Pyrimidinone-containing compound, pharmaceutical composition thereof, and use thereof

Abstract

The present invention provides a pyrimidinone-containing compound, a pharmaceutical composition thereof, and a use thereof. Specifically, disclosed is a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof. The compound of the present invention has strong inhibitory activity against hNE, and the compound or the pharmaceutical composition thereof can be used for treating related diseases caused by an abnormal increase in neutrophil elastase.

Description

Pyrimidinone-containing compounds, pharmaceutical compositions thereof, and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2024110618019, filed on August 5, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application. TECHNICAL FIELD

[0002] The present application relates to the field of medicine, in particular to a pyrimidinone-containing compound, a preparation method thereof, a pharmaceutical composition, and application in the treatment of diseases caused by abnormal increase of neutrophil elastase. BACKGROUND

[0003] Human neutrophil elastase (HNE) is a 32KDa serine protease found in the azurophilic granules of neutrophils. In the acute phase of inflammation, neutrophils are the first cells to be recruited to the site of inflammation and form the earliest defense line against invasion. HNE can degrade a variety of extracellular matrix proteins, such as elastin, proteoglycans, laminin, and fibronectin, etc. In normal physiological processes, HNE can degrade or repair damaged tissues by degrading these tissue structure proteins to maintain tissue homeostasis. HNE can also help neutrophils recruit to the site of inflammation by degrading the structural proteins of bacteria, reduce bacterial infection, and participate in inflammation regulation.

[0004] However, excessive release and enrichment of HNE can destroy normal physiological tissue structures, and also induce increased microvascular permeability and excessive mucus secretion. In addition, excessive release of NE can also cause some serious heart and lung system diseases. Pulmonary diseases and injuries associated with excessive expression of HNE include acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), bronchiectasis, sepsis, etc.

[0005] In the past few years of research, global researchers have designed and developed a variety of small molecule HNE inhibitor compounds with different structures. These include neopentanoate derivatives, such as Sivelestat, which is the first drug in the world for treating and improving acute lung injury (ALI) / acute respiratory distress syndrome (ARDS) of systemic inflammatory response syndrome (SIRS). Other types of small molecule HNE inhibitors include pyridinone derivatives (such as Alvelestat), dihydropyrimidinone derivatives (such as BAY 85-8501), and small molecule polypeptides (such as POL6014), etc.

[0006] To date, despite several oral small molecule HNE inhibitors entering clinical studies, only one has succeeded in reaching the market due to various factors. The present invention develops a series of structurally novel compounds that have excellent HNE inhibitory activity, selectivity, and high bioavailability. These compounds can be used for the treatment of various related diseases caused by abnormal increases in neutrophil elastase. SUMMARY

[0007] The present invention provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof,

[0008] wherein:

[0009] W is selected from CH or N;

[0010] R1or R2are each independently selected from H, halogen, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C(=O)R 1a , -C(=O)-O-R 1b , -C(=O)-NR 1c R 1d or -(CH2) n1 -Q; or, R1and R2are linked to form a 5-6 membered ring; the 5-6 membered ring is optionally substituted with one or more substituents selected from halogen, cyano, oxo, C 1-6 alkyl or C 1-6 alkoxy;

[0011] R 1a or R 1b are each independently selected from hydroxyalkyl, aminoalkyl, carboxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0012] or R 1a is selected from 5-6 membered heteroaryl;

[0013] R 1c or R 1d are each independently selected from H, hydroxyalkyl, aminoalkyl, carboxyalkyl, C 1-6 alkyl or C 1-6 alkoxy;

[0014] Q is selected from -NR 1c R 1d , hydroxy, amino, carboxyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0015] R3 is selected from phenyl or 5-6 heteroaryl, wherein the phenyl or 5-6 heteroaryl group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, pentafluorothio (-SF5), C 1-6 Halogenated alkyl or C 1-6 Substituents of haloalkoxy groups;

[0016] R4 is selected from H, halogen, cyano, C. 1-6 Alkyl or C 1-6 Alkoxy;

[0017] X, Y, or Z are each independently selected from -(CH2). n2 -, -C(=O)-, -NH-, -C(=O)-NH-, -NH-C(=O)-, -S(=O) r - or A; r is selected from 0, 1, or 2;

[0018] A is selected from phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclic group;

[0019] Each R a Each group is independently selected from halogen, cyano, hydroxyl, amino, nitro, carboxyl, oxo, and C groups. 1-6 Alkyl, C 1-6 Alkyl or TMS;

[0020] Or two Rs a Together with the carbon atoms they are bonded to, they form C 3-6 cycloalkyl;

[0021] n1, n2, or m are each independently selected from 0, 1, 2, or 3;

[0022] The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups may be selected from one or more groups selected from halogen, cyano, hydroxyl, amino, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Substituents of the alkoxycarbonyl group.

[0023] In some preferred embodiments, the compound of formula (I) is selected from compounds represented by formulas (II-a), (II-b), (II-c), or (II-d).

[0024] in:

[0025] R1, R2, R3, R4, W, A, Y, Z, R a, m or r have the same definition range as for formula (I);

[0026] said compound of formula (I), wherein X is selected from -S(=0) r - as shown in formula (II-a);

[0027] said compound of formula (I), wherein X is selected from -C(=0)-, as shown in formula (II-b);

[0028] said compound of formula (I), wherein X is selected from -NH-, as shown in formula (II-c);

[0029] said compound of formula (I), wherein X is selected from A, as shown in formula (II-d).

[0030] said compound of formula (I), (II-a), (II-b), (II-c) or (II-d):

[0031] In some preferred embodiments, R1is selected from cyano, carboxyl, -C(=0)R 1a or -C(=0)-0-R 1b ; R 1a or R 1b are each independently selected from C 1-3 alkyl or C 2-4 alkenyl;

[0032] In some preferred embodiments, R1is selected from -C(=0)R 1a , R 1a is selected from C 3-6 cycloalkyl;

[0033] In some preferred embodiments, R1is selected from -C(=0)R 1a , R 1a is selected from 5-6 membered heteroaryl;

[0034] In some preferred embodiments, R1is selected from -C(=0)-NR 1c R 1d ; R 1c or R 1d are each independently selected from H or C 1-3 alkyl;

[0035] In some preferred embodiments, R 1a or R 1b are each independently selected from methyl, ethyl, ethenyl or propenyl; R 1c or R 1d are each independently selected from H, methyl or ethyl; or, R 1a is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R 1aselected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, or oxazolyl;

[0036] In some preferred embodiments, R1is selected from cyano, carboxyl, -C(=0)-CH3, -C(=0)-0-CH3, -C(=0)-0-CH2-CH3, -C(=0)-0-CH2-CH=CH2, -C(=0)-NH2, -C(=0)-NH-CH3, or -C(=0)-N(CH3)2;

[0037] In some preferred embodiments, R1is selected from -C(=0)-CH2-CH3or

[0038] In some preferred embodiments, R1is selected from

[0039] In some preferred embodiments, R1is selected from cyano;

[0040] In some preferred embodiments, R1is selected from -C(=0)-CH3, -C(=0)-0-CH3;

[0041] In some preferred embodiments, R1is selected from -C(=0)-NH2, -C(=0)-N(CH3)2.

[0042] In some preferred embodiments, R2is selected from C 1-3 alkyl or -(CH2) n1 -Q; n1is selected from 0, 1, 2, or 3; Q is selected from -NR 1c R 1d , hydroxyl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl; R 1c or R 1d are each independently selected from H or C 1-3 alkyl;

[0043] In some preferred embodiments, R 1c or R 1d are each independently selected from H, methyl, or ethyl;

[0044] In some preferred embodiments, R2is selected from methyl, ethyl, -CH2-NH2, -CH2-NH-CH3, -CH2-N(CH3)2, or

[0045] In some preferred embodiments, R2is selected from methyl;

[0046] In some preferred embodiments, R2is selected from -CH2-N(CH3)2;

[0047] In some preferred embodiments, R2is selected from

[0048] In some preferred embodiments, R1and R2are joined to form a C 5-6 cycloalkyl or 5-6 membered heterocyclyl; said C 5-6 cycloalkyl or 5-6 membered heterocyclyl is optionally substituted with one or more substituents selected from oxo, C 1-3 alkyl or C 1-3 alkoxy;

[0049] In some preferred embodiments, R1and R2are joined to form a C 5-6 cycloalkyl or 5-6 membered heterocyclyl; said C 5-6 cycloalkyl or 5-6 membered heterocyclyl is optionally substituted with one or more oxo, methyl or ethyl;

[0050] In some preferred embodiments, R1and R2are joined to form a cyclopentenyl, cyclohexenyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyridazinyl, dihydropyridazinyl, tetrahydropyrimidyl or dihydropyrimidyl, optionally substituted with one or more oxo or methyl;

[0051] In some preferred embodiments, R1and R2are joined to form optionally substituted with one or two methyl groups.

[0052] In some preferred embodiments, R3is selected from phenyl or 6-membered heteroaryl; said phenyl or 6-membered heteroaryl is optionally substituted with one or more substituents selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl or C 1-3 haloalkoxy;

[0053] In some preferred embodiments, R3is selected from phenyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl, optionally substituted with one or more substituents selected from halogen, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl or fluorosubstituted methoxy;

[0054] In some preferred embodiments, R3is selected from phenyl or pyridyl, optionally substituted with one methyl, trifluoromethyl or difluoromethyl;

[0055] In some preferred embodiments, R3is selected from phenyl or pyridyl, optionally substituted with one F, Cl, Br or I;

[0056] In some preferred embodiments, R3is selected from phenyl substituted with one Br;

[0057] In some preferred embodiments, R3is selected from phenyl or pyridyl, optionally substituted with one pentafluorosulfonyl group (-SF5);

[0058] In some preferred embodiments, R3is selected from trifluoromethylphenyl;

[0059] In some preferred embodiments, R3is selected from trifluoromethylpyridyl;

[0060] In some preferred embodiments, R3is selected from difluoromethylphenyl.

[0061] In some preferred embodiments, R4is selected from H.

[0062] In some preferred embodiments, X, Y or Z is selected from one of the following conditions:

[0063] (1) one of X, Y or Z is selected from -S(=O) r - and the other two are each independently selected from -(CH2) n2 -, -C(=O)-, -NH-, -C(=O)-NH- or -NH-C(=O)-;

[0064] (2) one of X, Y or Z is selected from A and the other two are each independently selected from -(CH2) n2 -, -C(=O)-, -NH-, -C(=O)-NH- or -NH-C(=O)-;

[0065] In some preferred embodiments, X, Y or Z is selected from one of the following conditions:

[0066] (1) X is selected from -S(=O) r - and Y is selected from -(CH2) n2 -, -NH- or -NH-C(=O)- and Z is selected from -(CH2) n2 - or -C(=O)-;

[0067] (2) Y is selected from -S(=O) r - and X is selected from -(CH2) n2 -, -NH- or -C(=O)-NH- and Z is selected from -(CH2) n2 -;

[0068] (3) Z is selected from -S(=O) r - and X is selected from -(CH2) n2 -, -C(=O)-, -NH-, -C(=O)-NH- or -NH-C(=O)- and Y is selected from -(CH2) n2 -, -NH- or -C(=O)-NH-;

[0069] (4) X is selected from -C(=0)-, Y is selected from -(CH2) n2 - or -NH-, Z is selected from -(CH2) n2 -;

[0070] (5) Z is selected from -C(=0)-, X is selected from -(CH2) n2 -, -C(=0)-, -NH-, -C(=0)-NH- or -NH-C(=0)-, Y is selected from -(CH2) n2 - or -NH-;

[0071] (6) X is selected from -NH-, Y is selected from -(CH2) n2 - or -C(=0)-, Z is selected from -(CH2) n2 -;

[0072] (7) X is selected from -(CH2) n2 -, Y is selected from -(CH2) n2 -, -C(=0)-, -NH-, -C(=0)-NH- or -NH-C(=0)-, Z is selected from -(CH2) n2 -;

[0073] (8) X is selected from A, said A is selected from phenyl or 5-6 membered heteroaryl, Y is selected from -(CH2) n2 -, -C(=0)-, -NH-, -C(=0)-NH- or -NH-C(=0)-, Z is selected from -(CH2) n2 - or -C(=0)-;

[0074] (9) Y is selected from A, said A is selected from phenyl or 5-6 membered heteroaryl, X is selected from -(CH2) n2 -, -C(=0)-, -NH-, -C(=0)-NH- or -NH-C(=0)-, Z is selected from -(CH2) n2 - or -C(=0)-;

[0075] (10) Z is selected from A, said A is selected from phenyl or 5-6 membered heteroaryl, X is selected from -(CH2) n2 -, -C(=0)-, -NH-, -C(=0)-NH- or -NH-C(=0)-, Y is selected from -(CH2) n2 -, -NH-, -C(=0)-, -C(=0)-NH- or -NH-C(=0)-.

[0076] In some preferred embodiments, X, Y or Z is selected from one of the following conditions:

[0077] (1) X is selected from -S-, -S(=0)- or -S(=0)2-, Y is selected from -(CH2) n2- -NH-, Z is selected from -(CH2) n2 -;

[0078] (2) X is selected from -C(=0)-, Y is selected from -NH-, Z is selected from -(CH2) n2 -;

[0079] (3) X is selected from -NH-, Y is selected from -C(=0)-, Z is selected from -(CH2) n2 -;

[0080] (4) X is selected from A, said A is selected from 5-membered heteroaryl, Y is selected from -(CH2) n2 - or -C(=0)-, Z is selected from -(CH2) n2 -.

[0081] r is selected from 0 or 1 or 2; n2 is selected from 0, 1, 2 or 3.

[0082] In some preferred embodiments, said A is selected from phenyl or 5-6 membered heteroaryl;

[0083] In some preferred embodiments, said A is selected from phenyl or 5-membered heteroaryl;

[0084] In some preferred embodiments, said A is selected from 5-membered heteroaryl;

[0085] In some preferred embodiments, said A is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl;

[0086] In some preferred embodiments, said A is selected from pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, triazolyl or thiazolyl.

[0087] In some preferred embodiments, each R a is independently selected from halogen, cyano, hydroxyl, amino, nitro, oxo, C 1- 3alkyl, C 1-3 alkoxy or TMS; m is selected from 0, 1, 2 or 3.

[0088] or two R a together with the carbon atom to which they are both attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0089] In some preferred embodiments, each R a is independently selected from hydroxyl, amino, nitro, oxo, methyl or TMS; m is selected from 0, 1, 2 or 3.

[0090] In some preferred embodiments, each R aeach independently selected from amino, oxo, methyl or TMS; m is selected from 0, 1, 2 or 3.

[0091] In some preferred embodiments, the compound of formula (I) is selected from any one of the following:

[0092] Table 1

[0093] The compounds described herein further include stereoisomers, racemates thereof, when a chiral center is present.

[0094] The present application provides an intermediate compound of formula (V) or a pharmaceutically acceptable salt thereof,

[0095] wherein:

[0096] R1, R2, R3, R4, W, A or r are as described in formula (I);

[0097] R5is selected from halogen, hydroxyl, amino, nitro, carboxyl, -C(=O)R 5a , -C(=O)-O-R 5b , -C(=O)-NR 5c R 5d , -S(=O) r -NR 5c R 5d , -S(=O) r -(CH2) n3 -R 5e , -C 2-6 alkylene-R 5f or -A(R 5g ) u ;

[0098] R 5a and R 5b are each independently selected from hydroxyalkyl, aminoalkyl, carboxyalkyl, C 1-6 alkyl or C 2-6 alkenyl; R 5c or R 5d are each independently selected from H, hydroxyalkyl, aminoalkyl, carboxyalkyl, C 1-6 alkyl or C 1-6 alkoxy; R 5e is selected from halogen, hydroxyl, amino or carboxyl; R 5f is selected from TMS, TBS or SEM; each R 5g is each independently selected from halogen, C1-6 alkyl, C 1-6 alkoxy, R 5f , -(CH2) n3 -R 5e , -(CH2) n3 -C(=O)-R 5a , -(CH2) n3 -C(=O)-O-R 5b or -(CH2) n3 -O-R 5f ;

[0099] R6is selected from H, C 1-6 alkyl, -(CH2) n4 -C(=O)-R 6a , -(CH2) n4 -C(=O)-O-R 6b , -(CH2) n4 -R 6c or -(CH2) n4 A(R 5g ) u ; R 6a or R 6b are each independently selected from A(R 5g ) u , hydroxy, amino, C 1-6 alkyl or C 2-6 alkenyl; R 6c is selected from hydroxy, amino or carboxy;

[0100] the hydrogen atoms of -CH2- in said -(CH2) n3 - or -(CH2) n4 - are optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, nitro, carboxy, oxo, C 1-6 alkyl, C 1-6 alkoxy;

[0101] n3, n4or u are each independently selected from 0, 1, 2 or 3.

[0102] In some preferred embodiments, R5is selected from halogen, hydroxy, amino, nitro or carboxy;

[0103] In some preferred embodiments, R5is selected from -C(=O)R 5a or -C(=O)-O-R 5b ; R 5a and R 5b are each independently selected from C 1-3 alkyl or C 2-6 alkenyl; preferably, R 5a and R 5beach independently selected from methyl, ethyl, vinyl or propenyl;

[0104] In some preferred embodiments, R5is selected from -C(=O)-NR 5c R 5d or -S(=O) r -NR 5c R 5d ; R 5c or R 5d each independently selected from H, hydroxyalkyl or C 1-3 alkyl; preferably, R 5c or R 5d each independently selected from H, methyl, -CH2-OH, -(CH2)2-OH or -(CH2)3-OH;

[0105] In some preferred embodiments, R5is selected from -S(=O) r -(CH2) n3 -R 5e ; R 5e selected from halogen or hydroxyl;

[0106] In some preferred embodiments, R5is selected from

[0107] In some preferred embodiments, R5is selected from -C 2-6 alkynylene-R 5f ; R 5f selected from TMS, TBS or SEM; preferably, the C 2-6 alkynylene is selected from ethynylene or propynylene;

[0108] In some preferred embodiments, R5is selected from -A(R 5g ) u ; each R 5g each independently selected from halogen, C 1-3 alkyl, R 5f , -(CH2) n3 -R 5e , -(CH2) n3 -C(=O)-R 5a , -(CH2) n3 -C(=O)-O-R 5b or -(CH2) n3 -O-R 5f ;

[0109] In some preferred embodiments, R5is selected from F, CI, Br, hydroxyl, amino, nitro, carboxyl, -C(=0)-CH3, -C(=0)-0-CH3, -C(=0)-0-CH2-CH3, -C(=0)-0-CH2-CH=CH2, -C(=0)-NH-(CH2)2-OH, -S-(CH2)2-OH, -S-(CH2)3-OH, -S(=0)2-Cl, -S(=0)2-N(CH3)-(CH2)2-OH,

[0110] In some preferred embodiments, R6is selected from H;

[0111] In some preferred embodiments, R6is selected from -(CH2) n4 -C(=0)-R 6a ; R 6a is selected from -A(R 5g ) u , hydroxyl or amino;

[0112] In some preferred embodiments, R6is selected from -(CH2) n4 -C(=0)-0-R 6b ; R 6b is selected from methyl, ethyl, ethenyl or propenyl;

[0113] In some preferred embodiments, R6is selected from -(CH2) n4 -R 6c ; R 6c is selected from hydroxyl, amino, nitro or carboxyl;

[0114] In some preferred embodiments, R6is selected from -(CH2) n4 -A(R 5g ) u ; n4is selected from 0, 1, 2 or 3; u is selected from 0 or 1 or 2;

[0115] In some preferred embodiments, R6is selected from H, -CH2-C(=0)-0-CH3, -CH2-C(=0)-OH, -(CH2)2-OH, -(CH2)2-NH2or

[0116] In some preferred embodiments, the intermediate compound of formula (V) is selected from the following compounds of formula (V-a), (V-b), (V-c), (V-d), (V-e), (V-f) or (V-g):

[0117] wherein,

[0118] W, R1, R2, R3, R4, R5, A, R 5g or u is as described in formula (V);

[0119] R6' is selected from R6 and is not H;

[0120] R7 is selected from hydroxy, amino, C 1-6 alkyl, -O-R 7a or -NR 7b R 7c ; R 7a is selected from C 1-6 alkyl or C 2-4 alkenyl; R 7b or R 7c wherein one is selected from H or C 1-6 alkyl and the other is selected from hydroxyalkyl, aminoalkyl or carboxyalkyl; or, R7 is linked to R2 to form a 5-6 membered ring substituted with oxo;

[0121] In some preferred embodiments, R7 is selected from hydroxy, amino or -O-R 7a ; R 7a is selected from methyl, ethyl, ethenyl or propenyl;

[0122] In some preferred embodiments, R7 is selected from hydroxy, amino, -O-CH2-CH=CH2 or -O-CH3;

[0123] In some preferred embodiments, R7 is linked to R2 to form a C 5-6 cycloalkyl or 5-6 membered heterocyclyl; said C 5-6 cycloalkyl or 5-6 membered heterocyclyl is optionally substituted with one or more C 1-3 alkyl or C 1-3 alkoxy; preferably, said C 5-6 cycloalkyl or 5-6 membered heterocyclyl is optionally substituted with one or more methyl or ethyl groups;

[0124] In some preferred embodiments, R7 is linked to R2 to form a cyclopentenyl, cyclohexenyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyridazinyl, dihydropyridazinyl, tetrahydropyrimidyl or dihydropyrimidyl ring substituted with one oxo group, optionally substituted with one or more methyl groups;

[0125] In some preferred embodiments, R7 is linked to R2 to form or, optionally substituted with one or two methyl groups;

[0126] R8 is selected from H, C 1-6 alkyl or C 2-4 alkenyl;

[0127] In some preferred embodiments, R8is selected from H, methyl, ethyl, ethenyl or propenyl;

[0128] R9and R 10 each independently selected from H, halogen, hydroxyl, amino, nitro, carboxyl, C 1-6 alkyl or C 1-6 alkoxy; or R9and R 10 are joined to form oxo;

[0129] In some preferred embodiments, R9and R 10 each independently selected from H, hydroxyl, amino, nitro, carboxyl, methyl, ethyl or methoxy; or R9and R 10 are joined to form oxo;

[0130] In some preferred embodiments, R9and R 10 each independently selected from H or amino;

[0131] p is selected from 0 or 1 or 2;

[0132] R 11 is selected from -A(R 5g ) u .

[0133] In some preferred embodiments, the intermediate compound of formula (V) is selected from any one of the following compounds:

[0134] Table 2

[0135] The present application provides a method for preparing a compound of formula (II-b1) or a salt thereof,

[0136] wherein R1, R2, R3, R4, R6, R8, W, Z, R a or m are as previously described;

[0137] R5is selected from halogen, preferably R5is selected from F or Br;

[0138] characterized in that a carbonylation reaction of formula (V) under palladium catalysis gives formula (V-e), formula (V-e) is subjected to hydrolysis, deprotection and intramolecular cyclization to give formula (II-b1).

[0139] The present application provides a method for preparing a compound of formula (II-a2) or a salt thereof,

[0140] wherein R2, R3, R4, R7, R9, R 10, W or p are as described above;

[0141] R5 is selected from halogen, preferably R5 is selected from F or Br;

[0142] characterized in that formula (V-c) is reacted with a thiol under basic conditions to give formula (V-f), formula (V-f) is intramolecularly cyclized to give formula (II-a1), formula (II-a1) is further oxidized to give formula (II-a2).

[0143] The present application provides a method for preparing a compound of formula (II-d) or a salt thereof,

[0144] wherein R1, R2, R3, R4, R 11 , W, A, Y, Z, R a or m are as described above;

[0145] R5 is selected from halogen, preferably R5 is selected from F or Br;

[0146] characterized in that formula (V-a) is reacted with formula (VI) to give formula (V-g), formula (V-g) is intramolecularly cyclized to give formula (II-d).

[0147] The present application provides a pharmaceutical composition containing any of the compounds of the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0148] The present application provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for a disease caused by abnormal increase of neutrophil elastase.

[0149] The disease includes acute lung injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, bronchiectasis, sepsis, etc.

[0150] Terminology:

[0151] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0152] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms (C 1-6 alkyl), more preferably alkyl groups containing 1 to 3 carbon atoms (C 1-3Alkyl groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and their various branched isomers. Alkyl groups can be substituted or unsubstituted.

[0153] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described herein. Preferably, alkoxy groups (C-) contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. 1-12 Alkoxy groups, more preferably alkoxy groups containing 1 to 6 carbon atoms (C 1-6 Alkoxy groups, more preferably alkoxy groups containing 1 to 3 carbon atoms (C 1-3 Alkoxy groups. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0154] The term "alkenyl" refers to a linear or branched hydrocarbon group containing one or more double bonds and having 2 to 20 carbon atoms, preferably "C". 2-6 "Alkenyl". "C" 2-6 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, preferably having 2 or 3 carbon atoms (i.e., C46, ​​C56, C6 ... 2-3 Alkenyl). Non-limiting examples of alkenyl groups include: vinyl, propenyl, and butenyl. The alkenyl group may be substituted or unsubstituted.

[0155] The term "alkynyl" refers to a straight or branched hydrocarbon group that contains one or more triple bonds and has 2 to 20 carbon atoms, preferably "C". 2-6 "Alkyne group". "C" 2-6 "Alkyne group" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, preferably 2 or 3 carbon atoms (i.e., C46, ​​C56, C6 ... 2-3 (Alynyl group). Non-limiting examples of alkynyl groups include ethynyl and propynyl. The alkynyl group may be substituted or unsubstituted.

[0156] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms (C4, C5, C6, C7, C8, C9 ... 3-6 cycloalkyl), more preferably containing 5-6 carbon atoms (C5-6 Cycloalkyl groups. The ring atoms may optionally be oxidized (=O). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc. etc.; cycloalkyl groups can be substituted or unsubstituted.

[0157] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (=O) (i.e., forming sulfoxide or sulfone), but excluding the ring moiety of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon, wherein the ring carbon atoms may optionally be oxidized (=O). Preferably, it comprises 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of heterocyclic groups include pyrrolyl, dihydropyrrolyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridyl, dihydropyridyl, piperidyl, piperazinyl, tetrahydropyridazinyl, dihydropyridazinyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. The heterocyclic group can be substituted or unsubstituted.

[0158] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, more preferably phenyl. The aryl group may be substituted or unsubstituted.

[0159] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyrrole, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. The heteroaryl group can be substituted or unsubstituted.

[0160] The terms "alkyl", "alkoxy", "alkenyl", "alkynyl", "cycloalkyl", "heterocyclyl", "aryl", and "heteroaryl" and the like in the present text can be substituted or unsubstituted; when substituted, it can be substituted at any available attachment point with one or more, the same or different, substituents each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, nitro, carboxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0161] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein. Non-limiting examples include trifluoromethyl, difluoromethyl, monofluoromethyl.

[0162] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein.

[0163] The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same carbon atom, i.e., a carbonyl group replacing a methylene group.

[0164] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined herein, non-limiting examples of hydroxyalkyl include -CH2-OH, -(CH2)2-OH, or -(CH2)3-OH, and the like.

[0165] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, wherein alkyl is as defined herein, non-limiting examples of aminoalkyl include -CH2-NH2, -(CH2)2-NH2, or -(CH2)3-NH2, and the like.

[0166] The term "halogen" refers to F, CI, Br, or I.

[0167] The term "cyano" refers to -CN.

[0168] The term "hydroxy" refers to -OH.

[0169] The term "amino" refers to -NH2.

[0170] The term "nitro" refers to -NO2.

[0171] The term "carboxy" refers to -C(=O)OH.

[0172] The term "TMS" refers to trimethylsilyl.

[0173] The term "SEM" refers to (trimethylsilyl)ethoxymethyl.

[0174] The term "TBS" refers to tert-butyldimethylsilyl.

[0175] The term "pentafluorosulfonyl" means -SF5.

[0176] The compounds described herein The compounds described herein indicates the corresponding position of the carbon-carbon double bond in the pyrimidinone of formula (I).

[0177] The compounds described herein indicates the position of the substituent to which the substituent is attached.

[0178] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and this description includes situations where the event or circumstance occurs and situations where it does not. For example, "heterocyclic groups optionally substituted with alkyl" means that alkyl can or can not be present, and this description includes situations where the heterocyclic group is substituted with alkyl and situations where the heterocyclic group is not substituted with alkyl.

[0179] "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more, preferably 1, 2, 3 or 4.

[0180] "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of one another replaced with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can or cannot be possible (experimentally or theoretically) to determine by a person skilled in the art without undue effort. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0181] "pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and to facilitate absorption of the active ingredient(s) to elicit the biological activity.

[0182] "pharmaceutically acceptable" or "pharmacologically acceptable" means relatively non-toxic, safe, and suitable for use with humans and other animals.

[0183] "pharmaceutically acceptable salt" means a salt of a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic moiety, for example an amino group, base addition salts can be obtained by contacting the compound in a suitable inert solvent with a sufficient amount of the pharmaceutically acceptable base to produce the salt. When a compound contains a relatively basic moiety, for example a carboxyl group, acid addition salts can be obtained by contacting the compound in a suitable inert solvent with a sufficient amount of the pharmaceutically acceptable acid to produce the salt.

[0184] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. If there is an inconsistency between the definitions of terms as defined herein and as used in the art, the definition as used in the art shall prevail. DETAILED DESCRIPTION

[0185] The present application is described in detail below by way of Examples, but it is not meant to be limited by how the application is described. The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed from a combination of the other synthetic methods and equivalent substitutions well known to those skilled in the art, preferred embodiments but not limited to the Examples of the present application.

[0186] General Methods: The compounds of the present application can be prepared according to the following non-limiting general methods and Examples

[0187] Scheme 1: Intermediates of formula (V-a) or (V-b) can be synthesized according to Route 1, wherein R1, R2, R3, R4, R5, R6' or W are as previously described;

[0188] As shown in Route 1, intermediates of general formula (V-a) can be obtained by heating commercially available or synthesized aldehydes (III-1), ureas (III-2), and ketones (III-3) in the presence of an acid (such as acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, polyphosphoric acid) in a stable organic solvent, according to a method reported in the patent (WO2008003412). Intermediates of general formula (V-b) can be obtained by alkylation of (V-a) under basic conditions, or by reaction with an alcohol (R6'OH) (Mitsunobu).

[0189] Scheme 2: Intermediates (V-c) or (V-d) can be synthesized according to Route 2, wherein R1, R2, R3, R4, R5, R6', R7 or W are as previously described;

[0190] As shown in Scheme 2, intermediate general compound (VII) can be obtained by reacting commercially available or synthetically accessible aldehyde (III-1) with sodium benzenesulfmate and BocNH2 in the presence of formic acid (J. Am. Chem. Soc, 2012, 134, 18193-18196, Org. Syn., 2009, 86-11-17). Intermediate general compound (IX) can be obtained by reacting (VIII) with R3-NH2 catalyzed by ytterbium triflate (Synth. Commun. 2010, 40, 2506-2510, J. Heterocyclic Chem., 2002, 39-965-973). Intermediate general compound (XI) can be prepared by reacting (VII) with (IX) in the presence of an inorganic base such as NaH or potassium tert-butoxide. Intermediate general compound (XII) can be obtained by deprotection of (XI) by acid treatment such as hydrochloric acid. Intermediate general compound (V-c) can be prepared by reacting (XII) with phosgene, triphogene, or carbonyldiimidazole in the presence of a suitable inorganic or organic base such as sodium carbonate, DIEPA or pyridine (Tetrahedron Lett, 2011, 67, 8564-8571). Intermediate general compound (V-d) can be obtained by alkylation of (V-c) under basic conditions, or (Mitsunobu) reaction with an alcohol (R6OH).

[0191] Scheme 3: Formula (I-b1) can be synthesized according to the method of Scheme 3, wherein R1, R2, R3, R4, R6, R8, W, Z, R a or m is as described above;

[0192] R5is selected from halogen, preferably R5is selected from F or Br;

[0193] Palladium catalyzed carbonylation of formula (V) gives formula (V-e), which is subjected to hydrolysis, deprotection and intramolecular cyclization to give formula (II-b1).

[0194] Scheme 4: Formula (II-a1) or (II-a2) can be synthesized according to the method of Scheme 4, wherein R2, R3, R4, R7, R9, R 10 , W or p is as described above;

[0195] R5is selected from halogen, preferably R5is selected from F or Br;

[0196] (V-f) under basic conditions, intramolecular cyclization (Mitsunobu) of (V-f) to give (II-a1), and further oxidation of (II-a1) to give (II-a2).

[0197] Scheme 5: Formula (II-c) can be synthesized according to the method of Route 5, wherein R1, R2, R3, R4, R 11 , W, R a or m are as previously described;

[0198] R5is selected from halogen, preferably R5is selected from F or Br;

[0199] (V-a) with a Suzuki reaction with a heterocyclic boron ester of formula (VI) to give (V-g), intramolecular cyclization (Mitsunobu) of (V-g) to give (II-d).

[0200] When the compounds of the present application exist as stereoisomers, the stereoisomers can be resolved by methods known in the art, for example, the compounds of the present application can be purified by SFC to obtain two enantiomers (R and S). The specific SFC purification conditions are: column Chiracel AD-3 (460 mm I.D. x 5 cm L); eluent CO2: Ethanol (0.05% DEA) (70:30 v / v); detection wavelength: 254 nm, flow rate: 2.5 ml / min.

[0201] Preparations and Examples

[0202] The following examples are illustrative of the present application and are not meant to limit the application in any way. Unless otherwise indicated, all parts are parts by weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. All data are measured by Agilent 6120 and / or 1100. All reagents used in the present application are obtained from commercial sources, except for synthetic intermediates. The names of all compounds, except reagents, are generated by ChemDrew 20.0.

[0203] The following abbreviations are used: ACN acetonitrile Boc tert-butyloxycarbonyl (Boc)20 di-tert-butyl dicarbonate BH3 borane DCM dichloromethane DMF N,N-dimethylformamide DIEPA N,N-diisopropylethylamine EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EA ethyl acetate Et3N triethylamine HATU 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU O-benzotriazol-tetramethyluronium hexafluorophosphate HOAc acetic acid HOBt 1-hydroxybenzotriazole ee enantiomeric excess mL milliliter g gram mg milligram ng nanogram mol mole mmol millimole h hour MeOH methanol NaH sodium hydride NCS N-chlorosuccinimide PE petroleum ether Pd(dppf)2Cl2 [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium Pd2(dba)3 tris(dibenzylideneacetone)dipalladium Pd(PPh3)4 tetrakis(triphenylphosphine)palladium PMB p-methoxy cyanobenzyl PPh3 triphenylphosphine Pin2B2 pinacolatoboronic acid THF tetrahydrofuran TFA trifluoroacetic acid TsOH 4-toluenesulfonic acid Xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Burgess reagent N-(triethylammoniumsulfonyl)carbamate

[0204] 1. Intermediate I01:

[0205] a) To a solution of 3-bromo-4-formylbenzonitrile (101A, 15 g, 71.4 mmol), 1-(3- (trifluoromethyl)phenyl)urea (101B, 17.5 g, 85.8 mmol), allyl 3-oxobutanoate (101C, 15 mL, 109.5 mmol) in dioxane (200 mL) was added PPA (24 g) at room temperature. After stirring at 60 °C for 2.5 days, it was cooled to room temperature, dioxane was removed, and water (400 mL) was added. Ethyl acetate (500 mL x 3) was extracted, and the organic phase was washed with saturated NaHC03(500 mL) and saturated brine (500 mL) successively, dried over anhydrous Na2S04, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 5:1) to give the product 101D (23.4 g, 63%) as a white solid. MS (ESI): m / z 520.0 [M+H] + .

[0206] b) To a solution of 101D (15 g, 71.4 mmol), 1,3-dimethylbarbituric acid (12 g, 77 mmol) in THF (200 mL) was added Pd(PPh3)4(1.8 g, 1.55 mmol) at room temperature. After stirring at room temperature overnight, water (100 mL) was added. Ethyl acetate (100 mL x 3) was extracted, dried over anhydrous Na2S04, filtered, and concentrated to give the product 101E (6 g, 82%) as a yellow solid. MS (ESI): m / z = 482.0 [M+H] + The crude product was used directly in the next reaction without purification.

[0207] c) To a solution of 101E (5 g, 12.5 mmol) in DCM (100 mL) was added NH4HC03(2 g, 25 mmol), HATU (9.5 g, 25 mmol), and DIPEA (3.2 g, 25 mmol) at room temperature. After stirring at room temperature for 3 h, water (20 mL) was added. The organic phase was separated, dried over anhydrous Na2S04, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 5:1) to give the product 101F (5.8 g, 97%) as a white solid. MS (ESI): m / z = 481.0 [M+H] + .

[0208] d) To a solution of 101F (5.8 g, 12 mmol) in DCM (100 mL) was added Burgess reagent (5.7 g, 24 mmol) at room temperature. After stirring at room temperature for 30 min, water (20 mL) was added. The organic phase was separated, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 5:1) to give the product 101 (5 g, 90%) as a white solid. MS (ESI): m / z = 461.0 [M+H] + .

[0209] Example 1: Synthesis of compounds 1 and 2

[0210] a) A mixture of cyclopentane-1,3-dione (4 g, 40.8 mmol), 3-(trifluoromethyl)aniline (6.57 g, 40.8 mmol) and ytterbium triflate (127 mg, 0.2 mmol) was stirred at room temperature for 1 h. Then methanol was added until the reaction solution was homogeneous. Water (500 mL) was added and the solid was filtered, washed with water and dried to give the product 1a (9 g, 92%) as a brown solid. MS (ESI): m / z = 242.1 [M+H] + .

[0211] b) To a solution of 3-fluoro-4-formylbenzonitrile (5 g, 33.6 mmol) in THF (10 mL) was added formic acid (10.8 g, 234.9 mmol), BocNH2 (4.32 g, 36.9 mmol), sodium benzenesulfonate (6.05 g, 36.9 mmol) and water (100 mL) sequentially at room temperature. After stirring at room temperature overnight for 6 days, ethyl acetate (350 mL x 3) was added, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 5:1) to give the product 1b (10.7 g, 81%) as a white solid. MS (ESI): m / z = 413.2 [M+Na] + .

[0212] c) To a solution of 1a (4.45 g, 18.5 mmol) in 2-Me THF (100 mL) was added NaH (60% in mineral oil, 738 mg, 18.5 mmol) at room temperature. After stirring for 1 h, 1b (6 g, 18.4 mmol) was added and then stirred overnight. Water (300 mL) was added. Ethyl acetate (300 mL x 3) was added, dried over anhydrous Na2SO4, filtered, concentrated to give the product 1c (6 g, 82%) as a yellow solid. MS (ESI): m / z = 482.0 [M+H] + . The crude product was used directly in the next step without purification.

[0213] d) To a solution of 1c (5.8 g, 11.9 mmol) in dioxane (50 mL) was added HC1 / dioxane (17.8 mL, 4 mol / L, 71.2 mmol) at room temperature. After stirring at room temperature for 3 h, the reaction mixture was concentrated to give the product 1d (5.1 g, 95%) as a yellow solid. MS (ESI): m / z = 412.2 [M+Na] + .

[0214] e) To a solution of 1d (crude 5.1 g, 12.1 mmol) in MeCN (200 mL) was added CDI (2.46 g, 15.2 mmol) and TEA (609 mg, 6 mmol) sequentially at room temperature. After stirring at room temperature overnight, water (400 mL) was added. The reaction mixture was extracted with ethyl acetate (400 mL x 3), dried over anhydrous Na2S04, filtered, concentrated and purified by column chromatography (PE:EtOAc = 1:3) to give the product 1e (4.5 g, 90%) as a yellow solid. MS (ESI): m / z = 416.2 [M+H] + .

[0215] f) To a solution of 2-mercaptoethanol-1-ol (1.26 g, 16.2 mmol) in DMF (50 mL) was added NaH (640 mg, 16.2 mmol, purity: 60%) at 0 °C. After stirring for 1 h, 1e (4.8 g, 11.6 mmol) was added and then stirred at room temperature for 3 h. The reaction mixture was adjusted to pH 6 with acetic acid and purified directly by prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) to give the product 1f (1.2 g, 22%) as a yellow solid. MS (ESI): m / z = 474.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.16 (d, J = 1.6 Hz, 1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.85-7.67 (m, 5H), 5.86 (s, 1H), 3.63-3.52 (m, 2H), 3.22-3.09 (m, 2H), 2.33-2.18 (m, 4H).

[0216] g) To a solution of 1f (150 mg, 0.32 mmol) and PPh3 (167 mg, 0.63 mmol) in THF (10 mL) was added CBr4 (200 mg, 0.63 mmol) at room temperature.

[0217] DIAD (128 mg, 0.63 mmol) was added. After stirring at room temperature for 2 h, water (0.2 mL) was added. Concentration, prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) direct purification gave the product 2 (100 mg, 69%) as a white solid. MS (ESI): m / z = 416.2 [M+H] + . MS (ESI): m / z = 456.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.10 (d, J = 1.6 Hz, 1H), 7.84-7.83 (m, 2H), 7.81-7.78 (m, 1H), 7.75-7.68 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 5.80 (s, 1H), 4.56-4.52 (m, 1H), 3.59-3.52 (m, 1H), 3.26-3.22 (m, 1H), 2.78-2.71 (m, 1H), 2.62-2.51 (m, 2H), 2.48-2.39 (m, 2H).

[0218] h) To a solution of 2 (crude 880 mg, 0.978 mmol) in DCM (20 mL) was added m-CPBA (500 mg, 2.9 mmol) at 0 °C.

[0219] After stirring at room temperature for 2 h, DCM (250 mL) was added, then washed with saturated NaHCO3(3 x 50 mL), and saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) direct purification gave the product 1 (140 mg, 30%) as a white solid. MS (ESI): m / z = 488.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.35 (d, J = 1.6 Hz, 1H), 8.22-8.19 (m, 1H), 7.85-7.65 (m, 5H), 6.06 (s, 1H), 4.56-4.53 (m, 1H), 3.88-3.66 (m, 3H), 2.61-2.54 (m, 2H), 2.48-2.44 (m, 2H).

[0220] The following compounds were synthesized using a similar method:

[0221] Table 3

[0222] Example 2: Synthesis of compound 3

[0223] a) To a solution of 3a (3a was obtained by the same method as synthesis le, 1 g, 2.1 mmol) in THF (10 mL) was added tert-butyl carbamate (2-hydroxyethyl) (450 mg, 2.8 mmol), PPh3 (1.54 g, 6.9 mmol) and DIAD (1.4 g, 9 mmol) successively at room temperature. After stirring at room temperature overnight, water (30 mL) was added. Ethyl acetate (100 mL x 3) was extracted, dried over anhydrous Na2S04, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 3: 1) to give the brown solid product 3b (200 mg, 15%). MS (ESI): m / z = 565.0 [M-55] + .

[0224] b) A solution of 3b (200 mg, 0.32 mmol), Pd(OAc)2 (8 mg, 0.032 mmol), PPh3 (8 mg, 0.032 mmol) and TEA (65 mg, 0.64 mmol) in EtOH (5 mL) and DMF (2 mL) was stirred under carbon monoxide gas at 80 °C

[0225] overnight. Cooled to room temperature, water (10 mL) was added. Ethyl acetate (15 mL x 3) was extracted, dried over anhydrous Na2S04, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 3: 1) to give the brown solid product 3c (50 mg, 25%). MS (ESI): m / z = 613.0 [M+H] + .

[0226] c) To a solution of 3c (50 mg, 0.082 mmol) in dioxane (2 mL) was added 4N HC1 / dioxane (2 mL, 8 mmol) at room temperature. After 3 hours at room temperature, concentrated to give the yellow solid product 3d (35 mg, 77%). MS (ESI): m / z = 513.2 [M+H] + .

[0227] d) To a mixture of 3d (20 mg, 0.036 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH H2O (17 mg, 0.4 mmol) at room temperature and stirred overnight. The pH was adjusted to 1 with 1 N HC1 and extracted with ethyl acetate (15 mL x 3), dried over anhydrous Na2S04, filtered, concentrated and purified by column chromatography (3% MeOH / DCM) to give the product 3e (15 mg, 86%) as a white solid. MS (ESI): m / z = 485.1 [M+H] + .

[0228] e) To a solution of 3e (15 mg, 0.03 mmol) in DCM (4 mL) was added HOBt (8 mg, 0.06 mmol) HBTU (23 mg, 0.06 mmol) and DIPEA (8 mg, 0.06 mmol) at room temperature and stirred overnight. Water (10 mL) was added and extracted with DCM (30 mL x 3), dried over anhydrous Na2S04, filtered, concentrated and purified by column chromatography (PE:EtOAc = 3: 1) to give the product 3 (2 mg, 15%) as a brown solid. MS (ESI): m / z = 565.0 [M-55] + .

[0229] Example 3: Synthesis of compound 4

[0230] a) To a solution of 4a (4a was obtained by the same method as synthesis of le, 200 mg, 0.42 mmol) in THF (5 mL) was added LiHMDS (1 mol / L in THF, 0.84 mL, 0.84 mmol) dropwise at room temperature and stirred for 30 min. Methyl 2-bromoacetate (128 mg, 0.84 mmol) was added. After stirring at room temperature for 1 h, water (5 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2S04, filtered, concentrated and purified by column chromatography (PE:EtOAc = 3: 1) to give the product 4b (40 mg, 22%) as a brown solid. MS (ESI): m / z = 515.1 [M+H] + .

[0231] b) To a solution of 4b (40 mg, 0.08 mmol) in EtOH (5 mL) was added Fe (8.6 mg, 0.16 mmol) and NH4CI (17 mg, 0.32 mmol) at room temperature. The mixture was stirred at 80 °C overnight under N2. Cooled to room temperature, water (5 mL) was added. The mixture was extracted with EtOAc (10 mL x 3), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography (PE:EtOAc = 3: 1) to give the product 4c (30 mg, 80%) as a brown solid. MS (ESI): m / z = 485.1 [M+H] + .

[0232] c) To a mixture of 4c (30 mg, 0.06 mmol) in THF (2 mL) and H20 (2 mL) was added LiOH H20 (17 mg, 0.4 mmol) at room temperature. The mixture was stirred overnight. The pH was adjusted to 1 with 1 N HC1. The mixture was extracted with EtOAc (15 mL x 3), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography (3% MeOH / DCM) to give the product 4d (8 mg, 28%) as a white solid. MS (ESI): m / z = 471.1 [M+H] + .

[0233] d) To a solution of 4d (8 mg, 0.017 mmol) in DCM (4 mL) was added HATU (13 mg, 0.034 mmol) and DIPEA (4.4 mg, 0.034 mmol) at room temperature. The mixture was stirred overnight. Water (10 mL) was added. The mixture was extracted with DCM (30 mL x 3), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) to give the product 4 (1.9 mg, 5%) as a white solid. MS (ESI): m / z = 453.1 [M+H] + .

[0234] Example 4: Synthesis of compound 9

[0235] a) To a solution of 3-mercapto-propan-1-ol (138 mg, 1.5 mmol) in DMF (50 mL) was added NaH (NaH (60 mg, 1.5 mmol, 60% in mineral oil) at 0 °C. After stirring for 30 min, 9a (9a was obtained in the same way as synthesis I01, 300 mg, 0.75 mmol) was added, then stirred at room temperature for 1 h. Acetic acid (1 mL), water (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 3:1) to give the product 9b (150 mg, 44%) as an oil. MS (ESI): m / z = 473.1 [M+H] + .

[0236] b) To a solution of 9b (150 mg, 0.32 mmol) and PPh3 (250 mg, 0.96 mmol) in THF (15 mL) was added DIAD (192 mg, 0.96 mmol) at room temperature. Stirred at room temperature overnight, water (5 mL) was added. The mixture was extracted with ethyl acetate (5 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 3:1) to give the product 9c (100 mg, 69%) as a yellow oil. MS (ESI): m / z = 455.1 [M+H] + .

[0237] c) To a solution of 9c (100 mg, 0.22 mmol) in DCM (5 mL) was added m-CPBA (244 mg, 1.4 mmol) at room temperature.

[0238] Stirred overnight, DCM (30 mL) was added, then washed with saturated NaHCO3 (2 mL), saturated Na2S2O3 (2 mL) sequentially, dried over anhydrous Na2SO4, filtered, concentrated, and purified by prep-HPLC (A:0.1% TFA in water, B:CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) directly to give the product 9 (34.3 mg, 31%) as a white solid. MS (ESI): m / z = 487.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.43 (dd, J = 1.6, 8.0 Hz, 1H), 8.38 (d, J = 1.6 Hz, 1H), 8.34 (br s, 1H), 7.93-7.81 (m, 2H), 7.78-7.70 (m, 2H), 6.50 (s, 1H), 4.22-4.16 (m, 2H), 3.73-3.68 (m, 1H), 3.55-3.48 (m, 1H), 2.41-2.32 (m, 1H), 2.19-2.12 (m, 1H), 1.90 (s, 3H).

[0239] The following compounds were synthesized using similar methods:

[0240] Table 4

[0241] Example 5: Synthesis of compounds 10 and 11

[0242] a) To a solution of 10a (10a was obtained following the same procedure as for the synthesis of compound 2, 100 mg, 0.2 mmol) in DCM (16 mL) was added m-CPBA (321 mg, 1.8 mmol) at room temperature. After stirring for 6 h, saturated Na2S03(4 mL) was added, followed by washing with saturated NaHC03(20 mL x 3) and saturated brine (20 mL) successively, drying over anhydrous Na2S04, filtration, concentration and prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) direct purification to give the product 10 as a white solid (6 mg, 6%). MS (ESI): m / z = 517.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.33 (d, J = 1.6 Hz, 1H), 8.27-8.25 (m, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.82-7.80 (m, 1H), 7.73-7.69 (m, 2H), 7.22 (s, 1H), 6.64 (s, 1H), 4.15-4.09 (m, 1H), 3.63-3.58 (m, 1H), 3.47-3.40 (m, 1H), 3.26-3.23 (m, 2H), 3.87-3.81 (m, 1H), 2.33-2.01 (m, 4H).

[0243] b) To a solution of 10a ((104 mg, 0.21 mmol) in THF (10 mL) was added NaH (13 mg, 0.32 mmol) at 0 °C. After stirring for 1 h, Mel (305 mg, 2.15 mmol) was added. Stirring was continued at 0 °C for 3 h, and the product 10b (80 mg, 75%) was obtained as a white solid after purification by prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm). MS (ESI): m / z = 499.4 [M+H] + .

[0244] c) To a solution of 10b (70 mg, 0.2 mmol) in DCM (8 mL) was added m-CPBA (218 mg, 1.27 mmol) at room temperature. After stirring for 6 h, saturated Na2S03(5 mL) was added, followed by saturated NaHC03(15 mL x 3) and saturated brine (10 mL) successively. The mixture was dried over anhydrous Na2S04, filtered, concentrated, and purified by prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) directly to give the product 11 (7 mg, 9.5%) as a white solid. MS (ESI): m / z = 531.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.32 (d, J = 1.6 Hz, 1H), 8.26-8.23 (m, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.82-7.80 (m, 1H), 7.77-7.70 (m, 2H), 6.64 (s, 1H), 4.17-4.11 (m, 1H), 3.63-3.57 (m, 1H), 3.50-3.37 (m, 3H), 2.80-2.74 (m, 1H), 3.71 (m, 3H), 2.43-2.32 (m, 1H), 2.18-2.08 (m, 3H).

[0245] Example 6: Synthesis of compound 14

[0246] a) A mixture of 6-bromoisobenzofuran-l(3H)-one (3.5 g, 16.43 mmol), ZnCN2 (2.6 g, 24.65 mmol) and Pd(PPh3)4 (1.7 g, 1.64 mmol) in DMF (40 mL) was stirred at 100 °C under argon protection overnight.

[0247] Cooled to room temperature, water (150 mL) was added. Ethyl acetate (200 mL x 3) was extracted, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 3:1) to give the white solid product 14a (1.7 g, 65%). MS (ESI): m / z = 160.1 [M+H] + .

[0248] b) To a solution of 14a ((104 mg, 0.21 mmol) in DCE (20 mL) was added NBS (2 g, 11.76 mmol) and AIBN (71 mg, 0.43 mmol) at 0 °C. After stirring for 2 h, it was concentrated, and then water (150 mL) was added. After stirring at 100 °C for 1 h, it was cooled to room temperature, and the solid was filtered off. The filtrate was purified by reverse phase column (C18, CH3CN, NH4HCO3 in H2O) to give the white solid product 14b (1 g, 53%). MS (ESI): m / z = 174.1 [M-H] + .

[0249] c) To a solution of 14b (1 g, 5.7 mmol) in acetone (15 mL) was added allyl bromide (550 uL, 6.35 mmol) and DBU (950 uL, 6.37 mmol) sequentially at room temperature. After stirring at room temperature for 2 h, it was concentrated, and purified by column chromatography (PE:EtOAc = 3:1) to give the white solid product 14c (0.34 g, 27%). MS (ESI): m / z = 216.3 [M+H] + .

[0250] d) To a solution of allyl 5-cyano-2-formylbenzoate (14c, 15 g, 71.4 mmol), 1-(3- (trifluoromethyl)phenyl)urea (0.39 g, 1.91 mmol), methyl 3-oxobutanoate (0.26 mL, 2.41 mmol) in dioxane (200 mL) was added PPA (2 g) at room temperature. After stirring at 50 °C overnight, it was cooled to room temperature, and the dioxane was removed, and water (30 mL) was added. Ethyl acetate (30 mL x 3) was extracted, and the organic phase was washed with saturated NaHCO3 (30 mL), and saturated brine (30 mL) sequentially, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc = 2:1) to give the white solid product 14d (0.32 g, 40%). MS (ESI): m / z = 500.4 [M+H] + .

[0251] e) To a solution of 14d (270 mg, 0.54 mmol), 1,3-dimethylbarbituric acid (126 mg, 0.81 mmol) in DCM (5 mL) was added Pd(PPh3)4(62 mg, 0.054 mmol) at room temperature. After stirring at room temperature for 2 h, it was concentrated and purified by reverse phase column (C18, CH3CN, NH4HCO3 in H2O) to give the product 14e (170 mg, 68%) as a white solid. MS (ESI): m / z = 460.3 [M+H] + .

[0252] f) To a solution of 14e (145 mg, 0.316 mmol,) in DMF (5 mL) was added HOSu (50 mg, 0.43 mmol) and DCC (120 mg, 0.58 mmol) sequentially at room temperature. After stirring at room temperature for 1 h, 2-aminoethanol-1-ol (50 mg, 0.82 mmol) was added. Stirring was continued for 2 h and purified by reverse phase column (C18, CH3CN, NH4HCO3 in H2O) to give the product 14f (150 mg, 94%) as a white solid. MS (ESI): m / z = 503.1 [M+H] + .

[0253] g) To a solution of 14f (150 mg, 0.3 mmol) and PPh3 (126 mg, 0.48 mmol) in THF (5 mL) was added DIAD (130 uL, 0.66 mmol)) at room temperature.

[0254] After stirring for 1 h, it was concentrated and purified by TLC (PE:EtOAc = 3:1) to give the product 14 (5 mg, yield 3%) as a white solid. MS (ESI): m / z = 485.1 [M+H] + .

[0255] Example 7: Synthesis of compound 15

[0256] a) To a solution of 14b (2 g, 11.4 mmol) in acetone (30 mL) was added Mel (2.1 mL, 33.7 mmol) and Na2CO3(1.7 mL, 11.4 mmol) sequentially at room temperature. After stirring at room temperature for 2 h, it was concentrated and purified by column chromatography (PE:EtOAc = 3:1) to give the product 15a (0.65 g, 30%) as a white solid. MS (ESI): m / z = 190.1 [M+H] + .

[0257] b) To a solution of 15a ((0.65 g, 3.44 mmol), 1-(3-(trifluoromethyl)phenyl)urea (850 mg, 4.17 mmol), allyl 3-oxobutanoate (0.7 mL, 5.1 mmol) in dioxane (20 mL) was added PPA (5 g) at room temperature. Stirred at 50 °C overnight, cooled to room temperature, removed dioxane, added water (50 mL). Extracted with ethyl acetate (50 mL x 3), the organic phase was washed with saturated NaHC03(30 mL), and saturated brine (30 mL) successively, dried over anhydrous Na2S04, filtered, concentrated, purified by column chromatography (PE:EtOAc = 2:1) to give the product 15b (0.53 g, 30%) as a yellow solid. MS (ESI): m / z = 500.1 [M+H] + .

[0258] c) To a solution of 15b (500 mg, 1 mmol) in THF (7.5 mL) was added 0.3 N LiOH (7.5 mL, 2.25 mmol) dropwise at room temperature. After stirring for 10 min, the pH was adjusted to 3-4 with 1 N HC1, extracted with ethyl acetate (20 mL x 3), dried over anhydrous Na2S04, filtered, concentrated, purified by reverse phase column chromatography (C18, CH3CN, 0.01% TFA in H20) to give the product 15c (0.16 g, 32%) as a white solid. MS (ESI): m / z = 486.3 [M+H] + .

[0259] d) To a solution of 15c (150 mg, 0.309 mmol) in DCM (5 mL) was added HOSu (53 mg, 0.46 mmol) and DCC (95 mg, 0.46 mmol) successively at room temperature. After stirring at room temperature for 1 h, 2-aminoethan-1-ol (50 mg, 0.82 mmol) was added. Stirring was continued for 2 h, the solid was filtered off, and purified by column chromatography (PE:EtOAc = 2:1) to give the product 15d (100 mg, 61%) as a brown oil. MS (ESI): m / z = 529.1 [M+H] + .

[0260] e) To a solution of 15d (100 mg, 0.19 mmol) and PPh3 (80 mg, 0.305 mmol) in THF (5 mL) was added DIAD (80 uL 0.407 mmol) at room temperature.

[0261] Stirring was continued for 2 h, concentrated, and purified by column chromatography (PE:EtOAc = 2:1) to give the product 15e as a brown oil.

[0262] (60 mg, 61%). MS (ESI): m / z = 511.2 [M+H] + .

[0263] f) To a solution of 15e (50 mg, 0.098 mmol), 1,3-dimethylbarbituric acid (50 mg, 0.32 mmol) in DCM (5 mL) was added Pd(PPh3)4(15 mg, 0.013 mmol) at room temperature. After stirring at room temperature for 2 h, it was concentrated and purified by pre-TLC (DCM / MeOH 15 / 1, Rf= 0.25 in DCM / MeOH 15 / 1) to give the product 15f (37 mg, 80%) as a brown solid. MS (ESI): m / z = 471.1 [M+H] + .

[0264] g) To a solution of 15f (29 mg, 0.062 mmol) in DMF (2 mL) was added NH4HCO3(20 mg, 0.25 mmol), HATU (47 mg, 0.124 mmol), HOBt (17 mg, 0.126 mmol) and DIPEA (3.2 g, 25 mmol) at room temperature. After stirring at room temperature for 2 h, water (20 mL) was added. The organic phase was separated, dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (0-15% MeOH in DCM, Rf= 0.25 in DCM / MeOH 10 / 1) to give the product 15 (2 mg, 25%) as a white solid. MS (ESI): m / z = 470.1 [M+H] + .

[0265] Example 8: Synthesis of compound 16

[0266] a) To a solution of 3-fluoro-4-formylbenzonitrile (150 mg, 0.309 mmol) in DMF (80 mL) was added 3-mercapto-propan-1-ol (2.93 g, 31.8 mmol) and K2CO3(4.7 g, 34 mmol) successively at room temperature. After stirring at 50 °C for 2 h, it was cooled to room temperature. Water (500 mL) was added. The organic phase was extracted with ethyl acetate (150 mL x 3), washed with saturated brine (150 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (PE:EtOAc = 2:1) to give the product 16a (6.5 g, 87%) as a red oil. MS (ESI): m / z = 244.1 [M+Na] + .

[0267] b) To a solution of 16a (1.64 g, 3.25 mmol) and PPh3 (2.55 g, 9.73 mmol) in THF (30 mL) was added DIAD (2.6 mL, 13.22 mmol) at room temperature. After stirring for 2 h, water (20 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3), and the organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by column chromatography (PE:EtOAc = 2:1) to give the product 16c (1.5 g, 95%) as a yellow solid. MS (ESI): m / z = 488.3 [M+H]

[0268] DIAD (2.6 mL, 13.22 mmol) was added. After stirring for 2 h, water (20 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3), and the organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by column chromatography (PE:EtOAc = 2:1) to give the product 16c (1.5 g, 95%) as a yellow solid. MS (ESI): m / z = 488.3 [M+H] + .

[0269] c) A solution of 16c (350 mg, 0.72 mmol), NBS (128 mg, 0.72 mmol) and AIBN (12 mg, 0.073 mmol) in CCl4(10 mL) was stirred at 80 °C for 2 h. After cooling to room temperature, the mixture was concentrated and purified by SGC (0-25% EA in PE, Rf= 0.5 in PE / EA 3 / 1) to give the product 16d (300 mg, 73%) as a white solid. MS (ESI): m / z = 566.0 [M+H] + .

[0270] d) To a solution of 16d (290 mg, 0.51 mmol) in DCM (5 mL) was added m-CPBA (290 mg, 1.68 mmol) at room temperature. After stirring for 2 h, the mixture was washed with saturated NaHC03(3 mL) and saturated brine (3 mL) successively, dried over anhydrous Na2S04, filtered, and purified by SGC (0-50% EA in PE, Rf= 0.15 in PE / EA 3 / 1) to give the product 16e (80 mg, 26%) as a white solid. MS (ESI): m / z = 597.9 [M+H] + .

[0271] e) To a solution of 16e (75 mg, 0.125 mmol) in DMF (5 mL) was added 2-methylhydrazine-1-carboxylic acid tert-butyl ester (25 mg, 0.171 mmol) and K2C03(20 mg, 0.145 mmol) successively at room temperature. After stirring for 2 h, the solid was filtered off, and the filtrate was purified by reverse phase column (C18, CH3CN, NH4HC03in H20) to give the product 16f (39 mg, 47%) as a white solid. MS (ESI): m / z = 608.2 [M-55] + .

[0272] f) To a solution of 16f (35 mg, 0.053 mmol) in EtOH (1 mL) was added 4N HC1 in dioxane (160 uL) at room temperature. After stirring for 3 h, 4N HC1 in dioxane (80 uL) was added. After stirring for 45 min, it was concentrated. To the residue was added CH3CN (2 mL), TEA (100 uL) and AcOH (0.5 mL). After stirring for 1 h, it was concentrated and purified by prep-HPLC (Using TFA buffer: A: 0.05% TFA in water; B: 0.05% TFA in acetonitrile; Column: Waters XBridge Peptide BEH C18, 19 x 250 mm, 10 pm, 5 nm; Method: 1 mL / min, 10-50% B over 20 min) to give the product 16 as a white solid (9 mg, 26%). MS (ESI): m / z = 532.0 [M+H] ). + . 1 H NMR (400 MHz, DMSO-d6): d 8.33 (d, J = 2.0 Hz, 1H), 8.28 (dd, J = 2.0, 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.82-7.80 (m, 1H), 7.75-7.69 (m, 2H), 6.66 (s, 1H), 4.22-4.16 (m, 1H), 3.63-3.57 (m, 1H), 3.47-3.31 (m, 3H), 2.70-2.66 (m, 1H), 2.56 (s, 3H), 2.39-2.28 (m, 2).

[0273] Example 9: Synthesis of compound 17

[0274] a) A solution of 16c (1.7 g, 3.5 mmol), NBS (1.87 g, 10.5 mmol), AcOH (5 mL) in CCI4 (100 mL) was stirred at 80 °C overnight. Cooled to room temperature, adjusted pH to 7 with saturated NaHC03. Extracted with DCM (50 mL x 3), dried over anhydrous Na2S04, filtered, concentrated and purified by SGC (0-30% EA in PE, Rf = 0.8 in PE / EA 2 / 1) to give the product 17a as a white solid (0.5 g, 22%). MS (ESI): m / z = 645.9 [M+H] + .

[0275] b) To a solution of 17a (490 mg, 0.76 mmol) in DCM (10 mL) was added m-CPBA (367 mg, 2.13 mmol) at room temperature. After stirring for 3 h, DCM (10 mL) was added. Then washed with saturated NaHC03(3 mL) and saturated brine (3 mL), dried over anhydrous Na2S04, filtered, and purified by SGC (0-50% EA in PE, Rf= 0.15 in PE / EA 3 / 1) to give the product 17b (0.38 g, 73%) as a white solid. MS (ESI): m / z = 678.2 [M+H] + .

[0276] c) To a solution of 17b (150 mg, 0.22 mmol) in CH3CN (5 mL) was added 98% NH2NH2H20 (150 uL) at room temperature. After stirring at 50 °C for 6.5 h, it was cooled to room temperature. Water (20 mL) was added. The product was extracted with ethyl acetate (25 mL x 3), and the organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous Na2S04, filtered, and concentrated to give a red solid. The red solid was dissolved in CH3CN (3 mL), and AcOH (0.3 mL) was added. After stirring at 50 °C for 3 h, it was cooled to room temperature and concentrated. Ethyl acetate (30 mL) was added, and the mixture was washed with saturated NaHC03(5 mL), dried over anhydrous Na2S04, filtered, and concentrated. The product was purified by prep-HPLC (Using NH4HC03buffer: A: 10 mM NH4HC03in water; B: acetonitrile; Column: Waters XBridge Peptide BEH C18, 19 x 250 mm, 10 pm, 130 A; Method: 1 mL / min, 10-50% B over 20 min) to give the product 17 (6 mg, 5%) as a white solid. MS (ESI): m / z = 516.0 [M+H] . + . 1 H NMR (400 MHz, DMSO-d6): δ 12.9 (br s, 1H), 8.36 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.99 (br s, 1H), 7.90-7.88 (m, 1H), 7.82-7.78 (m, 2H), 7.03 (s, 1H), 6.88 (s, 1H), 4.32-4.26 (m, 1H), 3.67-3.62 (m, 1H), 3.49-3.42 (m, 1H), 2.70-2.66 (m, 1H), 2.22-2.18 (m, 2H).

[0277] Example 10: Synthesis of compound 18

[0278] a) To a solution of 16e (200 mg, 0.34 mmol) in DMF (5 mL) was added dimethylamine HC1 salt (41 mg, 0.5 mmol) and K2CO3(92 mg, 0.67 mmol) at room temperature. After stirring for 2 h, water (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated and purified by SGC (0-25% EA in PE) to give the product 18a (150 mg, 80%) as yellow oil. MS (ESI): m / z = 563.2 [M+H] + .

[0279] b) To a mixture of 18a (150 mg, 0.27 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH H2O (34 mg, 0.81 mmol) at room temperature and stirred overnight. 2 drops of TFA was added and concentrated. The product 18b (70 mg, 39%) was obtained as white solid by purification on a reverse phase column (C18, CH3CN, TFA in H2O). MS (ESI): m / z = 549.1 [M+H].

[0280] c) To a solution of 18b (80 mg, 0.12 mmol) in DCM (5 mL) was added NH4HCO3(25 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol) and DIPEA (39 mg, 0.3 mmol) at room temperature. The mixture was stirred at room temperature overnight, concentrated and purified by SGC (20-35% EA in PE) to give the product 18c (3 mg, yield 4%) as white solid. MS (ESI): m / z = 548.1 [M+H] + .

[0281] d) To a solution of 18c (3 mg, 0.0055 mmol) in DCM (2 mL) was added Burgess reagent (3.6 mg, 0.015 mmol) at room temperature. The mixture was stirred overnight, concentrated and purified by prep-HPLC (Using TFA buffer: A: 0.05% TFA in water; B: 0.05% TFA in acetonitrile; Column: Waters XBridge Peptide BEH C18, 19 x 250 mm, 10 μm, ) to give the product 18 (0.5 mg, 14%) as white solid. MS (ESI): m / z = 530.2 [M+H] + .

[0282] The following compounds were synthesized using similar procedures:

[0283] Table 5

[0284] Example 11: Synthesis of compound 20

[0285] a) To a solution of 20a (20a was obtained by a similar procedure to synthesis 01, 9.4 g, 22 mmol) in THF (50 mL) and EtOH (150 mL) was added Pd / C (3 g, 10% on C) at room temperature. Hydrogenation was carried out at room temperature for 48 h. The solid was filtered off and concentrated. The residue was purified by column chromatography (PE:EtOAc = 1:2) to give the product 20b (6.2 g, 71%) as a yellow solid. MS (ESI): m / z = 398.1 [M+H] + .

[0286] b) To a reaction flask containing 20b (1 g, 2.5 mmol) was added AcOH (12 mL), concentrated HCl (6 mL) and water (6 mL) at -10 °C. NaNO2 aqueous solution (348 mg in water 1 mL) was added dropwise. After stirring at -10 °C for 40 min, the reaction mixture was added to a solution of SO2-saturated acetic acid (20 ml). After stirring at -10 °C for 3 h, the reaction mixture was poured into ice water (500 mL). The solid was collected by filtration and dried to give the product 20c (700 mg, 13%) as a brown solid. MS (ESI): m / z = 481.0 [M+H] + .

[0287] c) To a solution of 20c (700 mg, purity: 23%, 0.34 mmol) in DCM (8 mL) was added 2-(methylamino)ethanol-1-ol (50 mg, 0.67 mmol) and DIPEA (130 mg, 1 mmol) at room temperature. The mixture was stirred for 3 h. The residue was concentrated and purified by prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) to give the product 20d (94 mg, 54%) as a brown solid. MS (ESI): m / z = 520.2 [M+H] + .

[0288] d) To a solution of 20d (94 mg, 0.18 mmol) and PPh3 (238 mg, 0.91 mmol) in THF (28 mL) was added DIAD (0.23 mL, 1.1 mmol) at room temperature.

[0289] DIAD (182 mg, 0.91 mmol) was added. Stirring for 2 h, water (0.1 mL) was added, and the mixture was concentrated. Purification by prep-HPLC (A: 0.08% NH4HCO3 in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) gave the product 20 (50 mg, 55%) as a white solid. MS (ESI): m / z = 502.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.37-8.28 (m, 3H), 7.89-7.83 (m, 2H), 7.76-7.72 (m, 2H), 6.65 (s, 1H), 4.21-4.15 (m, 1H), 3.99-3.93 (m, 1H), 3.70-3.64 (m, 1H), 2.98-2.92 (m, 1H), 2.67 (s, 3H), 1.92 (s, 3H).

[0290] Example 12: Synthesis of compounds 23 and 24

[0291] a) To a solution of I01 (1 g, 2.17 mmol) in DMF (50 mL) was added ethynyltrimethylsilane (425 mg, 4.34 mmol), Pd(PPh3)2Cl2 (304 mg, 0.43 mmol), CuI (83 mg, 0.43 mmol) and TEA (20 mL) at room temperature. Stirring at 40 °C overnight, cooling to room temperature, ethyl acetate (400 mL) was added, washed with water, dried over anhydrous Na2SO4, filtered, concentrated. Purification by column chromatography (PE:EtOAc = 2:1) gave the product 23a (800 mg, 77%) as a brown solid. MS (ESI): m / z = 479.1 [M+H] + .

[0292] b) A solution of 23a (1 g, 2.17 mmol), ethyl 2-azidoacetate (1025 mg, 7.9 mmol) in toluene (10 mL) was stirred at 120 °C for 2 days. Cooling to room temperature, concentrated. Purification by column chromatography (PE:EtOAc = 2:1) gave the product 23b (370 mg, 77%) as a brown solid. MS (ESI): m / z = 608.3 [M+H] + .

[0293] c) At room temperature, NaBH4 (347 mg, 9.1 mmol) was added to a 20 mL solution of MeOH containing 370 mg (0.61 mmol). After stirring for 1 hour, the solution was concentrated. Prep-HPLC (A: 0.08% NH4HCO3 in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm × 250 mm) was used to purify the product 23c (310 mg, 90%) into a white solid. MS (ESI): m / z = 566.3 [M+H] + .

[0294] d) At room temperature, add 23c (620 mg, 1.1 mmol) and PPh3 (238 mg, 0.91 mmol) to a 28 mL solution of THF.

[0295] Add DIAD (182 mg, 0.91 mmol). Stir for 2 hours, add water (2 mL), and concentrate. Purify by prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm × 250 mm) to obtain a white solid product 23 (390 mg, 65%). MS (ESI): m / z = 548.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.20-8.18(m,1H),8.08(d,J=8.4Hz,1H),7.96(d,J=1.6Hz,1H),7.85-7.84(m,2H),7.76-7.73(m,2H),5.04(dd, J1=15Hz,J2=5.2Hz,1H),4.82(s,1H),4.58(dd,J1=15Hz,J2=5.2Hz,1H),3.86-3.79(m,1H),3.35-3.29(m,1H),1.97(s,3H),0.13(s,9H).

[0296] e) At room temperature, add TBAF (215 mg, 0.82 mmol) to a 20 mL solution of 23 (300 mg, 0.55 mmol) of THF.

[0297] Stirred overnight, concentrated. prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19mmx250mm) purification afforded the product 24 (135mg, 52%) as white solid. MS (ESI): m / z = 476.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.18-8.15 (m, 1H), 8.10 (s, 1H), 8.06-8.02 (m, 2H), 7.85-7.83 (m, 2H), 7.75-7.70 (m, 2H), 5.17 (s, 1H), 5.00-4.97 (m, 1H), 4.56-4.51 (m, 1H), 4.01-3.95 (m, 1H), 3.45-3.88 (m, 1H), 1.96 (s, 3H).

[0298] Example 13: Synthesis of compound 26

[0299] a) 1-(1-Methyl-1H-pyrazol-5-yl)ethan-1-one (1000 mg, 8.06 mmol) was dissolved in 40 mL of tetrahydrofuran, N-bromosuccinimide (3587 mg, 20.15 mmol) was added, stirred at 25 °C for 16 hours, after the reaction was completed, the mixture was diluted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under vacuum to obtain a crude product, which was separated and purified by silica gel column (petroleum ether / ethyl acetate = 5 / 1 elution) to obtain white solid product 2-bromo-1-(4-bromo-1-methyl-1H-pyrazol-5-yl)ethan-1-one (26a, 400 mg, 17.6%). LC-MS: m / z (ESI) = 280.9 [M+H] + .

[0300] b) 2-Bromo-1-(4-bromo-1-methyl-1H-pyrazol-5-yl)ethan-1-one (26a, 400 mg, 1.42 mmol) was dissolved in 9 mL of acetonitrile, I01 (545 mg, 1.18 mmol) and potassium carbonate (196 mg, 1.42 mmol) were added, the reaction solution was stirred at 25 °C for 16 hours, after the reaction was completed, the reaction solution was concentrated to dryness under vacuum, the crude product was separated and purified by silica gel column (petroleum ether / ethyl acetate = 3 / 1 elution) to obtain white solid product (26b, 80 mg, 8.5%). LC-MS: m / z (ESI) = 662.3 [M+H] + .

[0301] c) 26b (80 mg, 0.12 mmol) was dissolved in 2 mL of dioxane and 0.5 mL of water, dichlorobis-(4-dimethylaminophenyl) palladium(II) (8.52 mg, 0.012 mmol), cesium fluoride (54.7 mg, 0.36 mmol) and pinacol diboronic acid (121.9 mg, 0.48 mmol) were added, nitrogen was bubbled three times, the temperature was raised to 90 °C and stirred for 1 h, after cooling, the reaction was concentrated to dryness under vacuum to obtain a crude which was purified by preparative high-performance liquid chromatography (solvent A: water + 0.1% formic acid; solvent B: acetonitrile; gradient: 38-48%) to obtain the product 26 as a yellow solid (1 mg 1.6%). LC-MS: m / z (ESI) = 503.0 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.04 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 4.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 4.0 Hz, 1H), 6.37 (s, 1H), 6.09 (s, 1H), 4.11 (s, 3H), 2.01 (s, 3H).

[0302] The following compounds were synthesized using a similar method:

[0303] Table 6

[0304] Example 14: Synthesis of compound 31

[0305] a) To a solution of 4-bromo-l-methyl-lH-pyrazole-3-carboxylic acid (5 g, 24.4 mmol) in DCM (100 mL) was added N, O-dimethylhydroxylamine hydrochloride (3.6 g, 36.9 mmol), HOBt (4.9 g, 36.3 mmol), HBTU (13.9 g, 36.7 mmol) and DIPEA (4.7 g, 36.6 mmol) successively at room temperature. Stirred at room temperature overnight, concentrated, purified by SGC (0-50% EA in PE) to give the product 31a as a white solid (5.6 g, 93%). MS (ESI): m / z = 250.1 [M+H] + .

[0306] b) To a solution of 31a (5.6 g, 22.5 mmol) in THF (100 mL) was added LiAIH4(1.4 g, 36.8 mmol) in portions at room temperature. Stirred at room temperature overnight, added Na2S04 10 H20 (5 g), concentrated, purified by SGC (0-50% EA in PE) to give the product 31b (2.8 g, 66%) as a white solid. MS (ESI): m / z = 191.1 [M+H] + .

[0307] c) To a solution of methyltriphenylphosphonium bromide (4.2 g, 11.8 mmol) in THF (30 mL) was added NaHMDS (2 M in THF, 6 mL, 12 mmol) dropwise at 0 °C. After stirring for 30 min, 31b (1.5 g, 7.9 mmol) was added. Stirred at 0 °C for 2 h. Added water (20 mL). Extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2S04, filtered, concentrated,

[0308] purified by SGC (0-50% EA in PE) to give the product 31c (1.2 g, 81%) as a white solid. MS (ESI): m / z = 187.1 [M+H] + .

[0309] d) To a solution of 31c (1.2 g, 6.4 mmol) in THF (20 mL) was added 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 38.4 mL, 19.2 mmol) dropwise at 0 °C, warmed to room temperature. Stirred for 16 h, added 30% hydrogen peroxide (24.7 mL) and 5 N sodium hydroxide (24.6 mL, 40 mmol) dropwise at 0 °C. Extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2S04, filtered, concentrated, purified by SGC (0-60% EA in PE) to give the product 31d (900 mg, 69%) as a white solid. MS (ESI): m / z = 205.1 [M+H] + .

[0310] e) To a solution of 31d (900 mg, 4.4 mmol) in DMF (10 mL) was added tert-butyldimethylsilyl chloride (660 mg, 4.4 mmol) and imidazole (450 mg, 6.6 mmol) sequentially at room temperature. Stirred at room temperature overnight, added water (50 mL). Extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2S04, filtered, concentrated, purified by SGC (0-35% EA in PE) to give the product 31e (1.1 g, 78%) as a colorless oil. MS (ESI): m / z = 319.1 [M+H] + .

[0311] f) At -78 °C, to a solution of 31e (1.1 g, 3.5 mmol) in THF (20 mL), dropwise added n-BuLi (2.5 M in THF, 2 ml, 5 mmol), after stirring for 30 min, dropwise added a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 7 mmol) in THF (5 ml). After being raised to room temperature and stirring for 1 h, saturated NH4Cl (20 mL) was added. Ethyl acetate (30 mL x 3) was extracted, dried over anhydrous Na2SO4, filtered, concentrated, and purified by SGC (0-35% EA in PE) to give the product 31f (1.1 g, 78%) as colorless oil. MS (ESI): m / z = 319.1 [M+H] + .

[0312] g) I01 (191 mg, 0.43 mmol) was dissolved in 5 mL of dioxane and 1 mL of water solution, 3f (200 mg, 0.52 mmol), potassium acetate (128 mg, 1.3 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg, 0.04 mmol) were added, replaced with nitrogen for three times, raised to 90 °C and stirred for 12 h. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in vacuum to give a crude product, which was then separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 1:1) to give the product 31g (80 mg, yield 29.7%) as a white solid. LC-MS: m / z (ESI) = 621.3 [M+H]+.

[0313] h) 31g (80 mg, 0.13 mmol) was dissolved in 4N hydrogen chloride / dioxane solution (5 mL), and stirred at room temperature for 3 h. After the reaction was completed, it was concentrated to dryness in vacuum to give the product 31h (50 mg, 75.3%) as a white solid. LC-MS: m / z (ESI) = 506.2 [M+H] + .

[0314] i) 31h (50 mg, 0.1 mmol) and triphenylphosphine (104 mg, 0.4 mmol) were dissolved in 5 mL of tetrahydrofuran, and diisopropyl azodicarboxylate (80 mg, 0.4 mmol) was added dropwise under nitrogen protection. The reaction was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product, which was then separated and purified by preparative high performance liquid chromatography (solvent A: water + 0.1% formic acid; solvent B: acetonitrile; gradient: 43-58%) to obtain white solid product 31 (11 mg, 22.8%). LC-MS: m / z (ESI) = 489.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.92 (dd, J = 8.0, 2.0 Hz, 1H), 7.88-7.83 (m, 3H), 7.76-7.69 (m, 2H), 5.36 (s, 1H), 3.87 (s, 3H), 3.75-3.51 (m, 2H), 3.16-3.11 (m, 1H), 2.76-2.69 (m, 1H), 1.95 (s, 3H).

[0315] The following compounds were synthesized using a similar method:

[0316] Table 7

[0317] Example 15: Synthesis of compound 40

[0318] a) To a solution of I01 (1 g, 2.17 mmol) in DMF (20 mL) was added sodium hydride (60% dispersion in mineral oil) (123 mg, 2.82 mmol) at -10 °C. After stirring for 30 minutes, a solution of methyl 2-bromoacetate (498 mg, 3.25 mmol) in DMF (5 ml) was added dropwise. After stirring for 1 hour, AcOH (1 mL) and EtOAc (300 mL) were added. The organic phase was washed with saturated brine (5 x 60 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (eluted with PE / EtOAc = 2 / 1 to 3 / 2, V / V) to obtain yellow solid product 40a (800 mg, 69%). MS (ESI): m / z = 535.1 [M+H] + .

[0319] b) A mixture of 40a (800 mg, 1.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bis(l,3,2-dioxaborinane) (571 mg, 2.25 mmol), Pd(dppf)Cl2(219 mg, 0.3 mmol) and AcOK (441 mg, 4.5 mmol) in DMSO (30 mL) was stirred at 90 °C for 4 h under argon. Cooled to room temperature, EtOAc (300 mL) was added. The organic phase was washed with saturated brine (5 x 150 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (eluted with PE / EtOAc = 2 / 1 to 3 / 2, V / V) to give the product 40b (900 mg, 99%) as brown oil. MS (ESI): m / z = 581.3 [M+H] + .

[0320] c) To a solution of 5-iodo-2-methyl-lH-imidazole (1.5 g, 7.2 mmol) in DCM (10 mL) was added DIPEA (1.86 g, 14.4 mmol) and SEMCl (1.32 g, 7.9 mmol) sequentially at room temperature. Stirred at room temperature overnight, concentrated and purified by prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) to give the product 40c (1.4 g, 58%) as colorless oil. MS (ESI): m / z = 339.0 [M+H] + .

[0321] d) A mixture of 40b (800 mg, 1.38 mmol), 40c (932 mg, 2.76 mmol), Pd(dppf)Cl2(202 mg, 0.28 mmol) and AcOK (406 mg, 4.14 mmol) in a mixture of DMSO (20 mL) and water (1 mL) was stirred at 90 °C for 4 h under argon. Cooled to room temperature, EtOAc (300 mL) was added. The organic phase was washed with saturated brine (5 x 30 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (eluted with PE / EtOAc = 1 / 4, V / V) to give the product 40d (64 mg, 6.8%) as brown solid.

[0322] MS (ESI): m / z = 665.3 [M+H] + .

[0323] e) To a solution of 40d (62 mg, 0.093 mmol) in MeOH (6 mL) was added NaBH4(71 mg, 1.87 mmol) at room temperature. After stirring for 1 h, it was concentrated. Purification by prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) afforded the product 40e (30 mg, 63%) as a white solid. MS (ESI): m / z = 637.2 [M+H] + .

[0324] f) To a solution of 40e (45 mg, 0.071 mmol) in DCM (6 mL) was added TFA (3 mL) at room temperature. After stirring overnight, it was concentrated. Purification by prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) afforded the product 40f (20 mg, 55%) as a white solid. MS (ESI): m / z = 507.0 [M+H] + .

[0325] g) To a solution of 40f (24 mg, 0.047 mmol) and PPh3(62 mg, 0.24 mmol) in THF (10 mL) was added DIAD (48 mg, 0.24 mmol) at room temperature. After stirring for 2 h, water (3 mL) was added and it was concentrated. Purification by prep-HPLC (A: 0.1% TFA in water, B: CH3CN; Column: Xbridge BEH peptide C18, 19 mm x 250 mm) afforded the product 40 (2 mg, 22%) as a white solid. MS (ESI): m / z = 489.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.22-8.20 (m, 1H), 8.16-8.03 (m, 1H), 7.88-7.40 (m, 6H), 6.12 (s, 0.4H), 5.31 (s, 0.8H), 4.68-4.36 (m, 2H), 3.74-3.64 (m, 2H), 2.68 (s, 1.8H), 2.57 (s, 1.2H), 1.99 (s, 1.8H), 1.66 (s, 1.2H).

[0326] The following compounds were synthesized according to the procedures described in Reference Examples 1-15:

[0327] Table 8

[0328] Bioactivity test

[0329] Compound preparation, all compounds were dissolved in DMSO with concentration of 10 mM, stored at -20℃.

[0330] Prepare 1x assay buffer, dilute positive compound (Sivelestat-2) and test compound in DMSO with 3-fold serial dilution for 3 times, totally 10 concentration points. Add 1 μL serial dilution compound and 65.67 μL assay buffer in well plate, get 3X positive compound and test compound working solution (DMSO final concentration is 1.5%). Seal well plate with sealing film, shake on shaker for 15 minutes.

[0331] Prepare 1x activation buffer, dilute rhELA2 in activation buffer containing DPPI. Incubate at 37℃ for 2 hours to activate rhELA2. Add 5 μl 3x dilution compound working solution in 384 well plate. Dilute rhELA2 with 1x assay buffer, get 3x rhELA2 working solution. Add 5 μl 3x rhELA2 working solution in each well of 384 well plate. Seal plate and incubate at room temperature for 30 minutes in dark.

[0332] Prepare 3x substrate solution in 1x assay buffer. Add 5 μl 3x substrate working solution in 384 well plate. Centrifuge 384 well plate at 1000 rpm for 1 minute. Incubate at room temperature for 1 hour in dark. Read fluorescence value FLU at 360 nm / 450 nm on plate reader.

[0333] Calculate inhibition rate, % inhibition rate = (1-(FLU compound-FLU positive well) / (FLU reference well-FLU positive well)). FLU reference well is well with only enzyme without inhibitor, FLU positive well is well with enzyme and 3000 nM Sivelestat-2. Then calculate IC50 value using Graphpad 8.0 software Y = Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)).

[0334] Table 9

[0335] The above data show that the compounds of the present application have strong inhibitory activity on hNE.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: W is selected from CH or N; R1and R2are each independently selected from H, halogen, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C(=O)R 1a , -C(=O)-O-R 1b , -C(=O)-NR 1c R 1d or -(CH2) n1 -Q; or, R1and R2are joined to form a 5-6 membered ring; said 5-6 membered ring is optionally substituted with one or more substituents selected from halogen, cyano, oxo, C 1-6 alkyl or C 1-6 alkoxy; R 1a and R 1b each independently is selected from hydroxyalkyl, aminoalkyl, carboxyalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; Or, R 1a Selected from 5-6 quinone heteroaryl groups; R 1c and R 1d each independently is selected from H, hydroxyalkyl, aminoalkyl, carboxyalkyl, C 1-6 alkyl or C 1-6 alkoxy; Q is selected from -NR 1c R 1d , hydroxyl, amino, carboxyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; R3is selected from phenyl or 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl optionally being substituted with one or more substituents selected from halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, pentafluorothioxy (-SF5), C 1-6 haloalkyl or C 1-6 haloalkoxy; R4is selected from H, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; X, Y and Z are each independently selected from -(CH2) n2 -, -C(=0)-, -NH-, -C(=0)-NH-, -NH-C(=0)-, -S(=0) r - or A; r is selected from 0 or 1 or 2; said A is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl; Each R a Each group is independently selected from halogen, cyano, hydroxyl, amino, nitro, carboxyl, oxo, and C groups. 1-6 Alkyl, C 1-6 Alkyl or TMS; or two R a with the carbon atom to which they are attached form C 3-6 cycloalkyl; n1, n2 and m are each independently selected from 0, 1, 2 or 3; said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, amino, carboxy, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxycarbonyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds of formula (II-a), (II-b), (II-c) or (II-d), wherein: R1, R2, R3, R4, W, A, Y, Z, R a , m and r are as defined in claim 1.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1is selected from cyano, carboxyl, -C(=O)R 1a or -C(=O)-O-R 1b ; R 1a or R 1b each independently selected from C 1-3 alkyl or C 2-4 alkenyl; Alternatively, R1is selected from -C(=O)R 1a , R 1a is selected from C 3-6 cycloalkyl; Alternatively, R1is selected from -C(=O)R 1a , R 1a is selected from 5-6 membered heteroaryl; or R1is selected from -C(=O)-NR 1c R 1d ; R 1c or R 1d each independently is selected from H or C 1-3 alkyl; preferably, R 1a or R 1b each independently is selected from methyl, ethyl, ethenyl or propenyl; R 1c or R 1d each independently is selected from H, methyl or ethyl; or R 1a is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R 1a is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl or oxazolyl; preferably, R1 is selected from cyano, carboxyl, -C(=O)-CH3, -C(=O)-O-CH3, -C(=O)-O-CH2-CH3, -C(=O)-O-CH2-CH=CH2, -C(=O)-NH2, -C(=O)-NH-CH3 or -C(=O)-N(CH3)2; Preferably, R1is selected from -C(=0)-CH2-CH3or Preferably, R1is selected from preferably, R1 is selected from cyano, -C(=O)-CH3, -C(=O)-O-CH3, -C(=O)-NH2 or -C(=O)-N(CH3)2; R2is selected from C 1-3 alkyl or -(CH2) n1 -Q; n1 is selected from 0, 1, 2 or 3; Q is selected from -NR 1c R 1d , hydroxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; R 1c or R 1d are each independently selected from H or C 1-3 alkyl; preferably, R 1c or R 1d are each independently selected from H, methyl or ethyl; Preferably, R2is selected from methyl, ethyl, -CH2-NH2, -CH2-NH-CH3, -CH2-N(CH3)2or Preferably, R2is selected from methyl, -CH2-N(CH3)2or or R1and R2are joined to form C 5-6 cycloalkyl or 5-6 membered heterocyclyl; said C 5-6 cycloalkyl or 5-6 membered heterocyclyl optionally substituted with one or more substituents selected from oxo, C 1-3 alkyl or C 1-3 alkoxy; R1and R2are joined to form a C 5-6 cycloalkyl or 5-6 membered heterocyclyl; said C 5-6 cycloalkyl or 5-6 membered heterocyclyl optionally substituted with one or more oxo, methyl or ethyl groups; preferably, R1 and R2 are linked to form a cyclopentenyl, cyclohexenyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyridazinyl, dihydropyridazinyl, tetrahydropyrimidyl or dihydropyrimidyl, optionally substituted with one or more oxo or methyl groups; Preferably, R1and R2are joined to form optionally substituted with one or two methyl groups.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R3is selected from phenyl or 6-membered heteroaryl; said phenyl or 6-membered heteroaryl is optionally substituted with one or more substituents selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl or C 1-3 haloalkoxy; preferably, R3 is selected from phenyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl, optionally substituted with one or more substituents selected from halogen, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl or fluoro-substituted methoxy; preferably, R3 is selected from phenyl or pyridyl, optionally substituted with one methyl, trifluoromethyl or difluoromethyl; preferably, R3 is selected from trifluoromethylphenyl, trifluoromethylpyridyl or difluoromethylphenyl; preferably, R3 is selected from phenyl or pyridyl, optionally substituted with one F, Cl, Br or I; preferably, R3 is selected from phenyl substituted with one Br; preferably, R3 is selected from phenyl or pyridyl, optionally substituted with one pentafluorosulfonyl group (-SF5); R4 is selected from H; each R is independently selected from halogen, cyano, hydroxyl, amino, nitro, oxo, C a alkyl, C 1-3 alkoxy, or trimethylsilane; preferably, each R is independently selected from halogen, cyano, hydroxyl, amino, nitro, oxo, C 1-3 alkyl, C a alkoxy, or trimethylsilane; preferably, each R is independently selected from halogen, cyano, hydroxyl, amino, nitro, oxo, C a alkyl, C m is selected from 0, 1, 2, or 3; or two R a with the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

5. The compound of formula (I) according to claim 1, wherein, or a pharmaceutically acceptable salt thereof. X, Y and Z are selected from one of the following conditions: (1) one of X, Y and Z is selected from -S(=O) r - and the other two are each independently selected from -(CH2) n2 -, -C(=O)-, -NH-, -C(=O)-NH- or -NH-C(=O)-; (2) one of X, Y and Z is selected from A, and the other two are each independently selected from -(CH2) n2 - C(=O)-, -NH-, -C(=O)-NH- or -NH-C(=O)-; preferably, X, Y and Z are selected from one of the following conditions: (1) X is selected from -S(=O) r -, Y is selected from -(CH2) n2 -, -NH- or -NH-C(=O)-, and Z is selected from -(CH2) n2 - or -C(=O)-; (2) Y is selected from -S(=O) r -; X is selected from -(CH2) n2 - or -C(=O)-NH-, Z is selected from -(CH2) n2 -; (3) Z is selected from -S(=O) r -, X is selected from -(CH2) n2 -, -C(=O)-, -NH-, -C(=O)-NH- or -NH-C(=O)-, Y is selected from -(CH2) n2 -, -NH- or -C(=O)-NH-; (4) X is selected from -C(=O)-, Y is selected from -(CH2) n2 - or -NH-, Z is selected from -(CH2) n2 - ; (5) Z is selected from -C(=O)-, X is selected from -(CH2) n2 -, -C(=O)-, -NH-, -C(=O)-NH- or -NH-C(=O)-, Y is selected from -(CH2) n2 - or -NH-; (6) X is selected from -NH-, Y is selected from -(CH2) n2 - or -C(=O)-, Z is selected from -(CH2) n2 -; (7) X is selected from -(CH2) n2 -, Y is selected from -(CH2) n2 -, -C(=O)-, -NH-, -C(=O)-NH- or -NH-C(=O)-, and Z is selected from -(CH2) n2 -; (8) X is selected from A, said A is selected from phenyl or 5-6 membered heteroaryl, Y is selected from -(CH2) n2 -,-C(=O)-, -NH-, -C(=O)-NH- or -NH-C(=O)-, Z is selected from -(CH2) n2 - or -C(=O)-; (9) Y is selected from A, said A is selected from phenyl or 5-6 membered heteroaryl, X is selected from -(CH2) n2 -,-C(=O)-, -NH-, -C(=O)-NH- or -NH-C(=O)-, Z is selected from -(CH2) n2 - or -C(=O)-; (10) Z is selected from A, said A is selected from phenyl or 5-6 membered heteroaryl, X is selected from -(CH2) n2 -, -C(=O)-, -NH-, -C(=O)-NH- or -NH-C(=O)-, Y is selected from -(CH2) n2 -, -NH-, -C(=O)-, -C(=O)-NH- or -NH-C(=O)-; preferably, X, Y and Z are selected from one of the following conditions: (1) X is selected from -S-, -S(=O)- or -S(=O)2-, Y is selected from -(CH2) n2 - or -NH-, Z is selected from -(CH2) n2 -; (2) X is selected from -C(=O)-, Y is selected from -NH-, Z is selected from -(CH2) n2 -; (3) X is selected from -NH-, Y is selected from -C(=O)-, and Z is selected from -(CH2) n2 -; (4) X is selected from A, said A is selected from 5-membered heteroaryl, Y is selected from -(CH2) n2 - or -C(=O)-, Z is selected from -(CH2) n2 -; r is selected from 0, 1, 2 or 3; n2 is selected from 0, 1, 2 or 3; said A is selected from phenyl or 5-6 membered heteroaryl; preferably, said A is selected from phenyl or 5 membered heteroaryl; preferably, said A is selected from 5 membered heteroaryl; preferably, said A is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl; preferably, said A is selected from pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, triazolyl or thiazolyl.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds, 7. An intermediate compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3, R4, W, A and r are as defined in claim 1; R5is selected from halogen, hydroxy, amino, nitro, carboxy, -C(=0)R 5a , -C(=0)-0-R 5b , -C(=0)-NR 5c R 5d , -S(=0) r -NR 5c R 5d , -S(=0) r -(CH2) n3 -R 5e , -C 2-6 alkylene-R 5f or -A(R 5g ) u ; R 5a and R 5b each independently is selected from the group consisting of hydroxyalkyl, aminoalkyl, carboxyalkyl, C 1-6 alkyl or C 2-6 alkenyl; R 5c or R 5d each independently is selected from the group consisting of H, hydroxyalkyl, aminoalkyl, carboxyalkyl, C 1-6 alkyl or C 1-6 alkoxy; R 5e is selected from the group consisting of halogen, hydroxy, amino or carboxy; R 5f is selected from the group consisting of TMS, TBS or SEM; each R 5g is independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, R 5f , -(CH2) n3 -R 5e , -(CH2) n3 -C(=O)-R 5a , -(CH2) n3 -C(=O)-O-R 5b or -(CH2) n3 -O-R 5f ; R6is selected from H, C 1-6 alkyl, -(CH2) n4 -C(=O)-R 6a , -(CH2) n4 -C(=O)-O-R 6b , -(CH2) n4 -R 6c or -(CH2) n4 A(R 5g ) u ; R 6a or R 6b are each independently selected from A(R 5g ) u , hydroxy, amino, C 1-6 alkyl or C 2-6 alkenyl; R 6c is selected from hydroxy, amino or carboxyl; The -(CH2) n3 -or-(CH2) n4 The hydrogen atom in -CH2- is optionally replaced by one or more groups selected from halogen, cyano, hydroxyl, amino, nitro, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; n3, n4 or u are each independently selected from 0, 1, 2 or 3.

8. The intermediate compound of formula (V) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein, R5 is selected from halogen, hydroxyl, amino, nitro or carboxyl; or R5is selected from -C(=O)R 5a or -C(=O)-O-R 5b ; R 5a and R 5b are each independently selected from C 1-3 alkyl or C 2-6 alkenyl; preferably, R 5a and R 5b are each independently selected from methyl, ethyl, ethenyl or propenyl; or R5is selected from -C(=O)-NR 5c R 5d or -S(=O) r -NR 5c R 5d ; R 5c and R 5d are each independently selected from H, hydroxyalkyl or C 1-3 alkyl; preferably, R 5c and R 5d are each independently selected from H, methyl, -CH2-OH, -(CH2)2-OH or -(CH2)3-OH; or R5is selected from -S(=O) r -(CH2) n3 -R 5e ; R 5e is selected from halogen or hydroxy; Alternatively, R5is selected from or R5is selected from -C 2-6 alkynylene-R 5f ; R 5f is selected from TMS, TBS or SEM; preferably, the C 2-6 alkynylene is selected from ethynylene or propynylene; or R5is selected from -A(R 5g ) u ; each R 5g is independently selected from halogen, C 1-3 1-6alkyl, R 5f , -(CH2) n3 -R 5e , -(CH2) n3 -C(=O)-R 5a , -(CH2) n3 -C(=O)-O-R 5b or -(CH2) n3 -O-R 5f ; Preferably, R5 is selected from F, Cl, Br, hydroxyl, amino, nitro, carboxyl, -C(=O)-CH3, -C(=O)-O-CH3, -C(=O)-O-CH2-CH3, -C(=O)-O-CH2-CH=CH2, -C(=O)-NH-(CH2)2-OH, -S-(CH2)2-OH, -S-(CH2)3-OH, -S(=O)2-Cl, -S(=O)2-N(CH3)-(CH2)2-OH, R6 is selected from H; or R6is selected from -(CH2) n4 -C(=O)-R 6a ; R 6a is selected from -A(R 5g ) u , hydroxy or amino; or R6is selected from -(CH2) n4 -C(=O)-O-R 6b ; R 6b is selected from methyl, ethyl, ethenyl or propenyl; or R6is selected from -(CH2) n4 -R 6c ; R 6c is selected from hydroxy, amino, nitro or carboxy; Alternatively, R6is selected from -(CH2) n4 -A(R 5g ) u ; Preferably, R6is selected from H, -CH2-C(=0)-0-CH3, -CH2-C(=0)-OH, -(CH2)2-OH, -(CH2)2-NH2or 9. The intermediate compound of Formula (V) according to claim 7, or a pharmaceutically acceptable salt thereof, said Formula (V) is selected from the following compounds of Formula (V-a), (V-b), (V-c), (V-d), (V-e), (V-f) or (V-g), wherein: W, R1, R2, R3, R4, R5, A, R 5g and u is as defined in claim 7; R6’ is selected from R6 and is not H; R7is selected from hydroxy, amino, C 1-6 alkyl, -O-R 7a or -NR 7b R 7c ; R 7a is selected from C 1-6 alkyl or C 2-4 alkenyl; R 7b or R 7c wherein one is selected from H or C 1-6 alkyl and the other is selected from hydroxyalkyl, aminoalkyl or carboxyalkyl; or, R7and R2are joined to form a 5-6 membered ring which is substituted with oxo; Preferably, R7is selected from hydroxy, amino or -O-R 7a ; R 7a is selected from methyl, ethyl, ethenyl or propenyl; Preferably, R7is selected from hydroxyl, amino, -0-CH2-CH=CH2or -0-CH3; or R7is connected to R2to form a C 5-6 cycloalkyl or 5-6 membered heterocyclyl; said C 5-6 cycloalkyl or 5-6 membered heterocyclyl optionally substituted with one or more C 1-3 alkyl or C 1-3 alkoxy; preferably, said C 5-6 cycloalkyl or 5-6 membered heterocyclyl optionally substituted with one or more methyl or ethyl groups; Preferably, R7is linked with R2to form a cyclopentenyl, cyclohexenyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyridazyl, dihydropyridazyl, tetrahydropyrimidyl or dihydropyrimidyl group, optionally substituted with one or more methyl groups, substituted with one oxo group; More preferably, R7is connected with R2to form optionally substituted with one or two methyl groups; R8is selected from H, C 1-6 alkyl or C 2-4 alkenyl; Preferably, R8is selected from H, methyl, ethyl, ethenyl or propenyl; R9and R 10 each independently selected from H, halogen, hydroxyl, amino, nitro, carboxyl, C 1-6 alkyl or C 1-6 alkoxy; or R9and R 10 are joined to form oxo; R9and R 10 each independently selected from H, hydroxyl, amino, nitro, carboxyl, methyl, ethyl or methoxy; or R9and R 10 to form an oxo group; Preferably, R9and R 10 each independently is selected from H or amino; p is selected from 0 or 1 or 2; R 11 selected from -A(R 5g ) u .

10. The compound of formula (V) according to claim 7, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds, 11. A method for producing a compound represented by formula (II-bl) or a salt thereof, wherein, R1, R2, R3, R4, R6, R8, W, Z, R a and m is as defined in claim 9; R5is selected from halogen, preferably R5is selected from F or Br; characterized in that a palladium catalyzed carbonylation of formula (V) gives formula (V-e), formula (V-e) is subjected to hydrolysis, deprotection and intramolecular cyclization to give formula (II-b1).

12. A process for the preparation of a compound of formula (II-a2), wherein, R2, R3, R4, R7, R9, R 10 , W and p are as defined in claim 9; R5is selected from halogen, preferably R5is selected from F or Br; characterized in that formula (V-c) is reacted with a thiol under basic conditions to give formula (V-f), formula (V-f) is subjected to intramolecular cyclization to give formula (II-a1), formula (II-a1) is further oxidized to give formula (II-a2).

13. A process for the preparation of a compound of formula (II-d), wherein, R1, R2, R3, R4, R 11 , W, A, Y, Z, R a and m are as defined in claim 9; R5is selected from halogen, preferably R5is selected from F or Br; characterized in that formula (V-a) is reacted with formula (VI) to give formula (V-g), formula (V-g) is subjected to intramolecular cyclization to give formula (II-d).

14. A pharmaceutical composition comprising a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. Use of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 14, for the manufacture of a medicament for a disease caused by an abnormal increase of neutrophil elastase; preferably the disease is acute lung injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, bronchiectasis or sepsis.

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