and heterocycloalkyl may be further substituted with alkyl, halogen, cyano, hydroxy, hydroxyalkyl, or alkoxy, and two R 3 It may be linked to the same atom, or to different atoms, or to two R 3 , or R 3 and R 4Each of these can selectively form 3- to 10-membered cycloalkyl, heterocycloalkyl, spiro ring, crosslinking ring, and condensed rings, each with the same carbon or nitrogen atom to which it is bonded, and the C and S in the cycloalkyl, heterocycloalkyl, spiro ring, crosslinking ring, and condensed ring may be selectively oxidized to -CO-, -SO-, and -SO2-, and one or more halogens, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, C 3-8 It may be selectively substituted with a heterocycline. Cy [ka] And X, Y, and Z are all CH, and R 2 When is hydrogen and both A and B are H, R 1 R 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 is one or more R 1a It may be replaced with (R 1a The definition is as described above, or S or 1-2 carbon atoms may be selectively oxidized. and / or R 1 teeth, [ka] Selected from, f is between 0 and 2. g is between 0 and 3. h is between 0 and 5. k is between 0 and 2. R 1a The definition is as described above, and R on the same ring 1a The same substituent may be selected simultaneously, or different substituents may be selected, and two R 1a The ring can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The C and S in the ring may be further selectively substituted, and the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-. R 3 and R 4 Unless otherwise specified, the definition is as stated above. f and g are not 0, R 1a If R is not hydrogen, 1b =H, R 1a And R 1b and R 1a , or two R 1a The ring can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The C and S in the ring may be further selectively substituted, and the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-. When f and g are 0, or when f and g are not 0, R 1a When R is hydrogen, 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<0000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​The ring can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The C and S in the ring may be further selectively substituted, and the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-. k is not 0, R 1a If R is not hydrogen, 5a , R 5 and R 6 =R 1a And, or, R 5a , R 5 , R 6 , 1-2 R 1a Two of these can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The C and S in the ring may be further selectively substituted, and the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-. k is 0, or k is not 0 and R 1a If it is hydrogen, R 5a However, 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)2NR 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, 5-6 member heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, heteroaralkyloxy are one or more R 3 It may be selectively replaced by R 5 and R 6 =R 1a And, or, R 5 , R 6 , R 5a and 1-2 R 1aTwo of these can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The C and S in the ring may be further selectively substituted, and the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-. R 5a When R is chlorine, fluorine, or CH3, 5 , R 6 =R 1a And, R 5a When H, R 6 =R 1a And R 5 This includes deuterium, hydroxy, amino, sulfhydryl, carboxy, sulfone, sulfoxide, oxo, thio, nitro, cyano, alkyl, alkyl substituted with 1-2 fluorines, alkyl substituted with 1-3 bromines, alkyl substituted with 1-3 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 (It is not H at the same time), alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR 3 -S(O)2C 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)2NR 3 R 4 (However, R 3 and R 4 Together with the bonded N atom, it can form heteroalkenyl, piperazinyl, 5-7 member azaalkyl, morpholinyl, or crosslinked morpholinyl rings containing at least one O atom, or R 3 and R 4 (It is substituted alone 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 The alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, heteroaralkyloxy are one or more R 3 It may be selectively replaced by, Alternatively, R 5a When R is H, chlorine, fluorine, or CH3, 1 teeth, [ka] Selected from, however, V is -O-, -S-, -Se-, -CH2-, -CF2-, -CO-, -SO-, -SO2-, -N(R 7 )-,-C(R 8 R 9Selected from )-, -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 -N(alkyl)-, -N(cycloalkyl)-, -N(cycloalkoxy)-, -N(oxetane)-, -N(tetrahydrofuran)-, -N(tetrahydropyran)-, and the aforementioned -N(C 4-8 Alkyl)-, -N(cycloalkyl)-, -N(cycloalkoxy)-, -N(oxetane)-, -N(tetrahydrofuran)-, -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) may be selectively substituted with 2 or 1-3 halogens, otherwise T is -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 And, or, R 8 , R 9Both can selectively form saturated or unsaturated cyclic groups with the atoms to which they were originally bonded, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The C and S in the ring may be further selectively substituted, and the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-. and / or pharmaceutically acceptable salts thereof or prodrugs thereof, and / or solvates, hydrates, metabolites, oxidnitrides, racemic mixtures, enantiomers, diastereomers and tautomers thereof or mixtures thereof in any proportion (including racemic mixtures), In the formula, Cy is [ka] And, p is between 0 and 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 These are, independently, deuterium, halogen, hydroxyl, cyano, sulfhydryl, amino, and 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 1-6Selected from alkyl, oxo, and thio, the alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy may all be optionally substituted with halogens and deuterium, and two R a R may be bonded to the same carbon atom or to different carbon atoms. a or two R a Together is C 1-4 Alkylene or ether chains containing 1 to 4 carbon atoms, such as -CH2-O-CH2-CH2-CH2-, -CH2-O-CH2-, and the alkylene or ether chain, together with the original ring, can form cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, condensed ring and spiro ring, which may or may not contain heteroatoms, wherein the heteroatoms include N, S, and O, and the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, condensed ring and spiro ring may be selectively substituted with deuterium, hydroxyl, halogen, alkyl and alkoxy, and C and S may be selectively oxidized to -C=O, -S=O, -S(O)2-, or two R a Each of these, together with the bonded carbon atom, forms a 6-membered aryl, 5-membered heteroaryl, and 6-membered heteroaryl ring, and also forms a fused ring with the original ring, and the fused ring may be selectively substituted with hydroxyl, halogen, cyano, alkyl, or alkoxy, and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl, and heterocycloalkoxy may each be optionally substituted with halogen and deuterium. A and B are independently selected from hydrogen, deuterium, and fluorine, or A and B together with the carbon atom to which they are bonded form 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 both sides of X, Y, or Z are directly linked, and the linked bond may be a single bond or a double bond. R 2 These are hydrogen, deuterium, halogens, cyano, and C 1-6 Alkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl, C 3-6 Selected from cycloalkoxys, the alkyl, alkoxy, cycloalkyl and cycloalkoxy may all be optionally substituted with halogens and deuterium. q is between 0 and 3. 1) Cy is [ka] If not, 2) If X, Y, and Z are not simultaneously CH, 3) R 2 If it is not hydrogen and q is not 0, 4) If A and B cannot be hydrogen at the same time (in the case of four, there is an and / or relationship), R 1 The cyclic group is selected from aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl, and the cyclic group may be monocyclic or bicyclic, and may selectively contain one or more heteroatoms of N, O, S, and Se, and the C and S in the ring may be selectively oxidized or sulfurized to -CO-, -CS-, -CO--SO-, and -SO2-, and the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl may contain one or more R 1a It may be selectively replaced by, R 1a This includes 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)2NR 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 The alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, heteroaralkyloxy are one or more R 3 It may be selectively substituted with two R 1a The two R atoms may be linked to the same carbon or nitrogen atom, or to different carbon or nitrogen atoms. 1a The ring can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 They may be further selectively substituted, and the C and S in the ring may be selectively oxidized or sulfurized to -CO-, -CS-, -SO-, and -SO2-. R 3 , R 4Each of these is independently selected from hydrogen, deuterium, halogen, cyano, halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, alkylcarbonyl, alkylsulfone group, alkyl C(O)NH-, alkyl S(O)2NH-, carboxy, and alkylcarbonyl, where amino, hydroxy, carboxy, alkyl, cycloalkyl, cycloalkoxy, heterocycloalkoxy, and heterocycloalkyl may be further substituted with alkyl, halogen, cyano, hydroxy, hydroxyalkyl, or alkoxy, and two R 3 It may be linked to the same atom, or to different atoms, or to two R 3 , or R 3 and R 4 Each of these can selectively form 3- to 10-membered cycloalkyl, heterocycloalkyl, spiro ring, crosslinking ring, and condensed rings, each with the same carbon or nitrogen atom to which it is bonded, and the C and S in the cycloalkyl, heterocycloalkyl, spiro ring, crosslinking ring, and condensed ring may be selectively oxidized to -CO-, -SO-, and -SO2-, and one or more halogens, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, C 3-8 It may be selectively substituted with a heterocycline. Cy [ka] And X, Y, and Z are all CH, and R 2 When is hydrogen and both A and B are H, R 1R 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 is one or more R 1a It may be replaced with (R 1a The definition is as described above, or S or 1-2 carbon atoms may be selectively oxidized. and / or R 1 teeth, [ka] Selected from, f is between 0 and 2. g is between 0 and 3. h is between 0 and 5. k is between 0 and 2. R 1a The definition is as described above, and R on the same ring 1a The same substituent may be selected simultaneously, or different substituents may be selected, and two R 1a The ring can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The C and S in the ring may be further selectively substituted, and the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-. R 3 and R 4 Unless otherwise specified, the definition is as stated above. f and g are not 0, R 1a If R is not hydrogen, 1b =H, R 1a And R1b and R 1a , or two R 1a The ring can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The C and S in the ring may be further selectively substituted, and the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-. When f and g are 0, or when f and g are not 0, R 1a When R is hydrogen, 1b This includes 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)2NR 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 The alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, heteroaralkyloxy are one or more R 3 It may be selectively substituted with R 1b and R 1a , or two R 1a The ring can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The C and S in the ring may be further selectively substituted, and the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-. k is not 0, R 1a If R is not hydrogen, 5a , R 5 and R 6 =R 1a And, or, R 5a , R 5 , R 6 , 1-2 R 1a Two of these can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The C and S in the ring may be further selectively substituted, and the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-. k is 0, or k is not 0 and R 1a If it is hydrogen, R5a However, 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)2NR 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, 5-6 member heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, heteroaralkyloxy are one or more R 3 When it is acceptable to selectively substitute with, R 5 and R 6 =R1a And, or, R 5 , R 6 , R 5a and 1-2 R 1a Two of these can selectively form saturated or unsaturated cyclic groups with carbon or nitrogen atoms in the original ring, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The C and S in the ring may be further selectively substituted, and the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-. R 5a When R is chlorine, fluorine, or CH3, 5 , R 6 =R 1a And, R 5a When H, R 6 =R 1a And R 5 This includes deuterium, hydroxy, amino, sulfhydryl, carboxy, sulfone, sulfoxide, oxo, thio, nitro, cyano, alkyl, alkyl substituted with 1-2 fluorines, alkyl substituted with 1-3 bromines, alkyl substituted with 1-3 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 (It is not H at the same time), alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, -SOR 3 -S(O)2C 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)2NR 3 R 4 (However, R 3 and R 4 Together with the bonded N atom, it can form heteroalkenyl, piperazinyl, 5-7 member azaalkyl, morpholinyl, or crosslinked morpholinyl rings containing at least one O atom, or R 3 and R 4 (It is substituted alone 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 The alkyl, alkoxy, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, heteroaralkyloxy are one or more R 3 It may be selectively replaced by, Alternatively, R 5a When R is H, chlorine, fluorine, or CH3, 1 teeth, [ka] Selected from, however, V is -O-, -S-, -Se-, -CH2-, -CF2-, -CO-, -SO-, -SO2-, -N(R 7 )-,-C(R 8 R9 Selected from )-, -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 -N(alkyl)-, -N(cycloalkyl)-, -N(cycloalkoxy)-, -N(oxetane)-, -N(tetrahydrofuran)-, -N(tetrahydropyran)-, and the aforementioned -N(C 4-8 Alkyl)-, -N(cycloalkyl)-, -N(cycloalkoxy)-, -N(oxetane)-, -N(tetrahydrofuran)-, -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) may be selectively substituted with 2 or 1-3 halogens, otherwise T is -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 And, or, R 8 , R9 Both can selectively form saturated or unsaturated cyclic groups with the atoms to which they were originally bonded, and the cyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridging ring, spiro ring, fused ring, aryl, and heteroaryl, and the cyclic group may be one or more R 3 The objective is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof, which may be further selectively substituted, and in which the C and S in the ring may be selectively oxidized to -CO-, -SO-, and -SO2-.

[0007] A preferred embodiment of the present invention is that Cy is [ka] Selected from, Ar is a pyridine and benzene ring. R b The compounds listed in general formula (I) or their pharmaceutically acceptable salts are chlorine, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, or trifluoromethoxy.

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

[0009] A preferred embodiment of the present invention is the compound of formula (I) or a pharmaceutically 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 R 2 The compound is one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen, fluorine, and methyl, and q is selected from 1.

[0011] A preferred embodiment of the present invention is R 1 teeth, [ka] selected from however, X1, Y1, Z1 are independently selected from CH, N, m, n, o are 0 to 3, U is -C(=O)-, -S(O)2-, -O-, -NR 7 -, -CR 8 R 9 - and may be selected, V is -C(=O)-, -S(O)2-, -O-, -S-, -Se-, -NR 7 -, -CR 8 R 9 - and may be selected, R 7 is hydrogen, CH3OCH2CH2-, oxetanyl, azetidine, tetrahydrofuryl, tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine, -C 1-3 alkyl, C 3-6 cycloalkyl, and the 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 are optionally substituted with one substituent selected therefrom, and R 7 at different positions in the same structure may select the same substituent or different substituents, <​​​​​​​​​​​​​​Form a cycloalkyl, oxetane, azetidine, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuryl, tetrahydropyranyl, and the cycloalkane, oxetane, azetidine, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuryl, tetrahydropyranyl are C 1-3 alkyl, cyclopropane, oxetane, azetidine, may be selectively substituted with cyclopropyloxy, C and D are independently -NR 7 C(O)-, -C(O)NR 7 -, -CH2-CH2-, -C(O)-O-, -O-C(O)-, -CH2-O-, -O-CH2-, -CH2-NR 7 -, -NR 7 -CH2-, -CH2-, or one of C and D is a bond (a single bond or double bond in the ring, with the atoms at both ends directly connected), Cy is

Chemical formula

[0012] A preferred embodiment of the present invention is R 1 teeth, [ka] Selected from, R 7 This is hydrogen, -CF2, -CHF, CH3OCH2CH2-, oxetanyl, tetrahydrofuryl, tetrahydropyran, -C 1-3 Alkyl, -C 3-6Selected from cycloalkoxy, the C 1-3 Alkyl, oxetanyl, tetrahydrofuryl, and tetrahydropyran may be optionally substituted with 1, 2, or 3 fluorine atoms, and / or hydroxy, -OC 1-3 Alkyl, -N(C 1-3 It may be optionally substituted with one substituent selected from alkyl)2 or cyclopropyl, and R at different positions in the same structure. 7 The same substituent may be selected, or different substituents may be selected. Cy [ka] And R 2 If is H, and 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 Selected from cycloalkoxy, -CH2-CH2-OCH3, -oxetane, -tetrahydrofuran, and -tetrahydropyran, wherein oxetane, tetrahydrofuran, and tetrahydropyran are C 1-3 It may be selectively substituted with alkyl or cyclopropyl, otherwise R 7a =R 7 It is the compound described in formula (I) or a pharmaceutically acceptable salt thereof.

[0013] Typical compounds of the present invention include, but are not limited to, the following, or pharmaceutically acceptable salts thereof.

[0014] [ka]

[0015] [ka]

[0016] [Chemical formula]

[0017] [Chemical formula]

[0018] [Chemical formula]

[0019] [Chemical formula]

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

[0021] Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in the preparation of a drug for treating the above diseases in patients suffering from or at risk of developing 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, eosinophilic diseases, neutrophilic diseases, ANCA-related inflammation, antineutrophil cytoplasmic antibody-related necrotizing crescentic glomerulonephritis, acute brain injury, acute myocarditis, acute kidney injury, a-1-antitrypsin deficiency (AATD) and related inflammation, liver fibrosis, fatty liver and hepatic steatosis, obesity, insulin resistance, diabetes, pathogenic microbial infections, infectious gastroenteritis diseases, lung cancer and / or radiation injury syndrome.

[0022] The beneficial effects of the present invention relate to a drug composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one medicinal carrier or excipient.

[0023] Furthermore, the drug composition comprises one or more compounds of formula (I) and a pharmaceutically active compound selected from the group consisting of other compounds, the other compounds including, but not limited to, b-mimants, 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] Furthermore, the drug composition further includes, but is not limited to, those used in combination with small molecule compounds and / or high molecular weight antibodies to treat cancer, inflammation, bone marrow-related diseases and autoimmune diseases, wherein the small molecule compounds and / or high molecular weight antibodies include 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-thymocrine-interstitial lymphocyte generating factor (TSLP) antibodies such as tezepelumab, and complement inhibitors.

[0025] The beneficial effects of the present invention relate to the use of a composition of the compound of formula (I) in a drug for treating and preventing diseases by cathepsin C and its downstream serine proteases NE, PR3, CaTG, and NSP4, wherein the disease is selected from respiratory diseases, metabolic diseases, cardiovascular diseases, autoimmune diseases, cancer, infectious diseases, or inflammatory infections.

[0026] The beneficial effect of the present invention is the aforementioned R 1 , R 2The present invention relates to a solvate, racemic mixture, enantiomer, diastereomer, tautomer, or mixture of any ratio thereof of a compound of formula (I), characterized in that Cy, A, B, X, Y, Z, and q each have substituents. [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. The optically pure form can be prepared by resolving the racemate or by using a chiral synthon or chiral reagent.

[0028] The compounds of the present invention may also include tautomer forms. Novel tautomer forms are generated when a single bond and an adjacent double bond are exchanged together through proton transfer.

[0029] The compounds of the present invention may contain all isotopic forms of atoms present in the intermediate or final compound. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

[0030] The present invention further comprises pharmaceutically acceptable salts of the compound of formula (I). A pharmaceutically acceptable salt refers to a derivative of the compound of formula (I) in which the parent compound is modified by converting the existing base portion to its salt form, or a derivative of the compound of formula (I) in which the parent compound is modified by converting the existing acid portion to its salt form.

[0031] Specifically, examples of pharmaceutically 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 pharmaceutically 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 a suitable 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 pharmaceutically acceptable salts further include solvates and hydrates. In general, solvates and hydrates are equivalent to non-solvates and non-hydrates, and both are within the scope of the present invention. Some compounds of the present invention may exist in multiple crystalline or amorphous forms. In short, all physical forms of the compounds are within the scope of the present invention.

[0033] The present invention further comprises prodrugs of compounds of formula (I). A prodrug is a pharmacological substance (i.e., a drug) derived from a parent drug, which, upon administration, is metabolized in the body to become the parent drug. Prodrugs can be prepared by substituting one or more functional groups present in the compound, where the substituents in the prodrug are thus removed in vivo to convert it back 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 ACSSymposium Series and Bioreversible. [Modes for carrying out the invention]

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

[0035] The present invention will be further described below with reference to examples, which are merely intended to illustrate preferred embodiments of the present invention in more detail and are not intended to limit the technical solutions of the present invention. All of the solutions of the present invention described above are technical solutions that can achieve the objectives of the present invention. The temperatures and reagents used in the following examples can all be replaced with the corresponding temperatures and reagents described above in order to achieve the objectives of the present invention.

[0036] Unless otherwise stated in the context, the following terms, collocations, and symbols used in this invention have the meanings described below.

[0037] A short horizontal line ("-") between two letters or symbols indicates a substituent linkage site. For example, -O(C 1-4 Alkyl) is a C atom linked to the rest of the molecule via an oxygen atom. 1-4 This refers to alkyl groups. However, the "-" may be omitted if the linking site of the substituent is obvious to those skilled in the art, for example, in the case of halogen substituents.

[0038] Unless otherwise specified, terms like "one" used refer to one or more people.

[0039] As used in this invention, the term "alkyl" refers to a linear or branched saturated hydrocarbon group containing 1 to 18 carbon atoms, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. For example, "C1-6 alkyl" is within the range of "alkyl" and represents an alkyl group having 1 to 6 carbon atoms as described above. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("n-Pr"), isopropyl ("i-Pr"), n-butyl ("n-Bu"), isobutyl ("i-Bu"), s-butyl ("sBu"), and t-butyl ("t-Bu").

[0040] As used in this invention, the term "alkenyl" refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds (C=C), for example, 1, 2, or 3 carbon-carbon double bonds, and containing 2 to 10 carbon atoms, for example, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, "C2-6 alkenyl" falls within the range of "alkenyl" and represents an alkenyl having 2 to 6 carbon atoms as described above. Examples of alkenyls include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl.

[0041] As used in this invention, the term "alkynyl" refers to a linear or branched hydrocarbon group containing one or more, for example, one, two, or three carbon-carbon triple bonds (C≡C), and 2 to 10 carbon atoms, for example, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, "C 2-6 "Alkynyl" refers to an alkynyl molecule that contains one carbon-carbon triple bond (C≡C) and has 2 to 6 carbon atoms. Examples of alkynyls include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.

[0042] In this invention, the term "halo" refers to fluoro, chloro, bromo, and iodine, while "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0043] As used in this invention, the term "haloalkyl" refers to an alkyl group as defined in this invention in which one or more hydrogen atoms, for example, 1, 2, 3, 4, or 5 hydrogen atoms, are substituted with halogen atoms, and if more than one hydrogen atom is substituted with a halogen atom, the halogen atoms may be the same or different. In one embodiment, the term "haloalkyl" as used in this invention refers to an alkyl group as defined in this invention in which two or more hydrogen atoms, for example, 2, 3, 4, or 5 hydrogen atoms, are substituted with halogen atoms, and the halogen atoms are the same. In another embodiment, the term "haloalkyl" as used in this invention refers to an alkyl group as defined in this invention in which two or more hydrogen atoms, for example, 2, 3, 4, or 5 hydrogen atoms, are substituted with halogen atoms, and the halogen atoms are different. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2CF3, etc.

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

[0045] As used in this invention, the term "cycloalkyl" 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, or 3 to 6 ring carbon atoms, and may have one or more rings, for example, one or two rings. For example, "C3-8 cycloalkyl" refers to the cycloalkyl group having 3 to 8 ring carbon atoms as described above. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and similar groups.

[0046] As used in this invention, the terms "heterocyclyl" or "heterocyclic" mean a ring selected from 4-12 member monocyclic, bicyclic, and tricyclic, saturated and partially unsaturated rings, comprising, for example, at least one heteroatom selected from O, S, and N, for example, 1 to 4 heteroatoms, further for example, 1 to 3, or further for example, 1 or 2 heteroatoms plus at least one carbon atom. The linkage of a heterocyclyl may be on a heteroatom or 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 a fused ring, a fused ring in which at least one ring contains at least one heteroatom selected from O, S, and N, and none of the other rings are heteroaryl or aryl, and the linkage may be on a heterocyclic ring or on another ring.

[0047] As used in this invention, the term "cycloalkoxy" refers to an -O-cycloalkyl group, where the definition of cycloalkyl is as described above. Examples of cycloalkoxys include, but are not limited to, cyclopropyloxy, cyclobutyloxy, and their isomers.

[0048] As used in this invention, the term "heterocycloalkoxy" refers to an -O-heterocycloalkyl group, where the definition of heterocycloalkyl is as described above. Examples of cycloalkoxys include, but are not limited to, azelidyloxy, epoxypropanoxy, azetidinyloxy, oxetanyloxy, and their isomers.

[0049] The "cycloalkenyl" described in the present invention refers to a non-aromatic cyclic hydroxyl molecule containing one or more, for example, one, two, or three carbon-carbon double bonds and 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 1 or 2 rings. For example, C 3-8 A cycloalkenyl having a ring carbon atom, preferably "C 3-6A "cycloalkenyl" is a cycloalkenyl having 3 to 6 ring carbon atoms as described above. Examples of cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0050] The "heterocycloalkenyl" described in this invention refers to a "cycloalkenyl" in which one or more carbon atoms are substituted with N, O, or S. For example, C 3-8 It is a heterocycloalkenyl ring atom, preferably "C 3-6 "Heterocycloalkenyls" are heterocycloalkenyls having 3 to 6 ring atoms as described above. Examples of heterocycloalkenyls include, but are not limited to, azetidinyl, oxetenyl, azetanyl, oxolinyl, and oxetenyl.

[0051] As used in this invention, the term "aryl" refers, unless otherwise explicitly defined, to a carbocyclic hydrocarbon group comprising 6 to 14 ring carbon atoms, for example, 6 to 12 ring carbon atoms, formed by the fusion of one or more rings, where at least one ring is an aromatic ring, and the other ring is not a heteroaryl as defined below, and its linkage may be on an aromatic ring or another ring. Examples of aryls include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetralinyl, indenyl, indanyl, and azlenyl, with phenyl and naphthyl being preferred. As used in this invention, "aryl" or "aromatic" conforms to Huckel's rule, where the number of π electrons is equal to 4n+2, and n is any positive integer from 0 to 6.

[0052] As used in this invention, the terms "heterocyclyl" or "heterocyclic" mean a ring selected from 4-12 member monocyclic, bicyclic, and tricyclic, saturated and partially unsaturated rings, comprising, for example, at least one heteroatom selected from O, S, and N, for example, 1 to 4 heteroatoms, further for example, 1 to 3, or further for example, 1 or 2 heteroatoms plus at least one carbon atom. The linkage of a heterocyclyl may be on a heteroatom or 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 a fused ring, a fused ring in which at least one ring contains at least one heteroatom selected from O, S, and N, and none of the other rings are heteroaryl or aryl, and the linkage may be on a heterocyclic ring or on another ring.

[0053] As used in this invention, the term "heteroaryl" refers, unless otherwise explicitly defined, to a monocyclic aromatic hydrocarbon group having 5, 6, or 7 ring atoms, for example 6, and containing one or more ring heteroatoms independently selected from N, O, and S (e.g., N), for example 1, 2, or 3, for example 1 or 2, with the remaining ring atoms being carbon atoms, and a dicyclic aromatic hydrocarbon group having 8 to 12 ring atoms, for example 9 or 10, and containing one or more ring heteroatoms independently selected from N, O, and S (e.g., N), for example 1, 2, 3, or 4, for example 1 or 2, with the remaining ring atoms being carbon atoms, and at least one ring being an aromatic ring. For example, a dicyclic heteroaryl includes a 5-6 membered heteroaryl ring fused with a 5-6 membered cycloalkyl ring, a heterocyclyl ring, or an aryl ring, where the linkage can be at the heteroaryl ring or the cycloalkyl / heterocyclyl / 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. Heteroaryls also include heteroaryls in which the N-ring heteroatom is in the form of an N-oxide, such as N-pyrimidinyl oxide. In some embodiments, the ring heteroatom in the above heteroaryl is an N atom, and such heteroaryls are called "nitrogen-containing heteroaryls." Nitrogen-containing heteroaryls also include heteroaryls in which the N-ring heteroatom is in the form of an N-oxide, such as N-pyridyl oxide.

[0054] Examples of heteroaryls include pyridyl, N-pyridyloxide, pyrazolyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazoyl, tetrazolyl, triazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyridadinyl, benzo[d]thiazolyl, benzom-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, 4) Includes, but is not limited to, triazolo[4,3-a]pyridyl and [1,2,4]triazolo[1,5-a]pyridyl, indazolyl, 2H-indazolyl, pyrrolopyrimidinyl, e.g., pyrrolo[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrazolopyrimidinyl, e.g., pyrazolo[1,5-a]pyrimidinyl, tetrazolopyrimyl, e.g., tetrazolo[1,5-a]pyridyl, benzothienyl, benzofuryl, benzimidazolinyl, indolyl, indolinyl, prinyl, e.g., 9H-prinyl and 7H-prinyl.

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

[0056] In this invention, the term "hydroxy" refers to the -OH group.

[0057] In this invention, the term "sulfhydryl" refers to the -SH group.

[0058] In this invention, the term "oxo" refers to the =O group.

[0059] In this invention, the term "carboxy" refers to the -C(O)-OH group.

[0060] In this invention, the term "cyano" refers to the -CN group.

[0061] In this invention, the term "amino" refers to the -NH2 group.

[0062] In this invention, the terms "group" and "-yl" are synonymous and are used to represent a functional group or molecular fragment that can be linked to other molecular fragments.

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

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

[0065] As used in this invention, the term “selective” means that the substitutions, events, or situations described below may occur once or multiple times, or not at all, and the description includes cases where such substitutions occur and cases where they do not. For example, “selectively substituted alkyl” includes “unsubstituted alkyl” and “substituted alkyl” as defined in this invention. Those skilled in the art will understand that for any group containing one or more substituents, the group does not contain any substitutions that are spatially impractical, chemically inaccurate, synthetically impossible, and / or intrinsically unstable.

[0066] The term "including, but not limited to," as used in this invention, means that the groups listed in the selection are preferred, but other groups may also be used.

[0067] As used in this invention, the terms “substituted” or “substituted with…” mean that one or more hydrogen atoms on the indicated atom or group are substituted with one or more substituents selected from the group consisting of the indicated substituents, provided that the valence of the atom 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 substituted with oxygen. Such combinations are permissible only if the combination of substituents and / or variables results in a chemically accurate and stable compound. A chemically accurate and stable compound means that it is stable enough that it can be separated from the reaction mixture, its chemical structure can be determined, and it can be formulated as a formulation with at least practical utility.

[0068] Unless otherwise specified, substituents are named in relation to the core structure. For example, if (cycloalkyl)alkyl is listed as a possible substituent, it should be understood that the linkage point of this substituent to the core structure is at the alkyl portion.

[0069] As used in this invention, the term "substituted with one or more substituents" means that one or more hydrogen atoms of the indicated atom or group are independently substituted 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 substituted with one, two, three, or four substituents selected independently from the indicated group.

[0070] Those skilled in the art will understand that some of the compounds of formula (I) may contain one or more chiral centers and therefore exist in two or more stereoisomers. Racemic mixtures of these isomers, mixtures enriched in individual isomers and certain enantiomers, as well as diastereomers containing two chiral centers, and mixtures partially enriched in certain diastereomers are within the scope of the present invention. Furthermore, those skilled in the art will understand that the present invention includes all individual stereoisomers (e.g., enantiomers), racemic mixtures or partially divided 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 with various stereoisomeric purities, i.e., diastereomeric purities or enantiomeric purities, expressed as various "ee" or "de" values. In some embodiments, the compound of formula (I) (for example, 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 enumerated values). In some embodiments, the compound of formula (I) (for example, as described in the present invention) has an enantiomeric purity greater than 99.9% ee, up to 100% ee. In some embodiments, the compound of formula (I) (for example, as described in the present invention) has a diastereomer 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 those enumerated values). In some embodiments, the compound of formula (I) (for example, as described in the present invention) has a diastereomer purity greater than 99.9%de.

[0072] The term "enantiomer excess" or "ee" indicates how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the enantiomer excess percentage 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 the optical rotation of chiral substances, the enantiomer excess percentage 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 “diastereomer excess” or “de” indicates how much of one diastereomer is present compared to the other, and is defined similarly to the enantiomer excess rate. Thus, in the case of a mixture of diastereomers D1 and D2, the diastereomer excess percentage is defined as |D1-D2|*100, where D1 and D2 are the moles or weight fractions of each diastereomer in the mixture such that D1+D2=1.

[0074] The diastereomer and / or enantiomer excess can be measured using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, and / or optical rotation measurement, and is achieved according to established protocols well known to those skilled in the art.

[0075] Racemic mixtures can be used as is, or they can be separated into their individual isomers for use. Separation yields stereochemically pure compounds or mixtures enriched with 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 diastereomer salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamhoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing these salts, then liberating one or both of the separated bases, and repeating this process to obtain one or both of the desired stereoisomers in a form that is substantially free of the other, i.e., with an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight. Alternatively, as is known to those skilled in the art, diastereomers can be obtained by covalently linking a racemic mixture with a chiral compound (auxiliary group), separating them by chromatography or fractional crystallization, and then chemically removing the chiral auxiliary group to obtain the pure enantiomers.

[0076] The “pharmaceutically acceptable salt” as described in this invention means a salt of the free form of the acid or base of the compound of formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject.

[0077] "Pharmacologically acceptable salts" include acid addition salts of the compound of formula (I) with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc., and acid addition salts of the compound of formula (I) with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, mesylate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and formula HOOC-(CH2) nThis includes, but is not limited to, salts of -COOH (where n is 0 to 4) with alkanedicarboxylic acids. "Pharmacologically acceptable salts" also include base addition salts of the compound of formula (I) having an acidic group with a pharmaceutically acceptable cation, 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 salts includes, but is not limited to, 1:1, 1:2, 1:3, and 1:4.

[0078] The “prodrug” as described in this invention refers to a pharmacological substance (i.e., a drug) derived from a parent drug, which, upon administration, is metabolized in the body to become the parent drug. Prodrugs can be prepared by substituting one or more functional groups present in the compound, where the substituents in the prodrug are thus removed in vivo to convert it back 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 ACSSymposium Series and Bioreversible. “Prodrugs” include, but are not limited to, esters of the compound of formula (I), such as phosphate esters, formate esters, and carbamates, and amides such as formamide and acetamide.

[0079] Furthermore, when the compound described in the present invention is obtained as an acid addition salt, the free base can be obtained by making the solution of the acid addition salt basic. Conversely, when the product is a free base, the acid addition salt, in particular a pharmaceutically acceptable acid addition salt, can be produced by dissolving the free base in a suitable solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to produce non-toxic, pharmaceutically acceptable acid addition salts without excessive experimentation.

[0080] The term "solvate" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to capture solvent molecules in a certain molar ratio in the solid state, thereby forming solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one or more molecules of water and one molecule of the substance, with the water maintaining its molecular state as H2O. Such combinations can form one or more hydrates, such as hemihydrates, monohydrates, and dihydrates, as well as various other hydrates.

[0081] In this invention, the terms "group" and "-yl" are synonymous and are used to represent a functional group or molecular fragment that can be linked to other molecular fragments.

[0082] The term “active ingredient” is used to refer to a chemical substance that has biological activity. In some embodiments, the “active ingredient” is a chemical substance that has pharmaceutical utility. In the United States, practical drug activity can be established by appropriate preclinical assays, whether in vitro or in vivo. Drug activity sufficient to be approved by a regulatory authority (e.g., the FDA in the United States) is a higher standard than that of preclinical assays. For such higher standard drug activity, success is generally not reasonably predictable from preclinical results, but can be established by appropriate and successful randomized, double-blind, controlled clinical trials in humans.

[0083] The terms “treatment” or “therapy” of a disease or disorder mean administering one or more active pharmaceutical ingredients, in particular a compound of formula (I) described in the present invention and / or a pharmaceutically acceptable salt thereof, to a subject (e.g., a human) having the disease or disorder, or symptoms of the disease or disorder, or a predisposition to the disease or disorder, for the purpose of curing, restoring, alleviating, reducing, altering, correcting, modifying, improving, or influencing the disease or disorder, the symptoms of the disease or disorder, or the predisposition to the disease or disorder, in a situation in which a beneficial therapeutic effect is achieved. In some embodiments, the disease or disorder is cancer.

[0084] In relation to chemical reactions, the terms “process,” “contact,” and “react” mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or desired product. Naturally, the reaction producing the indicated and / or desired product does not necessarily have to result directly from the combination of the two reagents initially added; rather, there may be one or more intermediates formed in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0085] As used in this invention, the term "effective dose" refers to an amount or dosage of a cathepsin C inhibitor sufficient to generally provide a therapeutic benefit to a patient requiring treatment for a disease or disorder mediated by cathepsin C and its downstream serine protease activity. The effective dose or dosage of the active ingredient in this invention may be determined by common methods (e.g., modeling, dose escalation studies, or clinical trials) and by considering 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 therapies of the subject, the subject's health status and response to the drug, and the judgment of the attending physician). In the United States, determining the effective dose is generally difficult to predict from preclinical studies. In fact, doses are not entirely predictable, and doses will develop into new, unpredictable dosing plans after initial use in randomized, double-blind, controlled clinical trials.

[0086] Exemplary doses are approximately 0.0001 to 200 mg of the active drug per kg of body weight per day, for example, in the range of approximately 0.001 to 100 mg / kg / day, or approximately 0.01 to 35 mg / kg / day, or approximately 0.1 to 10 mg / kg, administered once daily or in divided dose units (e.g., twice, three, or four times per day). For a 70 kg person, the preferred dose range is approximately 0.05 to 7 g / day, or approximately 0.2 to 5 g / day. Once improvement in the patient's disease or disorder is observed, the dose can be adjusted to maintain treatment. For example, the dose, frequency of administration, or both can be reduced to a level that maintains the desired therapeutic effect, depending on changes in symptoms. Naturally, treatment may be discontinued once symptoms have subsided to an appropriate level. However, patients may require intermittent treatment over a long period when symptoms recur.

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

[0088] As used in this invention, the term "subject" refers to mammals and non-mammals. Mammals refer to all members of the class Mammalia, and include, but are not limited to, humans, non-human primates such as chimpanzees, other apes and monkeys, farm animals such as cattle, horses, sheep, goats and pigs, domestic animals such as rabbits, dogs and cats, and laboratory animals such as rodents such as rats, mice and guinea pigs. Examples of non-mammals include, but are not limited to, birds. The term "subject" does not limit to a specific age or sex. In some embodiments, the subject is human.

[0089] Generally, the term "approximately" is used in this invention to adjust the given numerical value to within 20% above or below that value.

[0090] The general synthesis method for the compound 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 under basic conditions (e.g., using N,N-diisopropylethylamine as a base) with 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), and reacts with aqueous ammonia to obtain the compound of formula III. The deprotection product of the compound of formula III, the compound of formula IV, and the acid of the compound of formula V are obtained to obtain the amide compound of formula VI by a method reported in the general literature, for example, using N,N-diisopropylethylamine as a base and HATU or HBTU as the activating reagent.

[0092] The compound of formula VI and the borate compound of formula VIII are subjected to a Suzuki coupling reaction, and the compound of formula IX is obtained using a palladium catalyst such as dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium in a suitable solvent such as dioxane and a suitable base such as potassium acetate.

[0093] Another scheme involves converting the compound of formula VI to the borate compound of formula VII. The compound of formula VI and bispinacolate diborone are reacted in dimethyl sulfoxide under the catalysis of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, with potassium acetate as the base, to obtain the borate compound of formula VII. The compound of formula XI and the borate compound of formula VII are subjected to a Suzuki coupling reaction, and the compound of formula IX is obtained using a palladium catalyst such as dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, in a suitable solvent such as dioxane, and with a suitable base such as potassium acetate.

[0094] The amide of compound IX can be dehydrated with N-(triethylammonium sulfonyl)methylcarbamate in dichloromethane to obtain compound X. Deprotection of compound X yields the final product, compound I.

[0095] A compound of formula (I) described in the present invention (e.g., any compound in the present invention) and / or a pharmaceutically acceptable salt thereof can be prepared in a drug composition, either alone or in combination with one or more other active ingredients. The drug composition comprises (a) an effective amount of a compound of formula (I) described in the present invention and / or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0096] A pharmaceutically acceptable carrier is one that is compatible with the active ingredient in the composition (and in some embodiments can stabilize the active ingredient) and is not harmful to the target being treated. For example, solubilizers such as cyclodextrin (which form certain more soluble complexes with the compound of formula (I) described in the present invention and / or its pharmaceutically acceptable salts) can be used as pharmaceutical excipients for the delivery of the active ingredient. Other examples of carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and dyes such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are disclosed in the standard reference text of the art (Remington's Pharmaceutical Sciences, A. Osol).

[0097] A drug composition comprising a compound of formula (I) described in the present invention (for example, any compound described in the present invention) and / or a pharmaceutically acceptable salt thereof may be administered in various known modes, such as orally, topically, rectally, parenterally, by inhalation, or implantation. As used in the present invention, the term "parenterally" includes injection or infusion subcutaneously, intradermally, intravenously, intramuscularly, intra-arterially, intra-arterially, intra-sacrally, intrasternally, intra-spinally, intra-focally, and intracranially.

[0098] The drug compositions described in the present invention can be prepared in the form of tablets, capsules, sachets, sugar-coated tablets, powders, granules, lozenges, reconstituted powders, liquid formulations, or suppositories. In some embodiments, drug compositions comprising the compound of formula (I) and / or a pharmaceutically acceptable salt thereof 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. Common carriers for tablets include lactose and corn starch. Lubricants such as magnesium stearate are also commonly included in tablets. For oral administration in capsule form, lactose and dried corn starch are included as useful diluents. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oil phase combined with an emulsifier or suspending agent. Specific sweeteners, flavorings, or colorants may be added as desired.

[0100] In some embodiments, the compound of formula (I) and / or a pharmaceutically acceptable salt 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 a pharmaceutically acceptable salt 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 may be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Suitable pharmaceutically acceptable carriers and solvents include, in particular, mannitol, water, Ringer's solution, and isotonic sodium chloride solutions. In addition, sterile hydrogenated oils (e.g., synthetic monoglycerides or diglycerides) are also conventionally used as solvents or suspensions. Fatty acids, such as oleic acid and its glyceride derivatives, and naturally pharmaceutically acceptable oils such as olive oil or castor oil (especially their polyoxyethylated forms) are useful for injectable intermediates. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants.

[0102] Inhalation compositions can be prepared in accordance with well-known techniques in the field of pharmaceutical formulations, using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art, and can also be prepared as a solution in physiological saline.

[0103] Topical compositions can be formulated in the form of oils, creams, lotions, and ointments. Suitable carriers for these compositions include vegetable oils 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, pharmaceutically acceptable carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included, optionally, along with agents that impart color or fragrance. In addition, transdermal penetration enhancers may be used in these topical formulations. Examples of such enhancers can be found in U.S. Patents US No. 3,989,816 and 4,444,762.

[0104] The cream may be formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, to which a small amount of active ingredients dissolved in an oil, such as tonsil oil, is mixed. 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 tonsil oil. The ointment may be formulated by mixing a solution of the active ingredients in a vegetable oil, such as tonsil oil, with warm soft paraffin, and then cooling the mixture. An example of such an ointment contains about 30% by weight of tonsil oil and about 70% by weight of white soft paraffin.

[0105] Suitable in vitro assays are available to evaluate the substantial utility of the compound of formula (I) and / or its pharmaceutically acceptable salt described herein in inhibiting the activity of cathepsin C. The compound of formula (I) and / or its pharmaceutically acceptable salt described herein can also be further evaluated by in vivo assays for further substantial utility in treating lung diseases, inflammatory diseases, metabolic diseases, infections, cardiovascular diseases, or autoimmune diseases. For example, the compound of formula (I) and / or its pharmaceutically acceptable salt described herein can be administered to animals (e.g., mouse models) with lung diseases, inflammatory diseases, metabolic diseases, infections, cardiovascular diseases, cancer, or autoimmune diseases, and their therapeutic effects can be evaluated. If preclinical results are favorable, dose ranges and routes of administration for animals such as humans can be further planned. Alternatively, the effects in lung diseases for which there are no validated disease models, such as bronchiectasis, can be predicted by administering the compound to non-disease model animals (e.g., rats) and evaluating the inhibitory effect on serine proteases downstream of cathepsin C.

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

[0107] The term "lung disease" refers to pathological conditions related to the lung organs. Non-exclusive 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 that cause inflammation, particularly those caused by neutrophil chemotaxis. Non-exclusive examples of such diseases include inflammatory skin diseases (psoriasis and atopic dermatitis); systemic sclerosis and sclerosis; responses associated with inflammatory bowel disease (IBD) (e.g., Crohn's disease and ulcerative colitis); surgical tissue reperfusion injury, as well as ischemic reperfusion injury including myocardial infarction, cardiac arrest and other myocardial ischemia, reperfusion after cardiac surgery and abnormal coronary vasoconstriction after percutaneous transluminal coronary angioplasty, stroke and tissue reperfusion injury during abdominal aortic aneurysm surgery; and cerebral edema following stroke. Swelling; cranial trauma; hypovolemic shock; asphyxiation; adult respiratory distress syndrome; acute lung injury; Behçet's disease; dermatomyositis; polymyositis; autoimmune diseases such as rheumatoid arthritis (RA); inflammation of the lung including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitive pneumonia, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis; and other inflammations such as ANCA-associated inflammation and necrotizing crescent glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies.

[0109] The compounds of formula (I) and / or pharmaceutically acceptable salts described in the present invention can be used, for example, to achieve beneficial therapeutic or preventive effects in subjects with metabolic diseases, infections, cardiovascular diseases, cancer, and autoimmune diseases.

[0110] The term "autoimmune disease" refers to a disease or condition caused by damage to the body's own tissues or organs due to the body's immune response to its own antigens. 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 myelofibrosis, postpolycythemia vera / essential thrombocytosis myelofibrosis (PV / ET), and other myeloproliferative disorders.

[0111] The term "metabolic disease" refers to diseases caused by metabolic disorders or diseases related to metabolism, and non-exclusive examples include non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, AATD, obesity, diabetes, etc.

[0112] The term "infectious disease" refers to a pathological condition caused by infection with viruses, bacteria, parasites, etc. Non-specific examples of such diseases include leishmaniasis, COVID-19 pneumonia, and sepsis.

[0113] The term "cardiovascular disease" refers to diseases related to the cardiovascular system and brain organs. Non-exclusive examples of such diseases include ischemia-reperfusion injury, acute brain injury, heart failure, myocarditis, and myocardial infarction.

[0114] As used in this invention, the term "cancer" refers to a cytotoxicity characterized by uncontrolled or dysregulated cell proliferation, impaired cell differentiation, inappropriate ability to invade surrounding tissues, and / or the ability to establish new proliferation 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 cancers 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, compounds of formula (I) described in the present invention (e.g., any compound in the present invention) and / or pharmaceutically acceptable salts thereof may be used in combination with additional active ingredients in the treatment of respiratory diseases, inflammatory or autoimmune diseases and cancer. Additional active ingredients may be administered separately from compounds of formula (I) described in the present invention and / or pharmaceutically acceptable salts thereof, or may be included together with such ingredients in a drug composition in accordance with the present disclosure, such as a fixed-dose combination drug product. In exemplary embodiments, additional active ingredients are 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. This combination may enhance efficacy (for example, by including a combination of compounds that enhance the potency or effectiveness of the compound of formula (I) described in the present invention and / or a pharmaceutically acceptable salt thereof), reduce one or more side effects, or reduce the required dose of the compound of formula (I) described in the present invention and / or a pharmaceutically acceptable salt thereof. [Examples]

[0117] The following examples are illustrative and should not be considered limiting in any way. Unless otherwise specified, parts are in parts by weight, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure. All data were measured using Agilent 6120 and / or 1100. Except for the synthesized intermediates, all reagents used in this invention are commercially available. Except for the reagents, all compound names were prepared using ChemDraw 20.0.

[0118] The following abbreviations are used.

[0119] ACN Acetonitrile Boc t-Butoxycarbonyl (Boc)2O di-t-butyl pyrocarbonate BH3 Volan 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 hexaful Olophosfete HBTU O-benzotriazole-tetramethyluronium Hexafluorophosphate HOAc Acetic acid HOBt 1-Hydroxybenzotriazole ee Enantiomer excess mL milliliter g Grams mg milligrams ng Nanogram mol Mole mmol Millimol h time MeOH methanol NaH Hydrogenated sodium NCS N-chlorosuccinimide NMP N-methyl-2-pyrrolidone PE Petroleum ether Pd(dppf)2Cl2 dichloro[1,1'-bis(diphenylphosphate] [Fino)ferrocene]palladium Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium Pd(PPh3)4Tetrakis(triphenylphosphine)palladium PMB p-methoxybenzyl PPh3 Triphenylphosphine Pin2B2 Screw (Pinacolato) Diboron THF Tetrahydrofuran TFA Trifluoroacetic acid TsOH 4-methylbenzenesulfonic acid Xphos 2-Dicyclohexylphosphino-2',4', 6'-Triisopropylbiphenyl Burgess Reagents N-(triethylammonium sulfonyl) Methylcarbamate

[0120] 1. Intermediate 1 [ka]

[0121] a) At room temperature and under nitrogen protection, a solution of compound 2-amino-4-bromophenol (20.0 g, 106.4 mmol) in 2-MeTHF (300 mL) was mixed with CDI (20.7 g, 127.7 mmol), refluxed for 1 hour, cooled to room temperature, and sequentially washed with 2 M HCl (aqueous solution) (300 mL), 8% NaHCO3 (aqueous solution) (300 mL), and saturated saline (150 mL). The mixture was 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 and under nitrogen protection, a solution of compound 1a (1.0 g, 4.7 mmol) in DMF (15.0 mL) was sequentially added to 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 sieve (200 mg, dry powder). The mixture was then heated to 70°C and stirred for 6 hours. After cooling to room temperature, the molecular sieve was filtered off, washed with EA (50 mL), further diluted with EA (100 mL), washed with saturated saline solution (50 mL x 5), dried over Na2SO4, concentrated, and the crude product was obtained. The crude product was purified by preparative HPLC (using TFA as buffer, A being a 0.05% TFA aqueous solution and B being a 0.05% TFA acetonitrile solution; the chromatographic column was WatersXBridgePeptideBEHC18, 19×250 mm, 10 μm, 130A) to obtain 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) At room temperature, 1a (1.0 g, 4.7 mmol) and formaldehyde (37% aqueous solution, 610 μL) were added to water (5 mL). The reaction mixture was stirred overnight at 80°C, then cooled to room temperature, filtered, washed with water (3 × 10 mL), and the resulting crude product was vacuum-dried to obtain 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) At -50°C under nitrogen protection, DAST (265 μL, 2.0 mmol) was added dropwise to a solution of 2a (312 mg, 1.3 mmol) of dichloromethane (5 mL). After the addition was complete, the reaction mixture was gradually heated to room temperature and stirred overnight. Then, it was quenched with saturated NaHCO3 (10 mL), extracted with dichloromethane, washed with saturated saline (10 mL), dried over Na2SO4, concentrated to obtain 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, compound 2-amino-4-bromophenol (1.0 g, 5.3 mmol) and compound 3-oxetanone (764 mg, 10.6 mmol) were dissolved in dry THF (15.0 mL). Under ice cooling, BH3·THF (1 M, 5.3 mL) was gradually added dropwise. After the addition was complete, the reaction mixture was raised to room temperature and stirred for 6 hours. Then, compound 3-oxetanone (764 mg, 10.6 mmol) and BH3·THF (1 M, 5.3 mL) were added and stirred overnight. The reaction mixture was cooled on ice, and excess BH3 was quenched by gradually adding aqueous NaOH solution (1 M, 20 mL). The organic phase was separated, Na2SO4 was dried, and the mixture was concentrated to obtain the crude product. Column chromatography purification (eluent DCM / MeOH = 50 / 1) yielded 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 and under nitrogen protection, compound 3a (603 mg, 2.5 mmol) was dissolved in 2-MeTHF (10 mL) and CDI (535 mg, 3.3 mmol) was added. After heating under reflux for 1 hour, the reaction mixture was cooled to room temperature and sequentially washed with 2 M HCl (aqueous solution) (15 mL), 8% NaHCO3 (aqueous solution) (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 = 10:1~2:1, V / V) yielded a 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. Intermediate products 4 and 5 [ka]

[0130] a) At 0°C under nitrogen protection, Cs2CO3 (1.6 g, 5.1 mmol) and MeI (658 μL, 10.2 mmol) from DMF (15 mL) were sequentially added to a solution of 1a (1.1 g, 5.1 mmol) in DMF (15 mL). The mixture was heated to room temperature and stirred overnight. It was cooled to 0°C, and water (15 mL) was added dropwise. The mixture was filtered, washed with water, and vacuum-dried at 55°C to obtain 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 argon protection, 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), heated to 75°C, and stirred for 1 hour. After cooling to room temperature, the mixture was filtered and the solid was washed with EA (3 × 5 mL). The filtrate was concentrated and purified by column chromatography (eluent PE / DCM = 0%~100%, V / V) to obtain the gray 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. Intermediate products 6 and 7 [ka]

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

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

[0135] c) At room temperature, 20 mL of TFA was added to a 60 mL solution of 6b (crude product 4 g, approximately 14 mmol) in dichloromethane, and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure, and the solvent and TFA were removed. The resulting residue was dissolved in 100 mL of dichloromethane and spin-dried again. The crude product was dissolved in 10 mL of MeOH, 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 aqueous solution) to obtain a pale white solid 6c (1.75 g, 31% yield in 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 with MeOH (120 mL) and EtOH (120 mL) and refluxed overnight. After cooling to room temperature, the crude product was obtained by spin drying. Column chromatography purification (eluent DCM:MeOH = 20:1 to 15:1, Rf = 0.2 for DCM / MeOH 20 / 1 solution) yielded a light brown solid product 6d (680 mg, 53%). MS (ESI): m / z = 140.1 [M + H] + .

[0137] e) At 0°C, Br2 (300 uL, 5.85 mmol) was gradually added dropwise to 6d (745 mg, 5.36 mmol) in an AcOH (10 mL) / H2O (10 mL) solution, and the mixture was stirred for 2 hours. Then, 10% Na2SO3 (20 mL) and saturated NaHCO3 were added sequentially to adjust the pH to 7. The solution was extracted with EA (3 × 50 ml), dried, and concentrated to obtain a pale white solid 6 (1.09 g, 93%). MS (ESI): m / z = 218.2 [M + H] + . 1 HNMR (400MHz, CD3OD): δ7.29 (s, 1H), 4.39 (s, 2H).

[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 10 mL of DMF. After stirring for 30 minutes, MeI (205 μL, 3.29 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with H₂O (100 mL), neutralized to pH 7 with saturated NH₄Cl solution, extracted with EA (50 mL x 3), dried over Na₂SO₄, concentrated, and the crude product was obtained. By column chromatography purification (EA:PE = 2:1 ~ EA, Rf = 0.5 for EA), a light brown solid 7 (400 mg, 62%) was obtained. 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), and then 70 mL of aqueous NaNO2 (12 g, 173.9 mmol) was added dropwise. After stirring for 40 minutes, 70 mL of aqueous KI (57.73 g, 347.8 mmol) was added dropwise, and stirring continued for 1 hour. The reaction was quenched with saturated Na2SO3 (200 mL) and extracted with EA (3 × 500 mL). The mixture was dried over Na2SO4, concentrated, and the crude product was obtained. Purification by column chromatography (eluent PE / EA = 10:1, V / V) yielded the 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) At -70℃, in a solution of 8a (11g, 32.3 mmol) and 3-oxoazetidine-1-carboxylate t-butyl (6.08g, 35.5 mmol) in THF (230 mL), i PrMgCl-LiCl (27.3 ml, 35.5 mmol, 1.3 mol / L in THF) was gradually added dropwise, and the mixture was stirred for 30 minutes. The dry ice bath was removed, the mixture was heated to room temperature, and the mixture was stirred for 1 hour. The reaction mixture was quenched with saturated NaHCO3 (200 mL) aqueous solution and extracted with EA (3 × 500 mL). The mixture was dried over Na2SO4, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 10:1, V / V) yielded a 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) At room temperature, 2 mL of TFA was added to a solution of 8b (0.8 g, 2.35 mmol) in dichloromethane (20 mL). After stirring for 7 hours, the mixture was concentrated under reduced pressure to obtain 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 the mixture was stirred for 1 hour. Then, NaBH(OAc)3 (600 mg, 2.82 mmol) was added, and the mixture was stirred for another 30 minutes. This step was repeated 9 times, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, saturated NaHCO3 (150 mL) was added to the residue, and the mixture was extracted with EA (3 × 200 mL). The mixture was dried over Na2SO4, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 3:1 to 1:1, V / V) yielded a 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) At room temperature, LiBH4 (1.49 g, 67.8 mmol) in THF (100 mL) was added to a solution of 8b (6 g, 16.9 mmol) in THF (100 mL). After stirring for 24 hours, the reaction mixture was quenched with water (200 mL), extracted with EA (3 × 500 mL), dried over Na₂SO₄, concentrated to obtain crude product 9a. Purification by preparative HPLC (using aqueous NH₄HCO₃ as buffer, A being 10 mM aqueous NH₄HCO₃, B being acetonitrile, and a Waters XBridge Peptide BEH C18 column, 19 × 250 mm, 10 μm, 130 A) yielded a 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 multiple 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 minutes, the temperature was raised to room temperature and stirring continued for 48 hours. The mixture was concentrated under reduced pressure, water (200 mL) was added, and the mixture was extracted with EA (3 × 200 mL). The mixture was dried over Na₂SO₄, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 5:1, V / V) yielded a 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) At room temperature, TFA (3 mL) was added dropwise to a solution of 9b (1 g, 2.95 mmol) in dichloromethane (20 mL). After stirring for 3 hours, the mixture was concentrated under reduced pressure to obtain 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 the mixture was stirred for 1 hour. Then, NaBH(OAc)3 (629 mg, 2.97 mmol) was added, and the mixture was stirred for another 30 minutes. This step was repeated 9 times, and the reaction mixture was stirred overnight. The mixture was concentrated under reduced pressure, saturated NaHCO3 (200 mL) was added, and the mixture was extracted with EA (3 × 200 mL). The mixture was dried over Na2SO4, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 2:1 to 1:1, V / V) yielded a 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) At 70°C, AIBN (840 mg, 5.1 mmol) was added to a suspension of 2-methylthiophene-3-carboxylate methyl ester (8 g, 51.3 mmol) / NBS (9.1 g, 51.1 mmol) in carbon tetrachloride (120 mL). The reaction mixture was stirred at 70°C for 4 hours. 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 obtain a light brown oily crude product 10a (13 g). This crude product was used directly in the next step. MS(ESI): m / z = 155.4 [M-Br] + .

[0150] b) A 7N NH3 (30 mL, 210 mmol) MeOH solution was added to 10a (crude product 13 g, approximately 51.3 mmol) in a THF (100 mL) solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, and the remaining light brown solid was washed with EA / MeOH 10 / 1 (50 mL). The mixture was filtered to obtain a white solid 10b (3.5 g, yield 39%). 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) A solution of 10b (3.3g, 19.3 mmol) / K2CO3 (2.66g, 19.3 mmol) in MeOH (120 mL) was refluxed for 24 hours. The reaction mixture was then cooled to room temperature and evaporated. The residue was separated by silica gel chromatography (DCM:MeOH = 20:1, Rf = 0.5 for DCM / MeOH 20 / 1) and purified to obtain 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 μL, 6.24 mmol) was added to a 10c (0.86 g, 6.19 mmol) AcOH (10 mL) / H2O (10 mL) solution. The reaction mixture was then stirred at 0°C for 1 hour. Br2 (40 μL, 0.78 mmol) was added again to the reaction mixture, and the mixture was stirred again at 0°C for 1 hour. 10% Na2SO3 (20 mL) was added to the reaction mixture until it became colorless, then saturated NaHCO3 was added until the pH reached 7, and the mixture was 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 obtain 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, THF solution, 20 mL, 40 mmol) was added to 10a (crude product 3 g, approximately 11.54 mmol) in THF (20 mL) solution. The reaction mixture was stirred at room temperature for 2 hours. 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 obtain brown, oily 11a (1.4 g, 66% yield in two steps). MS (ESI): m / z = 186.4 [M + H] + .

[0155] b) A mixture of 11a (1.4 g, 7.57 mmol) / K2CO3 (1.05 g, 7.6 mmol) was added to MeOH (40 mL) and refluxed overnight. The reaction mixture was cooled to room temperature and evaporated until dry. Water (10 mL) was added to the residue and extracted with EA (3 × 20 mL). All EA layers were combined, dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography (EA:PE = 1:1~2:1~100% EA, Rf = 0.5 for EA / PE 2 / 1) to obtain 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 μL, 3.27 mmol) was added to 11b (500 mg, 3.27 mmol) in AcOH (5 mL) / H2O (5 mL) solution. The reaction mixture was stirred at 0°C for 1 hour. Br2 (35 μL, 0.68 mmol) was added to the reaction mixture and stirred again at 0°C for 2 hours. 10% Na2SO3 (10 mL) was added to the reaction mixture until it became colorless, then saturated NaHCO3 solution was added until the pH reached 7, and the mixture was extracted with EA (3 × 30 mL). The EA layers were combined, dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography (EA:PE = 1:1~2:1, Rf = 0.4 for EA / PE 2 / 1), yielding a light-colored solid 11 (400 mg, 52%).

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

[0158] a) At -70°C, iPrMgCl-LiCl (2.5 ml, 3.2 mmol, 1.3 mol / L in THF) was added dropwise to a solution of compound 8a (1 g, 2.9 mmol) and 3-oxetanone (232 mg, 3.2 mmol) in THF (25 mL). After stirring for 30 minutes, the mixture was heated to room temperature, saturated NaHCO3 (40 mL) was added, and the mixture was extracted with EA (3 × 100 mL). The mixture was dried over Na2SO4, concentrated, and the crude product was obtained. Purification by preparative HPLC (using TFA as buffer, A being a 0.05% aqueous TFA solution, B being acetonitrile, and a Waters XBridge Peptide BEH C18 column, 19 × 250 mm, 10 μm, 130A) yielded a white solid product 12 (300 mg, 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) At room temperature, LiBH4 (621 mg, 28.2 mmol) was added to a THF (70 mL) solution of compound 12. After stirring for 24 hours, water (200 mL) was added, and the mixture was extracted with EA (3 × 300 mL). The mixture was dried over Na₂SO₄, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 2:1, V / V) yielded a 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 multiple portions to a THF (50 mL) solution of 13a (1 g, 3.9 mmol) and TEA (19.5 g, 19.3 mmol). After stirring for 30 minutes, the temperature was raised to room temperature and stirring continued for 48 hours. The mixture was concentrated under reduced pressure, water (100 mL) was added, and the solution was extracted with EA (3 × 300 mL). The solution was dried over Na₂SO₄, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 10:1, V / V) yielded a 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] At room temperature, anhydrous K2CO3 (31.0 g, 224.1 mmol), D-serine methyl 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 sequentially added to DMF (250 mL). After stirring overnight at room temperature, the reaction mixture was added to water (1 L). Extraction was performed with ethyl acetate (500 mL x 3), followed by sequential washing with water (300 mL) and saturated saline (300 mL). The mixture was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (PE / EA = 9 / 1 to 8 / 2) to obtain a colorless oily liquid product (D54-b, 42.3 g, 88%). MS (ESI): m / z = 300.2 [M + H] + .

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

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

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

[0167] At 0°C, LAH (60 mL, 2.5 M in THF, 150 mmol) was added dropwise to a 500 mL solution of 54-c (37.8 g, 125 mmol) in THF. After reacting for 1 hour, 5.7 mL of water was carefully added. After reacting for 30 minutes, 5.7 mL of 15% NaOH was added. After stirring for 10 minutes, 17 mL of water was added. Anhydrous Na2SO4 was added, the solid was filtered off, and the mixture was concentrated to obtain 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)carbamate t-butyl ester (D54-e) [ka]

[0169] At room temperature, 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. The mixture was allowed to react overnight, the solid was filtered off, and the mixture was concentrated to obtain a colorless oily liquid product. Purification by column chromatography yielded (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] At room temperature, 20 mL of DCM was added to 120 mL of D54-e (10 g, 35.3 mmol). After reacting for 3 hours, the mixture was concentrated, dissolved in DCM, and 30 g of K2CO3 was added. After stirring for 20 minutes, the solid was filtered off, concentrated, and purified by reverse-phase column chromatography (C18, buffer 10 nm NH4HCO3) to obtain (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] At room temperature, 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). The mixture was stirred overnight at 55°C. After cooling to room temperature, the mixture was concentrated and purified by column chromatography to obtain 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-methanesulfonic acid fluoropropyl (D54-i) [ka]

[0175] At -10°C, a solution of MsCl (346 mg, 3.02 mmol) added to DCM (3 mL) was added dropwise to a DCM (12 mL) solution of 54-h (1.0 g, 2.88 mmol) and DIPEA (447 mg, 3.46 mmol). The mixture was reacted at -2°C for 1 hour, water (5 mL) was added, and the solution was extracted with DCM (10 mL x 3). The mixture was dried over anhydrous Na2SO4 and concentrated to obtain 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 multiple portions to a 15 mL solution of D54-h (1.2 g, 2.88 mmol) in THF (15 mL). The mixture was heated to room temperature and stirred overnight. A 5 mL solution of saturated NaHCO3 was added, the mixture was concentrated, and the THF was removed. The residue was extracted with ethyl acetate (50 mL x 3), washed sequentially with water (50 mL) and saturated saline (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to obtain 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] At room temperature, a compound prepared by adding D54-i (680 mg, 2.06 mmol), 10% Pd / C (100 mg), and 4M HCl in dioxane (1.03 mL, 4.12 mmol) to ethanol (20 mL) was placed in a hydrogenation apparatus. After hydrogenation for 4 hours, the solid was filtered off, and the filtrate was concentrated to obtain 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 (D54-l) [ka]

[0181] At room temperature, (Boc)2O (919 μL, 4.0 mmol) and TEA (1.4 mL, 10.0 mmol) were sequentially added to a 20 mL solution of DCM containing D54-k (382 mg, 2.0 mmol). After stirring for 4 hours, water (50 mL) was added, and the mixture was extracted with 3 × 20 mL of DCM. The solution was washed with saturated saline (20 mL), dried over anhydrous Na₂SO₄, and concentrated to obtain 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] At room temperature, water (3 mL), TEMPO (5.9 mg, 0.038 mmol), and Bu4NHSO4 (45 mg, 0.133 mmol) were sequentially added to a 13 mL solution of DCM containing D54-l (475 mg, 1.9 mmol). 6.8 mL of NaClO solution (10-15%) was adjusted to pH 8-9 with saturated NaHCO3. An aqueous solution of NaBr (60 mg, 5.8 mmol) (1.2 mL) was added to the prepared buffer solution. 10 mL of the buffer solution was taken out and added dropwise to the reaction system at 0°C. The mixture was stirred at room temperature for 3 hours and adjusted to pH 2-3 with KHSO4 (2N) solution. Extraction was performed with DCM (3 × 20 mL), dried over anhydrous Na2SO4, concentrated, and purified by reverse-phase column chromatography to obtain a white solid product (D54-m, 385 mg, 68% total yield in 3 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 by a similar method. [ka]

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

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

[0187] At room temperature, Pd(OH)2 / C (65 mg) was added to a solution of D62-a (530 mg, 4.17 mmol) in EtOH (20 mL). The reaction mixture was left overnight under hydrogen, the solid was filtered off, and HCl (4 M in dioxane, 2 mL) was added to the filtrate. The mixture was concentrated to obtain 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-imidazole-4-amine (D62-d) [ka]

[0189] At room temperature under argon, 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). The reaction mixture was stirred at 110 °C for 4 hours, cooled to room temperature, concentrated, and directly purified by column chromatography to obtain 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-imidazole-4-yl)aminophenol (D62-e) [ka]

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

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

[0193] At 0°C, Et3N (206 μL, 1.48 mmol) and triphosgene (109 mg, 0.37 mmol) were sequentially added to a 3 mL solution of DCM containing D62-e (165 mg crude product). The mixture was stirred overnight at room temperature, and saturated NH4Cl aqueous solution (20 mL) was added. Extraction was performed with DCM (20 mL x 3). The solution was dried over anhydrous Na2SO4, concentrated, and purified by reverse-phase column chromatography (C18, TFA buffer) to obtain a brown solid product (D62-f, 21 mg, 15% total yield in 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-pyrazole-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) added to dioxane (10 ml) was stirred for 7 hours under argon at 110°C. The mixture was cooled to room temperature, concentrated, and purified by column chromatography to obtain 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-pyrazole-4-yl)aminophenol (D63-d) [ka]

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

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

[0200] At 0°C, Et3N (840uL, 6 mmol) and triphosgene (297 mg, 1.0 mmol) were sequentially added to a 5 mL solution of DCM containing D63-d (450 mg crude product). The mixture was stirred overnight at room temperature, and saturated NH4Cl (20 mL) aqueous solution was added. Extraction was performed with DCM (20 mL x 3). The solution was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to obtain 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-triazole-3-amine (D64-c) [ka]

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

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

[0205] At 0°C, BBr3 (2.5 mL, 17% Wt in DCM) was added dropwise to a 5 mL solution of D64-c (340 mg, 1.42 mmol, 1 equivalent). The mixture was stirred overnight at room temperature, and saturated NaHCO3 (20 mL) was added. Extraction was performed with DCM (20 mL x 3). The solution was dried over anhydrous Na2SO4 and concentrated to obtain the product (D64-d, 340 mg crude product). 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]oxazole-2(3H)-one (D64-e) [ka]

[0207] At 0°C, Et3N (418 μL, 3.0 mmol, 2.0 equivalents) and triphosgene (222 mg, 0.75 mmol, 0.5 equivalents) were sequentially added to a 20 mL solution of DCM containing D64-d (340 mg crude product, 1.4 mmol, 1.0 equivalent). The mixture was stirred overnight at room temperature, and saturated NH4Cl (20 mL) was added. Extraction was performed with DCM (20 mL x 3). The solution was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to obtain 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]oxazole-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 minutes, D68-a (1.4 g, 9.4 mmol) was added. After stirring for 3 hours, the mixture was cooled to 0°C and water (20 mL, 1 / 1, v / v) was added. Extraction was performed with DCM (20 mL x 3). The solution was dried over anhydrous Na2SO4, concentrated, and purified by reverse-phase column chromatography to obtain 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] At -78°C, LDA (8.8 mL, 17.6 mmol, 2 mol / L) was added dropwise over 15 minutes to a solution of D73-a (1.5 g, 7 mmol) in THF (40 mL). After stirring for 15 minutes, MeI (10 g, 70.4 mmol) was added. The reaction mixture was heated to 0°C and stirred for 6 hours. Water (100 mL) was added, the mixture was extracted with ethyl acetate (250 mL x 3), dried over Na2SO4, concentrated, and purified by column chromatography to obtain 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] At room temperature, 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). After stirring for 1.25 hours, the borane-methyl sulfide complex (7.1 mL, 14.2 mmol, 2 M solution in tetrahydrofuran) was gradually added dropwise. The reaction mixture 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 heated to room temperature and stirred overnight. The mixture was concentrated, most of the THF was removed, and it was placed in a 1N HCl solution. Extraction was performed with ethyl acetate (200 ml x 3), washed with saturated brine (200 ml), dried over Na2SO4, concentrated, and purified by column chromatography to obtain 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] At room temperature, Pd(dppf)Cl2 (62 mg, 0.09 mmol) and TEA (171 mg, 1.7 mmol) were sequentially added to a 10 mL solution of DMF containing D122-b (200 mg, 0.85 mmol). The reaction system was packed with nitrogen three times, followed by carbon monoxide. The mixture was stirred at 130°C for 16 hours. After cooling to room temperature, the solution was concentrated and purified by column chromatography to obtain 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 by a similar method. [ka]

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

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

[0222] At -78°C, 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). After stirring for 1 hour, D76-b (900 mg, 4.86 mmol) was added all at once. The mixture was stirred at -78°C for another 2 hours. A saturated aqueous solution of NH4Cl (100 mL) was added, and the mixture was extracted with DCM / MeOH (9:1) (3 x 20 mL). The mixture was dried over Na2SO4, concentrated, and purified by reverse-phase column chromatography to obtain 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] At -78°C, 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). After stirring for 15 minutes, bromo(methoxy)methane (417.88 μL, 5.15 mmol) was added dropwise. The mixture was continued to stir at -78°C for 1 hour, and saturated NH4Cl aqueous solution (100 mL) was added. Extraction was performed with DCM / MeOH (9:1) (3 x 20 mL). The mixture was dried over Na2SO4, concentrated, and purified by reverse-phase column chromatography to obtain 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 2-(5-bromo-2-oxobenzo[d]oxazole-3(2H)-yl)ethyl acetate (D81-a) [ka]

[0228] At 0°C, 1-a (5g, 23.48 mmol) was added to DMF (40 mL) to a solution, to which NaH (1.03 g, 25.83 mmol) was added. After stirring for 30 minutes, BrCH2CO2Et (3.9 g, 23.48 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours, water was added, and the solution was extracted with ethyl acetate, dried over Na2SO4, concentrated, and purified by reverse-phase column chromatography to obtain 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] At room temperature, NH4OH (300 ml) was added to a solution of D81-a (4.8 g, 16.05 mmol) in EtOH (30 mL). The mixture was stirred at room temperature for 24 hours, 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]imidazole[2,1-b]oxazole-2(3H)-one (D81-c) [ka]

[0232] At 0°C, POCl3 (25 ml) was added to a solution of D81-b (2.4 g, 8.89 mmol) in toluene-e (25 mL). The mixture was stirred at 110°C for 1 hour, cooled to room temperature, ice water was added, and the solution was extracted with ethyl acetate. It was dried over Na2SO4, concentrated, and purified by reverse-phase column chromatography to obtain 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] 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 sequentially added to a 100 mL solution of DCM containing D84-b (10 g, 65.77 mmol). After stirring for 30 minutes, water was added, and the mixture was extracted with dichloromethane. The solution was then sequentially washed with dilute hydrochloric acid (4.0 M) and saturated saline, dried over Na2SO4, and concentrated to obtain a white solid product (D84-b, 12 g, 94%). ¹H NMR (400 MHz, DMSO-d6) showed 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] At -40°C, a mixture of D84-b (10g, 51.50 mmol) and KNO3 (5.31g, 52.53 mmol) was added to DCM (40 mL), to which TFAA:TFA (3:1, 37.5 mL) was added dropwise. The reaction mixture was gradually heated to room temperature and stirred overnight. Ice water was added, and the mixture was extracted with dichloromethane. It was dried over Na2SO4, concentrated, and purified by column chromatography to obtain a red solid product (D84-c, 10.3g, 83.6%).

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

[0239] At room temperature, NaOH (6.8g, 171.42 mmol) and water (800 mL) were sequentially added to a solution of D84-c (10g, 41.81 mmol) in MeOH (150 mL). After stirring for 5 minutes, AgNO3 (8.5g, 50.17 mmol) was added, and the mixture was stirred overnight at 85°C. The solid was filtered off, and the filtrate was adjusted to pH 2. Extraction with ethyl acetate, washing with saturated saline, drying over Na2SO4, and concentration yielded a yellow solid product (D84-d, 7g, 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] At room temperature, a solution of D84-d (13.45 g, 63.10 mmol) in HOAc (158 mL) was mixed with 47% HBr aqueous solution (79 mL). The reaction was carried out under reflux for 16 hours and then cooled to room temperature. The mixture was extracted with ethyl acetate, washed with water, dried over Na₂SO₄, and concentrated to obtain a yellow solid product (D84-e, 9 g, 71.6%).

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

[0243] At room temperature, D84-d (7.2 g, 36.16 mmol) was dissolved in MeOH (120 mL), and 10% Pd / C (0.6 g) was added. The mixture was then placed in a 40 Psi hydrogen atmosphere. When the hydrogen pressure stopped decreasing, the solid was filtered off, and the filtrate was concentrated to obtain a yellow solid product (D84-f, 3.6 g, 58.9%). LC-MS: 170.2 [M+H] + .

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

[0245] At 0°C, a suspension of D84-f (3.9 g, 23.06 mmol) in H2O (8 mL) was added, followed by the addition of 48% HBr aqueous solution (6 mL), and then a solution of NaNO2 (1.2 g, 17.29 mmol) in water (8 mL). After stirring at 0°C for 2 hours, a solution of CuBr (2.5 g, 17.29 mmol) in HBr (6 mL) was added. After stirring at 0°C for 1 hour, the mixture was stirred overnight at room temperature. The mixture was extracted with ethyl acetate, washed with water, dried over Na2SO4, and concentrated to obtain 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] At room temperature, a solution of (D84-g, 1.2g, 5.15 mmol) in EtOH (38 mL) was mixed with concentrated H2SO4 (2 mL), and stirred under reflux overnight. The mixture was cooled to room temperature, and EtOH was removed under reduced pressure. Ethyl acetate was added, and the mixture was sequentially washed with saturated NaHCO3 and saline solution. The mixture was dried over Na2SO4, concentrated, and purified by column chromatography to obtain a white solid product (D84-h, 0.537 g, 39.9%). LCMS: 261.0[M+H]+ .

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

[0249] At room temperature, Cs2CO3 (2.7g, 8.43 mmol) was added to a solution of D84-h (1.0g, 3.83 mmol) in DMF (8 mL), and the mixture was stirred for 1 hour. Then, CH2I2 (1.7g, 6.21 mmol) was added, and the mixture was reacted at 75°C for 12 hours. After cooling to room temperature, 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]-dioxoralyl-4-yl)methanol (D84-j) [ka]

[0251] At -78°C, 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). The reaction mixture was warmed to room temperature and stirred for 2 hours. Water was added, the mixture was extracted with ethyl acetate, dried over Na2SO4, and concentrated to obtain 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 to a solution of PBr3 (4897.14 mg, 18.09 mmol) in THF (20 mL). The mixture was stirred at 0°C for 2 hours, saturated NH4Cl was added, and the solution was extracted with ethyl acetate (300 mL x 4). The solution was dried over Na2SO4, concentrated, and purified by column chromatography to obtain a white solid product (D84-k, 2.6 g, 54%). GCMS: 294[M] + .

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

[0255] At -78°C, n-butyllithium (2.5 min hexane, 6.29 mL, 15.72 mmol) was added dropwise to a solution of D84-l (2895.79 mg, 15.72 mmol) in tetrahydrofuran (dried, 60 mL). After stirring for 30 minutes, a solution of D84-j (4200 mg, 14.29 mmol) in THF (dried, 20 mL) was added dropwise, and after stirring for 1 hour, a saturated NH4Cl solution was added. The solution was extracted with ethyl acetate, dried over Na2SO4, concentrated, and purified by column chromatography to obtain a white solid product (D84-m, 1800 mg, 32%). LCMS:[M+H] + :397.1

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

[0257] At room temperature, a 60 mL solution of D84-m (1800 mg, 4.53 mmol) in acetonitrile was mixed with 47.57 mL, 9.51 mmol of 0.2 M aqueous HCl. After stirring for 12 hours, the pH was adjusted to 8 with saturated NaHCO3 solution, extracted with ethyl acetate, dried over Na2SO4, concentrated, and purified by column chromatography to obtain 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] At room temperature, TBDPSCl (45.6 g, 165.7 mmol) and imidazole (37.6 g, 552.5 mmol) were sequentially added to a solution of D98-b (25 g, 138.1 mmol) in DCM (600 mL). The mixture was stirred at room temperature for 16 hours, concentrated, and dichloromethane was removed. Depositphotos (1000 mL) was added, and the mixture was sequentially washed with water (250 mL x 3) and saline solution (250 mL). The mixture was dried over Na₂SO₄, concentrated, and purified by column chromatography to obtain 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] Under nitrogen, a mixture of D98-b (70g, 143.2 mmol), BnNH2 (38.3g, 358 mmol), K2CO3 (39.8g, 286.4 mmol), and KI (23.8g, 143.2 mmol) was added to DMF (600 mL) and stirred at 70°C for 24 hours. After cooling to room temperature, toluene (1500 mL) was added, washed with saturated brine (350 mL x 4), dried over Na2SO4, concentrated, and purified by column chromatography to obtain a colorless oily product (D98-c, 41.5g, 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] Under nitrogen, D98-c (40g, 89.9 mmol) and D98-D (29.5g, 179.8 mmol) i The mixture was added to PrOH (200 mL) and stirred at 75°C for 72 hours. After cooling to room temperature, it was concentrated and purified by column chromatography to obtain 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, D98-e (58.4 g, 95.9 mmol), KF (55.6 g, 959 mmol), and TBAF (4 mL, 1 mol / l) were added to THF (1000 mL) and stirred at room temperature for 48 hours. The mixture was concentrated, and water (300 mL) was added. Extraction was performed with ethyl acetate (500 mL x 3), dried over Na2SO4, concentrated, and purified by column chromatography to obtain 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)methanesulfonate methyl (D98-g) [ka]

[0268] At -8°C, D98-f (15.3 g, 41.2 mmol) in a 250 mL solution of DCM was sequentially added dropwise to a 50 mL solution of DIPEA (6.92 g, 53.6 mmol) and MsCl (4.96 g, 43.3 mmol) in DCM. The mixture was then stirred at -8°C for 2 hours, 150 mL of ice water was added, and the mixture was extracted with 3 x 200 mL of DCM. The mixture was dried over Na₂SO₄, filtered, and concentrated to obtain 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] At -0°C, a suspension of NaH (8.24 g, 206 mmol, 60% purity) in THF (200 mL) was added dropwise to a solution of D98-g (18.5 g, 41.2 mmol) in THF (100 mL). The mixture was stirred at 50°C for 16 hours. After cooling to 0°C, a saturated NaHCO3 (500 mL) solution was added, and the mixture was extracted with ethyl acetate (500 mL x 3). The mixture was dried over Na2SO4, concentrated, and purified by column chromatography to obtain 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]decane-7-yl)methanol TFA salt (D98-i) [ka]

[0272] At room temperature, D98-h (5g, 14.2 mmol), Pd / C (2g, 10% C), TFA (1.61g, 14.2 mmol), and AcOH (10 mL) were used. i The mixture, added to PrOH (200 mL), was placed in a hydrogenation apparatus. After stirring at room temperature and allowing hydrogen absorption for 16 hours, the solid was filtered off, and the filtrate was concentrated to obtain 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 (D98-j) [ka]

[0274] At room temperature, 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) added to dioxane (150 mL) was stirred for 4 hours. Extraction with ethyl acetate (3 × 200 mL), drying over Na2SO4, concentration, and purification by column chromatography yielded 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] At room temperature, D98-j (1 g, 3.7 mmol), TEMPO (11 mg, 0.07 mmol), and Bu4NHSO4 (87 mg, 0.3 mmol) were sequentially added to DCM (20 mL) and water (9 mL). Simultaneously, 7.4 mL of NaClO solution (10-15%) was adjusted to pH 8-9 with saturated NaHCO3 (liquid + solid) (approximately 15 mL), and an aqueous solution of NaBr (64 mg, 0.6 mmol) (1 mL) was added to the buffer solution. At 0°C, the freshly prepared buffer solution was added dropwise to the reaction mixture. After stirring at room temperature for 3 hours, KHSO4 (2N) solution was added to adjust the pH to 2-3. Extraction was performed with DCM (100 mL x 3), dried over Na2SO4, and concentrated to obtain a white solid product (D98-k, 850 mg, 81%). MS(ESI): m / z = 310.2 [M + Na] + .

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

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

[0279] At 0°C, TMSCl (1.0 mL, 8.0 mmol, 4.0 equivalents) was added to a 10 mL solution of DMF (1.0 mL) containing D100-b (1.0 g, 4.0 mmol, 4 equivalents) and D100-a (376 mg, 2.0 mmol, 1 equivalent). After stirring at 0°C for 2 hours, BH3·THF (1 M, 10 mL, 5 equivalents) was added dropwise. After stirring at room temperature for 3 hours, saturated Na2CO3 (200 mL) and water (10 mL) were added. Extraction was performed with ethyl acetate (100 mL x 2), washed with water, dried over Na2SO4, concentrated, and purified by column chromatography to obtain an orange oily product (D100-c, 730 mg, 90%). MS(ESI): m / z = 353.0 [M-tBu+H] + .

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

[0281] Under argon, a mixture of D100-c (690 mg, 1.69 mmol) and CDI (330 mg, 2.03 mmol) added to dioxane (20 mL) was stirred at 110°C for 6 hours. The mixture was cooled to room temperature, concentrated, and purified by column chromatography to obtain 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-difluoropiperidine-4-yl)benzo[d]oxazole-2(3H)-one (D100-e) [ka]

[0283] Under argon, the mixture of D100-d (566 mg, 1.3 mmol) and TFA / DCM (1:6, 7 mL) was stirred at room temperature for 2 hours, concentrated, and the product obtained was 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-methylpiperidine-4-yl)benzo[d]oxazole-2(3H)-one (D100-f) [ka]

[0285] At room temperature, 250 μL of HCOOH was added to a mixture of D100-e (490 mg crude product, TFA salt, 1.1 mmol) in a 10 mL, 1:1 aqueous solution of MeOH / HCHO. The reaction mixture was stirred at 65°C for 24 hours. After cooling to room temperature, the mixture was concentrated and freeze-dried to obtain 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] At 0°C, BH3·THF (1M in THF, 17.8mL, 2.5 equivalents) was added dropwise to a solution of D115-a (2.0g, 7.1 mmol, 1.0 equivalent) in THF (20mL), and the mixture was stirred overnight at room temperature. MeOH (25mL) was added to the reaction mixture, and the mixture was concentrated to obtain a white solid product (D115-b, 1.9g, 99%). MS(ESI): m / z = 251.0 [M-OH] + .

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

[0290] At 0°C, PBr3 (522 μL, 5.5 mmol, 1.1 equivalent) was added dropwise to a 50 mL solution of DCM containing D115-b (1.34 g, 5.0 mmol, 1.0 equivalent). The mixture was stirred at 0°C for 1 hour, then stirred at room temperature for 2 hours, after which saturated NaHCO3 aqueous solution (100 mL) was added. The mixture was extracted with dichloromethane (20 mL x 2), dried over Na2SO4, concentrated, and purified by column chromatography to obtain 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 (D115-f) [ka]

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

[0293] 4) Preparation of 5'-Chlorospiro[azetidine-3,2'-indene]-1'(3'H)-one (D115-g) [ka]

[0294] At room temperature, D115-f (570 mg, 1.85 mmol) was dissolved in TFA / DCM (1:10, 5.5 mL), stirred for 2 hours, and then concentrated to obtain 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[azetidine-3,2'-indene]-1'-ol (D115-h) [ka]

[0296] At room temperature, paraformaldehyde (555 mg, 18.5 mmol, 10.0 equivalent) was added to a MeOH / AcOH (5:1, 24 mL) solution of D115-g (0.6 g crude product, 1.85 mmol, 1.0 equivalent). After stirring for 5 hours, NaBH3CN (465 mg, 7.4 mmol, 4.0 equivalent) was added. The mixture was stirred overnight at room temperature, the solid was filtered off, and the solution was concentrated. Saturated NaHCO3 aqueous solution (50 mL) was added to the residue, and the solution was extracted with a dichloromethane / methanol (9 / 1, 20 mL x 6) mixed solvent. The solution was dried over Na2SO4 and concentrated to obtain a pale yellow oily product (D115-h, 330 mg). MS(ESI): m / z = 224.2 [M + H] + .

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

[0298] At room temperature, dess-martin periodinane (642 mg, 1.51 mmol, 1.1 equivalent) was added to a 20 mL solution of DCM containing D115-h (308 mg, 1.38 mmol, 1.0 equivalent). After stirring for 1 hour, saturated aqueous NaHCO3 solution (30 mL) was added, and the mixture was extracted with DCM (20 mL x 3). The solution was dried over Na2SO4, concentrated, and purified by reverse-phase column chromatography to obtain 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-bromoselenophen (D121-b) [ka]

[0300] At 0°C, D121-a (5000 mg, 38.15 mmol) was added to a solution of DCM (60 mL) and CH3COOH (60 mL), to which NBS (6791 mg, 38.15 mmol) was added. The mixture was stirred at 0°C for 2 hours, water was added, and the solution was extracted with dichloromethane. It was dried over Na2SO4, concentrated, and purified by column chromatography to obtain a white oily product (D121-b, 5100 mg, 63.7%).

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

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

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

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

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

[0306] At 0°C, PBr3 (3079 mg, 11.37 mmol) was added dropwise to a solution of D121-c (2100 mg, 8.75 mmol) in diethyl ether (20 mL). After stirring at 0°C for 2 hours, water was added, and the mixture was extracted with dichloromethane, dried over Na2SO4, and concentrated to obtain 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 (4.95 mL, 12.38 mmol) was added dropwise to a solution of D84-l (1825 mg, 9.91 mmol) in THF (50 mL). After stirring for 1 hour, D121-f (2500 mg, 8.25 mmol) in THF (10 mL) was added dropwise. After reacting at -78°C for 2 hours, saturated NH4Cl aqueous solution was added, extracted with ethyl acetate, dried over Na2SO4, concentrated, and purified by column chromatography to obtain a white solid product (D121-e, 2000 mg, 59.7%). LCMS: 407.0[M+H] + .

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

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

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

[0312] a) At room temperature, compound D01a (1 g, 2.6 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (6 mL) was added dropwise. The mixture was stirred for 2 hours and then spin-dried to obtain a 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, 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 according to the scheme reported in patent (WO2015110826). Subsequently, TEMPO (107 mg, 0.68 mmol) and Bu4NHSO4 (812 mg, 2.4 mmol) were added sequentially. Simultaneously, a buffer solution was prepared. Saturated NaHCO3 solution (approximately 100 mL) was added to 68 mL of NaClO solution (10-15%) to adjust the pH to 8-9. Subsequently, 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 added dropwise to the reaction mixture. Since this reaction is exothermic, care should be taken to maintain the temperature in the flask below 10°C for 1 hour. The mixture was stirred overnight at room temperature, the pH was adjusted to 2-3 with KHSO4 (2N), the reaction mixture was extracted with dichloromethane (3 × 500 mL), dried, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 2:1-1:1, V / V) yielded a 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). DIPEA (11.71 g, 90.8 mmol), HOBt (3.06 g, 22.7 mmol), and HBTU (9.46 g, 25 mmol) were added sequentially, and the mixture was stirred overnight. Water (200 mL) was added to the reaction mixture, and it was further extracted with dichloromethane (3 × 400 mL). The mixture was dried, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 1:1~1:4, V / V) yielded a 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) At room temperature under argon, compounds D01c (9.7 g, 18.8 mmol) and Pin2B2 (9.53 g, 37.5 mmol) were dissolved in DMSO (250 mL), and then Pd(dppf)Cl2 (960 mg, 1.3 mmol) and KOAc (5.52 g, 56.3 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 8 hours. After cooling to room temperature, it was diluted with EA (1000 mL), washed with saturated brine (5 × 200 mL), dried over Na2SO4, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 1:1~1:6, V / V) yielded 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) and 6-bromoimidazo[1,2-a]pyridine (115 mg, 0.58 mmol) were dissolved in dioxane (8 mL) and water (0.8 mL). 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 hours. The reaction mixture was cooled to room temperature, EA (50 mL) was added, and the mixture was extracted. It was washed with saturated brine (10 mL), dried over Na2SO4, concentrated, and the crude product was obtained. Column chromatography purification (eluent EA ~ EA:MeOH = 10:1, Rf = 0.3 for EA / MeOH 10 / 1) yielded a 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) At room temperature, Burgess reagent (338 mg, 1.42 mmol) was added to a solution of D01e (120 mg, 0.237 mmol) in dichloromethane (10 mL). After stirring at room temperature for 4 hours, the reaction mixture 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 (using TFA as buffer, A being a 0.05% TFA aqueous solution, B being a 0.05% TFA acetonitrile solution, and a Waters XBridge Peptide BEH C18 column, 19 × 250 mm, 10 μm, 130A) and lyophilized. The obtained product was neutralized to pH 7 with saturated NaHCO3, the resulting solution was extracted with EA (3 × 50 mL), dried over Na2SO4, and concentrated to obtain a brown solid product D01f (15 mg, yield 12%). MS(ESI): m / z = 490.3[M+H] + .

[0318] g) At room temperature, compound D01f (10 mg, 0.02 mmol) was mixed with HCOOH (3 mL), then the mixture was heated to 50°C and stirred for 10 minutes. The reaction mixture was concentrated to obtain the crude product, which was purified by HPLC (using HCOOH as buffer, A as a 0.1% aqueous HCOOH solution, B as acetonitrile, and a Waters XBridge Peptide BEH C18 column, 19 × 250 mm, 10 μm, 130A) to obtain a white solid product D01 (1.5 mg, yield 17%). 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, 6-bromoimidazo[1,2-a]pyridine was substituted with different bromides and reacted to prepare the following compounds.

[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] Furthermore, by substituting 6-bromoimidazo[1,2-a]pyridine with different bromides according to the method of Example 1, the following compounds could also be prepared.

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

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

[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]pyrrole-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). The mixture was stirred overnight at 90°C. The reaction mixture was cooled to room temperature, and EA (50 mL) and saturated saline (10 mL) were added. The mixture was extracted with EA (3 × 300 mL), dried over Na2SO4, concentrated, and the crude product was obtained. Relatively pure products were obtained by column chromatography purification (eluent EA, EA:MeOH = 20:1 to 10:1, Rf = 0.5 when EA / MeOH = 10 / 1), and further purification was performed by preparative HPLC (C18, CH3CN, 10 mM NH4HCO3 aqueous solution) to obtain a white solid product D11a (120 mg, yield 58%). 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) At room temperature, 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), stirred for 4 hours, diluted with dichloromethane DCM (20 mL), washed with water (10 mL), dried over Na2SO4, concentrated to obtain the crude product. Column chromatography purification (eluent EA~EA:MeOH = 20:1, Rf = 0.1 for EA) yielded a white solid product D11b (130 mg, yield 88%). 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, 0.5 mL of 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 hours, 0.2 mL of 4N HCl was added, and stirring continued for another 2 hours. Subsequently, 40 mL of Et2O was added to the reaction mixture, and a small amount of white precipitate formed. The mixture was centrifuged for 2 minutes to remove the liquid, and the residue was purified by preparative HPLC (using aqueous NH4HCO3 solution as buffer, A being 10 mM aqueous NH4HCO3 solution, B being acetonitrile, and a Waters XBridge Peptide BEH C18 column, 19 × 250 mm, 10 μm, 130A) to obtain a white solid product D11, a white solid (20 mg, yield 47%). 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) At room temperature, ethyl cyanoethyl (20 g, 177 mmol), 1,2-dibromoethane (66.5 g, 354 mmol), and K2CO3 (73.3 g, 531 mmol) of the compound were sequentially added to acetone (300 mL). After heating under reflux overnight, the mixture was cooled to room temperature and the solid was filtered off. The filtrate was concentrated to obtain the yellow oily product D15a (22 g, 89%). MS(ESI): m / z = 140.4 [M + H] + .

[0332] b) At 0°C, D15a (22g, 158.3 mmol) was dissolved in dry THF (150 mL) and gradually added dropwise to THF (250 mL) containing LiAlH4 (24.06 g, 633.1 mmol). The reaction mixture was stirred overnight, then cooled to 0°C, diluted with Et2O (250 mL), and carefully quenched with water (22.06 mL), 15% NaOH aqueous solution (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 dioxane solution) was added, and the mixture was concentrated to obtain a brown oily crude product D15b (22g, 80%). 1 HNMR (400MHz, DMSO-d6): δ 8.09 (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 after stirring for 2 hours, NaBH4 (2.21 g, 58.2 mmol) was added in multiple portions. After stirring for 2 hours, the solid was filtered off, the filtrate was concentrated, and the brown oily product D15c (4.8 g, 87%) was obtained by column chromatography (eluent MeOH / DCM = 1:15, V / V). 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) At room temperature, compound D15c (9.3 g, 48.7 mmol) and (S)-benzylglycidyl ether (8.38 g, 51.1 mmol) i The mixture was added to PrOH (100 mL) and stirred at 50°C for 16 hours. After cooling to room temperature and concentrating, the mixture was purified by column chromatography (eluent PE / EA = 1:1 to 1:2, V / V) to obtain a 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), and then MsCl (3.9 g, 34.1 mmol) was gradually added dropwise over 1 hour. After stirring for 1 hour, ice water (100 mL) was added, and the mixture was extracted with dichloromethane (3 × 200 mL). The mixture was dried over Na₂SO₄ and concentrated to obtain a brown, oily crude product D15e. MS(ESI): m / z = 434.2 [M + H] + .

[0336] f) At 0°C, a suspension of NaH (3.88 g, 97 mmol, purity: 60% in oil) was added to THF (300 mL), and a solution of D15e (14 g, 32.3 mmol) dissolved in THF (100 mL) was gradually added dropwise. The mixture was stirred at 50°C for 16 hours, cooled to 0°C, saturated NaHCO3 (200 mL) was added, and the mixture was extracted with EA (3 × 400 mL). The mixture was dried over Na2SO4, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 6:1~5:1, V / V) yielded a 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 (4g, 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 hours. Then, HCl (1 ml, 12 mol / L, 12 mmol) was added, and hydrogenation continued for 16 hours. Pd / C was filtered off and concentrated to obtain a brown oily product D15 g (2.4 g, 90%). MS(ESI): m / z = 158.2 [M + H] + .

[0338] h) At room temperature, 15 g (4.8 g, 24.8 mmol) of D was dissolved in dioxane (150 mL) and water (150 mL), then (Boc)2O (10.82 g, 49.6 mL) and NaHCO3 (10.42 g, 124 mmol) were added. After stirring for 16 hours, the mixture was extracted with EA (3 × 500 mL). The mixture was dried over Na2SO4, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 2:1 to 1:1, V / V) yielded a 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 (2g, 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 sequentially. Simultaneously, 15.5 mL of NaClO solution (10-15%) was adjusted to pH 8-9 with saturated NaHCO3 (liquid + solid) (approximately 30 mL). An aqueous solution of NaBr (136 mg, 1.32 mmol) (1 mL) was added to the buffer solution. The resulting solution was cooled to 0°C and gradually added dropwise to the reaction mixture. After reacting at 0°C for 1 hour, the mixture was stirred overnight. The reaction mixture was adjusted to pH 2-3 with KHSO4 (2N). The solution was extracted with dichloromethane, dried over Na2SO4, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 2:1 to 1:1, V / V) yielded 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 sequentially added 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 hours, water (50 mL) was added and the mixture was extracted with dichloromethane (3 × 150 mL). The mixture was dried over Na₂SO₄ and concentrated to obtain the crude product. After purification by column chromatography (eluent PE / EA = 1:1 to 1:5, V / V), the crude product was obtained by flash column chromatography (C₁₄, CH₃CN, 10 mM NH₄HCO₃ aqueous solution), yielding 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 DMSO (30 mL) solution of D15j (1 g, 1.84 mmol). After removing air from the reaction flask under reduced pressure, argon was added. After repeating this three times, the mixture was stirred at 85°C and reacted for 5 hours. The mixture was cooled to room temperature, diluted with EA (500 mL), and washed with saturated brine (5 × 100 mL). It was dried over Na2SO4, concentrated, and the crude product was obtained. Column chromatography purification (eluent PE / EA = 1:2~1:6, V / V) yielded a 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]oxazole-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 sequentially. After removing air from the reaction flask under reduced pressure, argon was added. The reaction compounds were stirred at 85°C for 6 hours. After cooling to room temperature and concentrating, a relatively pure product was obtained by column chromatography (eluent PE / EA = 1:1~1:6, MeOH / DCM = 1:10, V / V). Further purification by column chromatography (C18, CH3CN, 10 mM NH4HCO3 aqueous solution) yielded a 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), and Burgess reagent (354 mg, 1.49 mmol) was added. After stirring at room temperature for 3 hours, the mixture was concentrated and purified by preparative HPLC (NH4HCO3 was used as buffer, A was a 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 a brown solid product D15m (80 mg, 59%). MS(ESI): m / z = 569.3 [M + Na] + .

[0344] n) At room temperature, 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). After stirring at room temperature for 1.5 hours, cold Et2O (45 mL) was added, and the mixture was centrifuged to remove the liquid phase. The residue was washed twice with Et2O (15 mL). Purification by preparative HPLC (A was a 0.8% aqueous solution of NH4HCO3, B was CH3CN, and the column was Xbridge BEH peptide C18, 19 mm × 250 mm) yielded a white solid product D15 (35 mg, 53%). The HPLC purity was 99.46%.

[0345] [Table 5]

[0346] The following compounds were prepared from different L-phenylalanine analogs using similar methods.

[0347] [Table 6]

[0348] The following compounds were prepared from different six-membered and seven-membered amino acids using a similar method.

[0349] [Table 7]

[0350] Example 4: Inhibition test on DPP1 activity in U937 cells Intracellular enzyme activity was measured in a 384-well plate, using 1640, 10% FBS, and 1*PS cell medium. 30 μL of cell suspension in cell medium containing U937 cells was added to the 384-well plate, and 2 × 10⁶ cells were placed in each well. 4Each well contained individual cells, and 30 nL of AZD7986, a vehicle control (100% DMSO), or a serially diluted solution of the test compound was added using Echo. After incubation at 37°C for 1 hour, 10 μL of h-Gly-phe-AFC was added to each well and allowed to react. After further incubation at 37°C for 1 hour, fluorescence absorption values ​​were read using EXλ400 nm and EMλ505 nm. The IC50 values ​​were calculated from the above detection results using Graphpad 8.0, 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 are, 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, This is DMSO purchased from Sigma-Aldrich.

[0353] Experimental method 1) Preparation and processing of the compound: The exact amount of the compound was weighed and dissolved in 10 mL of DMSO to prepare 10 mL of stock solution, which was further diluted as needed.

[0354] 2) Screening measurement: Recombinant human cathepsin rhCathepsin C / DPP1 and recombinant human cathepsin rhCathepsin L were diluted with activation buffer and incubated at 37°C for 60 minutes. 4 μL of the test compound was added to the white microwells of a 384-well plate. 4 μL of the enzyme mixture after incubation was added to the white microwells. The 384-well plate was closed and left at room temperature for 30 minutes, and 8 μL 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 4 μL 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 inhibition percentages using Prism Graphpad 8.0. The results are shown in the table below.

[0356] [Table 9]

[0357] The embodiments of this patent are provided for illustrative purposes only, not limiting purposes. Those skilled in the art will readily understand that substantially similar results can be obtained by changing or modifying each of the non-key parameters.

[0358] Although the technical methods of the present invention have been described and enumerated in detail, it will be obvious to those skilled in the art that the above embodiments can be modified or equivalent alternative means can be employed, and it should be understood that all such modifications or improvements made without departing from the spirit of the invention fall within the scope of the protection claimed in this invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, A and B are both H, X and Y are CH, Z is C, and q (R²) is substituted on Z. R ２ is selected from hydrogen and fluorine, and q is 1. Cy is, 【Chemistry 2】 And, R 1 is, 【Transformation 3】 Selected from, A compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized by the above.

2. The following compounds or their pharmaceutically acceptable salts. 【Chemistry 4】

3. Use of a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment and prevention of disease by cathepsin C and its downstream serine protease, wherein the serine protease is selected from elastase (NE), cathepsin G (CatG), protease 3 (PR3), and neutrophil serine protease (NSP4).

4. A drug composition comprising a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and at least one medicinal carrier or excipient.

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