Dipeptidyl peptidase i inhibitors and uses thereof

Abstract

The present application relates to a kind of dipeptidyl peptidase I inhibitor shown in general formula (I) and use, specifically, dipeptidyl peptidase I inhibitor shown in general formula (I) and its purposes in preparation, prevention and / or treatment with DPP-1 related disease drug.The compound of the present application is ideal high-activity DPP-1 inhibitor, can be used for treating and / or preventing clinical diseases, including non-cystic fibrosis bronchiectasis (NCFBE), asthma, chronic obstructive pulmonary disease (COPD) and respiratory distress syndrome and other lung-related diseases and ANCA-related vasculitis, lupus nephritis, inflammatory bowel disease, rheumatoid arthritis and other autoimmune diseases and sepsis, alpha 1 antitrypsin deficiency, cancer, diabetic cardiomyopathy.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, and particularly relates to a dipeptidyl peptidase I (DPP-1) inhibitor and use, including a compound and a pharmaceutical composition thereof, a preparation method and use thereof in preparing a drug for preventing and / or treating indications related to the DPP-1 signal pathway. BACKGROUND

[0002] Dipeptidyl peptidase I (DPP-1), also known as cathepsin-C, is a lysosomal cysteine exopeptidase belonging to the papain family. DPP-1 is the only homotetramer consisting of identical catalytically active subunits among the 11 human lysosomal cysteine cathepsins.

[0003] DPP-1 mainly exists in the lysosome / endosome of cells, and is widely distributed in lung, spleen, kidney, liver tissues and bone marrow cell lines such as neutrophils, mast cells, monocytes, macrophages and their precursor cells.

[0004] DPP-1 activates zymogens by removing the inhibitory N-terminal dipeptide of serine proteases (NSPs), and one of its important biological functions is to activate the NSPs of neutrophils: elastase (NE), cathepsin G (-CatG), proteinase 3 (PR3) and chymase, tryptase, etc. in mast cells.

[0005] Neutrophils play an important role in the innate immune defense against invading pathogens. The NSPs secreted by cells help to digest and kill microorganisms, and are one of the main mediators of inflammatory reactions. However, neutrophils contain a large amount of activated NSPs, and excessive secretion can lead to degradation of extracellular medium and release of other inflammatory factors (IL-1β, etc.) to damage normal tissues, leading to the occurrence of acute and chronic inflammation and related diseases. Neutrophil-driven diseases include lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, bronchiectasis, respiratory distress syndrome, autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus erythematosus, inflammatory bowel disease, etc.

[0006] Mast cells are mainly related to allergic diseases, especially asthma. After being stimulated by allergens, a large amount of tryptase in mast cells is released into the nasal cavity and bronchus, causing bronchial stenosis and airway remodeling.

[0007] Clinical and preclinical studies have confirmed that DPP-1 is a potential target for the treatment of various diseases. For example, the results of the phase II clinical trial (N-CT03218917) of DPP-1 inhibitor INS1007 showed that it can effectively reduce lung damage in non-cystic fibrosis bronchiectasis (James D.-Chalmers, et al., 2020, N Engl J Med, 383(22), 2127-2137).

[0008] Studies have shown that the binding of anti-neutrophil cytoplasmic antibodies (AN-CA) to membrane-bound PR3 activates neutrophils to release active PR3 and other NSPs, which cause vascular damage and lead to the occurrence of autoimmune vasculitis. Therefore, neutrophil PR3 and DPP-1 can be used as targets for the treatment of AN-CA-related vasculitis (Brice Korkmaz et al., 2013, Semin Immunopathol, 35(4), 411-421). Literature has shown that in a human-CD34+ hematopoietic stem cell model, DPP-1 inhibitors can effectively reduce the expression and activity of membrane-bound PR3 and cellular PR3 (Seda Seren et al., 2018, J Biol-Chem, 293(32), 12415-12428), and DPP-1 inhibitors can be used for the treatment of AN-CA-related vasculitis.

[0009] Literature reports that DPP-1 is involved in the pathogenesis of acute asthma induced by infection with Sendai virus - / - In a mouse model, the absence of DPP-1 expression can inhibit acute inflammatory response and subsequent myeloid metaplasia caused by viral infection, reduce the accumulation of neutrophils, -CX-CL2, IL-1β, IL-6 in the lung, and DPP-1 inhibitors are expected to be used for the treatment of asthma (Antonina M. Akk et al., 2008, J Immunol, 180(5), 3535-3542).

[0010] In addition, DPP-1 inhibitors have significant anti-arthritic activity in a mouse model of rheumatoid arthritis induced by monoclonal anti-collagen antibodies, and can continuously reduce arthritis scores and paw thickness (Brice Korkmaz et al., 2019, Biochem Pharmacol, 164, 349-367), and can be used for the treatment of rheumatoid arthritis.

[0011] Alpha-1 antitrypsin belongs to the family of serine protease inhibitors and protects lung tissue by inhibiting neutrophil elastase activity. Alpha-1 antitrypsin deficiency is a genetic metabolic disease that leads to excessive activation of lung elastase due to the lack of alpha-1 antitrypsin, thereby causing emphysema in infants and adults (Maria Paula Henao et al., 2017, Allergy Asthma Proc, 38(2), 98-107; -Cormac Mc-Carthy et al., 2016, Ann Am Thorac Soc, Suppl 4, s297-304). These literature evidences support the use of DPP-1 inhibitors for the treatment of alpha-1 antitrypsin deficiency.

[0012] There are also literature evidences that DPP-1 plays an important regulatory role in the occurrence and development of various tumors, for example, the growth of squamous cell tumors depends on the DPP-1 pathway (Brian Ruffell et al., 2013, Genes Dev, 27(19), 2086-2098); DPP-1 acts on the TNF-alpha / p38 MAPK signaling pathway to promote the proliferation and metastasis of hepatocellular carcinoma (Guo-Pei Zhang et al., 2020, -Cancer Res Treat, 52(1), 10-23); the deletion of DPP-1 can promote the apoptosis of prostate cancer cells (Tejinder Pal Khaket et al., 2018, -Cell Signal, 46, 92-102), etc., suggesting that DPP-1 inhibitors can be used for the treatment of cancer.

[0013] Studies have shown that the deletion of DPP-1 in mast cells can improve the survival rate of mice in a cecal ligation and puncture sepsis model (Jon Mallen-St-Clair et al., 2004, 113(4), 638-634), and DPP-1 inhibitors can be used for the treatment of sepsis.

[0014] In addition, DPP-1 deficient mice can significantly reduce myocardial cell apoptosis, fibrosis, and improve myocardial function in a diabetic model (Mikhail A Kolpakov et al., 2019, -Cell Physiol Biochem, 53(6), 982-998), suggesting that DPP-1 inhibitors can be used for the treatment of diabetic cardiomyopathy.

[0015] International patent application publication WO2019 / 157050 relates to the use of DPP-1 inhibitor INS1007 for the treatment of AN-CA associated vasculitis such as granulomatosis with polyangiitis (GPA).

[0016] International patent application publication WO2020 / 018547 relates to DPP-1 inhibitor INS1007 for treating lupus nephritis, examples show that INS1007 is effective on mouse model of lupus nephritis.

[0017] International patent application publication WO2020 / 018551 relates to DPP-1 inhibitor INS1007 for treating inflammatory bowel disease, examples show that INS1007 is effective on mouse intestinal inflammation model induced by sodium dextran sulfate. SUMMARY

[0018] The object of the present application is to provide a new DPP-1 inhibitor which has excellent inhibitory activity on DPP-1 and good selectivity, and also has excellent pharmacokinetic properties and higher safety, etc., is an ideal DPP-1 inhibitor.

[0019] To achieve the object of the present application, the present application adopts the following technical solutions:

[0020] The present application provides a compound having the structure shown in general formula (I), its deuterium compound, stereoisomer or pharmaceutically acceptable salt:

[0021]

[0022] Among them, A is selected from

[0023]

[0024] X is selected from O, S, NH;

[0025] Q is selected from CH or N;

[0026] R1 is selected from hydrogen, halogen, hydroxyl, cyano, -NH2, -C 1-6 alkyl, -C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2;

[0027] R2, R3 are each independently selected from hydrogen, halogen, hydroxyl, cyano, -O-C 1-3 alkylene-C 1-6 alkoxy, -NH2, -NH-R a , -CO-R a , -SO2-R a , -C 1-3 -alkylene-SO2-R a , -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-6 cycloalkyl, -C3-8 heterocycloalkyl, -C 3-8 heterocycloalkyl-R a , -C 3-8 unsaturated heterocyclyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-8 heterocycloalkyl, -C 1-3 alkylene-C 3-8 heterocycloalkyl-R a , -C 1-3 alkylene-C 3-8 unsaturated heterocyclyl;

[0028] R a selected from hydrogen, halogen, cyano, hydroxyl, -NH2, aldehyde, -C 1-4 alkyl, -C 3-6 cycloalkyl, -C 3-8 heterocycloalkyl;

[0029] said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, unsaturated heterocyclyl can be optionally substituted with 0-3 R b ;

[0030] R b selected from halogen, cyano, hydroxyl, amino, -C 1-4 alkyl;

[0031] m is selected from an integer from 0 to 3.

[0032] In one aspect, the present application provides a compound having a structure represented by Formula (I), a deuterated form, a stereoisomer or a pharmaceutically acceptable salt thereof:

[0033]

[0034] wherein A is selected from

[0035]

[0036] X is selected from O, S, NH;

[0037] Q is selected from CH or N;

[0038] R1is selected from hydrogen, halogen, hydroxyl, cyano, -NH2, -C 1-6 alkyl, -C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2;

[0039] R2, R3are each independently selected from hydrogen, halogen, hydroxyl, cyano, -NH2, -NH-R a , -CO-Ra -SO2-R a -C 1-3 -alkylene-SO2-R a -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-6 cycloalkyl, -C 3-8 heterocycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-8 heterocycloalkyl;

[0040] R a selected from hydrogen, hydroxyl, -NH2, aldehyde, -C 1-4 alkyl, -C 3-6 cycloalkyl, -C 3-8 heterocycloalkyl;

[0041] said alkyl, alkoxy, cycloalkyl, heterocycloalkyl can optionally be substituted with 0-3 R b ;

[0042] R b selected from halogen, cyano, hydroxyl, amino, -C 1-4 alkyl;

[0043] m is selected from an integer between 0 and 3.

[0044] As a preference:

[0045] said A is selected from

[0046]

[0047] wherein,

[0048] X is selected from O, S, NH;

[0049] Q is selected from CH or N;

[0050] R1, R2, R3, R a , R b , m are as defined in claim 1.

[0051] As a preference:

[0052] R1is selected from hydrogen or halogen;

[0053] R2, R3are each independently selected from hydrogen, halogen, hydroxyl, cyano, -NH2, -NH-R a , -CO-R a , -SO2-R a , -CH2-alkylene-SO2-R a , -C1-4 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -C 3-6 heterocycloalkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-C 3-6 heterocycloalkyl;

[0054] R a selected from hydrogen, hydroxyl, -NH2, aldehyde, -C 1-4 alkyl, -C 3-6 cycloalkyl, -C 3-8 heterocycloalkyl;

[0055] said alkyl, alkoxy, cycloalkyl, heterocycloalkyl can be optionally substituted with 0-3 R b substituents;

[0056] R b selected from halogen, cyano, hydroxyl, amino, -C 1-4 alkyl.

[0057] As a preference:

[0058] R1is selected from hydrogen or F;

[0059] R2, R3are independently selected from hydrogen, -C 1-4 alkyl, -CH2-SO2-R a , -C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-8 heterocycloalkyl;

[0060] R a selected from -C 1-4 alkyl;

[0061] said alkyl, cycloalkyl, heterocycloalkyl can be optionally substituted with 0-3 R b substituents;

[0062] R b selected from halogen, cyano, hydroxyl, amino, -C 1-4 alkyl.

[0063] As a preference:

[0064] R2, R3are independently selected from hydrogen, methyl, trifluoromethyl, 2-methylpropyl, cyclopropyl, -CH2-SO2-Me, cyclopropylmethyl, cyclopentylmethyl,

[0065] As a preference, the compound has the structure of formula (I):

[0066]

[0067] wherein A is selected from

[0068] R1is selected from hydrogen, halogen;

[0069] R2is selected from hydrogen, halogen, -C 1-3 alkyl, -C 1-3 alkoxy, -C 1-3 haloalkyl;

[0070] R3is selected from cyano, -C 3-6 cycloalkyl,

[0071] Z is selected from CH or N;

[0072] R a is selected from hydrogen, -C 1-3 alkyl;

[0073] r, p are selected from an integer from 1 to 3;

[0074] n is selected from an integer from 0 to 3.

[0075] As a preference:

[0076] R1is selected from hydrogen, F, Cl;

[0077] R2is hydrogen;

[0078] R3is selected from cyano, -C 3-6 cycloalkyl,

[0079] R a is selected from hydrogen, methyl, ethyl.

[0080] As a preference:

[0081] R3is selected from cyano, cyclopropyl,

[0082] As a preference, the compound has the structure of formula (II):

[0083]

[0084] R3is selected from cyclopropyl,

[0085] Further, in some specific embodiments, the compound has the structure of (II-1):

[0086]

[0087] As a preference, the compound has a structure represented by formula (III):

[0088]

[0089] R3is selected from cyano, cyclopropyl,

[0090] Further, in some specific embodiments, the compound has a structure represented by (III-1):

[0091]

[0092] As a preference, the compound has a structure represented by formula (IV):

[0093]

[0094] R1is selected from hydrogen, halogen;

[0095] R2is selected from halogen, -C 1-3 alkyl, -C 1-3 alkoxy, -C 1-3 haloalkyl, -C 1-3 haloalkoxy;

[0096] R3is selected from -C 1-3 alkyl, -(CH2) n -C 3-6 cycloalkyl,

[0097] Z is selected from CH or N;

[0098] R a is selected from hydrogen, -C 1-3 alkyl;

[0099] r, p are selected from an integer from 1 to 3;

[0100] n is selected from an integer from 0 to 3.

[0101] As a preference:

[0102] R2is selected from trifluoromethyl.

[0103] As a preference:

[0104] R1is selected from hydrogen, F, Cl;

[0105] R3is selected from -C 1-3 alkyl, -C 3-6 cycloalkyl,

[0106] R aselected from hydrogen, methyl, ethyl.

[0107] As preferred:

[0108] R3 is methyl.

[0109] Further, in some embodiments, the compound has the structure of (IV-1):

[0110]

[0111] In another aspect, the present application provides a compound, a deuterated form, a stereoisomer or a pharmaceutically acceptable salt thereof:

[0112]

[0113]

[0114]

[0115] In another aspect, the present application provides a pharmaceutical composition comprising the above-mentioned compound, a deuterated form, a stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0116] In another aspect, the present application provides a use of the above-mentioned compound, a deuterated form, a stereoisomer or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the manufacture of a medicament for treating and / or preventing a DPP-1 related disease.

[0117] As preferred, the DPP-1 related disease is selected from lung related diseases such as non-cystic fibrosis bronchiectasis, asthma, chronic obstructive pulmonary disease and respiratory distress syndrome, and autoimmune diseases such as anti-neutrophil cytoplasmic antibody associated vasculitis, lupus nephritis, inflammatory bowel disease, rheumatoid arthritis, and sepsis, alpha 1 antitrypsin deficiency, tumor, diabetic cardiomyopathy.

[0118] The present application has the following advantages: the compound has novel structure, strong kinase or cell activity, better pharmacokinetic activity and bioavailability compared with positive drugs, and is an ideal DPP-1 enzyme inhibitor.

[0119] Definitions:

[0120] As used herein, "optionally" or "optionally" means that any optional item can be selected or not selected. For example, "group A is optionally substituted with 1-3 groups B" includes four cases: group A is not substituted with group B, group A is substituted with 1 group B, group A is substituted with 2 groups B, and group A is substituted with 3 groups B.

[0121] As used herein, "substituted" or "substituted with" means that any atom of a group or moiety has any one or more of its hydrogen atoms replaced by a substituent, which can include deuterium and variations of hydrogen, as long as the valency of the particular atom is not normally exceeded and the resulting compound is stable. The term "optionally substituted" means that the group can or can not be substituted and, unless otherwise specified, the types and number of substituents are any that are chemically possible.

[0122] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each instance is independent of the definition of the other. Thus, for example, if a group is substituted with 0-2 R groups, then the group can optionally be substituted with up to two R groups, and at each occurrence R is selected independently.

[0123] When the number of a linking group is 0, such as -(CH2)n- where n is 0, it means that the linking group is a single bond. n - the number of n is 0, it means that the linking group is a single bond.

[0124] When one of the variables is selected from a bond / single bond, it means that the two groups it connects are directly connected, such as L1 represents a single bond in A-L1-R1 means that the structure is actually A-R1.

[0125] When a substituent is null, it means that the substituent is absent, such as X is null in A-X means that the structure is actually A. When a listed substituent is not designated by which atom of the substituent is connected to the group being substituted, the substituent can be bonded through any atom of the substituent, for example, a pyridyl group as a substituent can be connected to the group being substituted through any one of the carbon atoms of the pyridyl ring.

[0126] When a listed linking group is not designated by its direction of connection, its direction of connection is arbitrary, for example, in the ring A-L1-R1 where the linking group L1 is -M-W-, -M-W- can either connect ring A and R1 in the same direction as the reading order from left to right to form ring A-M-W-R1 or in the opposite direction to form ring A-W-M-R1. The combination of the linking groups, substituents, and / or variations thereof is only allowed if such combination results in a stable compound.

[0127] Unless otherwise specified, when a group has one or more available sites of attachment, any one or more of the sites of the group can be attached to other groups by a chemical bond. When the manner of attachment of the chemical bond is not specified, and an available site contains an H atom, the number of H atoms at the site is reduced by one for each chemical bond that is formed. The chemical bond by which the site is attached to other groups can be represented by a straight solid line a dashed line and a cross-hatched line . For example, the straight solid line in -OCH3represents attachment to other groups through the oxygen atom in the group; the straight dashed line or cross-hatched line in -CH2CH2represents attachment to two groups through the carbon atoms on one side of the ethyl group; the dashed line in -C6H4represents attachment to other groups through the carbon atoms at positions 1 and 4 in the phenyl group; represents that any available site of attachment on the piperidinyl group can be attached to other groups by one chemical bond, including at least the four ways of attachment shown for -N-; even though H atoms are shown, but including such groups connected by one chemical bond, the H atom at the site is reduced by one to form a corresponding monovalent piperidinyl group.

[0128] Unless otherwise specified, in spiro or fused ring groups, the site of attachment of a group or fragment is on the ring that is connected by the dashed line. For example, represents that any available site of attachment on the nitrogen-containing spiro ring of the group can be attached to other groups by one chemical bond, including at least the three ways of attachment shown; represents that any available site of attachment on the phenyl ring of the group can be attached to other groups by one chemical bond, including at least the four ways of attachment shown.

[0129] Unless otherwise specified, in bridged ring groups, the site of attachment of a group or fragment can be any available site of attachment. For example, represents that any available site of attachment on the nitrogen-containing spiro ring of the group can be attached to other groups by one chemical bond, including at least the two ways of attachment shown.

[0130] In general, in aromatic or heteroaromatic rings, double bonds and single bonds are not distinguished. For example, both refer to a benzene ring or phenyl group, in which the double bonds or specifically refer to delocalized pi bonds that lie in the plane of the benzene ring; In particular embodiments, when ring C is defined as C5 aryl or heteroaryl, ring B and ring C form a conjugated fused aryl or fused heteroaryl, in which case non-limiting examples include In particular embodiments, when ring C is defined as C5 aryl or heteroaryl, ring B and ring C form a conjugated fused aryl or fused heteroaryl, in which case non-limiting examples include In particular embodiments, when ring C is defined as C5 aryl or heteroaryl, ring B and ring C form a conjugated fused aryl or fused heteroaryl, in which case non-limiting examples include In particular embodiments, when ring C is defined as C5 aryl or heteroaryl, ring B and ring C form a conjugated fused aryl or fused heteroaryl, in which case non-limiting examples include In particular embodiments, when ring C is defined as C5 aryl or heteroaryl, ring B and ring C form a conjugated fused aryl or fused heteroaryl, in which case non-limiting examples include

[0131] As used herein, numerical ranges include endpoints and any number that falls within the range. For example, "0-3" can include 0, 1, 2, or 3, and "1-3" can include 1, 2, or 3.

[0132] As used herein, "C 1-n " includes C 1-2 , C 1-3 ,... C 1-n . For example, a "C 1-6 " group refers to a moiety having 1-6 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Thus, for example, a "C 1-4 alkyl" group refers to an alkyl group having 1-4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Numerical ranges as used herein, such as "1-6", are used to indicate each integer within the specified range.

[0133] A ring atom refers to a non-hydrogen atom in a ring group that is used to form a ring. For example In the group , the ring atoms are 3 carbon atoms and 1 oxygen atom; In the group , the ring atoms are 1 N atom and 5 carbon atoms;

[0134] It is important to note that in a cycloalkyl, aryl, heterocyclyl, heterocycloalkyl, or heteroaryl group, "C 1-n " refers to the number of ring atoms in the cycloalkyl, aryl, heterocyclyl, heterocycloalkyl, or heteroaryl group, including carbon atoms or other heteroatoms. For example, a "C 3-8 " group refers to a moiety having 3-8 ring atoms, i.e., the group contains 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, or 8 ring atoms. Thus, for example, a "-C 3-8 cycloalkyl" group refers to a saturated cyclic hydrocarbon group having 3-8 carbon atoms, i.e., the alkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A "-C 3-8"Heterocyclic alkyl" refers to a saturated cyclic hydrocarbon group containing 3-8 carbon atoms or heteroatoms, including propylene oxide, cycloazinopropyl oxide, propylene oxide, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, etc.

[0135] As used alone or in combination herein, the term "hydrocarbon group" refers to a group of atoms consisting only of carbon and hydrogen elements, including saturated, unsaturated, or aromatic hydrocarbon groups, such as alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, cycloynyl, and aryl. Unless otherwise specified, "hydrocarbon group" can be straight-chain, branched, or cyclic.

[0136] The term "alkyl" as used alone or in combination herein refers to a saturated aliphatic hydrocarbon that is optionally substituted with a straight chain or optionally substituted with a branched chain. "alkyl" as used herein preferably has 1-6 carbon atoms, for example, 1-5 carbon atoms, 1-4 carbon atoms, or 1-3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, etc. When "alkyl" appears in a numerical range in the group defined herein, for example, "C..." 1-6 "Alkyl" refers to an alkyl group that can be composed of 1, 2, 3, 4, 5, or 6 carbon atoms, and also includes cases where no numerical range is specified. Alkyl groups can be optionally substituted or unsubstituted.

[0137] The term “alkyl” as used in this article refers to an alkyl group linked to other groups, such as an alkyl group in an alkoxy group, and is defined the same as when used alone.

[0138] The term "alkylene," used alone or in combination, refers to a saturated aliphatic divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a straight- chain or branched-chain saturated aliphatic hydrocarbon. An "alkylene" group herein preferably can have 1 to 6 carbon atoms, for example, 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Non-limiting examples of alkylene groups include -CH2- (i.e., methylene), -CH2-CH2- (i.e., ethylene), -CH2-CH2-CH2-, -CH(CH3)CH2-, -C(CH3)2-, -CH2-C(CH3)-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C(CH3)-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-CH2-, and the like. An alkylene group can be optionally substituted or unsubstituted.

[0139] The term "alkoxy" or "-O-alkyl," used alone or in combination, means "alkyl-O-." Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, s-butyloxy, t-butyloxy, and the like. An alkoxy group can be optionally substituted or unsubstituted.

[0140] The term "cycloalkyl" or "ring," used alone or in combination, means a saturated monocyclic, bicyclic, or polycyclic carbocyclic ring, which can be spiro or bridged. Preferably, a cycloalkyl group herein is C 3-12 cycloalkyl group, preferably a C 3-12 cycloalkyl group, more preferably a C 3-10 cycloalkyl group.

[0141] The term "cycloalkyl" or "ring," used alone or in combination, means a saturated monocyclic, bicyclic, or polycyclic carbocyclic ring, which can be spiro or bridged. Preferably, a cycloalkyl group herein is C 3-12 cycloalkyl group, preferably a C 3-10 cycloalkyl group, more preferably a C 3-8Cycloalkyl. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, which can be optionally substituted or unsubstituted.

[0142] The term "heterocyclyl," used alone or in combination, refers to aliphatic heterocyclyl and heteroaryl groups in which one or more (such as one, two, three, or four) ring atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, including monocyclic, fused, bridged, and spirocyclic rings. Examples of heterocyclyl groups include heterocycloalkyl, heterocycloalkenyl, and heteroaryl groups as discussed below. Preferred herein are C 3-10 Monocyclic, bicyclic, or tricyclic heterocyclyl groups, which can contain 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and / or sulfur. Non-limiting examples of "heterocyclyl" groups include azetidinyl, azetidin-2-yl, oxetanyl, thietanyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, 2-oxo-piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, piperazin-2-one, dioxanyl, morpholinyl, and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, and the like. Heterocyclyl groups can be optionally substituted or unsubstituted.

[0143] The term "heterocycloalkyl," used alone or in combination, refers to saturated monocyclic, bicyclic, or polycyclic, wherein one or more (such as one, two, three, or four) ring atoms are heteroatoms, saturated heterocyclyl groups, which can be spirocyclic or bridged. Preferred herein are C 3-12 Heterocycloalkyl, more preferably C 3-10 Heterocycloalkyl, most preferably C 3-8 Heterocycloalkyl. Non-limiting examples of monocyclic heterocycloalkyl groups include, but are not limited to, oxetane, thietane, aziridine, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, oxazolidine, thiazolidine, imidazolidine, tetrahydropyran, piperidine, dioxane, azepane.

[0144] The term "unsaturated heterocyclyl," used alone or in combination, refers to monocyclic, bicyclic, or polycyclic, which do not have aromaticity, having 1 or more unsaturated bonds, wherein one or more (such as one, two, three, or four) ring atoms are heteroatoms, saturated heterocyclyl groups, which can be spirocyclic or bridged. Preferred herein are C 3-12 Heterocycloalkenyl, more preferably C 3-10 Heterocycloalkenyl, most preferably C 3-8 Heterocycloalkenyl. Non-limiting examples of heterocycloalkenyl groups include, but are not limited to, aziridinyl, oxiridinyl, thiridinyl, oxetidinyl, pyranyl,

[0145] The term "halogen" as used herein alone or in combination refers to fluorine, chlorine, bromine or iodine.

[0146] The term "hydroxyl" as used herein alone or in combination refers to -OH.

[0147] The term "cyano" as used herein alone or in combination refers to -CN.

[0148] The term "methanesulfonyl" as used herein alone or in combination refers to -S(O)2-CH3.

[0149] The term "substituted" or "substitution" as used herein refers to replacement of one or more hydrogens on a specified atom with the indicated group(s) such as halogen, alkyl, etc. provided that the indicated atom's normal valency is not exceeded and that the resulting compound is stable.

[0150] The term "pharmaceutically acceptable salt" as used herein is art-recognized and refers to a relatively non-toxic, inoffensive character.

[0151] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not abrogate the biological activity or properties of the compounds of the present application, and is relatively nontoxic, i.e., the material is not deleterious to individuals when administered in accordance with the dosage regimen contemplated.

[0152] The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally admixed with at least one pharmaceutically acceptable chemical ingredient including, but not limited to, carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients.

[0153] The term "carrier" as used herein refers to a relatively nontoxic chemical compound or agent that facilitates the introduction of a compound into a cell or tissue.

[0154] The term "stereoisomer" as used herein includes, but is not limited to, enantiomers, cis-trans isomers, and the like.

[0155] The term "enantiomer" as used herein refers to the phenomenon of isomerism in which two compounds having the same molecular formula exist as mirror images of each other and are not superimposable. The term "cis-trans isomer" as used herein refers to the phenomenon of stereoisomerism in which the spatial arrangement of groups in a molecule is different due to the presence of a restriction factor for free rotation. Organic molecules such as alkenes, azo compounds, alicyclic hydrocarbons, etc. are considered to be cis-trans isomers. In the present application, cis-trans isomerism is mainly embodied in alicyclic hydrocarbons. For example, in cyclohexane, cis-trans isomerism occurs when the cyclohexane is substituted with two substituents. When the two substituents are on the same side of the ring, it is a "cis" isomer, and when they are on different sides, it is a "trans" isomer.

[0156] The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, atropisomeric, and geometric (conformational) isomeric forms, and mixtures thereof such as racemates, are within the scope of the present application.

[0157] Unless otherwise indicated, structures depicted throughout this specification are also meant to include all isomeric forms (e.g., diastereomeric, enantiomeric, atropisomeric, and geometric (conformational) isomeric forms) and mixtures thereof, such as racemates, of the disclosed structures, for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, alicyclic ring cis and trans isomers, atropisomers, (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, atropisomeric, and geometric (conformational) mixtures of the present compounds are within the scope of the present application. Unless otherwise stated, all tautomeric forms of the structures depicted herein are within the scope of the present application. Therefore, structures depicted herein encompass both the cis and trans isomers, as appropriate, and the like. DETAILED DESCRIPTION

[0158] The present application is further described in detail by reference to the following specific examples. The present application is not limited in scope by the examples, which are intended as illustrations of single aspects of the application only.

[0159] The starting materials and reagents used in the present application can be prepared by conventional methods or purchased commercially.

[0160] The following are the partial preparation conditions used in the examples:

[0161] Pre-HPLC conditions: Instrument: GILSON-GX281; Wavelength: 220nm & 254nm; Column type: Waters X-bridge (30x100mm, 10pm) or Luna C18 (30x75mm, 3pm) or Luna C18 (30x75mm, 3pm); Mobile phase: A: 10mM ammonium bicarbonate or H20 (0.1% formic acid) or H20 (0.1% trifluoroacetic acid), B: acetonitrile; Run time: 15min; Flow rate: 25mL / min.

[0162] Reverse phase column purification was performed using C18 reverse phase silica gel column (Spherical C18, 40-60pm, 40g-120g) with water / acetonitrile (95 / 5~30 / 70) as mobile phase.

[0163] Example 1: (S)-N-((S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)-1- cyanoethyl)-1,4-oxazetidine-2-carboxamide (Compound 1)

[0164]

[0165] (1) (S)-tert-butyl 2-((((S)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl]phenyl]phenyl)-1- amino-1-oxopropan-2-)carbamoyl)-1,4-oxazetane-4-carboxylate

[0166] (S)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)-2-aminopropanamide (110 mg, 0.23 mmol), triethylamine (70 mg, 0.69 mmol) and (S)-4-(tert-butoxycarbonyl)-1,4- oxazetane-2-carboxylic acid (56 mg, 0.23 mmol) were dissolved in N,N- dimethylformamide (5 mL), propylphosphonic anhydride (190 mg, 0.30 mmol, 50% in ethyl acetate) was added to the reaction, and the mixture was stirred at room temperature for 1 hour. The reaction was dispersed in water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography to obtain (S)-tert-butyl 2-((((S)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl]phenyl]phenyl)-1- amino-1-oxopropan-2-)carbamoyl)-1,4-oxazetane-4-carboxylate (120 mg, white solid) in a yield of 100%. MS-ESI calculated value [M+H] + 509.2, found 509.1.

[0167] (2) (S)-tert-butyl 2-((((S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)-1- cyanoethyl)-1,4-oxazetidine-2-carboxamid

[0168] ((S)-tert-butyl 2-((((S)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl]phenyl]phenyl)-1- amino-1-oxopropan-2-)carbamoyl)-1,4-oxazetidine-4-carboxylate (120 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL), and N-(triethylsulfamidyl)carbamic acid methyl ester (121 mg, 0.48 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure to obtain a residue, and the residue was purified by reverse phase column to obtain (S)-tert-butyl 2-((((S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)-1- cyanoethyl)-1,4-oxazetidine-2-carboxamid (100 mg, yellow solid), yield: 85%. MS-ESI calculated value [M+H] + 491.2, found 491.1.

[0169] (3) (S)-N-((S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)-1- cyanoethyl)-1,4-oxazetidine-2-carboxamid

[0170] (S)-tert-butyl 2-((((S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)-1- cyanoethyl)-1,4-oxazetidine-2-carboxamid (90 mg, 0.18 mmol) was dissolved in formic acid (4 mL), and the mixture was stirred at room temperature for 2 hours. The reaction system was concentrated under reduced pressure to obtain a residue, and the residue was purified by preparative column chromatography to obtain (S)-N-((S)-2-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)-1- cyanoethyl)-1,4-oxazetidine-2-carboxamid (48 mg, white solid), yield: 68%. 1HNMR (400 MHz, DMSO-d6): δ = 12.13 (s, 1H), 9.08 (s, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.37 (d, J = 8.0 Hz, 2H), 8.22 (s, 1H), 7.57 (d, J = 3.2 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 6.60 (d, J = 3.2 Hz, 1H), 5.08-5.02 (m, 1H), 4.08-4.05 (m, 1H), 3.76-3.70 (m, 1H), 3.26-3.21 (m, 2H), 3.11-3.07 (m, 1H), 2.88-2.80 (m, 1H), 2.70-2.65 (m, 1H), 2.64-2.56 (m, 1H), 1.80-1.72 (m, 2H). MS-ESI calculated [M+H] + 391.2, found 391.2.

[0171] Example 2: (S)-N-((S)-1-cyano-2-(4-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2- yl)phenyl)ethyl)-1,4-oxazetidine-2-carboxamide (Compound 2)

[0172]

[0173] Referring to the method of Example 1, (S)-2-amino-3-(4-(7-methyl-7H-pyrrolo[2,3- d]pyrimidin-2-yl)phenyl)propanamide (160 mg, 0.45 mmol) as raw material, ((S)-N-((S)-1-cyano-2-(4-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)ethyl)-1,4- oxazetidine-2-carboxamide (35 mg, white solid) was obtained, yield: 59%. 1 HNMR (400 MHz, DMSO-d6): δ = 12.13 (s, 1H), 9.08 (s, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.37 (d, J = 8.0 Hz, 2H), 8.22 (s, 1H), 7.57 (d, J = 3.2 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 6.60 (d, J = 3.2 Hz, 1H), 5.08-5.02 (m, 1H), 4.08-4.05 (m, 1H), 3.76-3.70 (m, 1H), 3.26-3.21 (m, 2H), 3.11-3.07 (m, 1H), 2.88-2.80 (m, 1H), 2.70-2.65 (m, 1H), 2.64-2.56 (m, 1H), 1.80-1.72 (m, 2H). MS-ESI calculated [M+H] +405.2, found 405.2.

[0174] Example 3: (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)-1,4-oxazetidine-2-carboxamide (Compound 3)

[0175]

[0176] Referring to the method of Example 1 step (1), (3), starting from (S)-3-(4-(1H- pyrrolo[2,3-b]pyridine-6-yl)phenyl)-2-aminopropanenitrile (120 mg, 0.46 mmol) and (S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (112 mg, 0.46 mmol) to give (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)-1,4-oxazetidine-2-carboxamide (32.4 mg, white solid), yield: 33%. 1 HNMR (400 MHz, DMSO-d6): δ = 11.68 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H), 8.08-7.96 (m, 3H), 7.64 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 6.46 (t, J = 1.6 Hz, 1H), 5.08-5.02 (m, 1H), 4.08-4.05 (m, 1H), 3.88-3.80 (m, 1H), 3.78-3.70 (m, 1H), 3.24-3.18 (m, 2H), 3.16-3.12 (m, 1H), 3.11-3.07 (m, 1H), 2.88-2.56 (m, 2H), 1.80-1.72 (m, 2H). MS-ESI calculated [M+H] + 390.2, found 390.3.

[0177] Example 4: (S)-N-((S)-1-cyano-2-(4-(1-methyl-1H-pyrrolo[2,3-b]pyridine-6-6- yl)phenyl)ethyl)-1,4-oxazetidine-2-carboxamide (Compound 4)

[0178]

[0179] (1) (S)-tert-butyl 2-(((S)-1-cyano-2-(4-(1-methyl-1H-pyrrolo[2,3-b]pyridine-6- yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0180] To a solution of 6-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridine (80 mg, 0.38 mmol) in dioxane (2 mL) was added bis(pinacolato)diboron (101 mg, 0.4 mmol), potassium acetate (75 mg, 0.76 mmol) and l,l'-bis(diphenylphosphino)ferrocene palladium dichloride (14 mg, 0.02 mmol) under nitrogen. The mixture was heated to 90 °C and stirred for 6 h. After the reaction mixture was cooled to room temperature, (S)-tert-butyl 2-((((S)-l-amino-3-(4-iodophenyl)-l-oxopropan-2-yl)carbamoyl)- 1,4-oxazepane-4-carboxylate (196 mg, 0.38 mmol), potassium carbonate (105 mg, 0.76 mmol) and l,l'-bis(diphenylphosphino)ferrocene palladium dichloride (14 mg, 0.02 mmol) were added, and water (1 mL) was added. The reaction mixture was heated to 90 °C and stirred overnight under nitrogen. The reaction was monitored by LC-MS. The reaction mixture was concentrated and purified by silica gel column to give the target product (S)-tert-butyl 2-(((S)-l-cyano-2-(4-(l-methyl-lH-pyrrolo[2,3-b]pyridin-6- yl)phenyl)ethyl)carbamoyl)-l,4-oxazepane-4-carboxylate (132 mg, yellow oily liquid) in 58% yield. MS-ESI calculated for [M+H] C32H36N6O5, 604.3, found 604.2. + 522.3, found 522.2

[0181] (2) (S)-N-((S)-l-cyano-2-(4-(l-methyl-lH-pyrrolo[2,3-b]pyridin-6- yl)phenyl)ethyl)-l,4-oxazetidine-2-carboxamide

[0182] Referring to the method of Example 1, step (2), (3), (S)-tert-butyl 2-(((S)-l-cyano-2-(4-(l-methyl-lH-pyrrolo[2,3-b]pyridin-6- yl)phenyl)ethyl)carbamoyl)-l,4-oxazepane-4-carboxylate (132 mg, 0.25 mmol) was used as the starting material to give (S)-N-((S)-l-cyano-2-(4-(l-methyl-lH-pyrrolo[2,3-b]pyridin-6- yl)phenyl)ethyl)-l,4-oxazetidine-2-carboxamide (24.2 mg, white solid) in 35% yield. MS-ESI calculated for [M+H] C28H30N6O4, 518.2, found 518.3. + 404.2, found 404.3. 1HNMR (400 MHz, DMSO-d6): δ = 8.67 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 3.2 Hz, 1H), 7.40 (d, J = 4.0 Hz, 2H), 6.48 (d, J = 3.6 Hz, 1H), 5.06-5.00 (m, 1H), 4.08-4.01 (m, 1H), 3.90-3.80 (m, 4H), 3.78-3.70 (m, 1H), 3.25-3.18 (m, 2H), 3.12-3.04 (m, 1H), 2.84-2.78 (m, 1H), 2.70-2.55 (m, 2H), 1.78-1.72 (m, 2H).

[0183] Example 5: (S)-N-((S)-1-cyano-2-(4-(3-cyclopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)-1,4-oxazetidine-2-carboxamide (Compound 5)

[0184]

[0185] Referring to the method of Example 6, using 3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one 3 (90 mg, 0.3 mmol) as a starting material, (S)-N-((S)-1-cyano-2-(4-(3-cyclopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)- 1,4-oxazetidine-2-carboxamide 7 (60.0 mg, white solid) was obtained in a yield of 73%. 1 HNMR (400 MHz, DMSO-d6) 8.68 (d, J = 8.8 Hz, 1H), 8.23 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.44-7.38 (m, 5H), 5.06-5.00 (m, 1H), 4.09-4.06 (m, 1H), 3.89-3.70 (m, 2H), 3.26-2.50 (m, 7H), 1.81-1.73 (m, 2H), 1.08-0.99 (m, 4H). MS-ESI calculated [M+H] + 447.2, found 447.3.

[0186] Example 6: (S)-N-((S)-l-cyano-2-(4-(4-methyl-3-oxo-5-(trifluoromethyl)- 3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)phenyl)ethyl)-l,4-oxazetidine-2-carboxamide (Compound 6)

[0187]

[0188] (1) 4-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)-2H-benzo[b][l,4]oxazin-3(4H)-one

[0189] To a solution of 4-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (10 mg, 0.03 mmol) in acetonitrile / water (5 / 1 mL) was added (S)-tert-butyl 2-((((S)-l-amino-3-(4- iodophenyl)-l-oxopropan-2-yl)carbamoyl)-l,4-oxazepane-4-carboxylate (14 mg, 0.03 mmol), potassium carbonate (8 mg, 0.05 mmol) and PdCl2(dppf)2(3 mg, 0.003 mmol). The reaction mixture was stirred at 90 °C overnight. The reaction mixture was filtered directly and concentrated under reduced pressure. Purification on silica gel (ethyl acetate: petroleum ether = 1:3) gave 4-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (16 mg, yellow solid) in 94% yield. MS-ESI calc [M+H] + 621.3, found 621.1.

[0190] (2) 2-((((S)-l-cyano-2-(4-(3-methyl-2-oxo-7-(trifluoromethyl)-2,3- dihydrobenzo[d]oxazol-5-yl]phenyl]]ethyl))2-carbamoyl)-l,4-oxazepane-4- carboxylate

[0191] Referring to the method of example 1 step (2) and (3), starting from 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one, (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-7- (trifluoromethyl)-2,3-dihydrobenzo[d]oxazol-5-yl]phenyl)ethyl)-1,4-oxazepane-2- carboxamide (7 mg, white solid) was obtained in 87% yield. 1 HNMR (400 MHz, DMSO-d6) 8.62 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 7.40-7.30 (m, 5H), 7.07 (d, J = 8.8 Hz, 1H), 5.10-5.03 (m, 1H), 4.70 (s, 2H), 4.04-4.01 (m, 1H), 3.82-3.69 (m, 3H), 3.33 (s, 3H), 3.24-3.21 (m, 2H), 3.08-3.04 (m, 1H), 2.84-2.79 (m, 1H), 2.64-2.57 (m, 1H), 1.75-1.71 (m, 2H). MS-ESI calculated [M+H] + 503.2, found 503.3.

[0192] Example 7: (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-6-(trifluoromethyl)-2,3- dihydrobenzo[d]oxazol-5-yl]phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 7)

[0193]

[0194] Referring to the method of example 6, starting from 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzo[d]oxazol-2(3H)-one (18 mg, 0.05 mmol), (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-6-(trifluoromethyl)-2,3- dihydrobenzo[d]oxazol-5-yl]phenyl)ethyl)-1,4-oxazepane-2-carboxamide (3.6 mg, white solid) was obtained in 90% yield. 1HNMR (400 MHz, DMSO-d6) 8.62 (d, J = 8.4 Hz, 1H), 8.29 (s, 1H), 7.81 (s, 1H), 7.38-7.26 (m, 5H), 5.09-5.02 (m, 1H), 4.02-3.99 (m, 1H), 3.84-3.70 (m, 2H), 3.37-3.03 (m, 7H), 2.84-2.57 (m, 2H), 1.73-1.71 (m, 2H). MS-ESI calculated [M+H] + 489.2, found 489.3.

[0195] Example 8: (S)-N-((S)-1-cyano-2-(4-(3-isobutyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)-1,4-oxazetidine-2-carboxamide (Compound 8)

[0196]

[0197] Following the procedure of Example 6, using 3-isobutyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one as starting material, (S)-N-((S)-1-cyano-2-(4-(3- isobutyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazetidine-2-carboxamide (4.7 mg, white solid) was obtained in 57% yield. 1 HNMR (400 MHz, DMSO-d6): δ = 8.64 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H), 7.40-7.37 (m, 4H), 5.01 (q, J = 8.4 Hz, 1H), 4.04-4.01 (m, 1H), 3.87-3.81 (m, 1H), 3.75-3.69 (m, 3H), 3.23-3.18 (m, 2H), 3.08-3.04 (m, 1H), 2.82-2.77 (m, 1H), 2.67-2.50 (m, 2H), 2.20-2.17 (m, 1H), 1.76-1.72 (m, 2H), 0.94 (d, J = 6.8 Hz, 6H). MS-ESI calculated [M+H] + 463.2, found 463.3.

[0198] Example 9: (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)furan-2- yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 9)

[0199]

[0200] Following the method of Example 1, (S)-2-amino-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)furan-2-yl)propionamide (45 mg, 0.15 mmol) was used as a starting material to obtain (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)furan-2-yl)ethyl)-1,4-oxazolidine-2-carboxamide (18.0 mg, white solid), yield: 62%. 1 HNMR(400MHz,DMSO)δ8.68(d,J=8.8Hz,1H),7.54(d,J=1.6Hz,1H),7.46–

[0201] 7.44(m,1H),7.37(d,J=8.4Hz,1H),6.87(d,J=3.2Hz,1H),6.41(d,J=3.6Hz,1H),5.15–

[0202] 5.10(m,1H),4.06–4.03(m,1H),3.90–3.84(m,1H),3.76–3.70(m,1H),3.38(s,3H),3.28–

[0203] 3.23 (m, 2H), 3.14–3.09 (m, 1H), 2.83–2.77 (m, 1H), 2.64–2.51 (m, 2H), 1.80–1.68 (m, 2H). MS-ESI calculated values ​​[M+H] + 411, actual measurement 411.2.

[0204] Example 10: (S)-N-((S)-1-cyano-2-(4-(3-(cyclopropylmethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazolidine-2-carboxamide (Compound 10)

[0205]

[0206] Following the procedure of Example 6, using 3-cyclopropylmethyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one as the starting material, (S)-N- ((S)-1-cyano-2-(4-(3-(cyclopropylmethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl) ethyl)-1,4-oxazetidine-2-carboxamide (7.8 mg, white solid) was obtained in 63% yield. 1 HNMR (400 MHz, DMSO-d6): δ = 8.64 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 7.67-7.65 (m, 3H), 7.41-7.38 (m, 4H), 5.08-4.98 (m, 1H), 4.05-4.00 (m, 1H), 3.90-3.72 (m, 4H), 3.22-3.18 (m, 2H), 3.08-3.03 (m, 1H), 2.84-2.74 (m, 1H), 2.59-2.50 (m, 2H), 1.88-1.66 (m, 2H), 1.39-1.20 (m, 1H), 0.52-0.50 (m, 2H), 0.44-0.42 (m, 2H). MS-ESI calc [M+H] + 461.2, found 461.3.

[0207] Example 11 : (S)N-((S)-1-cyano-2-(4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl) ethyl)-1,4-oxazetidine-2-carboxamide (Compound 11)

[0208]

[0209] Following the procedure of Example 6, using 1-isobutyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine as the starting material, (S)N-((S)-1-cyano-2- (4-(1-isobutyl-1 H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)ethyl)-1,4-oxazetidine-2-carboxamide (49.6 mg, white solid) was obtained in 87% yield. 1HNMR (400 MHz, DMSO-d6) 8.68 (d, J = 8.1 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.1 Hz, 2H), 8.01 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 4.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 6.47 (d, J = 3.6 Hz, 1H), 5.09-4.97 (m, 1H), 4.14 (d, J = 7.2 Hz, 2H), 4.08-4.05 (m, 1H), 3.93-3.83 (m, 1H), 3.76-3.71 (m, 1H), 3.29-3.18 (m, 2H), 3.14-3.06 (m, 1H), 2.91-2.76 (m, 1H), 2.72-2.65 (m, 1H), 2.63-2.58 (m, 1H), 2.35-2.24 (m, 1H), 1.76 (s, 2H), 0.88 (d, J = 6.8 Hz, 6H). MS-ESI calculated [M+H] + 445.5, found 446.3.

[0210] Example 12: (S)N-((S)-1-cyano-2-(4-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 12)

[0211]

[0212] Referring to the method of Example 6, using 1-(cyclopropylmethyl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine as the starting material, (S)N-((S)-1- cyano-2-(4-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)ethyl)-1,4- oxazepane-2-carboxamide (49.9 mg, white solid) was obtained in a yield of 76%. 1HNMR (400 MHz, DMSO-d6) 8.72 (d, J = 8.2 Hz, 1H), 8.21 (s, 1H), 8.08 (d, J = 8.1 Hz, 2H), 8.01 (d, J = 8.8 Hz, 1H), 7.65-7.63 (m, 2H), 7.89 (d, J = 4.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 5.07-4.97 (m, 1H), 4.19-4.17 (m, 2H), 4.12-4.08 (m, 1H), 3.91-3.88 (m, 1H), 3.83-3.76 (m, 1H), 3.26-3.22 (m, 2H), 3.19-3.16 (m, 1H), 2.88-2.51 (m, 3H), 2.16 (s, 2H), 1.82-1.75 (m, 1H), 1.72-1.35 (m, 4H). MS-ESI calculated [M+H] + 443.5, found 444.2.

[0213] Example 13: (S)N-((S)-1-cyano-2-(4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-6- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 13)

[0214]

[0215] Referring to the method of Example 6, starting from 1-cyclopropyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (72 mg, 0.36 mmol), (S)N-((S)-1- cyano-2-(4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)ethyl)-1,4-oxazepane-2- carboxamide (17.0 mg, white solid) was obtained in yield of 71%. 1 HNMR (400 MHz, DMSO-d6) 8.72 (d, J = 8.2 Hz, 1H), 8.21 (s, 1H), 8.08 (d, J = 8.1 Hz, 2H), 8.01 (d, J = 8.8 Hz, 1H), 7.65-7.63 (m, 2H), 7.89 (d, J = 4.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 5.07-4.97 (m, 1H), 4.19-4.17 (m, 2H), 4.12-4.08 (m, 1H), 3.91-3.88 (m, 1H), 3.83-3.76 (m, 1H), 3.26-3.22 (m, 2H), 3.19-3.16 (m, 1H), 2.88-2.51 (m, 3H), 2.16 (s, 2H), 1.82-1.75 (m, 1H), 1.72-1.35 (m, 4H). MS-ESI calculated [M+H]

[0216] 3.80 (m, 1H), 3.78 - 3.62 (m, 2H), 3.30 - 3.14 (m, 2H), 3.09 (dd, J = 14.2, 3.6 Hz, 1H), 2.89 - 2.84 (m, 1H), 2.75 - 2.69 (m, 1H), 2.67 - 2.61 (m, 1H), 1.85 - 1.72 (m, 1H), 1.45 (t, J = 7.2 Hz, 3H). MS-ESI calculated [M+H] 418.3, found 418.3.

[0217] 2.55 (m, 2H), 1.76 (dt, J = 14.3, 9.0 Hz, 2H), 1.14 - 0.98 (m, 4H). MS-ESI calculated [M+H] 418.3, found 418.3. + 430.2, found 430.2.

[0218] Example 14: (S)-N-((S)-1-cyano-2-(4-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-6- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 14)

[0219]

[0220] Referring to the method of Example 6, starting from (1-ethyl-1H-pyrrolo[2,3-b]pyridin-6- yl)boronic acid (crude product, 1.34 mmol), (S)-N-((S)-1-cyano-2-(4-(1-ethyl-1H- pyrrolo[2,3-b]pyridin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (56 mg, white solid) was obtained in a yield of 58%. 1 HNMR (400 MHz, DMSO-d6): δ = 8.73 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 8.10 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 6.48 (d, J = 3.6 Hz, 1H), 5.06 - 5.01 (m, 1H), 4.37 - 4.14 (m, 2H), 4.11 - 4.05 (m, 1H), 3.90 - 3.83 (m, 1H), 3.76 (m, 1H), 3.26 - 3.18 (m, 2H), 3.15 (dd, J = 14.4 Hz, 1H), 2.90 - 2.84 (m, 1H), 2.75 - 2.69 (m, 1H), 2.67 - 2.61 (m, 1H), 1.85 - 1.72 (m, 1H), 1.45 (t, J = 7.2 Hz, 3H). MS-ESI calculated [M+H]

[0221] 4.09 (m, 1H), 3.90 - 3.83 (m, 1H), 3.76 (m, 1H), 3.26 - 3.18 (m, 2H), 3.15 (dd, J = 14.4 Hz, 1H), 2.90 - 2.84 (m, 1H), 2.75 - 2.69 (m, 1H), 2.67 - 2.61 (m, 1H), 1.85 - 1.72 (m, 1H), 1.45 (t, J = 7.2 Hz, 3H). MS-ESI calculated [M+H] + 418.3, found 418.3.

[0222] Example 15: (S)-N-((S)-1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 15)

[0223]

[0224] (1) (2S)-tert-butyl 2-((1-amino-3-(3-fluoro-4-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)-1-oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4- carboxylate

[0225] To a solution of (2S)-tert-butyl 2-((1-amino-3-(4-bromo-3-fluorophenyl)-1-oxopropan- 2-yl)carbamoyl)-1,4-oxepane-4-carboxylate (100 mg, 0.21 mmol) and 3-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoxazol-2(3H)-one (52 mg, 0.21 mmol) in dioxane / water (8 mL / 2 mL) was added [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (8 mg, 0.01 mmol) and potassium carbonate (87 mg, 0.63 mmol). The reaction was stirred overnight. After removing the solvent, direct purification with a silica gel column gave (2S)-tert-butyl 2-((1-amino-3-(3-fluoro-4-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)-1-oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4- carboxylate (80 mg, black solid). Yield: 68%. MS-ESI calculated [M+H] + 557.2, found 557.1.

[0226] (2) (2S)-tert-butyl-2-((1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0227] Referring to the method of Example 9, step (2), starting from ((2S)-tert-butyl-2-((1- amino-3-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-1- oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4-carboxylate (80 mg, 0.14 mmol) to give (2S)-tert-butyl 2-((1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (35 mg, white solid). Yield: 47%. MS-ESI calculated [M+H] 539.2, found 539.0. + 539.2, found 539.0.

[0228] (3) (S)-tert-butyl-2-(((R)-1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0229] Purification by hand column chromatography gave (S)-tert-butyl 2-(((S)-1-cyano-2-(3- fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4- oxazepane-4-carboxylate (13 mg, white solid, yield: 37%).

[0230] (4) (S)-N-((S)-1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0231] Referring to the method of Example 1, step (3), starting from (S)-tert-butyl 2-(((S)-1- cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl) carbamoyl)-1,4-oxazepane-4-carboxylate to give ((S)-N-((S)-1-cyano-2-(3-fluoro-4- (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2- carboxamide (5.1 mg, white solid, yield: 43%). 1HNMR (400 MHz, DMSO-d6): δ = 8.66 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 23.6 Hz, 2H), 7.40-7.27 (m, 2H), 7.26-7.21 (m, 1H), 5.01-4.99 (m, 1H), 3.98-3.89 (m, 2H), 3.73-3.67 (m, 2H), 3.24-3.14 (m, 4H), 2.82-2.50 (m, 4H), 1.79-1.75 (m, 2H). MS-ESI calculated [M+H] + 439.5, found 439.2.

[0232] Example 16: (S)-N-((R)-1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 16)

[0233]

[0234] Following the procedure of Example 15, (S)-N-((R)-1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (6.1 mg, white solid) was obtained. Yield: 51%. 1 HNMR (400 MHz, DMSO-d6): δ = 8.68 (d, J = 8.8 Hz, 1H), 8.22 (s, 1H), 7.50 (t, J = 8.8 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.29-7.22 (m, 3H), 5.09-2.07 (m, 1H), 4.06-4.03 (m, 1H), 3.85-3.82 (m, 2H), 3.76-3.73 (m, 1H), 3.24-3.21 (m, 3H), 3.09-3.06 (m, 1H), 3.05-2.50 (m, 4H), 1.77-1.75 (m, 2H). MS-ESI calculated [M+H] + 439.5, found 439.2.

[0235] Example 17: (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-7-(trifluoromethyl)-2,3-dihydrobenzo[d]oxazol-5-yl]phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 17)

[0236]

[0237] Referring to the method of example 6, starting from 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-7-(trifluoromethyl)benzo[d]oxazol-2(3H)-one (58 mg), (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-7-(trifluoromethyl)-2,3-dihydrobenzo[d]oxazol-5-yl]phenyl)ethyl)-1,4-oxazepane-2-carboxamide (7 mg, white solid) was obtained in 58% yield. 1 HNMR (400 MHz, DMSO-d6) 8.65 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.63 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 5.07-5.01 (m, 1H), 4.05-4.02 (m, 1H), 3.88-3.70 (m, 2H), 3.44 (s, 3H), 3.25-2.55 (m, 6H), 1.78-1.74 (m, 2H). MS-ESI calculated [M+H] + 489.2, found 489.2.

[0238] Example 18: (S)-N-((S)-1-cyano-2-(4-(3-(2-cyclopentylethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 18)

[0239]

[0240] Referring to the method of example 6, starting from (3-(2-cyclopentylethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)boronic acid (112 mg, 0.41 mmol), (S)-N-((S)-1-cyano-2-(4-(3-(2-cyclopentylethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (28 mg, white solid) was obtained in 32.5% yield. 1HNMR (400 MHz, DMSO-d6): δ = 9.07-9.05 (m, 1H), 8.86-8.83 (m, 2H), 7.68-7.66 (t, J = 8 Hz, 2H), 7.57 (s, 1H), 7.41-7.38 (m, 4H), 5.06-5.00 (m, 1H), 4.77-4.44 (m, 1H), 3.92-3.76 (m, 2H), 3.78-2.57 (m, 1H), 3.56-3.52 (m, 2H), 3.27-2.25 (m, 4H), 1.99-1.96 (m, 2H), 1.77-1.73 (m, 5H), 1.59-1.57 (m, 4H), 1.56-1.53 (m, 2H). MS-ESI calculated [M+H] + 503.2, found 503.1.

[0241] Example 19: (S)-N-((S)-1-cyano-2-(4-(3-cyclopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-5- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 19)

[0242]

[0243] Following the procedure of Example 6, using 3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxobenzothiolane-2-yl)benzo[d]thiazol-2(3H)-one (crude product, 0.44 mmol) as the starting material, (S)-N-((S)-1-cyano-2-(4-(3-cyclopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-5- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (1.5 mg, white solid) was obtained in 4% yield. 1HNMR (400 MHz, DMSO-d6): δ = 8.67 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H), 7.70-7.65 (m, 3H), 7.59 (s, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 5.06-5.00 (m, 1H), 4.06-4.05 (dd, J = 8.0 Hz, 1H), 3.88-3.82 (m, 1H), 3.75-3.69 (m, 1H), 3.26-3.16 (m, 2H), 3.10 (dd, J = 14.0 Hz, 1H), 3.03-2.97 (m, 1H), 2.85-2.79 (m, 1H), 2.69-2.61 (m, 1H), 2.59-2.55 (m, 1H), 1.78-1.73 (m, 2H), 1.20-1.15 (m, 2H), 0.97-0.94 (m, 2H). MS-ESI calc [M+H] + 463.2, found 463.2.

[0244] Example 20: (S)-N-((S)-2-(3-chloro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)-1-cyanoethyl)-1,4-oxazetidine-2-carboxamide (Compound 20)

[0245]

[0246] Referring to the method of Example 15, starting from (2S)-tert-butyl 2-((1-amino-3-(4- bromo-3-chlorophenyl)-1-oxopropan-2-yl)carbamoyl)-1,4-oxazepin-4-carboxylate (203.0 mg, 0.40 mmol), (S)-N-((S)-2-(3-chloro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)-1-cyanoethyl)-1,4-oxazetidine-2-carboxamide (1.6 mg, white solid) was obtained in a yield of 10%. 1 HNMR (400 MHz, DMSO-d6): δ = 8.68 (d, J = 8.8 Hz, 1H), 8.24 (s, 1H), 7.52 (s, 3H), 7.41-7.33 (m, 3H), 7.29 (s, 1H), 7.13 (d, J = 7.2 Hz, 1H), 5.11-5.05 (m, 1H), 4.05-

[0247] 4.02 (m, 1H), 3.87-3.82 (m, 1H), 3.76-3.70 (m, 1H), 3.35 (s, 1H), 3.23-3.21 (m, 2H), 3.08 (dd, J = 14.0 Hz, 1H), 2.85-2.79 (m, 1H), 2.68-2.62 (m, 1H), 1.77-1.71 (m, 2H). MS-ESI calculated [M+H] + 455.2, found 455.2.

[0248] Example 21: (S)-N-((R)-2-(3-chloro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)-1-cyanoethyl)-1,4-oxazetidine-2-carboxamide (Compound 21)

[0249]

[0250] Following the procedure of Example 20, (S)-N-((R)-2-(3-chloro-4-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)-1-cyanoethyl)-1,4-oxazetidine-2-carboxamide (1.2 mg, white solid) was obtained in 9% yield. 1 HNMR (400 MHz, DMSO-d6): δ = 8.65 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 7.52 (s, 1H), 7.41-7.32 (m, 4H), 7.19 (dd, J = 8.4 Hz, 1H), 5.02-4.96 (m, 1H), 3.97-3.87 (m, 2H), 3.74-3.68 (s, 1H), 3.36 (s, 3H), 3.23 (d, J = 7.6 Hz, 2H), 3.17 (dd, J = 14.0 Hz, 1H), 2.88-2.82 (m, 1H), 2.76-2.66 (m, 2H), 1.80-1.71 (m, 2H). MS-ESI calculated [M+H]

[0251] 3.92 (m, 1H), 3.91-3.87 (m, 1H), 3.74-3.68 (s, 1H), 3.36 (s, 3H), 3.23 (d, J = 7.6 Hz, 2H), 3.17 (dd, J = 14.0 Hz, 1H), 2.88-2.82 (m, 1H), 2.76-2.66 (m, 2H), 1.80-1.71 (m, 2H). MS-ESI calculated [M+H] + 455.2, found 455.2.

[0252] Example 22: (S)-N-((R)-2-(4-(2-aminobenzo[d]oxazol-5-yl)phenyl)-1-cyanoethyl)-1,4- oxazetidine-2-carboxamide (Compound 22)

[0253]

[0254] Following the procedure of Example 6, step (1), with (S)-tert-butyl 2-((S)-1- cyano-2-(4-iodophenyl)ethyl)carbamate (200.0 mg, 0.40 mmol), (Z)-tert-butyl 2- ((tert-butoxycarbonyl)imino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d] oxazole-3(2H)-carboxylate (crude product, 0.40 mmol), followed by chiral resolution of the product, following the procedure of Example 6, step (3), afforded (S)-N-((R)-2-(4-(2-aminobenzo[d]oxazol-5-yl)phenyl)-1- cyanoethyl)-1,4-oxazetidine-2-carboxamide (1.1 mg, white solid) in 41% yield. 1 HNMR (400 MHz, DMSO-d6): δ = 8.65 (d, J = 8.0 Hz, 1H), 8.23 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 6.0 Hz, 3H), 7.36 (dd, J = 12.4 Hz, 3H), 7.24 (d, J = 8.0 Hz, 1H), 4.97-4.91 (m, 1H), 3.98 (d, J = 8.0 Hz, 1H), 3.92-3.87 (m, 1H), 3.74-3.68 (m, 1H), 3.19-3.15 (m, 2H), 2.90–

[0255] 2.84 (m, 1H), 2.78-2.49 (m, 2H), 1.81-1.75 (m, 2H). MS-ESI calc. [M+H] + 406.3, found 406.3.

[0256] Example 23: (S)-N-((S)-2-(4-(2-aminobenzo[d]oxazol-5-yl)phenyl)-1- cyanoethyl)-1,4-oxazetidine-2-carboxamide (Compound 23)

[0257]

[0258] Following the procedure of Example 6, with (Z)-tert-butyl 2-((tert- butoxycarbonyl)imino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole- 3(2H)-carboxylate (crude product, 0.40 mmol) as starting material, afforded (S)-N-((S)- 2-(4-(2-aminobenzo[d]oxazol-5-yl)phenyl)-1-cyanoethyl)-1,4-oxazetidine-2-carboxamide (6.6 mg, white solid) in 33% yield. 1HNMR (400 MHz, DMSO-d6): δ = 8.69 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.43 (s, 3H), 7.3641 (dd, J = 10.8 Hz, 3H), 7.23 (d, J = 8.4 Hz, 1H), 5.04-5.01 (m, 1H), 4.10-4.04 (m, 1H), 3.88-3.80 (m, 1H), 3.76-3.69 (m, 1H), 3.23-3.16 (m, 2H), 3.14-3.05 (m, 1H), 2.89-2.83 (m, 1H), 2.74-2.67 (m, 1H), 2.65-2.59 (m, 1H), 1.79-1.76 (m, 2H). MS-ESI calculated [M+H] + 406.3, found 406.3.

[0259] Example 24: (S)-N-((S)-1-cyano-2-(4-(4-methyl-3-oxo-5-(trifluoromethyl)-3,4- dihydroquinoxalin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 24)

[0260]

[0261] Following the procedure of Example 1, using (S)-2-amino-3-(4-(4-methyl-3-oxo-5- (trifluoromethyl)-3,4-dihydroquinoxalin-6-yl)phenyl)propan-1-amine (24 mg, 0.06 mmol) as the starting material, (S)-N-((S)-1-cyano-2-(4-(4-methyl-3-oxo-5- (trifluoromethyl)-3,4-dihydroquinoxalin-6-yl)phenyl)ethyl)-1,4-oxazepane-2- carboxamide (8.0 mg, white solid) was obtained in 64% yield. 1 HNMR (400 MHz, DMSO) δ 8.68 (d, J = 8.6 Hz, 1H), 8.22 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.94 - 7.76 (m, 4H), 7.48 (d, J = 8.2 Hz, 2H), 5.07 (dd, J = 16.0, 8.6 Hz, 1H), 4.03 (dd, J = 8.0, 3.6 Hz, 1H), 3.90 - 3.81 (m, 1H), 3.81 - 3.69 (m, 4H), 3.28 - 3.18 (m, 2H), 3.05 (dd, J = 14.2, 3.7 Hz, 1H), 2.84 - 2.75 (m, 1H), 2.69 - 2.54 (m, 2H), 1.83 - 1.65 (m, 2H). MS-ESI calculated [M+H] +500.2, found 500.2.

[0262] Example 25: (S)-N-((S)-1-cyano-2-(4-(1-methyl-1H-benzo[d]imidazol-6- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 25)

[0263]

[0264] Following the procedure of Example 1, starting from (S)-2-amino-3-(4-(1- methyl-1H-benzo[d]imidazol-6-yl)phenyl)propan-1-ol (74.6 mg), (S)-N-((S)-1- cyano-2-(4-(1-methyl-1H-benzo[d]imidazol-6-yl)phenyl)ethyl)-1,4-oxazepane-2- carboxamide (7.0 mg, white solid) was obtained in 29% yield. 1 HNMR (400 MHz, DMSO) δ 8.61 (d, J = 8.5 Hz, 1H), 8.20 (s, 1H), 7.84 (d, J = 1.3 Hz, 1H), 7.70 (dd, J = 8.3, 1.5 Hz, 3H), 7.51 (dd, J = 8.4, 1.7 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 5.03 (dd, J = 15.9, 8.6 Hz, 1H), 4.00 (dd, J = 7.9, 3.7 Hz, 1H), 3.91 - 3.82 (m, 4H), 3.77 - 3.69 (m, 1H), 3.23 - 3.18 (m, 2H), 3.04 (dd, J = 14.1, 3.7 Hz, 1H), 2.81 - 2.55 (m, 3H), 1.80 - 1.65 (m, 2H). MS-ESI calc [M+H]

[0265] 3.18 (m, 2H), 3.04 (dd, J = 14.1, 3.7 Hz, 1H), 2.81 - 2.55 (m, 3H), 1.80 - 1.65 (m, 2H). MS-ESI calc [M+H] + 404.2, found 404.3.

[0266] Example 26: (S)-N-((S)-1-cyano-2-(4-(imidazo[1,2-a]pyridin-7-yl)phenyl)ethyl)-1,4- oxazepane-2-carboxamide (Compound 26)

[0267]

[0268] Following the procedure of Example 6, starting from imidazo[1,2-a]pyridin-7- ylboronic acid (37 mg, 0.23 mmol), (S)-N-((S)-1-cyano-2-(4-(imidazo[1,2-a]pyridin-7- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (2.2 mg, white solid) was obtained in 9.5% yield.1 HNMR (400 MHz, DMSO-d6): δ = 8.61-8.59 (t, J = 12 Hz, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.79-7.77 (m, 2H), 7.60 (s, 1H), 7.41-7.39 (t, J = 8 Hz, 2H), 7.28-7.26 (m, 1H), 5.04-5.02 (m, 1H), 4.00-3.98 (m, 1H), 3.97-3.81 (m, 1H), 3.75-3.82 (m, 1H), 3.24-3.16 (m, 1H), 3.04-3.02 (m, 1H), 3.00-2.73 (m, 1H), 2.56-2.52 (m, 1H), 1.73-1.70 (m, 2H). MS-ESI calculated [M+H] + 390.1, found 390.1.

[0269] Example 27: (S)-N-((S)-1-cyano-2-(4-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)phenyl)ethyl)-1,4- oxazepane-2-carboxamide (Compound 27)

[0270]

[0271] Referring to the method of Example 6, starting from 1-(2,2-difluoroethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxobenzene-2-yl)-1H-indazole, (S)-N-((S)-1-cyano-2-(4-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (5.1 mg, white solid), yield: 32%. 1 HNMR (400 MHz, DMSO-d6): δ = 8.64-8.62 (m, 1H), 8.30 (s, 1H), 8.11-8.05 (m, 3H), 7.73-7.71 (m, 1H), 7.58 7.57 (d, 1H), 7.41 7.39 (d, 2H), 6.57 6.56 (d, 1H), 5.06-5.00 (m, 1H), 4.84-4.75 (m, 2H), 4.02-4.00 (m, 1H), 3.87-3.68 (m, 5H), 3.26-3.20 (m, 1H), 2.75-2.50 (m, 4H), 1.76-1.70 (m, 1H). MS-ESI calculated [M+H] + 453, found 461.3.

[0272] Example 28: (S)-N-((S)-1-cyano-2-(4-(2-(trifluoromethyl)pyridin-4- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 28)

[0273]

[0274] Following the procedure of Example 6, using (2-(trifluoromethyl)pyridin-4- yl)boronic acid (37 mg, 0.19 mmol) as starting material, (S)-N-((S)-1-cyano-2-(4-(2- (trifluoromethyl)pyridin-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (22 mg, white solid) was obtained in 44% yield. 1 HNMR (400 MHz, DMSO-d6) 8.81 (d, J = 5.2 Hz, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 8.18-8.16 (m, 1H), 8.05 (dd, J = 1.6, 5.2 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 5.09-5.03 (m, 1H), 4.06-5.03 (m, 1H), 3.87-3.82 (m, 1H), 3.75-3.69 (m, 1H), 3.26-3.23 (m, 2H), 3.09-3.05 (m, 1H), 2.84-2.79 (m, 1H), 2.69-2.64 (m, 1H), 2.59-2.51 (m, 1H), 1.78-1.72 (m, 2H). MS-ESI calculated [M+H] + 419.4, found 419.2.

[0275] Example 29: (S)-N-((S)-1-cyano-2-(4-(2,3-dihydrobenzofuran-6-yl)phenyl)ethyl)- 1,4-oxazepane-2-carboxamide (Compound 29)

[0276]

[0277] Following the procedure of Example 6, using 2-(2,3-dihydrobenzofuran-6-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (crude product, 0.31 mmol) as starting material, (S)-N-((S)-1-cyano-2-(4-(2,3-dihydrobenzofuran-6-yl)phenyl)ethyl)-1,4-oxazepane-2- carboxamide (35 mg, white solid) was obtained in 49% yield. 1HNMR (400 MHz, DMSO-d6): δ = 8.69 (d, J = 6.0 Hz, 1H), 8.22 (s, 1H), 7.57-7.36 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.32 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 5.03 - 4.97 (m, 1H), 4.57 - 4.53 (m, 2H), 4.10 - 4.08 (m, 1H), 3.87 - 3.82 (m, 1H), 3.75 - 3.69 (m, 1H), 3.21 - 3.10 (m, 4H), 2.89 - 2.83 (m, 1H), 2.72 - 2.69 (m, 1H), 2.67 - 2.61 (m, 1H), 2.58 - 2.49 (m, 1H), 1.76 (s, 1H). MS-ESI calculated [M+H] 392.3, found 392.3.

[0278] 4.97 (m, 1H), 4.57 - 4.53 (m, 2H), 4.10 - 4.08 (m, 1H), 3.87 - 3.82 (m, 1H), 3.75 - 3.69 (m, 1H), 3.21 - 3.10 (m, 4H), 2.89 - 2.83 (m, 1H), 2.72 - 2.69 (m, 1H), 2.67 - 2.61 (m, 1H), 2.58 - 2.49 (m, 1H), 1.76 (s, 1H). MS-ESI calculated [M+H]

[0279] 4.97 (m, 1H), 4.57 - 4.53 (m, 2H), 4.10 - 4.08 (m, 1H), 3.87 - 3.82 (m, 1H), 3.75 - 3.69 (m, 1H), 3.21 - 3.10 (m, 4H), 2.89 - 2.83 (m, 1H), 2.72 - 2.69 (m, 1H), 2.67 - 2.61 (m, 1H), 2.58 - 2.49 (m, 1H), 1.76 (s, 1H). MS-ESI calculated [M+H]

[0280] 4.97 (m, 1H), 4.57 - 4.53 (m, 2H), 4.10 - 4.08 (m, 1H), 3.87 - 3.82 (m, 1H), 3.75 - 3.69 (m, 1H), 3.21 - 3.10 (m, 4H), 2.89 - 2.83 (m, 1H), 2.72 - 2.69 (m, 1H), 2.67 - 2.61 (m, 1H), 2.58 - 2.49 (m, 1H), 1.76 (s, 1H). MS-ESI calculated [M+H]

[0281] 4.97 (m, 1H), 4.57 - 4.53 (m, 2H), 4.10 - 4.08 (m, 1H), 3.87 - 3.82 (m, 1H), 3.75 - 3.69 (m, 1H), 3.21 - 3.10 (m, 4H), 2.89 - 2.83 (m, 1H), 2.72 - 2.69 (m, 1H), 2.67 - 2.61 (m, 1H), 2.58 - 2.49 (m, 1H), 1.76 (s, 1H). MS-ESI calculated [M+H] + 392.3, found 392.3.

[0282] Example 30: (S)N-((S)-1-cyano-2-(4-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 30)

[0283]

[0284] Following the procedure of Reference Example 6, using 1-isobutyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine as starting material, (S)-N-((S)-1-cyano-2-(4-(1-methyl-1H-indazol-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (49.6 mg, white solid) was obtained in 87% yield. 1HNMR (400 MHz, DMSO-d6) 8.69 (d, J = 8.1 Hz, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.81 (d, J = 6.4 Hz, 1H), 7.73 (d, J = 7.4 Hz, 2H), 7.44 (t, J = 8.0 Hz, 3H), 5.07-5.01 (m, 1H), 4.09-4.05 (m, 4H), 3.89-3.83 (m, 1H), 3.76-3.68 (m, 1H), 3.25-3.23 (m, 2H), 3.12-3.08 (m, 1H), 2.86-2.56 (m, 3H), 1.81-1.74 (m, 2H). MS-ESI calculated [M+H] + 403.4, found 404.3.

[0285] Example 31: (S)-N-((S)-2-(4-(benzofuran-6-yl)phenyl)-1-cyanoethyl)-1,4-oxazepane-2- carboxamide (Compound 31)

[0286]

[0287] Following the procedure of Example 6, using 2-(benzofuran-6-yl)-4,4,5,5-tetramethyl-1,3,2- dioxobenzene (crude product, 0.41 mmol) as starting material, (S)-N-((S)-2-(4-(benzofuran-6- yl)phenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (35 mg, white solid) was obtained in 49% yield. 1 HNMR (400 MHz, DMSO-d6): δ = 8.67 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 4.0 Hz, 1H), 7.88 (s, 1H), 7.73-7.68 (m, 3H), 7.57 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 6.99–

[0288] 6.98 (m, 1H), 5.06-5.00 (m, 1H), 4.07-

[0289] 4.04 (m, 1H), 3.88-3.82 (m, 1H), 3.76-3.70 (m, 3H), 3.23-

[0290] 3.15 (m, 2H), 3.10 (dd, J = 14.4 Hz, 1H), 2.86-2.80 (m, 1H), 2.70-2.64 (m, 1H), 2.62-2.56 (m, 1H), 1.80-1.71 (m, 1H). MS-ESI calculated [M+H] + 390.3, found 390.3.

[0291] Example 32: (S)N-((S)-2-(4-(lH-indazol-6-yl)phenyl)-l-cyanoethyl)-l,4-oxazolidine-2- carboxamide (Compound 32)

[0292]

[0293] Referring to the method of Example 1, using (S)-3-(4-(lH-indazol-6-yl)phenyl)-2- aminopropylamine (180 mg, 0.47 mmol) as starting material, (S)N-((S)-2-(4-(lH- indazol-6-yl)phenyl)-l-cyanoethyl)-l,4-oxazolidine-2-carboxamide (1.2 mg, white solid) was obtained in 5% yield. 1 HNMR (400 MHz, DMSO-d6): δ = 13.11 (s, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 7.72-7.66 (m, 4H), 7.40 (d, J = 8.0 Hz, 3H), 5.09-4.95 (m, 1H), 4.11-3.76 (m, 2H), 3.71-3.68 (m, 1H), 3.23-3.19 (m, 3H), 3.11-3.00 (m, 1H), 2.82-2.61 (m, 2H), 1.72 (s, 2H). MS-ESI calculated [M+H] + 389.4, found 390.2.

[0294] Example 33: (S)-N-((S)-l-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-5-yl)phenyl)ethyl)-l,4-oxazepine-2-carboxamide (Compound 33)

[0295]

[0296] Following the procedure of Example 6, using (1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzo[d]imidazol-2(3H)-one (53 mg, 0.2 mmol) as starting material, (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (10.0 mg, white solid) was obtained in 25% yield. 1 HNMR (400 MHz, DMSO) δ 10.87 (s, 1H), 8.60 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.37 (dd, J = 10.1, 4.8 Hz, 3H), 7.28 (dd, J = 8.1, 1.6 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 5.01 (dd, J = 16.0, 8.5 Hz, 1H), 3.99 (dd, J = 7.9, 3.7 Hz, 1H), 3.89 - 3.79 (m, 1H), 3.77 - 3.67 (m, 1H), 3.31 (s, 3H), 3.23 - 3.12 (m, 2H), 3.03 (dd, J = 14.3, 3.7 Hz, 1H), 2.84 - 2.71 (m, 1H), 2.64 - 2.53 (m, 2H), 1.85 - 1.62 (m, 2H). MS-ESI calculated [M+H] + 420.2, found 420.1.

[0297] Example 34: (S)-N-((S)-1-cyano-2-(4-(2-methylbenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2- carboxamide (Compound 34)

[0298]

[0299] Following the procedure of Example 6, using (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole as starting material, (S)-N-((S)-1-cyano-2-(4-(2-methylbenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2- carboxamide (6.1 mg, white solid) was obtained in 17% yield. 1H NMR (400MHz, DMSO-d6) 8.72–8.65 (m, 1H), 8.24–8.20 (m, 1H), 7.90 (s, 1H), 7.72–7.60 (m, 4H), 7.38 (d, J = 8.4Hz, 2H), 5.03 (q, J = 8.0Hz, 1H), 4.12–4.04 (m, 1H), 3.88–3.83 (m, 1H), 3.76–3.70 (m, 1H), 3.25–3.09 (m, 3H), 2.86–2.83 (m, 1H), 2.70–2.58 (m, 5H), 1.77–1.70 (m, 2H). MS-ESI calculated values ​​[M+H] + 405.5, actual measurement 405.0.

[0300] Example 35: (S)-N-((S)-1-cyano-2-(4-(1-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)ethyl)-1,4-oxazane-2-carboxamide (Compound 35)

[0301]

[0302] Following the method of Example 6, (S)-N-((S)-1-cyano-2-(4-(1-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)boronic acid (crude product, 0.33 mmol) was used as a starting material to obtain (S)-N-((S)-1-cyano-2-(4-(1-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)ethyl)-1,4-oxazane-2-carboxamide (26 mg, white solid), yield: 36%. 1 HNMR (400MHz, DMSO-d6): δ = 8.70 (d, J = 6.0Hz, 1H), 8.42 (s, 1H), 8.28 (s, 1H), 8.16–

[0303] 8.13(m,3H),7.89(d,J=8.4Hz,1H),7.85(d,J=4.0Hz,1H),7.43(d,J=8.4H z,2H),6.79(d,J=4.0Hz,1H),5.08–5.02(m,1H),4.09–4.08(m,1H),3.89–

[0304] 3.84 (m, 1H), 3.76–3.70 (m, 1H), 3.27–3.09 (m, 2H), 3.12 (d, J = 14.0 Hz, 1H), 2.87–2.84 (m, 1H), 2.71–2.70 (m, 1H), 2.67–2.60 (m, 1H), 1.76 (s, 1H). MS-ESI calculated values ​​[M+H]+ 440.0, found 440.0.

[0305] Example 36: (S)-N-((S)-2-(4-(lH-benzo[d]imidazol-5-yl)phenyl)-l- cyanoethyl)-l,4-oxazepan-2-carboxamide (Compound 36)

[0306]

[0307] (1) (S)-tert-butyl 2-(((S)-3-(4-(lH-benzo[d]imidazol-5-yl)phenyl)-l- amino- 1-oxopropan-2-yl)carbamoyl)- 1,4-oxazepin-4-carboxylate

[0308] Referring to the method of Example 6, step (1), using tert-butyl 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[d]imidazole-l-carboxylate (231 mg, 0.67 mmol) as starting material, (S)-tert-butyl 2-(((S)-3-(4-(lH-benzo[d]imidazol-5- yl)phenyl)-l-amino-l-oxopropan-2-yl)carbamoyl)-l,4-oxazepin-4-carboxylate (150 mg, colorless oil) was obtained in 37% yield. MS-ESI calculated [M+H] + 508.2, found 452.0 (MS-56).

[0309] (2) (S)-tert-butyl 2-(((S)-l-amino-3-(4-(l-(tert-butoxycarbonyl)-lH- benzo[d]imidazol-5-yl)phenyl)-l-oxopropan-2-yl)carbamoyl)-l,4-oxazepin-4- carboxylate

[0310] (S)-tert-butyl 2-(((S)-3-(4-(lH-benzo[d]imidazol-5-yl)phenyl)-l-amino-l- oxopropan-2-yl)carbamoyl)-l,4-oxazepin-4-carboxylate (150 mg, 0.3 mmol), di-tert- butyl dicarbonate (70 mg, 0.3 mmol) and triethylamine (60 mg, 0.6 mmol) and DMAP (4 mg, 0.03 mmol) were dissolved in dichloromethane (5 mL) and the reaction was stirred at room temperature overnight. The reaction was directly spin dried and purified on silica gel to give (S)-tert-butyl 2-(((S)-l-amino-3-(4-(l-(tert- butoxycarbonyl)-lH-benzo[d]imidazol-5-yl)phenyl)-l-oxopropan-2-yl)carbamoyl)- 1,4-oxazepin-4-carboxylate (50 mg, colorless oil) in 28% yield. MS-ESI calculated [M+H] +608.3, found 608.2.

[0311] (3) (S)-N-((S)-2-(4-(lH-benzo[d]imidazol-5-yl)phenyl)-l-cyanoethyl)-l,4- oxazepane-2-carboxamide

[0312] Referring to the method of Example 1, step (1), (2), starting from (S)-tert-butyl 2-(((S)- 1-amino-3-(4-(l-(tert-butoxycarbonyl)-lH-benzo[d]imidazol-5-yl)phenyl)-l- oxopropan-2-yl)carbamoyl)-l,4-oxazepane-4-carboxylate (25 mg, 0.04 mmol) to give (S)-N-((S)-2-(4-(lH-benzo[d]imidazol-5-yl)phenyl)-l-cyanoethyl)-l,4-oxazepane-2- carboxamide (2.0 mg, white solid), yield: 61%. 1 HNMR (400 MHz, DMSO) δ 8.65 (d, J = 8.6 Hz, 1H), 8.24 (d, J = 4.3 Hz, 3H), 7.81 (s, 1H), 7.64 (d, J = 8.2 Hz, 3H), 7.48 (dd, J = 8.4, 1.4 Hz, 1H), 7.37 (d, J = 8.1 Hz, 2H), 5.03 (dd, J = 15.9, 8.5 Hz, 1H), 4.04 (dd, J = 8.0, 3.6 Hz, 1H), 3.90 - 3.81 (m, 1H), 3.77 - 3.68 (m, 1H), 3.21 (dd, J = 12.5, 7.4 Hz, 2H), 3.07 (dd, J = 14.2, 3.6 Hz, 1H), 2.89 - 2.72 (m, 2H), 2.72 - 2.54 (m, 2H), 1.84 - 1.66 (m, 2H). MS-ESI calc [M+H]

[0313] 3.68 (m, 1H), 3.21 (dd, J = 12.5, 7.4 Hz, 2H), 3.07 (dd, J = 14.2, 3.6 Hz, 1H), 2.89 - 2.72 (m, 2H), 2.72 - 2.54 (m, 2H), 1.84 - 1.66 (m, 2H). MS-ESI calc [M+H]

[0314] 2.72 (m, 1H), 2.70 - 2.54 (m, 2H), 1.84 - 1.66 (m, 2H). MS-ESI calc [M+H] + 390.2, found 390.1.

[0315] Example 37: (S)-N-((S)-l-cyano-2-(4-(5-cyano furan-2-yl)phenyl)ethyl)-l,4- oxazepane-2-carboxamide (Compound 37)

[0316]

[0317] Following the procedure of Example 1, (S)-5-(4-(2,3-diamino-3-oxopropyl)phenyl)furan-2- carboxamide (210 mg of crude product, 0.54 mmol) was used as starting material to give (S)-N- ((S)-1-cyano-2-(4-(5-cyanofuran-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (24 mg, white solid) in 43% yield. 1 HNMR (400 MHz, DMSO-d6): δ = 8.69 (d, J = 8.8 Hz, 1H), 8.22 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 4.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 3.6 Hz, 1H), 5.07-5.01 (m, 1H), 4.07-4.04 (m, 1H), 3.88-3.82 (m, 1H), 3.75-3.69 (m, 1H), 3.23-3.16 (m, 2H), 3.10-3.05 (m, 1H), 2.88-2.82 (m, 1H), 2.71-2.66 (m, 1H), 2.58-2.49 (m, 1H), 1.81-1.73 (m, 2H). MS-ESI calculated [M+H] 365.2, found 365.1.

[0318] Example 38: (S)-N-((S)-1-cyano-2-(4-(2-oxo-3-(piperidin-4-ylmethyl)-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 38)

[0319]

[0320] Following the procedure of Example 6, tert-butyl 4-((2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzo[d]oxazol-3(2H)-yl)methyl)piperidine-1-carboxylate was used as starting material to give (S)-N-((S)-1-cyano-2-(4-(2-oxo-3-(piperidin-4-ylmethyl)-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide 8 (14.5 mg, white solid) in 29% yield. 1HNMR (400 MHz, DMSO-d6) 8.63 (d, J = 14.4 Hz, 1H), 8.28 (s, 2H), 7.65-7.63 (m, 2H), 7.41-7.38 (m, 3H), 5.04-4.94 (m, 1H), 4.05-3.98 (m, 1H), 3.88-3.72 (m, 4H), 3.20-3.11 (m, 6H), 2.75-2.49 (m, 4H), 2.20-2.02 (m, 2H), 1.78-1.64 (m, 3H), 1.39 (d, J = 6.0 Hz, 2H). MS-ESI calculated [M+H] + 504.2, found 504.1.

[0321] Example 39: (S)-N-((S)-1-cyano-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethyl)- 1,4-oxazepane-2-carboxamide (Compound 39)

[0322]

[0323] Referring to the method of Example 1, starting from (S)-2-amino-3-(4-(5-methyl-1,3,4- oxadiazol-2-yl)phenyl)propanamide (crude product, 0.20 mmol), (S)-N-((S)-1-cyano-2-(4-(5- methyl-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (1.1 mg, white solid) was obtained in a yield of 6%. 1 HNMR (400 MHz, DMSO-d6): δ = 8.67 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 5.10–5.04 (m, 1H), 4.02–3.87 (m, 1H), 3.85–

[0324] 3.81 (m, 1H), 3.74-3.68 (m, 1H), 3.26-3.24 (m, 2H), 3.04–

[0325] 2.99 (m, 1H), 2.82-2.76 (m, 1H), 2.67–2.59 (m, 1H), 2.57 (s, 3H), 1.75 (s, 1H). MS-ESI calculated [M+H] + 356.1, found 356.0.

[0326] Example 40: (S)-N-((S)-l-cyano-2-(4-(5-cyanooxazol-2-yl)phenyl)ethyl)- 1,4-oxazepane-2-carboxamide (Compound 40)

[0327]

[0328] (1) (S)-tert-butyl 2-((S)-l-amino-3-(4-(5-(ethoxycarbonyl)oxazol-2-yl)phenyl)- 1-oxapropyl-2-yl)carbamoyl)-l,4-oxazepane-4-carboxylate

[0329] Referring to the method of Example 1, step (1), using (S)-methyl 2-(4-(2,3- diamino-3-oxapropyl)phenyl)oxazole-5-carboxylate (crude product, 0.22 mmol) as starting material, (S)-tert-butyl 2-((S)-l-amino-3-(4-(5-(ethoxycarbonyl)oxazol-2- yl)phenyl)-l-oxapropyl-2-yl)carbamoyl)-l,4-oxazepane-4-carboxylate (100 mg, white solid) was obtained in 85% yield. MS-ESI calculated [M+H] + 531.1, found 531.1.

[0330] (2) (S)-tert-butyl 2-((S)-2-(4-(5-carbamoyloxazol-2-yl)phenyl)-l-cyanoethyl) carbamoyl)-l,4-oxazepane-4-carboxylate

[0331] (S)-tert-butyl 2-((S)-l-amino-3-(4-(5-(ethoxycarbonyl)oxazol-2-yl)phenyl)- 1-oxapropyl-2-yl)carbamoyl)-l,4-oxazepane-4-carboxylate (90.0 mg, 0.17 mmol) was dissolved in ammonium hydroxide (5 mL) and the reaction was stirred at room temperature overnight. Direct spin dry and purification by reverse phase column gave (S)-tert-butyl 2-((S)-2-(4-(5- carbamoyloxazol-2-yl)phenyl)-l-cyanoethyl)carbamoyl)-l,4-oxazepane-4-carboxylate (60 mg, white solid) in 63% yield. MS-ESI calculated [M+H] + 484.2, found 484.2.

[0332] (3) (S)-N-((S)-l-cyano-2-(4-(5-cyanooxazol-2-yl)phenyl)ethyl)- 1,4-oxazepane-2-carboxamide

[0333] Referring to the method of example 1 step (2), (3), starting from (S)-tert-butyl 2-((S)-2-(4-(5- carbamoyloxazol-2-yl)phenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (60.0 mg, 0.12 mmol) to give (S)-N-((S)-1-cyano-2-(4-(5-cyanooxazol-2-yl)phenyl)ethyl)-1,4- oxazepane-2-carboxamide (10.1 mg, white solid), yield: 31%. 1 HNMR (400 MHz, DMSO-d6): δ = 8.72 (d, J = 8.0 Hz, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 5.11 - 5.05 (m, 1H), 4.06 - 4.04 (m, 1H), 3.88 - 3.69 (m, 2H), 3.29 - 3.25 (m, 2H), 3.08 (d, J = 14.0 Hz, 1H), 2.86 - 2.66 (m, 2H), 2.54 - 2.51 (m, 1H), 1.76 (s, 2H). MS-ESI calculated [M+H]

[0334] 3.82 (m, 1H), 3.75 - 3.69 (m, 1H), 3.29 - 3.25 (m, 2H), 3.08 (d, J = 14.0 Hz, 1H), 2.86 - 2.66 (m, 2H), 2.54 - 2.51 (m, 1H), 1.76 (s, 2H). MS-ESI calculated [M+H]

[0335] 2.83 (m, 1H), 2.69 - 2.66 (m, 1H), 2.54 - 2.51 (m, 1H), 1.76 (s, 2H). MS-ESI calculated [M+H] + 366.1, found 366.1.

[0336] Example 41: (S)-N-((S)-1-cyano-2-(4-(4-fluoro-2,3-dihydrobenofuran-6-yl)phenyl)ethyl)-1,4- oxazepane-2-carboxamide (Compound 41)

[0337]

[0338] Referring to the method of example 6, starting from 2-(4-fluoro-2,3-dihydro-benofuran-6-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane to give (S)-N-((S)-1-cyano-2-(4-(4-fluoro-2,3-dihydrobenofuran-6- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (13.8 mg, white solid), yield: 21%. 1HNMR (400 MHz, DMSO-d6): δ = 8.69 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 6.98 (m, 2H), 5.04 - 4.98 (m, 1H), 4.66 - 4.62 (m, 2H), 4.09 - 4.07 (m, 1H), 3.88 - 3.82 (m, 1H), 3.75 - 3.69 (m, 2H), 3.27 - 3.22 (m, 2H), 3.20 - 3.17 (m, 2H), 3.15 - 3.09 (m, 1H), 2.89 - 2.85 (m, 1H), 2.73 - 2.61 (m, 1H), 2.59 - 2.57 (m, 1H), 1.76 (s, 2H). MS-ESI calculated [M+H] 410.2, found 410.2.

[0339] 4.07 (m, 1H), 3.88 - 3.82 (m, 1H), 3.75 - 3.69 (m, 2H), 3.27 - 3.22 (m, 2H), 3.20 - 3.17 (m, 2H), 3.15 - 3.09 (m, 1H), 2.89 - 2.85 (m, 1H), 2.73 - 2.61 (m, 1H), 2.59 - 2.57 (m, 1H), 1.76 (s, 2H). MS-ESI calculated [M+H]

[0340] 4.07 (m, 1H), 3.88 - 3.82 (m, 1H), 3.75 - 3.69 (m, 2H), 3.27 - 3.22 (m, 2H), 3.20 - 3.17 (m, 2H), 3.15 - 3.09 (m, 1H), 2.89 - 2.85 (m, 1H), 2.73 - 2.61 (m, 1H), 2.59 - 2.57 (m, 1H), 1.76 (s, 2H). MS-ESI calculated [M+H]

[0341] 4.07 (m, 1H), 3.88 - 3.82 (m, 1H), 3.75 - 3.69 (m, 2H), 3.27 - 3.22 (m, 2H), 3.20 - 3.17 (m, 2H), 3.15 - 3.09 (m, 1H), 2.89 - 2.85 (m, 1H), 2.73 - 2.61 (m, 1H), 2.59 - 2.57 (m, 1H), 1.76 (s, 2H). MS-ESI calculated [M+H] + 410.2, found 410.2.

[0342] Example 42: (S)-N-((S)-1-cyano-2-(4-(3-(2-morpholinoethyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 42)

[0343]

[0344] Following the procedure of Example 6, using 3-(2-morpholinoethyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxobenzothiazole-2-yl)benzo[d]oxazol-2(3H)-one (crude product, 3.1 mmol) as the starting material, (S)-N-((S)-1-cyano-2-(4-(3-(2-morpholinoethyl)-2- oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (101 mg, white solid) was obtained in 15% yield. 1HNMR (400 MHz, DMSO-d6): δ = 8.68 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 8.4 Hz, 3H), 7.38 (t, J = 6.0 Hz, 1H), 5.05 - 4.99 (m, 1H), 4.02 - 3.97 (m, 3H), 3.87 - 3.81 (m, 1H), 3.75-3.69 (m, 1H), 3.49 - 3.47 (m, 4H), 3.23-3.17 (m, 2H), 3.05-3.00 (m, 1H), 2.79-2.72 (m, 1H), 2.67-2.64 (m, 2H), 2.62-2.59 (m, 1H), 2.58 - 2.52 (m, 1H), 2.47 (s, 4H), 1.77 (s, 2H). MS-ESI calculated [M+H] + 520.3, found 520.3.

[0345] Example 43: (S)-N-((S)-1-cyano-2-(4-(3-cyanobenzo[d]isoxazol-5-yl)phenyl)ethyl)-1,4- oxazepane-2-carboxamide (Compound 43)

[0346]

[0347] Referring to the method of Example 6, starting from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole-3-carboxamide, (S)-N-((S)-1-cyano-2-(4-(3-cyanobenzo[d]isoxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide 11 (18.2 mg, white solid) was obtained in a yield of 28%.

[0348] 1 HNMR (400 MHz, DMSO-d6): δ = 8.68 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 8.4 Hz, 3H), 7.38 (t, J = 6.0 Hz, 1H), 5.05 - 4.99 (m, 1H), 4.02 - 3.97 (m, 3H), 3.87 - 3.81 (m, 1H), 3.75-3.69 (m, 1H), 3.49 - 3.47 (m, 4H), 3.23-3.17 (m, 2H), 3.05-3.00 (m, 1H), 2.79-2.72 (m, 1H), 2.67-2.64 (m, 2H), 2.62-2.59 (m, 1H), 2.58 - 2.52 (m, 1H), 2.47 (s, 4H), 1.77 (s, 2H). MS-ESI calculated [M+H] + 416.1, found 416.1.

[0349] Example 44: (S)-N-((S)-1-cyano-2-(4-(3-((methylsulfonyl)methyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 44)

[0350]

[0351] Referring to the method of Example 1, starting from (S)-2-amino-3-(4-(3-((methylsulfonyl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propan-1- amine (100 mg, 0.257 mmol), ((S)-N-((S)-1-cyano-2-(4-(3-((methylsulfonyl)methyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (6.7 mg, white solid) was obtained in 16% yield. 1 HNMR (400 MHz, DMSO-d6): 8.59 (d, J = 10.4 Hz, 1H), 7.78 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.49-7.30 (m, 4H), 5.48 (s, 2H), 5.11-4.95 (m, 1H), 4.00-3.91 (m, 1H), 3.90-3.68 (m, 2H), 3.28-3.21 (m, 2H), 3.12-3.10 (m, 3H), 3.09-2.94 (m, 1H), 2.78-2.50 (m, 3H), 1.71 (s, 2H). MS-ESI calculated [M+H] + 498.5, found 499.0.

[0352] Example 45: (S)-N-((S)-1-cyano-2-(3'-carboxamide-4'-hydroxy-[1,1'-biphenyl]-4-yl)ethyl)-1,4- oxazepane-2-carboxamide (Compound 45)

[0353]

[0354] Referring to the method of Example 6, starting from 5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzo[d]oxazol)2 (247 mg, 1.0 mmol), (S)-N-((S)-1-cyano-2-(3'-carboxamide-4'-hydroxy-[1,1'-biphenyl]-4-yl)ethyl)-1,4- oxazepane-2-carboxamide (2.0 mg, white solid) was obtained in 50% yield. 1HNMR (400MHz, DMSO) δ9.65 (s, 1H), 8.60 (d, J = 8.3Hz, 1H), 8.43–

[0355] 8.23(m,3H),7.47(d,J=8.2Hz,2H),7.33(d,J=8.2Hz,2H),7.21(dd,J=8.3,2. 3Hz,1H),6.94(d,J=8.3Hz,1H),4.99(dd,J=15.8,8.4Hz,1H),4.00(d,J=4.7H z,1H),3.88–3.79(m,1H),3.76–3.66(m,1H),3.17(dd,J=7.8,5.6Hz,1H),3.0 4(d,J=14.3Hz,2H),2.83–2.72(m,1H),2.68–2.52(m,2H),1.82–1.62(m,2H). MS-ESI calculated value [M+H] + 409.2, actual measurement 409.1.

[0356] Example 46: (S)-N-((S)-2-(4-(1-carbamoyl-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)-1-cyanoethyl)-1,4-oxane-2-carboxamide (Compound 46)

[0357]

[0358] (1)(S)-tert-butyl-2-((S)-3-(4-(1H-indazol-6-yl)phenyl)-1-amino-1-oxopropane-2-yl)carbamoyl)-1,4-oxazhecyclic-4-carboxylic acid ester

[0359] Following the methods in steps (1) and (2) of Example 6, using 6-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine as a starting material, (S)-tert-butyl-2-((S)-3-(4-(1H-indazol-6-yl)phenyl)-1-amino-1-oxopropane-2-yl)carbamoyl)-1,4-oxazhecyclic-4-carboxylic acid ester (300 mg, yellow solid) yield: 88%. MS-ESI calculated value [M+H] + 619.8

[0360] (2) (S)-tert-butyl-2-((S)-2-(4-(1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazhecyclic-4-carboxylic acid ester

[0361] (S)-tert-butyl 2-((S)-3-(4-(1H-indazol-6-yl)phenyl)-1-amino-1-oxopropan-2- yl)carbamoyl)-1,4-oxazepane-4-carboxylate (300 mg, 0.40 mmol) was dissolved in tetrahydrofuran (5 mL), TBAF reagent (632 mg, 2.4 mmol) was added to the reaction, the mixture was stirred at room temperature 70 °C for 5 h. The reaction was concentrated under reduced pressure to obtain a residue, the residue was purified by reverse phase column to obtain (S)-tert-butyl 2-((S)-2-(4-(1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)-1- cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (100 mg, white solid), yield: 42%. MS-ESI calculated value [M+H] + 489.5.

[0362] (3) (S)-tert-butyl 2-((S)-2-(4-(1-carbamoyl-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)-1- cyanoethyl)carbamoyl)-1,4-oxazepanone-4-carboxylate

[0363] ((S)-tert-butyl 2-((S)-2-(4-(1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)-1-cyanoethyl)carbamoyl)- 1,4-oxazepane-4-carboxylate (35 mg, 0.40 mmol), 2,2,2-trichloroacetyl isocyanate (16 mg, 0.08 mmol) was dissolved in tetrahydrofuran (5 mL), stirred at room temperature overnight, rotary evaporation, TEA (5 mL) was added, the mixture was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to obtain a residue, the residue was purified by reverse phase column to obtain (S)-tert-butyl 2-((S)-2-(4-(1-carbamoyl-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)-1- cyanoethyl)carbamoyl)-1,4-oxazepanone-4-carboxylate (30 mg, white solid), yield: 78%. MS-ESI calculated value [M+H] + 532.5.

[0364] (4) (S)-N-((S)-2-(4-(1-carbamoyl-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl)-1-cyanoethyl)-1,4- oxazepane-2-carboxamide

[0365] Following the procedure of Example 1, step (3), (S)-tert-butyl 2-((S)-2-(4-(l- carbamoyl-lH-pyrrolo[2,3-b]pyridin-6-yl)phenyl)-l-cyanoethyl)carbamate-4-carboxylate (30 mg, 0.14 mmol) was used as starting material to give (S)-N-((S)-2-(4-(l- carbamoyl-lH-pyrrolo[2,3-b]pyridin-6-yl)phenyl)-l-cyanoethyl)-l,4-oxazepane-2- carboxamide (1.3 mg, white solid) in 5% yield. 1 HNMR (400 MHz, DMSO-d6): δ = 9.14 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.22-8.15 (m, 3H), 8.04-7.87 (m, 4H), 7.45 (d, J = 9.6 Hz, 2H), 6.74 (d, J = 7.0 Hz, 1H), 5.09-4.96 (m, 1H), 4.06-3.75 (m, 3H), 3.41-3.05 (m, 3H), 2.86-2.50 (m, 3H), 1.81-1.70 (m, 2H). MS-ESI calculated [M+H] + 432.4, found 433.3.

[0366] Example 47: (S)-N-((S)-2-(4-(3-(2-(azetidin-l-yl)ethyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)-l-cyanoethyl)-l,4-oxazepane-2-carboxamide (Compound 47)

[0367]

[0368] Following the procedure of Example 1, (S)-2-amino-3-(4-(3-(2-(azetidin-l- yl)ethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanamide (110 mg crude product, 0.21 mmol) was used as starting material to give (S)-N-((S)-2-(4-(3-(2-(azetidin-l- yl)ethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-l-cyanoethyl)-l,4-oxazepane-2- carboxamide (17 mg, white solid) in 37% yield. MS-ESI calculated [M+H] + 390.2, found 490.3. 1HNMR (400 MHz, DMSO-d6): δ = 8.65 (d, J = 8.4 Hz, 1H), 8.21-8.20 (m, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.18 (dd, J = 3.0, 8.8 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.04-4.09 (m, 1H), 4.23 (t, J = 4.0 Hz, 2H), 4.03 (dd, J = 2.8, 7.2 Hz, 1H), 3.92 (t, J = 7.6 Hz, 4H), 3.87-3.82 (m, 1H), 3.75-3.68 (m, 1H), 3.65 (t, J = 4.4 Hz, 2H), 3.21-3.12 (m, 2H), 3.08-3.04 (m, 1H), 2.82-2.77 (m, 1H), 2.68-2.54 (m, 2H), 2.23-2.11 (m, 2H), 1.79-1.69 (m, 2H).

[0369] Example 48: (S)-N-((S)-1-cyano-2-(4-(3-cyclopropylbenzo[d]isoxazol-6- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 48)

[0370]

[0371] Referring to the method of Example 6, starting from (3-cyclopropyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole (88 mg, 0.309 mmol), (S)-N- ((S)-1-cyano-2-(4-(3-cyclopropylbenzo[d]isoxazol-6-yl)phenyl)ethyl)-1,4-oxazepane-2- carboxamide (1.2 mg, white solid) was obtained in a yield of 4.2%. 1HNMR (400 MHz, DMSO-d6): δ = 9.06-9.03 (m, 1H), 8.81-8.80 (m, 2H), 7.96-7.91 (m, 2H), 7.77-7.75 (m, 2H), 7.75-7.69 (m, 2H), 7.43-7.41 (m, 2H), 5.08-5.02 (m, 1H), 4.46-4.43 (m, 1H), 3.93-3.87 (m, 1H), 3.50-3.46 (m, 1H), 3.31-3.26 (m, 1H), 3.24-3.11 (m, 4H), 2.98-2.94 (m, 1H), 2.66-2.50 (m, 1H), 2.32-1.99 (m, 2H), 1.28-1.23 (m, 4H). MS-ESI calculated [M+H] + 431.2, found 431.0.

[0372] Example 49: (S)-N-((S)-1-cyano-2-(4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H- benzo [b] [1,4] oxazin-6-yl) phenyl) ethyl)-1,4-oxazepane-2-carboxamide (Compound 49)

[0373]

[0374] Following the procedure of Example 6, using 2,2,4-trimethyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (crude product, 0.33 mmol) as starting material, (S)-N-((S)-1-cyano-2-(4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl) phenyl) ethyl)-1,4-oxazepane-2-carboxamide (26 mg, white solid) was obtained in 46% yield. 1 HNMR (400 MHz, DMSO-d6): δ = 8.68 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.37-7.31 (m, 2H), 7.29 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 5.04-4.98 (m, 1H), 4.08-

[0375] 4.05 (m, 3H), 3.89-

[0376] 3.83 (m, 1H), 3.76-3.70 (m, 1H), 3.38 (s, 3H), 3.22-3.12 (m, 2H), 3.11-3.07 (m, 1H), 2.72-

[0377] 2.60 (m, 1H), 1.80 (s, 2H), 1.46 (s, 6H). MS - ESI calculated for [M+H] + 463.1, found 463.1.

[0378] Example 50: (S)-N-((S)-1-cyano-2-(4-(2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 50)

[0379]

[0380] Referring to the method of Example 6, starting from 5-(4,4,5,5-tetramethyl-1,3,2- dioxobenzothiazole-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (200 mg, 0.77 mmol), (S)-N-((S)-1-cyano-2-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (2.0 mg, white solid) was obtained in yield: 31%. MS - ESI calculated for [M+H] + 406.2, found 406.0. 1 HNMR (400 MHz, DMSO) δ 10.67 (d, J = 9.2 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.22-7.20 (m, 1H), 7.13 (d, J = 1.2 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 5.04-4.98 (m, 1H), 4.00-3.98 (m, 1H), 3.87-3.72 (m, 2H), 3.19-3.18 (m, 2H), 3.05-2.99 (m, 1H), 2.80-2.71 (m, 3H), 1.76-1.67 (m, 2H).

[0381] 3.01 (m, 1H), 2.80-2.71 (m, 3H), 1.76-1.67 (m, 2H).

[0382] Example 51: (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 51)

[0383]

[0384] Following the procedure of Example 1, (S)-2-amino-3-(5-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)propanamide hydrochloride (196 mg, 0.62 mmol) was used as starting material to give (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (8.4 mg) as a white solid in 17.3% yield. 1 HNMR (400 MHz, DMSO-d6): δ = 8.70-8.67 (m, 1H), 7.51 (s, 1H), 7.50-7.00 (m, 3H), 7.01 (d, J = 4 Hz, 1H), 5.03-4.91 (m, 1H), 4.04-3.87 (m, 2H), 3.77-3.55 (m, 1H), 3.46-3.36 (m, 2H), 3.35 (s, 3H), 3.02-2.99 (m, 1H), 2.85-2.75 (m, 1H), 2.67-2.62 (m, 2H), 1.81-1.66 (m, 2H). MS-ESI calc [M+H] + 427.1, found 427.0.

[0385] Example 52: (S)-N-((S)-1-cyano-2-(4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-4- yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 52)

[0386]

[0387] Following the procedure of Example 6, 1-methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2- dioxobenzothiole-2-yl)phenyl)sulfonyl)piperazine (424.7 mg, 1.16 mmol) was used as starting material to give (S)-N-((S)-1-cyano-2-(4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'- biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (67 mg, white solid) in 16% yield. 1HNMR (400 MHz, DMSO-d6): δ = 8.68 (d, J = 8.0 Hz, 1H), 7.91 (s, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 5.08 - 5.01 (m, 1H), 4.00 - 3.97 (m, 1H), 3.87 - 3.81 (m, 1H), 3.74-3.68 (m, 1H), 3.24 - 3.21 (m, 2H), 3.03 (d, J = 3.6 Hz, 1H), 2.92 (s, 4H), 2.78 - 2.72 (m, 1H), 2.62-2.52 (m, 2H), 2.35 (s, 4H), 2.12 (s, 3H), 1.77 (s, 2H). MS-ESI calculated [M+H] + 512.3, found 512.3.

[0388] Example 53: (S)-N-((S)-1-cyano-2-(4-(3-(cyclopropanecarbonyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 53)

[0389]

[0390] (1) (S)-tert-butyl 2-(((S)-1-cyano-2-(4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0391] Referring to the method of Example 1, step (1), (2), using (S)-2-amino-3-(4-(2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)propanamide (37 mg, 0.15 mmol) as the starting material, (S)-tert-butyl 2-(((S)-1-cyano-2-(4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (15 mg, colorless oil) was obtained in a yield of 75%.

[0392] (2) (S)-tert-butyl-2-(((S)-1-cyano-2-(4-(3-(cyclopropanecarbonyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0393] (S)-tert-butyl 2-(((S)-1-cyano-2-(4-(3-(cyclopropanecarbonyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (20 mg, 0.04 mmol), and triethylamine (9 mg, 0.08 mmol) were dissolved in DMF (5 mL), cyclopropanecarbonyl chloride (9 mg, 0.08 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction system was dispersed in water (20 mL), extracted with ethyl acetate (20 mL x 2), and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (PE:EA = 3:1) to obtain ((S)-tert-butyl 2-(((S)-1-cyano-2-(4-(3-(cyclopropanecarbonyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (15 mg, colorless oil) in a yield of 66%. MS-ESI calculated value [M+H] + 575.2, found 575.2.

[0394] (3) (S)-N-((S)-1-cyano-2-(4-(3-(cyclopropanecarbonyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0395] Referring to the method of Example 1, step (3), (S)-tert-butyl 2-(((S)-1-cyano-2-(4-(3- (cyclopropanecarbonyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4- oxazepane-4-carboxylate (15 mg, 0.02 mmol) was used as a raw material to obtain (S)-N-((S)-1- cyano-2-(4-(3-(cyclopropanecarbonyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4- oxazepane-2-carboxamide (3.0 mg, white solid) in a yield of 25%. 1 HNMR (400MHz, DMSO) δ 8.87-8.75 (m, 1H), 7.6 (d, J = 8.0 Hz, 2H), 7.38-7.28 (m, 5H), 5.06-4.97 (m, 1H), 4.28-3.86 (m, 3H), 3.70-3.48 (m, 3H), 3.05-2.96 (m, 4H), 1.89-1.69 (m, 3H), 0.75-0.60 (m, 4H). MS-ESI calculated value [M+H]

[0396] HNMR (400MHz, DMSO) δ 8.87-8.75 (m, 1H), 7.6 (d, J = 8.0 Hz, 2H), 7.38-7.28 (m, 5H), 5.06-4.97 (m, 1H), 4.28-3.86 (m, 3H), 3.70-3.48 (m, 3H), 3.05-2.96 (m, 4H), 1.89-1.69 (m, 3H), 0.75-0.60 (m, 4H). MS-ESI calculated value [M+H] +475.2, found 475.0.

[0397] Example 54: (S)-N-((S)-1-cyano-2-(4-(3-((1-methylpiperidin-4-yl)methyl)-2- oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 54)

[0398]

[0399] Referring to the method of Example 6, starting from (3-(cyclopentylmethyl)-2- oxo-2,3-dihydrobenzo[d]oxazol-5-yl)boronic acid (875 mg, 3.35 mmol), (S)-N-((S)-1- cyano-2-(4-(3-(cyclopentylmethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4- oxazepane-2-carboxamide (119 mg, white solid) was obtained in a yield of 53.7%. 1 HNMR (400 MHz, DMSO-d6): δ = 9.70-9.66 (m, 1H), 8.67-8.56 (m, 1H), 7.70-7.67 (t, J = 10 Hz, 2H), 7.46-7.43 (m, 4H), 5.06-4.94 (m, 1H), 4.01 (s, 1H), 3.88-3.74 (m, 4H), 3.33-2.96 (m, 4H), 2.78-2.75 (m, 1H), 2.49-2.41 (m, 1H), 1.72-1.53 (m, 8H), 1.34-1.27 (m, 2H). MS-ESI calculated [M+H] + 489.2, found 489.3.

[0400] Example 55: (S)-N-((S)-1-cyano-2-(4-(3-((1-methylpiperidin-4-yl)methyl)-2- oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 54)

[0401]

[0402] Referring to the method of Example 1, (S)-2-amino-3-(4-(3-((1-methylpiperidin-4- yl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propan-1-ol (280 mg, 0.68 mmol) as the starting material, (S)-N-((S)-1-cyano-2-(4-(3-((1-methylpiperidin-4-yl)methyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide 9 (90 mg, white solid) was obtained in yield of 36%. 1 HNMR (400 MHz, DMSO) δ 8.60 (d, J = 8.8 Hz, 1H), 7.64 (t, J = 8.4 Hz, 3H), 7.40 - 7.38 (m, 4H), 5.06 - 4.99 (m, 1H), 4.00 - 3.98 (m, 1H), 3.87 - 3.69 (m, 4H), 3.26 - 3.15 (m, 2H), 3.05 - 3.00 (m, 1H), 2.79 - 2.71 (m, 3H), 2.63 - 2.51 (m, 2H), 2.11 (s, 3H), 1.80 - 1.67 (m, 5H), 1.60 - 1.57 (m, 2H), 1.35 - 1.25 (m, 2H). MS-ESI calculated [M+H] 518.3, found 518.4.

[0403] 7.38 (m, 4H), 5.06 - 4.99 (m, 1H), 4.00 - 3.98 (m, 1H), 3.87 - 3.69 (m, 4H), 3.26 - 3.15 (m, 2H), 3.05 - 3.00 (m, 1H), 2.79 - 2.71 (m, 3H), 2.63 - 2.51 (m, 2H), 2.11 (s, 3H), 1.80 - 1.67 (m, 5H), 1.60 - 1.57 (m, 2H), 1.35 - 1.25 (m, 2H). MS-ESI calculated [M+H]

[0404] 3.15 (m, 2H), 3.05 - 3.00 (m, 1H), 2.79 - 2.71 (m, 3H), 2.63 - 2.51 (m, 2H), 2.11 (s, 3H), 1.80 - 1.67 (m, 5H), 1.60 - 1.57 (m, 2H), 1.35 - 1.25 (m, 2H). MS-ESI calculated [M+H]

[0405] 1.67 (m, 5H), 1.60 - 1.57 (m, 2H), 1.35 - 1.25 (m, 2H). MS-ESI calculated [M+H] + 518.3, found 518.4.

[0406] Example 56: (S)-N-((S)-1-cyano-2-(4-(3-(oxetan-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 56)

[0407]

[0408] (1) 4-bromo-2-(oxetan-3-ylamino)phenol

[0409] To a solution of 3-oxetanone (250 mg, 3.47 mmol) in methanol (10 mL) was added 2-amino-4-bromophenol (978 mg, 5.20 mmol), sodium cyanoborohydride (1.09 g, 17.35 mmol) and glacial acetic acid (0.1 mL) successively. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (20 mL). The organic phase was washed with saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (180 mg, brown solid) in 21% yield. MS (ESI): m / z 244.0 [M+H] + .

[0410] (2) 5-Bromo-3-(oxetan-3-yl)benzo[d]oxazol-2(3H)-one

[0411] To a solution of 4-bromo-2-(oxetan-3-ylamino)phenol (160 mg, 0.65 mmol) in dichloromethane (10 mL) was added N,N'-carbonyldiimidazole (300 mg, 1.97 mmol). The reaction mixture was stirred at 40 °C for 12 h under nitrogen. The reaction mixture was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 2) to give the title compound (140 mg, brown solid) in 80% yield. MS (ESI): m / z 269.8 [M+H] + .

[0412] (3) 3-(Oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one

[0413] To a solution of 5-bromo-3-(oxetan-3-yl)benzo[d]oxazol-2(3H)-one (140 mg, 0.52 mmol) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (145 mg, 0.57 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (42.5 mg, 0.05 mmol) and potassium acetate (102 mg, 1.04 mmol). The mixture was heated to 90 °C and stirred for 12 h under nitrogen. The reaction mixture was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (120 mg, brown solid) in 75% yield. MS (ESI): m / z 318.0 [M+H] + .

[0414] (4) tert-Butyl (S)-2-(((S)-1-amino-3-(4-(3-(oxetan-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)-1-oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0415] (S)-2-(((S)-1-amino-3-(4-(3-(oxetan-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-1- oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (200 mg, 0.34 mmol) was dissolved in dichloromethane (10 mL), and Burgess reagent (245 mg, 1.03 mmol) was added. The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (40 mg, yellow solid) at a yield of 21%. MS (ESI): m / z 563.0 [M+H] + .

[0416] (5) tert-Butyl (S)-2-(((S)-1-cyano-2-(4-(3-(oxetan-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0417] (S)-2-(((S)-1-amino-3-(4-(3-(oxetan-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-1- oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (200 mg, 0.34 mmol) was dissolved in dichloromethane (10 mL), and Burgess reagent (245 mg, 1.03 mmol) was added. The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (40 mg, yellow solid) at a yield of 21%. MS (ESI): m / z 563.0 [M+H] + .

[0418] (6) (S)-N-((S)-1-cyano-2-(4-(3-(oxetan-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl) ethyl)-1,4-oxazepane-2-carboxamide

[0419] In a 50 mL single necked flask was added (S)-2-(((S)-1-cyano-2-(4-(3-(oxetan-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol), after addition of formic acid (2.0 mL) the reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution to pH 7, the aqueous phase was extracted with dichloromethane / methanol (10 mL / 1 mL). The organic phase was concentrated under reduced pressure, then dry methanol (2.0 mL) was added, then purified by Prep-HPLC to give the title compound (4.5 mg, white solid), yield: 14%. MS (ESI): m / z 463.1 [M+H] + 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.34-7.32 (m, 1H), 7.20 (d, J = 9.2 Hz, 1H), 5.54-5.51 (m, 1H), 5.20-5.13 (m, 5H), 4.11-4.08 (m, 1H), 4.01-3.98 (m, 1H), 3.78-3.73 (m, 1H), 3.31 (dd, J = 14.4, 4.0 Hz, 1H), 3.16-3.15 (m, 2H), 3.04 (dd, J = 14.4, 6.4 Hz, 1H), 2.98-2.85 (m, 2H), 1.85-1.83 (m, 2H).

[0420] Example 57: (S)-N-((S)-1-cyano-2-(4-(3'-oxo-3'H-spiro[azetidine-3,1'-isochromen]-6'- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 57)

[0421]

[0422] (1) 6'-Bromo-3'-oxo-3'H-spiro[azetidine-3,1'-isochromen]-1-carboxylic acid tert-butyl ester

[0423] Methyl 4-bromo-2-iodobenzoate (1.0 g, 2.9 mmol) and tert-butyl 3-oxoazetidine-1- carboxylate (553.0 mg, 3.2 mmol) were dissolved in tetrahydrofuran (10 mL) and isopropylmagnesium chloride lithium chloride tetrahydrofuran complex (1.3 M, 2.5 mL, 3.2 mmol) was added dropwise at -78 °C. The mixture was stirred at room temperature overnight under nitrogen protection. Water (20 mL) was added to the reaction system, and diatomite was used for filtration. The mixture was extracted with ethyl acetate (20 mL x 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (580 mg, colorless oil), with a yield of 56%. MS (ESI): m / z 297.8 [M+H-56] + .

[0424] (2) (1-tert-butoxycarbonyl-3'-oxo-3'H-spiro[azetidine-3,1'-isobenzofuran]-6'-yl)boronic acid

[0425] Tert-butyl 6'-bromo-3'-oxo-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate (200 mg, 0.57 mmol) and pinacol diboronic acid (158 mg, 0.62 mmol) were dissolved in 1,4-dioxane (10 mL), and PdCl2(dppf) (49 mg, 0.06 mmol) and potassium acetate (112 mg, 1.14 mmol) were added. The reaction system was stirred at 90 °C overnight. The reaction solution was directly used in the next reaction. MS (ESI): m / z 263.8 [M+H-56] + .

[0426] (3) tert-Butyl 6'-(4-((S)-3-amino-2-((S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2- carboxamido)-3-oxopropyl)phenyl)-3'-oxo-3'H-spiro[azetidine-3,1'-isobenzofuran]-1- carboxylate

[0427] To the reaction solution from previous step, was added dioxane / water (5 mL / 1 mL), (S)-2-(((S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4- carboxylic acid tert-butyl ester (293 mg, 0.57 mmol), potassium carbonate (157 mg, 1.1 mmol) and PdCl2(dppf) (47 mg, 0.05 mmol), the reaction mixture was stirred at 90 °C overnight. The reaction mixture was filtered directly, concentrated under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (100 mg, yellow solid) in 27% yield. MS (ESI): m / z 609.0 [M+H-56] + .

[0428] (4) 6'-(4-((S)-2-((S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxamido)-2- cyanoethyl)phenyl)-3'-oxo-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylic acid tert-butyl ester

[0429] To a solution of 6'-(4-((S)-3-amino-2-((S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2- carboxamido)-3-oxopropyl)phenyl)-3'-oxo-3'H-spiro[azetidine-3,1'-isobenzofuran]-1- carboxylic acid tert-butyl ester (100 mg, 0.15 mmol) in dichloromethane (5 mL) was added Burgess reagent (107 mg, 0.4 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was directly dried by rotary evaporation, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (75 mg, white solid) in 77% yield. MS (ESI): m / z 647.0 [M+H] + .

[0430] (5) (S)-N-((S)-1-cyano-2-(4-(3'-oxo-3'H-spiro[azetidine-3,1'-isobenzofuran]-6'- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0431] Tert-butyl 6'-(4-((S)-2-((S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2- formamido)-2-cyanoethyl)phenyl)-3'-oxo-3'H-spiro[azetidine-3,1'- isobenzofuran]-1-carboxylate (40 mg, 0.06 mmol) was dissolved in formic acid (4 mL) and the mixture was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, neutralized with aqueous sodium bicarbonate solution and directly purified by Prep-HPLC to give the title compound (6.3 mg, white solid) in 23% yield. MS (ESI): m / z 447.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.8 Hz, 1H), 8.32 (s, 1H), 7.90 (dd, J = 8.0, 0.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 5.09 - 5.03 (m, 1H), 4.04 - 3.98 (m, 3H), 3.92 - 3.83 (m, 3H), 3.75 - 3.69 (m, 1H), 3.25 - 3.19 (m, 2H), 3.02 (dd, J = 14.0, 4.0 Hz, 1H), 2.79 - 2.73 (m, 1H), 2.61 - 2.53 (m, 2H), 1.77 - 1.68 (m, 2H).

[0432] Example 58: (S)-N-((S)-1-cyano-2-(4-(1-methyl-3'-oxo-3'H-spiro[azetidine-3,1'- isobenzofuran]-6'-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 58)

[0433]

[0434] (1) 6'-Bromo-3'H-spiro[azetidine-3,1'-isobenzofuran]-3'-one

[0435] Tert-butyl 6'-bromo-3'-oxo-3'H-spiro[azetidine-3,1'-isobenzofuran]-1- carboxylate (380 mg, 1.1 mmol, Example 57, Step 1) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added. The reaction was stirred at room temperature overnight. The reaction was concentrated to give the title compound which was used directly in the next step. MS (ESI): m / z 253.8 [M+H] + .

[0436] (2) 6'-Bromo-1-methyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-3'-one

[0437] Dissolve 6'-bromo-3'H-spiro[azetidine-3,1'-isobenzofuran]-3'-one (270 mg, 1.1 mmol) and 37% aqueous formaldehyde solution (800 mg, 10.6 mmol) in methanol (10 mL), stir at room temperature for half an hour, add sodium cyanoborohydride (126 mg, 2.1 mmol), stir the reaction at room temperature overnight. Concentrate the reaction, purify the residue by column chromatography (100% ethyl acetate) to obtain the title compound (180 mg, colorless oil), yield: 63%. MS (ESI): m / z 267.8 [M+H] + .

[0438] (3) (1-Methyl-3'-oxo-3'H-spiro[azetidine-3,1'-isobenzofuran]-6'-yl)boronic acid

[0439] Dissolve 6'-bromo-1-methyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-3'-one (180 mg, 0.67 mmol) and pinacol diboronic acid (205 mg, 0.81 mmol) in dioxane (10 mL), add PdCl2(dppf) (55 mg, 0.06 mmol) and potassium acetate (131 mg, 1.3 mmol), stir the reaction at 90 °C overnight. Concentrate the reaction to obtain the title compound (212 mg, crude), which is used directly in the next step.

[0440] (4) (S)-2-(((S)-1-Amino-3-(4-(1-methyl-3'-oxo-3'H-spiro[azetidine-3,1'-isobenzofuran]-6'- yl)phenyl)-1-oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester

[0441] (S)-2-(((S)-1 -amino-3-(4-(1 -methyl-3'-oxo-3'H-spiro[azetidine-3,1 '-iso- benzofuran]-6'-yl)phenyl)-1 -oxopropan-2-yl)carbamoyl)-1,4-oxaheptane-4- carboxylic acid tert-butyl ester (30 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), triethylamine (30 mg, 0.3 mmol) was added to the reaction solution, trifluoroacetic anhydride (21 mg, 0.1 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL x 3), and concentrated. The residue was purified by thin layer chromatography to obtain the title compound (10 mg, colorless oil), yield: 34%. MS (ESI): m / z 561.0 [M+H] + .

[0442] (5) (S)-2-(((S)-1 -cyano-2-(4-(1 -methyl-3'-oxo-3'H-spiro[azetidine-3,1 '-iso- benzofuran]-6'-yl)phenyl)ethyl)carbamoyl)-1,4-oxaheptane-4-carboxylic acid tert-butyl ester

[0443] (S)-2-(((S)-1 -amino-3-(4-(1 -methyl-3'-oxo-3'H-spiro[azetidine-3,1 '-iso- benzofuran]-6'-yl)phenyl)-1 -oxopropan-2-yl)carbamoyl)-1,4-oxaheptane-4- carboxylic acid tert-butyl ester (30 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), triethylamine (30 mg, 0.3 mmol) was added to the reaction solution, trifluoroacetic anhydride (21 mg, 0.1 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL x 3), and concentrated. The residue was purified by thin layer chromatography to obtain the title compound (10 mg, colorless oil), yield: 34%. MS (ESI): m / z 561.0 [M+H] + .

[0444] (6) (S)-N-((S)-1 -cyano-2-(4-(1 -methyl-3'-oxo-3'H-spiro[azetidine-3,1 '-iso- benzofuran]-6'-yl)phenyl)ethyl)-1,4-oxaheptane-2-carboxamide

[0445] (S)-2-(((S)-1-cyano-2-(4-(1-methyl-3'-oxo-3'H-spiro[azetidine-3,1'- isochromene]-6'-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (10 mg, 0.02 mmol) was dissolved in formic acid (4 mL), the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, neutralized with aqueous sodium bicarbonate solution and purified by Prep-HPLC to obtain the title compound (1.8 mg, white solid), yield: 25%. MS (ESI): m / z 461.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 8.8 Hz, 1H), 8.16 (s, 1H), 7.92-7.87 (m, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 5.09-5.03 (m, 1H), 4.00 (dd, J = 7.6, 3.6 Hz, 1H), 3.88-3.82 (m, 1H), 3.75-3.70 (m, 3H), 3.64 (d, J = 8.4 Hz, 2H), 3.25-3.20 (m, 2H), 3.04 (dd, J = 14.0, 4.0 Hz, 1H), 2.81-2.74 (m, 1H), 2.68-2.59 (m, 2H), 2.44 (s, 3H), 1.78-1.69 (m, 2H).

[0446] Example 59: (S)-N-((S)-1-cyano-2-(4-(3-oxo-3H-spiro[isochromene-1,4'- piperidin]-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 59)

[0447]

[0448] (1) 6-bromo-3-oxo-3H-spiro[isochromene-1,4'-piperidin]-1'-carboxylic acid tert-butyl ester

[0449] The title compound (3.0 g, colorless oil) was obtained in reference to the method of Example 57, Step 1, using methyl 4-bromo-2-iodobenzoate (2.0 g, 5.8 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (1.27 g, 6.4 mmol) as raw materials. MS (ESI): m / z 382.1 [M+H] + .

[0450] (2) 6-bromo-3H-spiro[isochromene-1,4'-piperidin]-3-one

[0451] tert-Butyl 6-bromo-3-oxo-3H-spiro[isobenzofuran-l,4'-piperidin]-l'-carboxylate (3.0 g, 7.8 mmol) was placed in a solution of 50% trifluoroacetic acid in dichloromethane (30 mL) and allowed to react at room temperature for 2 hours. The reaction was concentrated to give the title compound (1.0 g, grey oil) in 45% yield. MS (ESI): m / z 281.8 [M+H] + .

[0452] (3) (3-oxo-3H-spiro[isobenzofuran-l,4'-piperidin]-6-yl)boronic acid

[0453] 6-Bromo-3H-spiro[isobenzofuran-l,4'-piperidin]-3-one (140 mg, 0.49 mmol) was placed in a solution of 1,4-dioxane (1.4 mL) and pinacol diboronic acid (189 mg, 0.74 mmol), [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride (364 mg, 0.49 mmol) and potassium acetate (98 mg, 0.49 mmol) were added sequentially and the reaction was allowed to proceed at 70 °C for 2 hours under nitrogen. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to give the title compound (30 mg, grey oil) in 24.5% yield.

[0454] (4) (S)-2-(((S)-l-amino-l-oxo-3-(4-(3-oxo-3H-spiro[isobenzofuran-l,4'- piperidin]-6-yl)phenyl)propan-2-yl)carbamoyl)-l,4-oxazepane-4-carboxylic acid tert-butyl ester

[0455] (3-oxo-3H-spiro[isobenzofuran-l,4'-piperidin]-6-yl)boronic acid (30 mg, 0.12 mmol) was placed in a solution of 1,4-dioxane (0.3 mL) and (S)-2-(((S)-l-amino-3-(4- iodophenyl)-l-oxopropan-2-yl)carbamoyl)-l,4-oxazepane-4-carboxylic acid tert-butyl ester (37 mg, 0.12 mmol), [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride (9 mg, 0.012 mmol), potassium carbonate (50 mg, 0.36 mmol) and water (0.3 mL) were added sequentially and the reaction was allowed to proceed at 80 °C for 2 hours under nitrogen. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to give the title compound (30 mg, black oil) in 41% yield. MS (ESI): m / z 593.0 [M+H] + .

[0456] (5) (S)-2-(((S)-1-cyano-2-(4-(3-oxo-3H-spiro[isobenzo-furan-1,4'-piperidin]-6- yl)phenyl)ethyl)carbamoyl)-1,4-oxaheptane-4-carboxylic acid tert-butyl ester

[0457] (S)-2-(((S)-1-amino-1-oxo-3-(4-(3-oxo-3H-spiro[isobenzo-furan-1,4'-piperidin]-6- yl)phenyl)propan-2-yl)carbamoyl)-1,4-oxaheptane-4-carboxylic acid tert-butyl ester (30 mg, 0.05 mmol) was taken in dichloromethane (0.3 mL), borogrs reagent (20 mg, 0.084 mmol) was added and the reaction was allowed to proceed at room temperature for 3 h. The reaction was concentrated and the residue was purified by column chromatography to get the title compound (10 mg, black oil) in 30% yield. MS (ESI): m / z 575.2 [M+H] + .

[0458] (6) (S)-N-((S)-1-cyano-2-(4-(3-oxo-3H-spiro[isobenzo-furan-1,4'-piperidin]-6- yl)phenyl)ethyl)-1,4-oxaheptane-2-carboxamide

[0459] (S)-2-(((S)-1-cyano-2-(4-(3-oxo-3H-spiro[isobenzo-furan-1,4'-piperidin]-6- yl)phenyl)ethyl)carbamoyl)-1,4-oxaheptane-4-carboxylic acid tert-butyl ester (10 mg, 0.017 mmol) was taken in formic acid (0.1 mL). The reaction was allowed to proceed at room temperature for 1 h. It was directly purified by Pre-HPLC after basification with sodium bicarbonate to get the title compound (3 mg, white solid) in 36.3% yield. MS (ESI) m / z: 475.1 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.91 - 7.84 (m, 3H), 7.72 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 6.16 - 6.11 (m, 1H), 4.12 - 4.09 (m, 1H), 4.00 - 3.94 (m, 1H), 3.80 - 3.74 (m, 1H) 3.27 - 3.04 (m, 7H) 2.92 - 2.86 (m, 1H), 2.80 - 2.74 (m, 1H), 2.67 - 2.62 (m, 1H), 2.28 - 2.20 (m, 2H), 1.91 - 1.81 (m, 2H), 1.72 - 1.69 (m, 2H).

[0460] Example 60: (S)-N-((S)-2-(4-(3-(azetidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)-l-cyanoethyl)-l,4-oxazepane-2-carboxamide (Compound 60)

[0461]

[0462] (1) 3-(5-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)azetidine-1-carboxylate

[0463] Dissolve 5-bromobenzo[d]oxazol-2(3H)-one (2.1 g, 10 mmol) in dimethyl sulfoxide (20 mL), add 3-iodoazetidine-1-carboxylate tert-butyl ester (3.1 g, 11 mmol) and potassium carbonate (2.7 g, 20 mmol) successively, stir the system at 90 °C for 18 hours under nitrogen protection. Add water (300 mL) to the reaction solution, extract with ethyl acetate (100 mL x 3), dry the organic phase, and concentrate. Purify the residue by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain the title compound (1.7 g, yellow solid), yield: 46%. MS (ESI): m / z 369.0 [M+H] + .

[0464] (2) 3-(2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-3(2H)-yl)azetidine-1-carboxylate

[0465] Dissolve 3-(5-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)azetidine-1-carboxylate tert-butyl ester (369.0 mg, 1 mmol) in 1,4-dioxane (15 mL), add pinacol diboronic acid (305.0 mg, 1.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73.1 mg, 0.1 mmol) and potassium acetate (294.0 mg, 3.0 mmol) successively, stir the system at 85 °C for 18 hours under nitrogen protection. Concentrate the reaction solution under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate = 8 / 1) to obtain the title compound (235 mg, yellow solid), yield: 56%. MS (ESI): m / z 361.0 [M+H-56] + .

[0466] (3) (S)-2-(((S)-l-amino-3-(4-(3-(l-(tert-butoxycarbonyl)azetidin-3-yl)-2-oxo- 2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-l-oxopropan-2-yl)carbamoyl)-l,4- oxacycloheptane-4-carboxylic acid tert-butyl ester

[0467] tert-Butyl 3-(2-oxo-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]oxazol- 3(2H)-yl)azetidine-l-carboxylate (235.0 mg, 0.56 mmol) and (S)-2-(((S)-l-amino- 3-(4-iodophenyl)-l-oxopropan-2-yl)carbamoyl)-l,4-oxacycloheptane-4-carboxylic acid tert-butyl ester (243.0 mg, 0.47 mmol) were dissolved in 1,4-dioxane / water (4 mL / 1 mL), and pinacol diboronic acid (41.0 mg, 0.056 mmol) and potassium carbonate (193.0 mg, 1.4 mmol) were added sequentially, and stirred at 85 °C overnight. The reaction was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 15 / 1) to give the title compound (173 mg, brown solid) in 54% yield. MS (ESI): m / z 680.0 [M+H] + .

[0468] (4) (S)-2-(((S)-2-(4-(3-(l-(tert-butoxycarbonyl)azetidin-3-yl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)-l-cyanoehtyl)carbamoyl)-l,4-oxacycloheptane-4- carboxylic acid tert-butyl ester

[0469] tert-Butyl (S)-2-(((S)-l-amino-3-(4-(3-(l-(tert-butoxycarbonyl)azetidin-3-yl)-2- oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-l-oxopropan-2-yl)carbamoyl)-l,4- oxacycloheptane-4-carboxylate (173.0 mg, 0.255 mmol) was dissolved in dichloromethane (7 mL), and Burgess reagent (303.0 mg, 1.275 mmol) was added, and stirred at 30 °C for 3 hours. The reaction was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (106 mg, white solid) in 63% yield. MS (ESI): m / z 684.0 [M+Na] + .

[0470] (5) (S)-N-((S)-2-(4-(3-(azetidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)- 1-cyanoethyl)-1,4-oxazepane-2-carboxamide

[0471] (S)-2-(((S)-2-(4-(3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4- carboxylic acid tert-butyl ester (64.0 mg, 0.097 mmol) was dissolved in formic acid (1 mL) and stirred at room temperature for 2 hours. A saturated solution of sodium bicarbonate was added dropwise to the reaction solution and adjusted to basic. A dichloromethane / methanol mixture (10 / 1, 30 mL) was added and extracted three times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Pre-HPLC to obtain the title compound (3.4 mg, white solid) at a yield of 7.6%. MS (ESI): m / z 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.80-8.60 (m, 1H), 7.98 (s, 1H), 7.62 (s, 2H), 7.42-7.39 (m, 4H), 5.12-5.02 (m, 2H), 4.04-3.69 (m, 8H), 3.21-3.19 (s, 3H), 3.02 (d, J = 14.0 Hz, 1H), 2.69-2.54 (m, 2H), 1.74-1.70 (m, 2H).

[0472] Example 61: (S)-N-((S)-1-cyano-2-(4-(3-(piperazin-1-ylmethyl)benzo[d]isoxazol-5- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 61)

[0473]

[0474] (1) 5-bromo-3-(bromomethyl)benzo[d]isoxazole

[0475] In a 100 mL single-neck flask, 5-bromo-3-methylbenzo[d]isoxazole (2.99 g, 14.1 mmol), dibenzoyl peroxide (682 mg, 2.82 mmol), and N-bromosuccinimide (3.01 g, 16.9 mmol) were added and dissolved in carbon tetrachloride (20 mL) and refluxed at 90°C for 24 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the title compound (3 g, yellowish solid) at a yield of 73.5%.

[0476] (2) 4-((5-bromobenzo[d]isoxazol-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0477] To a solution of 5-bromo-3-(bromomethyl)benzo[d]isoxazole (1.5 g, 3.8 mmol) in N,N-dimethylformamide (10 mL) was added piperazine-1-carboxylic acid tert-butyl ester (1.04 g, 10.4 mmol) and N,N-diisopropylethylamine (1.34 g, 10.4 mmol) and reacted at 65 °C for three hours. The reaction was poured into water (100 mL) and extracted with ethyl acetate (2 x 50 mL). The organic phase was combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (500 mg, white solid), yield: 24%, MS (ESI): m / z 395.8 [M+H] + .

[0478] (3) 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazol-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0479] To a 50 mL single neck flask was added 4-((5-bromobenzo[d]isoxazol-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (395 mg, 1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (73 mg, 0.1 mmol), potassium acetate (294 mg, 3 mmol), pinacol diboron (305 mg, 1.2 mmol) and 1,4-dioxane (8 mL) and reacted at 80 °C for 16 hours under nitrogen protection. The reaction was used directly for the next step. MS (ESI): m / z 444.0 [M+H] + .

[0480] (4) (S)-2-(((S)-1-amino-3-(4-(3-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzo[d]isoxazol-5-yl)phenyl)-1-oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester

[0481] To the reaction solution of previous step, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (73 mg, 0.1 mmol), potassium carbonate (414 mg, 3 mmol), (S)-2-(((S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (517 mg, 1 mmol) and water (2 mL) were added. The mixture was reacted at 80 °C for 16 h under nitrogen protection. Concentration under reduced pressure, the residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (395 mg, brown oil), yield: 56%. MS (ESI): m / z 707.1 [M+H] + .

[0482] (5) (S)-2-(((S)-2-(4-(3-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzo[d]isoxazol-5-yl)phenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester

[0483] To a solution of (S)-2-(((S)-1-amino-3-(4-(3-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzo[d]isoxazol-5-yl)phenyl)-1-oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (250 mg, 0.35 mmol) in dichloromethane (10 mL) was added Burgess reagent (252 mg, 1.06 mmol) and the mixture was stirred at room temperature for 16 h. Concentration under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (224 mg, colorless oil), yield: 93%. MS (ESI): m / z 689.1 [M+H] + .

[0484] (6) (S)-N-((S)-1-cyano-2-(4-(3-(piperazin-1-ylmethyl)benzo[d]isoxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0485] In a 25 mL single necked flask, (S)-2-(((S)-2-(4-(3-((4-(tert- butoxycarbonyl)piperazin-1-yl)methyl)benzo[d]isoxazol-5-yl)phenyl)-1- cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (100 mg, 0.145 mmol) and formic acid (1 mL) were added and the reaction was allowed to proceed at room temperature for 3 h. The reaction was slowly added to saturated aqueous sodium bicarbonate solution (40 mL) and extracted with a mixture solvent (dichloromethane / methanol / triethylamine = 10 / 1 / 1) (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the title compound (13 mg, white solid) in 18% yield. MS (ESI): m / z 489.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.61 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 7.62 (d, J = 10.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 5.08 - 5.02 (m, 1H), 4.01 - 3.98 (m, 1H), 3.94 (s, 2H), 3.86 - 3.69 (m, 2H), 3.24 - 3.20 (m, 3H), 3.05 - 3.00 (m, 1H), 2.78 - 2.69 (m, 5H), 2.63 - 2.54 (m, 2H), 2.45 - 2.40 (m, 4H), 1.78 - 1.64 (m, 2H).

[0486] Example 62: (S)-N-((S)-1-cyano-2-(4-(3-((4-methylpiperazin-1-yl)methyl)benzo[d]isoxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 62)

[0487]

[0488] (1) 5-bromo-3-((4-methylpiperazin-1-yl)methyl)benzo[d]isoxazole

[0489] The title compound (420 mg, light brown solid) was obtained in 26% yield using the procedure described in Example 61, Step 2, starting from 5-bromo-3- (bromomethyl)benzo[d]isoxazole (2.05 g, 5.19 mmol) and 1-methylpiperazine (1.04 g, 10.4 mmol). MS (ESI): m / z 309.9 [M+H] + .

[0490] (2) (S)-tert-buty l ( 1 -amino-3-(4-(3-((4-methylpiperazin- 1 -yl)methyl)benzo[d]isoxazol-5- yl)phenyl)-l-oxopropan-2-yl)carbamate

[0491] Into a 50 mL single necked flask was added 5-bromo-3-((4-methylpiperazin-l- yl)methyl)benzo[d]isoxazole (217 mg, 0.7 mmol), [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride (51 mg, 0.07 mmol), potassium carbonate (290 mg, 2.1 mmol) and (S)-(4-(3-amino-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)boronic acid (216 mg, 0.7 mmol), followed by 1,4-dioxane (8 mL) and water (4 mL). The mixture was reacted at 80 °C for 16 h under nitrogen protection. Concentration under reduced pressure, the residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (244 mg, light brown solid), yield: 71%, MS (ESI): m / z 494.0 [M+H] + .

[0492] (3) (S)-2-amino-3-(4-(3-((4-methylpiperazin-l-yl)methyl)benzo[d]isoxazol-5-yl)phenyl) propanamide hydrochloride

[0493] To a solution of (S)-(l-amino-3-(4-(3-((4-methylpiperazin-l-yl)methyl)benzo[d]isoxazol-5- yl)phenyl)-l-oxopropan-2-yl)carbamate (244 mg, 0.49 mmol) in dichloromethane (10 mL) was added hydrochloric acid dioxane solution (2 mL, 4 M) and reacted at room temperature for 3 h. Concentration under reduced pressure gave the title compound (220 mg, gray solid), yield: >100% (with solvent residue). MS (ESI): m / z 394.0 [M+H] + .

[0494] (4) (S)-2-(((S)-l-amino-3-(4-(3-((4-methylpiperazin-l-yl)methyl)benzo[d]isoxazol-5- yl)phenyl)-l-oxopropan-2-yl)carbamoyl)-l,4-oxazepane-4-carboxylic acid tert-butyl ester

[0495] To a solution of (S)-2-amino-3-(4-(3-((4-methylpiperazin-1-yl)methyl)benzo[d]isoxazol-5- yl)phenyl)propanamide hydrochloride (171.5 mg, 0.7 mmol) in N,N-dimethylformamide (5 mL) was added (S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (200 mg, 0.465 mmol), N,N-diisopropyl ethylamine (360 mg, 2.79 mmol) and HATU (353 mg, 0.93 mmol) and the reaction was stirred at room temperature for 3 hours. The reaction was purified by reverse phase column to give the title compound (150 mg, yellowish oil) in 100% yield. MS (ESI): m / z 621.0 [M+H] + .

[0496] (5) (S)-2-(((S)-1-cyano-2-(4-(3-((4-methylpiperazin-1-yl)methyl)benzo[d]isoxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester

[0497] To a solution of (S)-2-(((S)-1-amino-3-(4-(3-((4-methylpiperazin-1-yl)methyl)benzo[d]isoxazol-5-yl)phenyl)-1- oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (150 mg, 0.24 mmol) in dichloromethane (5 mL) was added pyridine (95 mg, 0.8 mmol) followed by the slow addition of trifluoroacetic anhydride (151 mg, 0.72 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction was poured into saturated aqueous sodium bicarbonate solution (40 mL) and the aqueous phase was extracted with dichloromethane (2 x 20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (120 mg, grey solid) in 82% yield. MS (ESI): m / z 603.1 [M+H] + .

[0498] (6) (S)-N-((S)-1-cyano-2-(4-(3-((4-methylpiperazin-1-yl)methyl)benzo[d]isoxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2- carboxamide

[0499] (S)-2-(((S)-1-cyano-2-(4-(3-(((4-methylpiperazin-1-yl)methyl)benzo[d]isoxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxepane-4-carboxylic acid tert-butyl ester (63 mg, 0.105 mmol) and formic acid (0.5 mL) were added to a 25 mL single-necked flask and reacted at room temperature for 3 hours. The reaction solution was slowly added dropwise to a saturated sodium bicarbonate aqueous solution (40 mL), and extracted with a mixed solvent (dichloromethane / methanol / triethylamine = 10 / 1 / 1) (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the title compound (13 mg, white solid), yield: 25%. MS (ESI): m / z 503.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.62(d,J=8.8Hz,1H),8.19(s,1H),7.93(d,J=8.4Hz,1 H),7.80(d,J=8.0Hz,1H),7.67(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),5.06-5 .04(m,1H),3.97-3.59(m,6H),3.24-3.21(m,2H),3.05-3.00(m,1H),2.75-2.6 0(m,2H),2.55-2.53(m,4H),2.39-2.31(m,4H),2.13(s,3H),1.77-1.65(m,2H).

[0500] Example 63: (S)-N-((S)-1-cyano-2-(4-(3-cyclopropylbenzo[d]isoxazol-5-yl)phenyl)ethyl)-1,4-oxacycloheptane-2-carboxamide (Compound 63)

[0501]

[0502] (1)(5-bromo-2-fluorophenyl)(cyclopropyl)methyl ketone oxime

[0503] (5-Bromo-2-fluorophenyl)(cyclopropyl) methyl ketone (100 mg, 0.4 mmol) was dissolved in pyridine (1 mL), and hydroxylamine hydrochloride (200 mg, 2.9 mmol) was added. The reaction was carried out at 150 °C for 3 hours under nitrogen protection. The mixture was cooled, quenched in water (10 mL), and the pH was adjusted to 3 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL), dried, and concentrated to give the title compound (100 mg, yellow solid), yield: 94%. MS (ESI): m / z 257.9 [M+H] + .

[0504] (2) 5-bromo-3-cyclopropylbenzo[d]isoxazole

[0505] (5-bromo-2-fluorophenyl)(cyclopropyl)methanone oxime (800 mg, 3.1 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (320 mg, 7.8 mmol) was added, heated to 70 °C and stirred for 2.5 hours. Cooled, poured into water (10 mL) and quenched, extracted with ethyl acetate (10 mL), dried, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (300 mg, yellow oil), yield: 40%. MS (ESI): m / z 237.8 [M+H] + .

[0506] (3) 3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole

[0507] 5-bromo-3-cyclopropylbenzo[d]isoxazole (200 mg, 0.84 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (50 mg), potassium acetate (240 mg, 2.6 mmol) and bis(pinacolato)diboron (260 mg, 1 mmol) were dissolved in dioxane (5 mL). The reaction was heated to 80 °C under nitrogen and stirred for 18 hours. Cooled, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (150 mg, yellow oil), yield: 63%.

[0508] (4) (S)-2-(((S)-1-amino-3-(4-(3-cyclopropylbenzo[d]isoxazol-5-yl)phenyl)-1- oxopropan-2-yl)carbamoyl)-1,4-oxacycloheptane-4-carboxylic acid tert-butyl ester

[0509] (S)-2-(((S)-1 -amino-3-(4-(3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzo[d]isoxazol-5-yl)phenyl)-1 -oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4- carboxylic acid tert-butyl ester (50 mg, 0.09 mmol), [1,1 '-bis(diphenylphosphino) ferrocene]dichloropalladium (10 mg), potassium carbonate (26 mg, 0.19 mmol) and 4-iodo-2- methylpyridine (30 mg, 0.1 1 mmol) were dissolved in dioxane / water (5 mL / 1 mL). The reaction was heated to 90 °C under nitrogen for 18 hours. The reaction was cooled, concentrated under reduced pressure and the residue purified by column chromatography (dichloromethane / methanol = 15 / 1 ) to give the title compound (30 mg, white solid) in 60% yield. MS (ESI): m / z 573.0 [M+H] + .

[0510] (5) (S)-2-(((S)-1 -cyano-2-(4-(3-cyclopropylbenzo[d]isoxazol-5-yl)phenyl)ethyl)carbamoyl)- 1,4-oxazepane-4-carboxylic acid tert-butyl ester

[0511] To a solution of (S)-2-(((S)-1 -amino-3-(4-(3-cyclopropylbenzo[d]isoxazol-5-yl)phenyl)-1 - oxopropan-2-yl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (60 mg, 0.1 1 mmol) in dichloromethane (2 mL) was added boroguanidine (78 mg, 0.3 mmol) and the reaction stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 ) to give the title compound (50 mg, colourless oil) in 86% yield. MS (ESI): m / z 531.0 [M+H] + .

[0512] (6) (S)-N-((S)-1 -cyano-2-(4-(3-cyclopropylbenzo[d]isoxazol-5-yl)phenyl)ethyl)-1,4- oxazepane-2-carboxamide

[0513] (S)-2-(((S)-1 -cyano-2-(4-(3-cyclopropylbenzo[d]isoxazol-5-yl)phenyl)ethyl)carbamoyl)- 1,4-oxazepane-4-carboxylic acid tert-butyl ester (50 mg) was dissolved in formic acid (0.5 mL) and stirred for 3 hours. After removing the solvent by rotary evaporation, the residue was purified by Pre-HPLC to give the title compound (20.1 mg, white solid) in 50% yield. MS (ESI): m / z 431.1 [M+H] + . 1H NMR (400 MHz, CDC13) δ 7.82 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.61-7.58 (m, 3H), 7.43 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 5.24-5.18 (m, 1H), 4.12-4.09 (m, 1H), 4.02-3.97 (m, 1H), 3.79-3.72 (m, 1H), 3.34-2.88 (m, 6H), 2.27-2.22 (m, 1H), 1.88-1.81 (m, 2H), 1.31-1.16 (m, 5H).

[0514] Example 64: (S)-N-((S)-l-cyano-2-(4-(5-fluoro-4-methyl-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazin-6-yl)phenyl)ethyl)-l,4-oxazepane-2-carboxamide (Compound 64)

[0515]

[0516] (l) 6-Bromo-5-fluoro-4-methyl-2H-benzo[b][l,4]oxazin-3(4H)-one

[0517] Dissolve 6-bromo-5-fluoro-2H-benzo[b][l,4]oxazin-3(4H)-one (246 mg, 1.0 mmol) in tetrahydrofuran (15 mL), then add iodomethane (284 mg, 2.0 mmol) and cesium carbonate (978 mg, 3.0 mmol), stir for 1 hour at room temperature under nitrogen protection. Pour the reaction solution into water (100 mL), extract with ethyl acetate (30 mL x 3), wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (500 mg, light yellow solid) with a yield of 96%. MS (ESI): m / z 259.8 [M+H] + .

[0518] (2) to (6) steps refer to (2) to (6) steps of Example 62, and the title compound 64 (30.7 mg, white solid) is obtained through similar procedures. MS (ESI): m / z 453.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 6.8 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 5.07 - 5.01 (m, 1H), 4.67 (s, 2H), 3.99 (dd, J = 8.0, 3.6 Hz, 1H), 3.85 - 3.79 (m, 1H), 3.74 - 3.68 (m, 1H), 3.40 (d, J = 6.8 Hz, 3H), 3.26 - 3.18 (m, 2H), 3.03 (dd, J = 14.4, 3.6 Hz, 1H), 2.80 - 2.73 (m, 1H), 2.62 - 2.52 (m, 2H), 1.76 - 1.67 (m, 2H).

[0519] Example 65: (S)-N-((S)-1-cyano-2-(4-(3-oxo-4-(piperidin-4-ylmethyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 65)

[0520]

[0521] (1) 4-((6-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)piperidine-1- carboxylic acid tert-butyl ester

[0522] (1) 4-((6-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)piperidine-1- carboxylic acid tert-butyl ester + .

[0523] (2) to (5) Refer to the steps (3) to (6) of Example 61, the title compound 65 (58 mg, white solid) was obtained through similar procedures. MS (ESI): m / z 518.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.41 - 7.26 (m, 4H), 7.08 (d, J = 8.0 Hz, 1H), 5.06 - 5.02 (m, 1H), 4.67 (s, 2H), 4.00 - 3.71 (m, 6H), 3.21 - 3.12 (m, 4H), 3.06 - 2.72 (m, 4H), 2.61 - 2.57 (m, 1H), 2.38 - 2.35 (m, 1H), 1.91 - 1.25 (m, 6H), 1.13 - 1.06 (m, 1H).

[0524] Example 66: (S)-N-((S)-l-cyano-2-(4-(3-cyano-l-methyl-lH-indazol-5- yl)phenyl)ethyl)-l,4-oxazepane-2-carboxamide (Compound 66)

[0525]

[0526] (1) 5-bromo-l-methyl-lH-indazole-3-carbonitrile

[0527] To a solution of 5-bromo-lH-indazole-3-carbonitrile (300 mg, 1.4 mmol) in N,N- dimethylformamide (5 mL) was added iodomethane (289 mg, 2.0 mmol) and cesium carbonate (887 mg, 2.7 mmol). The reaction was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (285 mg, white solid) in a yield of 89%. MS (ESI): m / z 235.8 [M+H] + .

[0528] (2) to (6) Refer to steps (2) to (6) of Example 62, and the title compound 66 (45 mg, white solid) was obtained through similar procedures. MS (ESI): m / z 429.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.92 (dd, J = 8.8, 1.2 Hz, 1H) 7.77 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 5.08 - 5.02 (m, 1H), 4.23 (s, 3H), 4.00 (dd, J = 7.6, 3.6 Hz, 1H), 3.88 - 3.82 (m, 1H), 3.76 - 3.70 (m, 1H), 3.24 - 3.21 (m, 2H), 3.03 (dd, J = 14.4, 7.6 Hz, 1H), 2.78 - 2.72 (m, 1H), 2.63 - 2.53 (m, 2H), 1.76 - 1.67 (m, 2H).

[0529] Example 67: (S)-N-((S)-l-cyano-2-(4-(l'-methyl-3-oxo-3H-spiro[isobenzofuran-l,4'- piperidin]-6-yl)phenyl)ethyl)-l,4-oxazepane-2-carboxamide (Compound 67)

[0530]

[0531] The title compound 67 (18.0 mg, white solid) was obtained from the 6-bromo-3-oxo- 3H-spiro[isobenzofuran-l,4'-piperidin]-l'-carboxylic acid tert-butyl ester (Example 59, step 1) as starting material in an analogous procedure as described in Example 58. MS (ESI): m / z 489.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.87 (s, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 5.09 - 5.02 (m, 1H), 3.99 (dd, J = 7.6, 3.6 Hz, 1H), 3.87 - 3.81 (m, 1H), 3.75 - 3.69 (m, 1H), 3.24 - 3.22 (m, 2H), 3.02 (dd, J = 14.0, 4.0 Hz, 1H), 2.83 - 2.72 (m, 3H), 2.63 - 2.53 (m, 2H), 2.37 - 2.28 (m, 7H), 1.76 - 1.62 (m, 4H).

[0532] Example 68: (S)-N-((S)-1-cyano-2-(4-(3-cyanoimidazo[1,2-a]pyridin-6- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 68)

[0533]

[0534] (1) (S)-tert-butyl (1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl)carbamate

[0535] (S)-2-amino-3-(4-iodophenyl)propanamide (6.0 g, 20.7 mmol) was dissolved in dichloromethane (100 mL), di-tert-butyl dicarbonate (6.78 g, 30.9 mmol) and N,N- diisopropylethylamine (2.67 g, 20.7 mmol) were added, and the reaction system was stirred at 25 °C for 12 hours. The reaction solution was concentrated to obtain the title compound (8.5 g, white solid). MS (ESI): m / z 290.9 [M+H-100] + .

[0536] (2) (S)-tert-butyl (1-cyano-2-(4-iodophenyl)ethyl)carbamate

[0537] To a solution of (S)-tert-butyl (1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl)carbamate (8.5 g, 21.8 mmol) in dichloromethane (100 mL) was added the Burgess reagent (15.7 g, 65.4 mmol) at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (5.6 g, white solid) with a yield of 69.1%. MS (ESI): m / z 373.0 [M+H] + .

[0538] (3) (S)-tert-butyl (1-cyano-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)ethyl)carbamate

[0539] To a solution of (S)-(1-cyano-2-(4-iodophenyl)ethyl)carbamic acid tert-butyl ester (3.72 g, 10 mmol) in 1,4-dioxane (80 mL) was added [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (731 mg, 1 mmol), potassium acetate (2.94 g, 30 mmol) and pinacol diborane (3.81 g, 15 mmol). The mixture was reacted at 80 °C for 16 h under nitrogen protection. Concentration under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the title compound (2.6 g, pink oil), yield: 70%. MS (ESI): m / z 317.2 [M+H-56] + .

[0540] (4) (S)-(1-cyano-2-(4-(3-cyanoimidazo[1,2-a]pyridin-6-yl)phenyl)ethyl)carbamic acid tert-butyl ester

[0541] To a solution of (S)-(1-cyano-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamic acid tert-butyl ester (446 mg, 1.2 mmol) in 1,4-dioxane (10 mL) was added 6-bromoimidazo[1,2-a]pyridine-3-carbonitrile (222 mg, 1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol), potassium carbonate (414 mg, 3 mmol) and water (2 mL). The mixture was reacted at 100 °C for 18 h under nitrogen protection. Concentration under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (86 mg, orange solid), yield: 22%, MS (ESI): m / z 388.1 [M+H] + .

[0542] (5) (S)-6-(4-(2-amino-2-cyanoethyl)phenyl)imidazo[1,2-a]pyridine-3-carbonitrile

[0543] To a solution of (S)-(1-cyano-2-(4-(3-cyanoimidazo[1,2-a]pyridin-6-yl)phenyl)ethyl)carbamic acid tert-butyl ester (58 mg, 0.15 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure to give the title compound (43 mg, yellow oil), yield: 100%. MS (ESI): m / z 288.1 [M+H] + .

[0544] (6) (S)-2-(((S)-l-cyano-2-(4-(3-cyanoimidazo[l,2-a]pyridin-6- yl)phenyl)ethyl)carbamoyl)-l,4-oxazepane-4-carboxylic acid tert-butyl ester

[0545] To a solution of (S)-6-(4-(2-amino-2-cyanoethyl)phenyl)imidazo[l,2- a]pyridine-3-carbonitrile (43 mg, 0.15 mmol) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (155 mg, 1.2 mmol), (S)-4-(tert- butoxycarbonyl)-l,4-oxazepane-2-carboxylic acid (73.5 mg, 0.3 mmol) and HATU (114 mg, 0.3 mmol) and the reaction was allowed to proceed at room temperature for 3 hours. The reaction was poured into saturated aqueous sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phase was combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (35 mg, colorless oil) in a yield of 45% and MS (ESI): m / z 515.2 [M+H] + .

[0546] (7) (S)-N-((S)-l-cyano-2-(4-(3-cyanoimidazo[l,2-a]pyridin-6- yl)phenyl)ethyl)-l,4-oxazepane-2-carboxamide

[0547] To a solution of (S)-2-(((S)-l-cyano-2-(4-(3-cyanoimidazo[l,2-a]pyridin-6- yl)phenyl)ethyl)carbamoyl)-l,4-oxazepane-4-carboxylic acid tert-butyl ester (35 mg, 0.068 mmol) in a 25 mL single neck flask was added formic acid (1 mL) and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was slowly added to saturated aqueous sodium bicarbonate solution (40 mL) and extracted with a mixed solvent (dichloromethane / methanol / triethylamine = 10 / 1 / 1) (2 x 20 mL). The organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the title compound (10.4 mg, white solid) in a yield of 37%. MS (ESI): m / z 415.0 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.48 (s, 1H), 7.94 (s, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 5.08-5.02 (m, 1H), 4.01-3.98 (m, 1H), 3.88-3.70 (m, 2H), 3.26-3.18 (m, 3H), 3.02 (dd, J = 14.4, 3.6 Hz, 1H), 2.79-2.73 (m, 1H), 2.67-2.53 (m, 2H), 1.77-1.68 (m, 2H).

[0548] Example 69: (S)-N-((S)-1-cyano-2-(3'-(3-methyl-2-oxo-2,3-dihydrooxazol-5-yl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 69)

[0549]

[0550] (1) 3-(2-(3-bromophenyl)-2-oxoethyl)thiazolidine-2,4-dione

[0551] (1) 3-(2-(3-bromophenyl)-2-oxoethyl)thiazolidine-2,4-dione + .

[0552] (2) 5-(3-bromophenyl)oxazol-2(3H)-one

[0553] To a solution of 3-(2-(3-bromophenyl)-2-oxoethyl)thiazolidine-2,4-dione (500 mg, 1.6 mmol) in tetrahydrofuran / water (5 mL / 5 mL) was added lithium hydroxide (335 mg, 8.0 mmol) and the reaction was stirred at room temperature for two hours. Water (20 mL) was added to the reaction mixture and the product was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (350 mg, yellow oil) in a yield of 92%. MS (ESI): m / z 240.0 [M+H] + .

[0554] (3) 5-(3-bromophenyl)-3-methyloxazol-2(3H)-one

[0555] To a solution of 5-(3-bromophenyl)oxazol-2(3H)-one (350.0 mg, 1.5 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (386.0 mg, 2.8 mmol) and iodomethane (312.0 mg, 2.2 mmol) and the reaction was stirred at room temperature for two hours. Water (20 mL) was added to the reaction mixture and the product was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (210 mg, white solid) in a yield of 57%. MS (ESI): m / z 253.9 [M+H] + .

[0556] (4) to (8) Steps were performed by analogy with steps (2) to (6) of Example 62 to give the title compound 69 (25 mg, white solid). MS (ESI): m / z 447.1 [M+H] +.1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.71 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.51 - 7.45 (m, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.07 - 5.01 (m, 1H), 4.00 (dd, J = 8.0, 3.6 Hz, 1H), 3.87 - 3.82 (m, 1H), 3.75 - 3.69 (m, 1H), 3.25 - 3.20 (m, 5H), 3.04 (dd, J = 14.4, 3.6 Hz, 1H), 2.79 - 2.73 (m, 1H), 2.63 - 2.57 (m, 2H), 1.76 - 1.68 (m, 2H).

[0557] Example 70: (S)-N-((S)-l-cyano-2-(2'-(3-methyl-2-oxo-2,3-dihydrooxazol-5-yl)- [l,l'-biphenyl]-4-yl)ethyl)-l,4-oxazepane-2-carboxamide (Compound 70)

[0558]

[0559] The title compound 70 (24 mg, white solid) was obtained by following a similar procedure as described in Example 69 using 2-bromo-l-(2-bromophenyl)ethan-l-one as the starting material. MS (ESI): m / z 447.1 [M+H] +.1 H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 9.2 Hz, 1H) 7.57 (d, J = 7.6 Hz, 1H) 7.45 (t, J = 7.6 Hz, 1H) 7.39 - 7.37 (m, 3H), 7.24 - 7.19 (m, 3H), 5.72 (s, 1H), 5.10 - 5.04 (m, 1H), 3.99 (d, J = 8.0, 3.6 Hz, 1H), 3.91 - 3.85 (m, 1H), 3.76 - 3.70 (m, 1H), 3.23 - 3.20 (m, 2H), 3.03 - 2.99 (m, 4H), 2.79 - 2.74 (m, 1H), 2.79 - 2.57 (m, 2H), 1.77 - 1.70 (m, 2H).

[0560] Example 71: (S)-N-((S)-l-cyano-2-(4-(3-cyanopyrazolo[l,5-a]pyridin-5-yl)phenyl)ethyl)- 1,4-oxazepane-2-carboxamide (Compound 71)

[0561]

[0562] (1) 5-bromopyrazolo[l,5-a]pyridine-3-carbaldehyde

[0563] Dissolve 5-bromopyrazolo[l,5-a]pyridine (500 mg, 2.54 mmol) in dichloromethane (20 mL), add (chloromethylene)dimethylammonium chloride (1.3 g, 10.16 mmol), and stir the system at 44 °C for 18 hours. Concentrate the reaction solution under reduced pressure, dissolve the residue in 80 mL of saturated sodium bicarbonate solution, extract the resulting mixture with ethyl acetate (30 mL x 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (485 mg, yellow solid) with a yield of 85%. MS (ESI): m / z 225.0 [M+H] + .

[0564] (2) 5-bromopyrazolo[1,5-a]pyridine-3-carbaldehyde oxime

[0565] 5-bromopyrazolo[1,5-a]pyridine-3-carbaldehyde (485.0 mg, 2.16 mmol) was dissolved in ethanol / water (20 mL / 10 mL), hydroxylamine hydrochloride (225 mg, 3.24 mmol) was added, the system was stirred at 85 °C for 18 hours. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate solution was added to adjust the pH to neutral, suction filtration, and the filter cake was dried under vacuum to obtain the title compound (490 mg, light yellow solid), yield: 95%. MS (ESI): m / z 240.0 [M+H] + .

[0566] (3) 5-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0567] 5-bromopyrazolo[1,5-a]pyridine-3-carbaldehyde oxime (490 mg, 2.04 mmol) was dissolved in acetic anhydride (10 mL), stirred at 140 °C overnight. The reaction solution was added to 40 mL of water, extracted with ethyl acetate (30 mL x 3), concentrated and then filtered with petroleum ether to obtain the title compound (255 mg, yellow solid), yield: 53%. MS (ESI): m / z 221.9 [M+H] + .

[0568] (4) to (7) steps refer to the steps (3) to (6) of Example 56, through similar procedures to obtain the title compound 71 (18.2 mg, white solid). MS (ESI): m / z 415.1 [M+H] +.1 HNMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 7.2 Hz, 1H), 8.66 (s, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 0.8 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.58 (dd, J = 7.2, 2.0 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 5.10-5.04 (m, 1H), 3.99 (dd, J = 7.6, 3.6 Hz, 1H), 3.88-3.82 (m, 1H), 3.76-3.70 (m, 1H), 3.28-3.22 (m, 2H), 3.03 (dd, J = 14.4, 3.6 Hz, 1H), 2.79-2.72 (m, 1H), 2.63-2.52 (m, 2H), 1.79-1.67 (m, 2H).

[0569] Example 72: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(4-methyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 72)

[0570]

[0571] (1) (E)-3-(4-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)acrylate

[0572] (E)-3-(4-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)acrylate (500 mg, 1.34 mmol) was dissolved in anhydrous methanol (10 mL), (+)-1,2-bis((2S,5S)-2,5- diethylphospholanyl)benzene (cyclooctadiene)rhodium(I) trifluoromethanesulfonate (CAS: 142184-30-3, 97.4 mg, 0.13 mmol) was added, and the mixture was reacted under hydrogen gas at 50 °C for 12 hours. The reaction solution was cooled to room temperature, filtered through diatomite, and the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (338 mg, white solid) at a yield of 67.2%. MS (ESI): m / z 320.0 [M+H-56] + .

[0573] (2) (S)-3-(4-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0574] (E)-3-(4-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)acrylate (500 mg, 1.34 mmol) was dissolved in anhydrous methanol (10 mL), (+)-1,2-bis((2S,5S)-2,5- diethylphospholanyl)benzene (cyclooctadiene)rhodium(I) trifluoromethanesulfonate (CAS: 142184-30-3, 97.4 mg, 0.13 mmol) was added, and the mixture was reacted under hydrogen gas at 50 °C for 12 hours. The reaction solution was cooled to room temperature, filtered through diatomite, and the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (338 mg, white solid) at a yield of 67.2%. MS (ESI): m / z 320.0 [M+H-56] + .

[0575] (3) (S)-(1-amino-3-(4-bromo-2-fluorophenyl)-1-oxopropan-2-yl)carbamic acid tert-butyl ester

[0576] To a solution of (S)-3-(4-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino) propanoic acid methyl ester (930 mg, 2.47 mmol) in methanolic ammonia (1 M, 30 mL) was added anhydrous calcium chloride (274 mg, 2.47 mmol) and the reaction was stirred at 26 °C under nitrogen for 12 h. The reaction was filtered through celite, the filtrate was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give the title compound (634 mg, white solid) in 71.3% yield. MS (ESI): m / z 261.0 [M+H-100] + .

[0577] (4) (S)-(2-(4-bromo-2-fluorophenyl)-1-cyanoethyl)carbamic acid tert-butyl ester

[0578] To a solution of (S)-(1-amino-3-(4-bromo-2-fluorophenyl)-1-oxopropan-2-yl)carbamic acid tert-butyl ester (634 mg, 1.76 mmol) in dichloromethane (10 mL) was added boroguanidine reagent (1.26 g, 5.27 mmol) and the reaction was stirred at 26 °C under nitrogen for 12 h. The reaction was poured into water and extracted with ethyl acetate (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (541 mg, white solid) in 89.9% yield. MS (ESI): m / z 243.0 [M+H-100] + .

[0579] (5) (S)-(1-cyano-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamic acid tert-butyl ester

[0580] To a solution of (S)-(2-(4-bromo-2-fluorophenyl)-1-cyanoethyl)carbamic acid tert-butyl ester (190 mg, 0.54 mmol) in dioxane (10 mL) was added pinacol diboronic acid (155 mg, 0.61 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (46 mg, 0.06 mmol) and potassium acetate (109 mg, 1.1 mmol) and the mixture was stirred at 90 °C under nitrogen overnight. The reaction was used directly in the next step. MS (ESI): m / z 335.1 [M+H-56] + .

[0581] (6) (S)-tert-Butyl (1-cyano-2-(2-fluoro-4-(4-methyl-3-oxo-3,4-dihydro-2H- benzo [b] [1,4] oxazin-6-yl) phenyl) ethyl) carbamate

[0582] To the reaction solution of Step 1, 6-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (149 mg, 0.62 mmol) was added, followed by [1,1'-bis(diphenylphosphino) ferrocene] palladium dichloride (40.9 mg, 0.05 mmol), potassium carbonate (142 mg, 1.02 mmol) and pure water (1 mL), and the mixture was stirred at 100 °C under nitrogen protection overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (190 mg, orange oil) in a yield of 87.2%. MS (ESI): m / z 426.1 [M+H] + .

[0583] (7) (S)-2-amino-3-(2-fluoro-4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl) phenyl) propanenitrile

[0584] (S)-(1-cyano-2-(2-fluoro-4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl) phenyl) ethyl) carbamic acid tert-butyl ester (190 mg, 0.45 mmol) was dissolved in dichloromethane (5 mL), and formic acid (5 mL) was slowly added dropwise, and the reaction was stirred at 26 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (100 mg, orange solid) in a yield of 69.0%. MS (ESI): m / z 326.1 [M+H] + .

[0585] (8) (S)-tert-butyl 2-(((S)-1-cyano-2-(2-fluoro-4-(4-methyl-3-oxo-3,4-dihydro-2H- benzo [b] [1,4] oxazin-6-yl) phenyl) ethyl) carbamoyl) -1,4-oxacycloheptane-4- carboxylate

[0586] (S)-2-amino-3-(2-fluoro-4-(4-methyl-3-oxo-3,4-dihydro-2H- benzo [b] [1,4] oxazin-6-yl) phenyl) propanenitrile (100 mg, 0.31 mmol), (S)-4-(tert- butoxycarbonyl)-1,4-oxacycloheptane-2-carboxylic acid (98 mg, 0.40 mmol) were dissolved in dichloromethane (5 mL), 1 -propylphosphonic anhydride (197 mg, 0.61 mmol), triethylamine (156 mg, 1.54 mmol) were added. The mixture was stirred at 26 °C for 3 h. The reaction was concentrated under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 ) to give the title compound (149 mg, orange oil) in 87.6% yield. MS (ESI): m / z 553.1 [M+H] + .

[0587] (9) (S)-N-((S)-1 -cyano-2-(2-fluoro-4-(4-methyl-3-oxo-3,4-dihydro-2H- benzo [b] [1,4] oxazin-6-yl) phenyl) ethyl)-1,4-oxacycloheptane-2-carboxamide

[0588] (S)-2-(((S)-1 -cyano-2-(2-fluoro-4-(4-methyl-3-oxo-3,4-dihydro-2H- benzo [b] [1,4] oxazin-6-yl) phenyl) ethyl) carbamoyl)-1,4-oxacycloheptane-4- carboxylic acid tert-butyl ester (149 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), formic acid (5 mL) was added dropwise slowly. The mixture was stirred at 26 °C for 3 h. The reaction was concentrated under reduced pressure, the residue was purified by Prep-HPLC to give the title compound (24.5 mg, white solid) in 20.1 % yield. MS (ESI): m / z 453.1 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.0, 1.6 Hz, 1H), 7.53 (dd, J = 8.0, 1.6 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.08 - 5.01 (m, 1H), 4.69 (s, 2H), 4.00 (dd, J = 7.6, 3.6 Hz, 1H), 3.89 - 3.70 (m, 2H), 3.38 (s, 3H), 3.29 - 3.25 (m, 1H), 3.21 - 3.15 (m, 1H), 3.05 (dd, J = 14.4, 3.6 Hz, 1H), 2.79 - 2.74 (m, 1H), 2.68 - 2.53 (m, 2H), 1.77 - 1.69 (m, 2H).

[0589] Example 73: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(4-methyl-3-oxo-5-(trifluoromethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 73)

[0590]

[0591] The title compound 73 (20.5 mg, white solid) was obtained from (S)-(1-cyano-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamic acid tert-butyl ester and 6-bromo-4-methyl-5-(trifluoromethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one as starting materials in an analogous procedure as described in Example 72, steps (6) to (9). MS (ESI): m / z 521.0 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 8.8 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.24 (dd, J = 10.4, 1.2 Hz, 1H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.12 - 5.06 (m, 1H), 4.71 (s, 2H), 4.00 (dd, J = 8.4, 3.6 Hz, 1H), 3.85 - 3.69 (m, 2H), 3.34 (s, 3H), 3.29 - 3.21 (m, 2H), 3.05 (dd, J = 14.4, 3.6 Hz, 1H), 2.83 - 2.76 (m, 1H), 2.62 - 2.53 (m, 2H), 1.75 - 1.67 (m, 2H).

[0592] Experimental Example 1: DPP-1 enzyme activity assay

[0593] Recombinant human DPP-1 enzyme activity was determined by cleavage of the fluorescent substrate Gly-Arg-AM-C to release AM-C. The assay was performed in a 384-well plate at room temperature with a final volume of 20 μL. The assay conditions were as follows: 25 mM HEPES (pH 6.0), 0.01% Triton X-100, 5 mM DTT, 50 mM Na-Cl, 20 μM Gly-Arg-AM-C (GL Biochem, 824598) and 1.5 nM human recombinant DPP-1 (Sino Biological, 10484-H08H). The positive control compound INS-1007 and other test compounds were diluted in DMSO to a 1000x final concentration with a maximum final concentration of 10 μM, 3-fold dilution, 10 concentration points, and duplicate wells. The final concentration of DMSO was 0.1%.

[0594] Except for the MIN wells which were added with assay buffer, the human recombinant DPP-1 protein solution was added to each well with different concentrations of test compounds (DMSO in MAX / MIN wells), centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 15 minutes. An equal volume of Gly-Arg-AM-C solution was then added, centrifuged at 1000 rpm for 1 minute and read using a Biotek Synergy2 microplate reader.

[0595] Inhibition % = (Slope_sample - Slope_min) / (Slope_max - Slope_min) x 100, with the concentration log value as the X axis and the percentage inhibition as the Y axis, the log (agonist) vs. response- Variableslope dose-effect curve was fitted using the analysis software GraphPad Prism 5 and the IC50was calculated.50 value.

[0596] The positive compound used in Examples 1-3 was INS-1007, which was prepared according to the method of Example 2 in patent CN201580005484.1.

[0597] IC50 of each compound 50 The values ​​are shown in the table below: where A represents the range ≤10nM, B represents the range 10-100nM, and C represents the range >100nM.

[0598] Table 1 DPP-1 enzyme IC 50 value

[0599]

[0600]

[0601] Experimental Example 2: DPP-1 Cell Viability Detection:

[0602] The initial concentration of the analyte was 10 μM, diluted 3-fold, and tested in replicates of 10 concentrations, with INS-1007 as a positive control. The analyte was serially diluted in the plate to a final concentration of 1000-fold. 50 nL of 100% DMSO was transferred to each of the 550 wells in a 384-well reaction plate. 50 nL of DMSO was also transferred to each of the Max and Min wells.

[0603] Add a concentration of 6.25 × 10⁻⁶ to each Max well. 4 40 μL of U937 cells / mL (purchased from ATCC, catalog number CRL-1593.2) was added to each well of the reaction plate, along with 40 μL of PBS solution. The cells were centrifuged at 1000 rpm for 1 min and incubated at 37°C for 1 h. 5× peptide solution (Gly-Phe-AFC, purchased from ChemCruz, catalog number sc-506265A) was prepared using PBS, and 10 μL was added to each well of the reaction plate to bring the final peptide concentration to 200 μM. The cells were centrifuged at 1000 rpm for 1 min and incubated at 37°C for 30 min. The fluorescence fluorescence value (RFF) was read using Ensight, and the inhibition rate was calculated.

[0604] Calculation formula:

[0605] %Inh=(RFU_sample-RFU_min) / (RFU_max-RFU_min)×100

[0606] Fitted dose-response curve:

[0607] The log value of concentration was used as X axis and the percentage of inhibition as Y axis, and the dose-effect curve fitting was performed by using analysis software GraphPad Prism 5.

[0608] The IC50values of each compound are shown in the following table: wherein the range shown by ++ is ≤10 nM, and the range shown by + is 10-100 nM. 50

[0609] Table 2DPP-1 cell activity IC50values 50

[0610] Compound IC 50 (nM) 5 ++ 43 ++ 63 ++ Positive +

[0611] Experimental Example 3: PK test

[0612] 1. Experimental method

[0613] Experimental animals: SD rats, male; body weight: 210.7-252.7 g;

[0614] Preparation of test sample: the target compound was prepared into 0.2 mg / mL (for intravenous administration) and 0.5 mg / mL (for oral administration). Route of administration: oral administration / intravenous injection. Administration volume and frequency: 5 mL / kg (intravenous injection) or 10 mL / kg (oral administration), single administration. Administration preparation: 5% DMSO+95% (30% SBE-β-CD) for intravenous administration, and 0.5% HPMC+0.1% Tween 80 for oral administration.

[0615] Sample collection: blood was collected at the following time points: 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr and 24 hr after administration.

[0616] 2. Sample analysis and results

[0617] Sample analysis: the collected samples were detected by using LC-MS / MS method. The instrument model was Shimadzu LC30AD and QTRAP 5500.

[0618] Pharmacokinetic data analysis: the obtained blood drug concentration data were fitted and calculated according to non-compartment model method, and part of the results are summarized in Table 3.

[0619] Table 3 Bioavailability

[0620] Compound F 6 97.7％ Positive 86.3％ ​​

Claims

1. A compound or pharmaceutically acceptable salt thereof according to the following formula: 。 2. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt according to any one of claims 1 and a pharmaceutically acceptable carrier therefor.

3. Use of a compound or pharmaceutically acceptable salt according to claim 1 or a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the treatment and / or prevention of a DPP-1 associated disease.

4. Use according to claim 3, characterized in that: The DPP-1 associated disease is selected from the group consisting of non-cystic fibrosis bronchiectasis, asthma, chronic obstructive pulmonary disease and respiratory distress syndrome, and anti-neutrophil cytoplasmic antibodies associated vasculitis, lupus nephritis, inflammatory bowel disease, rheumatoid arthritis, and sepsis, alpha 1 antitrypsin deficiency, tumors, diabetic cardiomyopathy.

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