Novel reversible DPP1 inhibitors and their uses

Abstract

Provided herein are compounds of formula (I), or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 、 L and R 1 is defined herein. Also provided herein are pharmaceutical compositions comprising the compound of formula (I) or a pharmaceutically acceptable salt or deuterated form thereof, and methods of using the compound of formula (I) or a pharmaceutically acceptable salt or deuterated form thereof, for example, in the treatment of diseases treatable by administration of a DPP1 inhibitor. [Formula 1] JPEG2026503035000405.jpg27123

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 437,557, filed January 6, 2023, and U.S. Provisional Application No. 63 / 485,243, filed February 15, 2023, the contents of which are incorporated by reference herein in their entireties for all purposes. [Background technology]

[0002] Dipeptidyl peptidase 1 (DPP1, EC 3.4.14.1), also known as cathepsin C, is a lysosomal cysteine ​​protease belonging to the papain family with a molecular weight of 200 kDa. DPP1 was first discovered by Gutman and Fruton in 1948 (J. Biol. Chem. 174, 851-858). However, the cDNA for the human enzyme was first described in 1995 (Paris et al. 1995, FEBS Lett. 369, 326-330). DPP1 is the only member of the papain family that functions as a tetramer consisting of four identical subunits. Each subunit consists of an N-terminal fragment, a heavy chain, and a light chain (Dolenc et al. 1995, J. Biol. Chem. 270, 21626-21631).

[0003] DPP1 is constitutively expressed in many tissues, with highest levels in the lungs, kidneys, liver, and spleen. DPP1 catalyzes the removal of dipeptides from the N-terminus of polypeptide substrates with broad specificity. Recent data suggest that in addition to being a key enzyme in lysosomal proteolysis, DPP1 also functions as a key enzyme in the activation of granule serine proteases in cytotoxic T lymphocytes and natural killer cells (granzymes A and B), mast cells (chymase and tryptase), and neutrophils (cathepsin G, neutrophil elastase, and proteinase-3).

[0004] Mast cells are found in many tissues, but are more abundant along the epithelial linings of the body, such as the skin, airways, and gastrointestinal tract. Two types of mast cells have been identified in humans: T-type mast cells, which express only tryptase, and MC-type mast cells, which express both tryptase and chymase. In humans, T-type mast cells are primarily located in alveolar tissue and intestinal mucosa, while TC-type cells predominate in the skin and conjunctiva. Tryptase and chymase are thought to be important mediators of allergic diseases and are involved in the processes of inflammation, bronchoconstriction, and mucus secretion.

[0005] Neutrophils play a crucial role in host defense against invading pathogens. They are produced in the bone marrow and fully mature upon release into the circulatory system, where they serve as the first line of cellular defense. Proinflammatory mediators and chemoattractants activate neutrophils and draw them to the site of infection, where they engulf bacteria by phagocytosis and attack them by accumulating antimicrobial compounds using both oxidative and nonoxidative methods. Neutrophil elastase, a potent serine protease, is one of the antimicrobial compounds clearly involved in bacterial destruction. Neutrophil elastase is released into the phagolysome that surrounds microorganisms, furthering their destruction. Neutrophil elastase can attack the outer membrane protein OmpA of Gram-negative bacteria, degrading their membranes and thereby not only directly killing pathogens but also allowing other antimicrobial compounds to access them. Furthermore, neutrophil elastase can help process other antimicrobial compounds, converting inactive propeptides into active forms, such as cathelicidin.

[0006] However, neutrophil elastase can also cause problems for its host. It is one of the most destructive enzymes in the body, capable of degrading extracellular matrix proteins (including collagen, proteoglycans, fibronectin, platelet receptors, complement receptors, thrombomodulin, pulmonary surfactant, and cadherins) and important plasma proteins (including coagulation and complement factors, immunoglobulins, and several proteases and protease inhibitors). Under physiological conditions, endogenous protease inhibitors such as α1-antitrypsin tightly regulate the activity of neutrophil elastase. However, at sites of inflammation, neutrophil elastase can escape regulation, and once deregulated, it can induce the release of proinflammatory cytokines such as interleukin-6 and interleukin-8, resulting in acute lung injury. It can even impair host defense against infection by degrading phagocyte surface receptors and opsonins. Its negative role is exemplified by its involvement in the tissue destruction and inflammation that characterize many diseases, including hereditary emphysema, chronic obstructive pulmonary disease, cystic fibrosis, adult respiratory distress syndrome, ischemia-reperfusion injury, and rheumatoid arthritis.

[0007] Therefore, there is a need in the art to provide novel DPP1 inhibitors for the treatment of the aforementioned diseases, as well as other diseases associated with DPP1 and neutrophil elastase. Summary of the Invention

[0008] In embodiments, provided herein are compounds of formula (I)

[0009] [ka] or a pharmaceutically acceptable salt or deuterated form thereof; During the ceremony, R 0 teeth

[0010] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, N(C 1~6 alkyl), CHO, R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 alkylene-heteroaryl, heteroaryl or carbocyclyl; R B is C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-aryl, C 1~6 alkylene-heteroaryl, heteroaryl, or carbocyclyl; R A and R B together form a heterocyclyl, L is aryl, heterocyclyl, heteroaryl, or

[0011] [ka] and L is independently 0 to 4 R 10 and ring B is a carbocyclic or heterocyclic ring; R 1 teeth

[0012] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R 3 are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF2; Y is O, S, or CH2; Q is CH or N; R 6 is C 1~6 alkyl, optionally substituted with 1, 2 or 3 F, or OH, OC 1~6 Alkyl, N(C 1~6 alkyl)2, N(C 1~6 Alkyl)(C 1~6 Alkylene-OC 1~6 optionally substituted with alkyl), cycloalkyl, or heterocyclyl; R 7 is H, F, Cl, Br, or C 1~6 is alkyl, Each R 8 and R 12 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 Alkylene-heteroaryl, halogenated C 1~6 alkoxy, heteroaryl, or carbocyclyl; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; Each R10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1~6 Alkyl, N(C 1~6 Alkyl)2, COOH, COC 1~6 Alkyl, COOC 1~6 Alkyl, CON 1-6 Alkyl, CON(C 1~6 alkyl) 2、 NHCOC 1~6 alkyl, or heterocycle, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and COOH; W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~6 alkyl, alkylene-O-alkyl, or heterocyclyl; i and j are each independently 1, 2, or 3, provided that the sum of i+j is 2, 3, or 4.

[0013] In one aspect, the present disclosure provides a compound of formula (I)

[0014] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R 0 teeth

[0015] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, N(C 1~6 alkyl), OCH2, or SCH2; R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 alkylene-heteroaryl, heteroaryl or carbocyclyl; R B is C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-aryl, C 1~6 alkylene-heteroaryl, heteroaryl, or carbocyclyl; R A and R B together form a heterocyclyl, L is aryl, heterocyclyl, heteroaryl, or

[0016] [ka] and L is independently 0 to 4 R 10 and ring B is a carbocyclic or heterocyclic ring; R 1 teeth

[0017] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R 3 are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF2; Y is O, S, or CH2; Q is CH or N; R 6 is C 1~6 alkyl, optionally substituted with 1, 2 or 3 F, or OH, OC 1~6 Alkyl, N(C 1~6 alkyl)2, N(C 1~6 Alkyl)(C 1~6 Alkylene-OC 1~6 optionally substituted with alkyl), cycloalkyl, or heterocyclyl; R 7 is H, F, Cl, Br, or C 1~6 is alkyl, Each R 8 and R 12 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 Alkylene-heteroaryl, halogenated C 1~6 alkoxy, heteroaryl, or carbocyclyl; Each R 13are independently H, F, Cl, Br, I, or C1-C6 alkyl; Each R 10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1~6 Alkyl, N(C 1~6 Alkyl)2, COOH, COC 1~6 Alkyl, COOC 1~6 Alkyl, CON 1-6 Alkyl, CON(C 1~6 alkyl) 2、 NHCOC 1~6 alkyl, or heterocycle, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and COOH; W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~6 alkyl, alkylene-O-alkyl, or heterocyclyl; i and j are each independently 1, 2, or 3, provided that the sum of i+j is 2, 3, or 4.

[0018] In embodiments, the present disclosure provides a compound of formula (I)

[0019] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R0 teeth

[0020] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1~6 alkyl), R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 alkylene-heteroaryl, heteroaryl or carbocyclyl; R B is C 1~6 Alkyl, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-aryl, C 1~6 alkylene-heteroaryl, heteroaryl, or carbocyclyl; R A and R B together form a heterocyclyl, L is aryl, heterocyclyl, heteroaryl, or

[0021] [ka] and L is independently 0 to 4 R 10 and ring B is a carbocyclic or heterocyclic ring; R 1 teeth

[0022] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R 3 are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF2; Y is O or S; Q is CH or N; R 6 is C 1~6 alkyl, optionally substituted with 1, 2 or 3 F, or OH, OC 1~6 Alkyl, N(C 1~6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl; R 7 is H, F, Cl, Br, or C 1~6 is alkyl, Each R 8 and R 12 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 Alkylene-heteroaryl, halogenated C 1~6 alkoxy, heteroaryl, or carbocyclyl; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; Each R 10 are independently oxo, halogen, C1~6 Alkyl, C 1~6 Alkoxy, SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1~6 Alkyl, N(C 1~6 Alkyl)2, COOH, COC 1~6 Alkyl, COOC 1~6 Alkyl, CON 1-6 Alkyl, CON(C 1~6 alkyl) 2、 NHCOC 1~6 alkyl, or heterocycle, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and COOH; W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~6 alkyl, alkylene-O-alkyl, or heterocyclyl; i and j are each independently 1, 2, or 3, provided that the sum of i+j is 2, 3, or 4.

[0023] In one aspect, the present disclosure provides a compound of formula (I)

[0024] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R 0 teeth

[0025] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1~6 alkyl), R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; R B is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; or R A and R B together form a heterocyclyl, L is an aryl, heterocycle, heteroaryl, or

[0026] [ka] and L independently represents 0 to 4 R 10 and Ring B is a carbocycle, heterocycle, or heteroaryl; R 1 teeth

[0027] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R 3are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF2; Y is O or S; Q is CH or N; R 6 is one, two or three F, OH, OC 1~6 Alkyl, N(C 1~6 C substituted with alkyl, cycloalkyl, or heterocyclyl 1~6 is alkyl, R 7 is H, F, Cl, Br or C 1~6 is alkyl, R 8 and R 12 are independently H, OH, halogen, NH2, COOH, unsubstituted C 1~6 Alkyl, halogen, hydroxyl substituted C 1~6 Alkyl, unsubstituted C 1~6 Alkoxy or halogenated C 1~6 is an alkoxy; Each R 13 are independently H, F, Cl, Br, I or C 1~6 is alkyl, Each R 10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, -SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1~6 Alkyl, -N(C 1~6 Alkyl)2, -COOH, -COC 1~6 Alkyl, -COOC 1~6 Alkyl, -CON 1-6 Alkyl, -CON(C1~6 alkyl)2, -NHCOC 1~6 alkyl, or heterocyclyl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and —COOH; W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~6 alkyl, -alkylene-O-alkyl, heterocyclyl; i and j are each independently 1, 2, or 3, provided that the sum of i+j is 2, 3, or 4.

[0028] In embodiments, the present disclosure provides a compound of formula (II)

[0029] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 and R 1 is defined herein, n is 0 or 1, and R 10 is F.

[0030] In embodiments, the present disclosure provides a compound of formula (III)

[0031] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 , R 6 , R 7 , X, R 10 is F and n is 0 or 1.

[0032] In embodiments, the present disclosure provides a compound of formula (III-A)

[0033] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 , R 6 , R 7 , n, and X are defined as described above for formula (III).

[0034] In embodiments, the present disclosure provides a compound of formula (III-B)

[0035] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 , R 6 , R 7 and X are defined herein; R 10 is -H or -F.

[0036] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I), (II) or (III), (III-A), or (III-B) or a pharmaceutically acceptable salt or deuterated form thereof), and a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0037] In yet another aspect of the present disclosure, there is provided a method of treatment, which in embodiments comprises administering to a subject in need thereof an effective amount of a composition comprising a compound of Formula (I), (II), or (III), (III-A), or (III-B), or a pharmaceutically acceptable salt or deuterated form thereof.

[0038] In one embodiment, the method of treatment is for treating an obstructive airway disease, such as cystic fibrosis (CF), asthma, or bronchiectasis (e.g., non-CF bronchiectasis). In another embodiment, the method of treatment is for treating chronic rhinosinusitis (CRS).

[0039] In some embodiments, the method of treatment is a method for treating hidradenitis suppurativa (HS).

[0040] In some embodiments, the method of treatment is a method for treating cancer.

[0041] In some embodiments, the method of treatment is a method of treating lupus nephritis.

[0042] In some embodiments, the method of treatment is a method of treating rheumatoid arthritis.

[0043] In some embodiments, the method of treatment is a method of treating inflammatory bowel disease (IBD). DETAILED DESCRIPTION OF THE INVENTION

[0044] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure for all purposes in order to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. In the event of any conflict between the cited patents, patent applications, and publications and this disclosure, the present disclosure shall control.

[0045] definition Listed below are definitions of various terms used in the specification and claims to describe this disclosure.

[0046] Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0047] The term "about," when immediately preceding a numerical value, refers to a range encompassing the numerical value plus or minus an acceptable amount of variation in the art (e.g., plus or minus 10% of the value). For example, unless the context of this disclosure indicates otherwise or contradicts such an interpretation, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc. For example, in a list of numerical values ​​such as "about 49, about 50, about 55, ...," "about 50" refers to a range extending to less than half the interval between the preceding and succeeding values, e.g., from greater than 49.5 to less than 50.5. Furthermore, the phrase "less than about" a value or "greater than about" a value should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about" when preceding a series of numerical values ​​or ranges of values ​​(e.g., "about 10, 20, 30," or "about 10 to 30") refers to the endpoints of all values ​​in the series or ranges, respectively.

[0048] As used herein, the following terms have the following meanings unless otherwise specified.

[0049] "Cyano" refers to the radical -CN.

[0050] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0051] "Oxo" refers to the =O substituent.

[0052] "Alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain radical having from 1 to 12 carbon atoms, which is attached to the rest of the molecule by a single bond. Alkyl containing any number of carbon atoms from 1 to 12 is included. Alkyl containing up to 12 carbon atoms is C1-C 12 Alkyl, containing up to 10 carbon atoms, is C1-C10 An alkyl having up to 6 carbon atoms is a C1-C6 alkyl, and an alkyl having up to 5 carbon atoms is a C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties listed above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10 Alkyl includes all of the moieties listed above for C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9 and C 10 Also includes alkyl. Similarly, C1-C 12 Alkyl includes all of the above moieties, but C 11 and C 12 Including alkyl. C1~C 12 Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0053] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain radical having 1 to 12 carbon atoms. 12 Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise in the specification, an alkylene chain can be optionally substituted.

[0054] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain group having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms are C2-C 12 Alkenyl, containing up to 10 carbon atoms, is C2-C 10 An alkenyl group containing up to 6 carbon atoms is C2-C6 alkenyl, and an alkenyl containing up to 5 carbon atoms is C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all of the moieties listed above for C2-C5 alkenyl, but also includes C6 alkenyl. C2-C 10 Alkenyl includes all of the moieties listed above for C2-C5 alkenyl and C2-C6 alkenyl, but also includes C7, C8, C9 and C 10 Alkenyl is also included. Similarly, C2-C 12 Alkenyl includes all of the above moieties, but C 11 and C 12 Includes alkenyl. C2-C 12Non-limiting examples of alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, and 3-nonenyl. , 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise in the specification, an alkenyl group may be optionally substituted.

[0055] "Alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms are C2-C 12 Alkynyl, containing up to 10 carbon atoms, is C2-C 10An alkynyl group containing up to 6 carbon atoms is C2-C6 alkynyl, and an alkynyl containing up to 5 carbon atoms is C2-C5 alkynyl. C2-C5 alkynyl includes C5 alkynyl, C4 alkynyl, C3 alkynyl, and C2 alkynyl. C2-C6 alkynyl includes all of the moieties listed above for C2-C5 alkynyl, but also includes C6 alkynyl. C2-C 10 Alkynyl includes all of the moieties listed above for C2-C5 alkynyl and C2-C6 alkynyl, but also includes C7, C8, C9 and C 10 Alkynyl is also included. Similarly, C2-C 12 Alkynyl includes all of the above moieties, but C 11 and C 12 Alkynyl is included. C2-C 12 Non-limiting examples of alkenyls include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise in the specification, an alkynyl group may be optionally substituted.

[0056] "Alkoxy" means a group of the formula -OR a where R a is an alkyl, alkenyl, or alkynyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise in the specification, an alkoxy group may be optionally substituted.

[0057] "Alkylamino" refers to a group of the formula -NHR a or -NR a R a In the formula, each R a is independently an alkyl, alkenyl, or alkynyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise in the specification, an alkylamino group can be optionally substituted.

[0058] "Aryl" refers to a hydrocarbon ring system group containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For purposes of this disclosure, aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In embodiments where "L" is aryl, the aryl group is a diradical. Unless otherwise noted herein, the term "aryl" is meant to include optionally substituted aryl groups.

[0059] An "aralkyl" or "arylalkyl" is an alkyl group of the formula -R b -R c where R b is an alkylene group as defined above, and R c is one or more aryl groups as defined above, e.g., benzyl, diphenylmethyl, etc. Unless stated otherwise in the specification, an aralkyl group may be optionally substituted.

[0060] "Carbocyclyl," "carbocyclic ring," or "carbocycle" refers to a ring structure in which each atom forming the ring is carbon. A carbocyclic ring can contain from 3 to 20 carbon atoms in the ring. Carbocyclic rings include cycloalkyl, cycloalkenyl, and cycloalkynyl as defined herein. Unless stated otherwise in the specification, a carbocyclyl group can be optionally substituted.

[0061] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon group, consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems having from 3 to 20 carbon atoms, e.g., from 3 to 10 carbon atoms, and is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specified in the specification, cycloalkyl groups can be optionally substituted.

[0062] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group, consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which may include fused or bridged ring systems, having 3 to 20 carbon atoms, e.g., 3 to 10 carbon atoms, and attached to the remainder of the molecule by a single bond. Monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Polycyclic cycloalkenyl groups include, for example, bicyclo[2.2.1]hept-2-enyl, and the like. Unless otherwise specified in the specification, cycloalkenyl groups can be optionally substituted.

[0063] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group, consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which may include fused or bridged ring systems, having 3 to 20 carbon atoms, e.g., 3 to 10 carbon atoms, and attached to the remainder of the molecule by a single bond. Monocyclic cycloalkynyl groups include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise specified in the specification, cycloalkynyl groups can be optionally substituted.

[0064] "Cycloalkylalkyl" refers to a group of the formula -R b -Rd where R b is an alkylene, alkenylene, or alkynylene group as defined above, and R d is a cycloalkyl, cycloalkenyl, cycloalkynyl group as defined above. Unless stated otherwise in the specification, a cycloalkylalkyl group may be optionally substituted.

[0065] "Haloalkyl" or "halogenated alkyl" refers to an alkyl group, as defined above, that is substituted with one or more halo groups, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise in the specification, a haloalkyl group may be optionally substituted.

[0066] "Haloalkenyl" refers to an alkenyl group, as defined above, that is substituted by one or more halo groups, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless stated otherwise in the specification, a haloalkenyl group can be optionally substituted.

[0067] "Haloalkynyl" refers to an alkynyl group as defined above that is substituted by one or more halo groups as defined above, e.g., 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless stated otherwise in the specification, a haloalkynyl group can be optionally substituted.

[0068] "Heterocyclyl," "heterocyclic ring," or "heterocycle" refers to a stable 3- to 20-membered non-aromatic or partially aromatic group, consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, or sulfur. Unless stated otherwise in the specification, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocyclyl group can be optionally oxidized. The nitrogen atom can be optionally quaternized, and the heterocyclyl group can be partially or fully saturated. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In embodiments where "L" is heterocyclyl, the heterocyclyl group is a diradical. Unless stated otherwise in the specification, a heterocyclyl group may be optionally substituted.

[0069] "Heteroaryl" refers to a 5- to 20-membered ring system containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of this disclosure, a heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl group can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoin ... Examples of heteroaryl groups include, but are not limited to, dolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophene (i.e., thienyl). In embodiments where "L" is heteroaryl, the heteroaryl group is a diradical. Unless stated otherwise in the specification, a heteroaryl group may be optionally substituted.

[0070] The term "substituted" as used herein means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl), wherein at least one hydrogen atom is replaced with a halogen atom such as F, Cl, Br, and I; a hydroxyl group, an alkoxy group, an alkoxy group, an aryl ... and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups.

[0071] "Substituted" also refers to any of the above groups in which one or more hydrogen atoms have been replaced by a higher bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. For example, "substituted" refers to any group in which one or more hydrogen atoms have been replaced by -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -ORg , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h "Substituted" also includes any of the above groups in which one or more hydrogen atoms have been replaced with -C(=O)R. g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above, R g and R h are the same or different and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Substituted" further includes any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl group. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.

[0072] As used herein, the symbols

[0073] [ka] (which may hereafter be referred to as "bond points") represent a bond that is a point of attachment between two chemical entities, one of which is shown as being attached to the bond point and the other of which is not shown as being attached to the bond point. For example,

[0074] [ka] indicates that the chemical entity "XY" is attached to another chemical entity through a point of attachment. Furthermore, specific points of attachment to chemical entities not shown can be identified by inference. For example, the compound CH3-R L , where R L is H, or

[0075] [ka] is R L If "XY" is the connection point, R L is the same bond shown as being attached to CH3.

[0076] In embodiments, a chemical group (e.g., R 0 , L, and R 1 Any chemical group in the definition of (a) can exist in more than one orientation within a chemical structure. For example, it is understood that a group can exist in any possible orientation unless the context clearly limits the orientation of the group within a chemical structure to a particular orientation; for example, a CHO group can exist in a CHO orientation or an OCH orientation within a chemical structure.

[0077] As used herein, unless otherwise specified, the term "pharmaceutically acceptable" is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as appropriate for use in accordance with sound medical judgment. Generally, a pharmaceutically acceptable moiety has one or more benefits that outweigh any adverse effects that the moiety may have. Adverse effects may include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0078] The term "pharmaceutically acceptable salts" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form a salt, such as, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, and the like. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with the appropriate inorganic or organic acid by any of a number of known methods.

[0079] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomers that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms, whether or not specifically indicated herein. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When a compound described herein contains an olefinic double bond or other center of geometric asymmetry, unless otherwise specified, the compound is intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0080] "Stereoisomer" refers to a compound composed of the same atoms joined by the same bonds, but having different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0081] The term "treating" as used herein with respect to a patient refers to improving at least one symptom of the patient's disorder. Treatment can be improving or at least partially reversing the disorder or a symptom associated with the disorder.

[0082] An "effective amount" means the amount of a compound or pharmaceutical preparation that, when administered to a patient for treating a state, disorder or condition, is sufficient to effect such treatment.

[0083] The terms "subject," "individual," and "patient" are used interchangeably herein to refer to a vertebrate, such as a mammal. The mammal may be, for example, a mouse, rat, rabbit, cat, dog, pig, sheep, horse, non-human primate (e.g., cynomolgus monkey, chimpanzee), or human.

[0084] compound In one aspect of the disclosure, a DPP1 inhibitor is provided, wherein the DPP1 inhibitor is a compound of Formula (I), (II), (III), (III-A), (III-B), or Table 1.

[0085] In embodiments, provided herein are compounds of formula (I)

[0086] [ka] or a pharmaceutically acceptable salt or deuterated form thereof; During the ceremony, R 0 teeth,

[0087] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, N(C 1~6 alkyl), CHO, R A is H, C 1~6 Alkyl, C 1~6Alkylene-carbocyclyl, C 1~6 alkylene-heteroaryl, heteroaryl or carbocyclyl; R B is C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-aryl, C 1~6 alkylene-heteroaryl, heteroaryl, or carbocyclyl; R A and R B together form a heterocyclyl, L is aryl, heterocyclyl, heteroaryl, or

[0088] [ka] and L is independently 0 to 4 R 10 and ring B is a carbocyclic or heterocyclic ring; R 1 teeth

[0089] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R 3 are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF2; Y is O, S, or CH2; Q is CH or N; R 6 is C 1~6 alkyl, optionally substituted with 1, 2 or 3 F, or OH, OC 1~6 Alkyl, N(C 1~6 alkyl)2, N(C 1~6 Alkyl)(C 1~6 Alkylene-OC 1~6 optionally substituted with alkyl), cycloalkyl, or heterocyclyl; R 7 is H, F, Cl, Br, or C 1~6 is alkyl, Each R 8 and R 12 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-heteroaryl, halogenated C 1~6 Alkoxy, halogenated C 1~6 alkyl, heteroaryl or carbocyclyl; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; Each R 10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1~6 Alkyl, N(C 1~6 Alkyl)2, COOH, COC 1~6 Alkyl, COOC 1~6 Alkyl, CON 1-6Alkyl, CON(C 1~6 alkyl) 2、 NHCOC 1~6 alkyl, or heterocycle, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and COOH; W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~6 alkyl, alkylene-O-alkyl, or heterocyclyl; i and j are each independently 1, 2, or 3, provided that the sum of i+j is 2, 3, or 4.

[0090] In one aspect, the present disclosure provides a compound of formula (I)

[0091] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R 0 teeth

[0092] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, N(C 1~6alkyl), OCH2, or SCH2; R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 alkylene-heteroaryl, heteroaryl or carbocyclyl; R B is C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-aryl, C 1~6 alkylene-heteroaryl, heteroaryl, or carbocyclyl; R A and R B together form a heterocyclyl, L is aryl, heterocyclyl, heteroaryl, or

[0093] [ka] and L is independently 0 to 4 R 10 and ring B is a carbocyclic or heterocyclic ring; R 1 teeth

[0094] [ka] or R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R 3 are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF2; Y is O, S, or CH2; Q is CH or N; R 6 is C 1~6 alkyl, optionally substituted with 1, 2 or 3 F, or OH, OC 1~6 Alkyl, N(C 1~6 alkyl)2, N(C 1~6 Alkyl)(C 1~6 Alkylene-OC 1~6 alkyl), cycloalkyl, or heterocyclyl, and R 7 is H, F, Cl, Br, or C 1~6 is alkyl, Each R 8 and R 12 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 Alkylene-heteroaryl, halogenated C 1~6 alkoxy, heteroaryl, or carbocyclyl; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; Each R 10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1~6 Alkyl, N(C 1~6 Alkyl)2, COOH, COC1~6 Alkyl, COOC 1~6 Alkyl, CON 1-6 Alkyl, CON(C 1~6 alkyl) 2、 NHCOC 1~6 alkyl, or heterocycle, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and COOH; W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~6 alkyl, alkylene-O-alkyl, or heterocyclyl; i and j are each independently 1, 2, or 3, provided that the sum of i+j is 2, 3, or 4.

[0095] In embodiments, the present disclosure provides a compound of formula (I)

[0096] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R 0 teeth

[0097] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1~6 alkyl), R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 alkylene-heteroaryl, heteroaryl or carbocyclyl; R B is C 1~6 Alkyl, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-aryl, C 1~6 alkylene-heteroaryl, heteroaryl, or carbocyclyl; R A and R B together form a heterocyclyl, L is aryl, heterocyclyl, heteroaryl, or

[0098] [ka] and L is independently 0 to 4 R 10 and ring B is a carbocyclic or heterocyclic ring; R 1 teeth

[0099] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R 3 are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF2; Y is O or S; Q is CH or N; R 6 is C 1~6 alkyl, optionally substituted with 1, 2 or 3 F, or OH, OC 1~6 Alkyl, N(C 1~6 alkyl), cycloalkyl, or heterocyclyl; R 7 is H, F, Cl, Br, or C 1~6 is alkyl, Each R 8 and R 12 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 Alkylene-heteroaryl, halogenated C 1~6 alkoxy, heteroaryl, or carbocyclyl; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; Each R 10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1~6 Alkyl, N(C 1~6 Alkyl)2, COOH, COC 1~6 Alkyl, COOC 1~6 Alkyl, CON 1-6 Alkyl, CON(C 1~6 alkyl)2、 NHCOC 1~6 alkyl, or heterocycle, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and COOH; W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~6 alkyl, alkylene-O-alkyl, or heterocyclyl; i and j are each independently 1, 2, or 3, provided that the sum of i+j is 2, 3, or 4.

[0100] In embodiments, the present disclosure provides a compound of formula (I)

[0101] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R 0 teeth

[0102] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1~6 alkyl), R A is H, C1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; R B is C 1~6 Alkyl, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-aryl, or C 1~6 alkylene-heteroaryl; or R A and R B together form a heterocyclyl, L is aryl, heterocyclyl, heteroaryl, or

[0103] [ka] and L is independently 0 to 4 R 10 and ring B is a carbocyclic or heterocyclic ring; R 1 teeth

[0104] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R 3 are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF2; Y is O or S; Q is CH or N; R 6 is C 1~6 alkyl, optionally substituted with 1, 2 or 3 F, or OH, OC 1~6 Alkyl, N(C 1~6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl; R 7 is H, F, Cl, Br, or C 1~6 is alkyl, Each R 8 and R 12 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 Alkylene-heteroaryl or halogenated C 1~6 is an alkoxy; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; Each R 10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1~6 Alkyl, N(C 1~6 Alkyl)2, COOH, COC 1~6 Alkyl, COOC 1~6 Alkyl, CON 1-6 Alkyl, CON(C 1~6 alkyl) 2、 NHCOC 1~6alkyl, or heterocycle, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and COOH; W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~6 alkyl, alkylene-O-alkyl, or heterocyclyl; i and j are each independently 1, 2, or 3, provided that the sum of i+j is 2, 3, or 4.

[0105] In embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or deuterated form thereof:

[0106] [ka] During the ceremony, R 0 teeth

[0107] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1~6 alkyl), R A is H, C 1~6 Alkyl, C 1~6Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; R B is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; or R A and R B together form a heterocyclyl, L is an aryl, heterocycle, heteroaryl, or

[0108] [ka] and L independently represents 0 to 4 R 10 and Ring B is a carbocycle, a heterocycle (in embodiments, the heterocycle is not aromatic and contains 1-3 heteroatoms selected from N, S, and O. In embodiments, the heterocycle is a heteroaryl containing 1-3 heteroatoms selected from N, S, and O); R 1 teeth

[0109] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R 3 are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF2; Y is O or S; Q is CH or N; R 6 is C 1~6 alkyl, C 1~6 Alkyl is one, two or three of F, OH, OC 1~6 Alkyl, N(C 1~6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl; R 7 is H, F, Cl, Br, or C 1~6 is alkyl, R 8 and R 12 are independently H, OH, halogen, NH, COOH, unsubstituted C alkyl, halogen, hydroxyl-substituted C alkyl, unsubstituted C alkoxy or halogenated C alkoxy; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; Each R 10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2NH-C 1~6 Alkyl, N(C 1~6 Alkyl)2, COOH, COC 1~6 Alkyl, COOC 1~6 Alkyl, CON 1-6 Alkyl, CON(C 1~6 alkyl)2, NHCOC 1~6 alkyl, or heterocyclyl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and COOH; W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~3 -alkyl, -alkylene-O-alkyl, or heterocyclyl; i and j are each independently 1, 2, or 3, provided that the sum of i+j is 2, 3, or 4.

[0110] In embodiments, the present disclosure provides a compound of formula (II)

[0111] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R 0 teeth

[0112] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1~6 alkyl), R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; R B is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; or R A and R B together form a heterocyclyl, R 1 teeth

[0113] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R 3 are H, F, Cl, Br, CN, CF3, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring, X is O, S or CF2; Y is O or S; Q is CH or N; R 6 is C 1~6 alkyl, C 1~6 Alkyl is one, two or three of F, OH, OC 1~6 Alkyl, N(C 1~6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl; R 7 is H, F, Cl or CH3, R 8 and R 12 are independently H, OH, halogen, NH2, COOH, unsubstituted C1-C4 alkyl, halogen, hydroxyl substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy or halogenated C1-C6 alkoxy; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; R 10 is F, n is 0 or 1, W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~6 alkyl, CH3OCH2CH2-, oxetanyl, tetrahydrofuranyl, 4-tetrahydropyranyl or 3-tetrahydropyranyl; i and j are each independently 1, 2, or 3, provided that the sum of i+j is 2, 3, or 4.

[0114] In embodiments, the present disclosure provides a compound of formula (III)

[0115] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 0 teeth

[0116] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1~6 alkyl), R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; R B is C1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; or R A and R B together form a heterocyclyl, X is O, S or CF2; R 6 is C 1~6 alkyl, C 1~6 Alkyl is one, two or three of F, OH, OC 1~6 Alkyl, N(C 1~6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl; R 7 is H, F, Cl or CH3, R 8 and R 12 are independently H, OH, halogen, NH2, COOH, unsubstituted C1-C6 alkyl, halogen, hydroxyl-substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy or halogenated C1-C6 alkoxy; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; R 10 is F and n is 0 or 1.

[0117] In embodiments, the present disclosure provides a compound of formula (III-A)

[0118] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R 0 teeth

[0119] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1~6 alkyl), R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; R B is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; or R A and R B together form a heterocyclyl, X is O, S or CF2; R 6 is C 1~6 alkyl, C 1~6 Alkyl is one, two or three of F, OH, OC 1~6 Alkyl, N(C 1~6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl; R 7 is H, F, Cl or CH3, R 8 and R 12 are independently H, OH, halogen, NH2, COOH, unsubstituted C1-C4 alkyl, halogen, hydroxyl substituted C1-C4 alkyl, unsubstituted C1-C4 alkoxy or halogenated C1-C4 alkoxy; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; R 10 is F and n is 0 or 1.

[0120] In embodiments, the present disclosure provides a compound of formula (III-B)

[0121] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R 0 teeth

[0122] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1~6 alkyl), R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; R B is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; or R A and R B together form a heterocyclyl, X is O, S or CF2; R 6 is C 1~6 alkyl, C 1~6 Alkyl is one, two or three of F, OH, OC 1~6 Alkyl, N(C 1~6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl; R 7 is H, F, Cl or CH3, R 8 and R 12 are independently H, OH, halogen, NH2, COOH, unsubstituted C1-C4 alkyl, halogen, hydroxyl substituted C1-C4 alkyl, unsubstituted C1-C4 alkoxy or halogenated C1-C4 alkoxy; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; R 10 is F and n is 0 or 1.

[0123] In some embodiments, the compound of formula (III-B)

[0124] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0125] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X is O, S, CHF, or CF.

[0126] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X is O, S, or CF2.

[0127] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X is O.

[0128] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X is S.

[0129] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X is CF2.

[0130] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0131] [ka] is.

[0132] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0133] [ka] is.

[0134] In one embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0135] [ka] In a further embodiment, R 0 teeth

[0136] [ka] In still further embodiments, R 0 teeth

[0137] [ka] is.

[0138] In one embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0139] [ka] In a further embodiment, R 0 teeth

[0140] [ka] In still further embodiments, R 0 teeth

[0141] [ka] is.

[0142] In another embodiment of the compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0143] [ka] In a further embodiment, R 0 teeth

[0144] [ka] In still further embodiments, R 0 teeth

[0145] [ka] is.

[0146] In another embodiment of the compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0147] [ka] In a further embodiment, R 0 teeth

[0148] [ka] In still further embodiments, R 0 teeth

[0149] [ka] is.

[0150] In some embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0151] [ka] is.

[0152] In some embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0153] [ka] In some embodiments, X1 is O and X2 is NH. In some embodiments, R 8 OH, unsubstituted C 1~6 Alkoxy, or O-cycloalkyl.

[0154] In some embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0155] [ka] In some embodiments, X1 is O and X2 is NH. In some embodiments, X1 is CH2 and X2 is NH. In some embodiments, R 8 OH, unsubstituted C 1~6 Alkoxy, or O-cycloalkyl.

[0156] In some embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0157] [ka] In some embodiments, X1 is CH2 and X2 is NH. In some embodiments, R 8 OH, unsubstituted C 1~6 Alkoxy, or O-cycloalkyl.

[0158] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0teeth

[0159] [ka] is.

[0160] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0161] [ka] is.

[0162] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0163] [ka] is.

[0164] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0165] [ka] is.

[0166] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0167] [ka] is.

[0168] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0169] [ka] In an embodiment, X1 is O and X2 is NH.

[0170] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0171] [ka] In an embodiment, X1 is O and X2 is NH. In an embodiment, X1 is CH2 and X2 is NH.

[0172] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0173] [ka] In an embodiment, X1 is CH2 and X2 is NH.

[0174] In yet another embodiment of the compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0175] [ka] In one embodiment, R 0 teeth

[0176] [ka] In a further embodiment, R 0 teeth

[0177] [ka] In still further embodiments, R 0 teeth

[0178] [ka] is.

[0179] In yet another embodiment of the compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0180] [ka] In a further embodiment, R 0 teeth

[0181] [ka] In still further embodiments, R 0teeth

[0182] [ka] In another embodiment, R 0 teeth

[0183] [ka] In a further embodiment, R 0 teeth

[0184] [ka] is.

[0185] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, each R 8 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 Alkylene-heteroaryl, halogenated C 1~6 It is alkoxy, heteroaryl, or carbocyclyl.

[0186] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, each R 8 are independently H, OH, halogen, NH2, COOH, C1-6 alkyl, C1-6 alkyl-OH, C1-6 alkoxy, or halogenated C1-6 alkoxy.

[0187] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, each R 8 are independently H, OH, halogen, NH2, COOH, unsubstituted C1-6 alkyl, C1-6 alkyl-OH, unsubstituted C1-6 alkoxy, or halogenated C1-6 alkoxy.

[0188] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, each R 8 are independently OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, C 1~6 Alkylene-heteroaryl, halogenated C 1~6 Alkyl or halogenated C 1~6 It is an alkoxy.

[0189] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, each R 8 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, or halogenated C 1~6 Alkoxy with the proviso that one R 8 is not H.

[0190] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, each R 8 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C1~6 Alkoxy, O-cycloalkyl, cycloalkyl, C 1~6 Alkylene-heteroaryl, halogenated C 1~6 Alkyl or halogenated C 1~6 Alkoxy with the proviso that one R 8 is not H.

[0191] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, one R 8 OH, unsubstituted C 1~6 alkoxy, or O-cycloalkyl, and the other R 8 is the unsubstituted C 1~6 It is alkyl or cycloalkyl.

[0192] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, one R 8 is OH, and the other R 8 is the unsubstituted C 1~6 Alkyl, halogenated C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, or C 1~6 It is alkylene-heteroaryl.

[0193] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, each R 8 are independently OH, unsubstituted C 1~6 Alkoxy, or O-cycloalkyl.

[0194] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 8 are independently OH or CH3.

[0195] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 12 is H, OH, halogen, NH2, COOH, unsubstituted C1-4 alkyl, C1-4 alkyl-OH, unsubstituted C1-4 alkoxy, or halogenated C1-4 alkoxy.

[0196] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 12 is hydrogen.

[0197] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 8 is hydrogen, methoxy, ethoxy, or hydroxy.

[0198] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 8 is methoxy.

[0199] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 8 is OH.

[0200] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 8 is hydrogen.

[0201] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl.

[0202] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 13 are independently H, F, or C1-C6 alkyl.

[0203] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 13 is H.

[0204] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth,

[0205] [ka] is.

[0206] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0207] [ka] is.

[0208] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0209] [ka] is.

[0210] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0211] [ka] is.

[0212] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0213] [ka] is.

[0214] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0215] [ka] is.

[0216] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 In an embodiment, at least X1 is O, S, NH, N(C 1~6 alkyl).

[0217] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X1 and X2 are independently O, S, or NH, N(C 1~6 alkyl).

[0218] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X1 and X2 are independently O or NH.

[0219] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0220] [ka] is.

[0221] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 It is alkylene-heteroaryl, heteroaryl, or carbocyclyl.

[0222] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 It is alkylene-heteroaryl.

[0223] In one embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, RA is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; R B is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; or R A and R B together form a heterocyclyl.

[0224] In another embodiment of the compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R A is H or C 1~6 It is alkyl.

[0225] In yet another embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R A is H.

[0226] In yet another embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R A is C 1~6 It is alkyl.

[0227] In one embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R A is -CH3.

[0228] In one embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R A is butyl. In an embodiment, R A is isobutyl.

[0229] In one embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R A is isopropyl.

[0230] In one embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R A X3 and R B together form oxetanyl, thietanyl, tetrahydrofuranyl. In embodiments, R A X3 and R B taken together form oxetanyl. In embodiments, R A X3 and R B together form thietanyl. In an embodiment, R A X3 and R B together to form tetrahydrofuranyl.

[0231] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 0 teeth

[0232] [ka] R B is methyl, ethyl, isopropyl,

[0233] [ka] is.

[0234] In another embodiment of the compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is C 1~6 Alkyl, C1~6 Haloalkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-aryl, C 1~6 alkylene-heteroaryl, heteroaryl, or carbocyclyl; or R A and R B together form a heterocyclyl.

[0235] In another embodiment of the compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-aryl, C 1~6 It is alkylene-heteroaryl, heteroaryl, or carbocyclyl.

[0236] In another embodiment of the compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is C 1~6 Alkyl, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-aryl, C 1~6 It is alkylene-heteroaryl, heteroaryl, or carbocyclyl.

[0237] In another embodiment of the compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C1~6 It is alkylene-heteroaryl.

[0238] In another embodiment of the compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 It is alkylene-aryl.

[0239] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 It is alkylene-heteroaryl.

[0240] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is C 1~6 Alkyl, C 1~6 Alkylene-aryl, or -C 1~6 alkylene-5-6 membered heteroaryl.

[0241] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is C 1~6 It is alkyl.

[0242] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B CF 3 is.

[0243] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is isopropyl.

[0244] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is -CH=CH2.

[0245] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is CH2OH.

[0246] In embodiments of the compounds of Formula (I), (II), (III), (III-A), or (III-B), or pharmaceutically acceptable salts thereof, R B is CH2-CH=CH2.

[0247] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R B is n-propyl.

[0248] In embodiments of compounds of Formula (I), (II), (III), (III-A), or (III-B), R A and R B taken together form a heterocyclyl. In embodiments, the heterocyclyl is a 3- to 6-membered heterocyclyl. In embodiments, the heterocyclyl is oxetanyl, tetrahydrofuranyl, thietanyl, or tetrahydrothiophenyl.

[0249] In embodiments of compounds of Formula (I), (II), (III), (III-A), or (III-B), X3 is O, S, NH, N(C 1~6 alkyl), OCH2, CH2O, CH2S, or SCH2.

[0250] In embodiments of compounds of Formula (I), (II), (III), (III-A), or (III-B), X3 is O, S, NH, N(C 1~6 alkyl), OCH2, or SCH2.

[0251] In embodiments of the compounds of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X3 is O, S, NH, or N(C 1~6 alkyl).

[0252] In an embodiment of the compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X3 is O, S, NH.

[0253] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X 3 is O.

[0254] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L is aryl, heterocycle, heteroaryl, or

[0255] [ka] and L independently represents 0 to 4 R 10 and Ring B is a carbocycle, heterocycle, or heteroaryl.

[0256] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L is aryl, heterocycle, heteroaryl, or

[0257] [ka] and L independently represents 0 to 4 R 10 and Ring B is a carbocycle, a heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, or a heteroaryl containing 1 to 3 heteroatoms selected from N, S, and O.

[0258] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L is selected from aryl, heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, heteroaryl containing 1 to 3 heteroatoms selected from N, S, and O, or

[0259] [ka] and L independently represents 0 to 4 R 10 and Ring B is a carbocycle, a heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, or a heteroaryl containing 1 to 3 heteroatoms selected from N, S, and O.

[0260] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L is selected from 0 to 4 R 10 is an aryl substituted by

[0261] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L is selected from the group consisting of 0 R 10 is an aryl substituted by

[0262] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L is selected from the group consisting of one R 10 is an aryl substituted with

[0263] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L is selected from the group consisting of two R 10 In an embodiment of the compound of formula (I), L is aryl substituted with three R 10 Thus, it is a substituted aryl.

[0264] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L is selected from the group consisting of four R 10 is an aryl substituted with

[0265] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, L is phenyl optionally substituted with fluoro. In a further embodiment of the compound of Formula (I), L is phenyl and is substituted with fluoro.

[0266] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, -SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1~6 Alkyl, -N(C 1~4 Alkyl)2, -COOH, -COC 1~6 Alkyl, -COOC 1~6 Alkyl, -CON 1-6 Alkyl, -CON(C 1~6 alkyl)2, -NHCOC 1~6 alkyl, or heterocycle, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and —COOH.

[0267] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, -SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1~6Alkyl, -N(C 1~4 Alkyl)2, -COOH, -COC 1~6 Alkyl, -COOC 1~6 Alkyl, -CON 1-6 Alkyl, -CON(C 1~6 alkyl)2, -NHCOC 1~6 alkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1-3 substituents independently selected from halogen, cyano, hydroxyl, NH, and —COOH.

[0268] In embodiments of the compounds of Formula (I) or pharmaceutically acceptable salts thereof, R 10 are independently halogen, C 1~4 Alkyl, C 1~6 Alkoxy, -SC 1~6 Alkyl, cyano, hydroxy, NH2, -NH-C 1~6 Alkyl, -N(C 1~6 Alkyl)2, -COOH, -COC 1~6 Alkyl, -COOC 1~6 Alkyl, -CON 1~6 Alkyl, -CON(C 1~6 alkyl)2, or -NHCOC 1~6 alkyl, wherein each alkyl and alkoxy is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH2, and -COOH.

[0269] In embodiments of the compounds of Formula (I), (II), (III), (III-A) or (III-B), or pharmaceutically acceptable salts thereof, R 10 is a halogen.

[0270] In embodiments of the compounds of Formula (II), (III), (III-A) or (III-B), or pharmaceutically acceptable salts thereof, R 10 is fluoro.

[0271] In an embodiment of a compound of Formula (II), (III), or (III-A), or a pharmaceutically acceptable salt thereof, n is 0.

[0272] In an embodiment of a compound of Formula (II), (III), or (III-A), or a pharmaceutically acceptable salt thereof, n is 1.

[0273] In embodiments of the compound of Formula (II), (III), or (III-A), or a pharmaceutically acceptable salt thereof, n is 1 and R 10 The substituents are R on the phenyl ring. 1 It is in the ortho position relative to the substituent.

[0274] In embodiments of the compound of Formula (II), (III), or (III-A), or a pharmaceutically acceptable salt thereof, n is 1 and R 10 The substituents are R on the phenyl ring. 1 It is in the meta position relative to the substituent.

[0275] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0276] [ka] is.

[0277] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0278] [ka] is.

[0279] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0280] [ka] is.

[0281] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0282] [ka] is.

[0283] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0284] [ka] is.

[0285] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0286] [ka] is.

[0287] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0288] [ka] is.

[0289] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0290] [ka] is.

[0291] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0292] [ka] is.

[0293] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0294] [ka] is.

[0295] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0296] [ka] is.

[0297] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0298] [ka] is.

[0299] In embodiments of the compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof, R 1 or

[0300] [ka] In embodiments of the compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1

[0301] [ka] In embodiments of the compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1

[0302] [ka] is.

[0303] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0304] [ka] is.

[0305] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0306] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6It is alkyl.

[0307] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0308] [ka] and R 2 is H, F, Cl or C 1~6 It is alkyl.

[0309] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0310] [ka] and R 2 is H, F or C 1~6 It is alkyl.

[0311] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0312] [ka] and R 3 are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl.

[0313] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0314] [ka] and R 3 are H, F, Cl, Br, CN, CF3, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl.

[0315] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 3 are H, F, Cl, Br, CN, CF3, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring.

[0316] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 3 is H, F, Cl, CN or SO2C 1~6 It is alkyl.

[0317] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 3 is H, F or CN.

[0318] In an embodiment of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, Y is O, S, or CH2.

[0319] In an embodiment of the compounds of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, Y is O or S.

[0320] In an embodiment of the compounds of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, Q is CH or N.

[0321] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, W, X4, and Y2 are each independently selected from CH and N, provided that at most one of W, X4, and Y2 can be N.

[0322] In an embodiment of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, DE is N(H)—C(O), N(C 1~3 -alkyl)-C(O), CH2CH2, C(O)-O and CH2-O.

[0323] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, DE is N(H)-C(O), N(CH)-C(O), CHCH, C(O)-O, or CH-O.

[0324] In an embodiment of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, DE is CH2-O; In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 11 is H, C 1~3 It is alkyl, alkylene-O-alkyl, or heterocyclyl.

[0325] In embodiments of the compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof, R 11 is H, alkylene-O-alkyl, or heterocyclyl.

[0326] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 11 is H, CH3, CH3OCH2CH2 or heterocyclyl.

[0327] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 11 is H, CH3OCH2CH2, or heterocyclyl.

[0328] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 11 is H, alkylene-O-alkyl, or oxetanyl, tetrahydrofuranyl, 4-tetrahydropyranyl or 3-tetrahydropyranyl.

[0329] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 11 is H, C 1~3 -alkyl, CH3OCH2CH2, oxetanyl, tetrahydrofuranyl, 4-tetrahydropyranyl or 3-tetrahydropyranyl.

[0330] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 11 is H, CH3- or oxetanyl.

[0331] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 11 is CH3.

[0332] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, i and j are each independently 1, 2, or 3, with the proviso that the sum of i+j is 2, 3, or 4.

[0333] In an embodiment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 11is H, CH or oxetanyl, W is CH or N, X is CH or N, and Y is CH, provided that at most one of W, X, and Y can be N. DE is selected from N(CH)-C(O), CHCH, C(O)-O, and CH-O, i is 1 or 2, and j is 1 or 2, provided that the sum of i+j is 2, 3, or 4.

[0334] In embodiments of the compounds of Formula (I), (II), (III), (III-A), or (III-B), or pharmaceutically acceptable salts thereof, R 6 is C 1~6 alkyl, C 1~6 Alkyl is one, two, or three of F, OH, OC 1~6 Alkyl, N(C 1~6

[0023] In one embodiment, the cycloalkyl is cyclopropyl. In another embodiment, the heterocyclyl is tetrahydropyran.

[0335] In embodiments of the compounds of Formula (I), (II), (III), (III-A), or (III-B), or pharmaceutically acceptable salts thereof, R 6 is C 1~6 alkyl, C 1~6 The alkyl is optionally substituted with 1, 2, or 3 F.

[0336] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 6 is methyl or ethyl.

[0337] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 6 is CH2CH3 or CH3.

[0338] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 6 is CH2CH3.

[0339] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 6 is CH3.

[0340] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 7 is H, F, Cl, or CH3.

[0341] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 7 is H.

[0342] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X is O, S, or CF2.

[0343] In an embodiment of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, X is O.

[0344] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0345] [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 are H, F, Cl, Br, OSOC 1~3 Alkyl or C 1~3 alkyl, and R 3are hydrogen, F, Cl, Br, CN, CF3, SO2C 1~3 Alkyl, CONH2 or SO2NR 4 N 5 wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring.

[0346] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0347] [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 is H, F, Cl or C 1~3 alkyl, and R 3 is H, F, Cl, CN or SO2C 1~3 It is alkyl.

[0348] In embodiments of the compounds described herein or pharmaceutically acceptable salts thereof, R 1 teeth

[0349] [ka] and R 2 is H, F or C 1~3 alkyl, and R 3 is H, F or CN.

[0350] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0351] [ka] and X is O, S or CF2; Y is O or S; Q is CH or N; R 6 is one, two or three F, OH, OC 1~3 Alkyl, N(C 1~3 C optionally substituted with alkyl, cycloalkyl, or heterocyclyl 1~3 is alkyl, R 7 is H, F, Cl or CH3.

[0352] In an embodiment of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 1 teeth

[0353] [ka] X is O, S or CF2, Y is O or S, and R 6 is C 1~3 alkyl, C 1~3 Alkyl is one, two or three of F, OH, OC 1~3 Alkyl, N(C 1~3 alkyl), cyclopropyl, or tetrahydropyran; 7 is hydrogen, F, Cl or CH3.

[0354] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 1 teeth

[0355] [ka] and X is O, S or CF2; R 6 is C 1~3 alkyl, C 1~3 alkyl is optionally substituted by 1, 2 or 3 F; R 7is hydrogen, F, Cl or CH3.

[0356] In embodiments of a compound of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable salt thereof, R 1 teeth

[0357] [ka] and X is O, R 6 is C 1~3 alkyl, C 1~3 alkyl is optionally substituted by 1, 2 or 3 F; R 7 is hydrogen.

[0358] Another embodiment is a product obtainable by any of the processes or examples disclosed herein.

[0359] In embodiments, provided herein are compounds of Formula (I), (II) or (III), (III-A), or (III-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0360] In embodiments, provided herein are pharmaceutically acceptable salts of compounds of Formula (I), (II) or (III), (III-A), or (III-B). Further embodiments of the present disclosure relate to deuterated compounds of Formula (I), (II) or (III), (III-A), or (III-B), or pharmaceutically acceptable salts thereof.

[0361] In embodiments, provided herein are compounds of Table 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0362] In embodiments, provided herein are compounds of Table 1, or pharmaceutically acceptable salts thereof.

[0363] In one embodiment, provided herein are compounds set forth in Table 1.

[0364] In some embodiments, provided herein are pharmaceutically acceptable salts of the compounds of Table 1.

[0365] [Table 1-1]

[0366] [Table 1-2]

[0367] [Table 1-3]

[0368] [Table 1-4]

[0369] [Table 1-5]

[0370] [Table 1-6]

[0371] [Table 1-7]

[0372] [Table 1-8]

[0373] [Table 1-9]

[0374] Table 1-10

[0375] Table 1-11

[0376] Table 1-12

[0377] Table 1-13

[0378] Table 1-14

[0379] Table 1-15

[0380] Table 1-16

[0381] Table 1-17

[0382] Table 1-18

[0383] Table 1-19

[0384] [Table 1-20]

[0385] [Table 1-21]

[0386] [Table 1-22]

[0387] [Table 1-23]

[0388] [Table 1-24]

[0389] [Table 1-25]

[0390] composition The compounds of formula (I), (II) or (III), (III-A), (III-B) or Table 1, or pharmaceutically acceptable salts thereof, or deuterated versions of the foregoing, may be used on their own, but will generally be administered in the form of a pharmaceutical composition in which a compound / salt of formula (I), (II) or (III), (III-A), (III-B) or Table 1 (active ingredient) is associated with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional procedures for the selection and preparation of appropriate pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", MEAulton, Churchill Livingstone, 2nd Ed. 2002.

[0391] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (II) or (III), (III-A), (III-B) or Table 1, as defined above, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0392] The present disclosure further provides a process for the preparation of a pharmaceutical composition of the present disclosure, which process comprises mixing a compound of Formula (I), (II) or (III), (III-A), (III-B) or Table 1 as defined above, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0393] Pharmaceutical compositions may be administered topically (e.g., to the skin or lungs and / or airways), for example, in the form of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, such as those in the inhaler known as Turbuhaler®, or systemically by oral administration, for example, in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration (including intravenous, subcutaneous, intramuscular, intravascular or infusion) in the form of a sterile solution, suspension or emulsion for injection, or by rectal administration in the form of a suppository.

[0394] For oral administration, the compound of the present invention can be mixed with adjuvants, diluents or carriers, such as lactose, saccharose, sorbitol, mannitol; starches, such as potato starch, corn starch or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; disintegrants, such as cellulose derivatives, and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets.If coated tablets are required, the core prepared as described above can be coated with a suitable polymer dissolved or dispersed in water or a readily volatile organic solvent.Alternatively, tablets can be coated with a concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talc and titanium dioxide.

[0395] For the preparation of soft gelatin capsules, the compounds of the present disclosure can be mixed with, for example, vegetable oil or polyethylene glycol.Hard gelatin capsules can contain granules of the compounds using pharmaceutical excipients such as those mentioned above for tablets.In addition, liquid or semi-solid formulations of the compounds of the present disclosure can be filled into hard gelatin capsules.

[0396] Liquid preparations for oral administration can be in the form of syrup, solution or suspension.Solution may contain, for example, the compound of the present disclosure, and the remainder is a mixture of sugar, ethanol, water, glycerol and propylene glycol.Optionally, such liquid preparations may contain coloring agents, flavoring agents, saccharin and / or carboxymethylcellulose as thickeners.In addition, when preparing preparations for oral administration, other excipients known to those skilled in the art may be used.

[0397] therapeutic use In embodiments, the compounds of Formula (I), (II) or (III), (III-A), (III-B) or Table 1, and their pharmaceutically acceptable salts, are DPP1 inhibitors and may therefore be used in any disease area in which DPP1 plays a role. Accordingly, in one aspect of the present disclosure, a method of treatment is provided. The method of treatment, in one embodiment, comprises administering to a subject in need of treatment, an effective amount of a compound of Formula (I), (II) or (III), (III-A), (III-B) or Table 1, or a composition comprising a pharmaceutically acceptable salt of (I), (II) or (III), (III-A), (III-B) or Table 1. In embodiments, the composition is administered to the patient for an administration period.

[0398] In embodiments, the compounds or compositions of the present disclosure are used to treat obstructive airway diseases, chronic rhinosinusitis (CRS), hidradenitis suppurativa (HS), cancer (e.g., cancer metastasis), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpasture's disease), rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, systemic sclerosis, inflammatory bowel disease, and the like. and methods for treating IBD (e.g., ulcerative colitis, Crohn's disease), diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcer, Duchenne muscular dystrophy, bronchiolitis obliterans, long-term coronavirus infection) - prophylaxis of ILD, atopic dermatitis, pyoderma gangrenosum, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatosis, uveitis, Behcet's disease, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, and ventilator-induced lung injury.

[0399] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating an obstructive airway disease. In one embodiment, the obstructive airway disease is selected from the group consisting of asthma (e.g., bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin- and NSAID-induced and dust-induced asthma, both intermittent and persistent, and all severities), airway hyperresponsiveness, chronic obstructive pulmonary disease (COPD), bronchitis (e.g., infectious bronchitis, eosinophilic bronchitis), emphysema, cystic fibrosis (CF), bronchiectasis (e.g., non-CF bronchiectasis (NCFBE) and CF-associated bronchiectasis), cystic fibrosis; sarcoidosis; alpha-1 antitrypsin (alpha-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, hypersensitivity pneumonitis, interstitial lung disease, pulmonary fibrosis (including idiopathic pulmonary fibrosis, fibrosing alveolitis of unknown cause, idiopathic interstitial pneumonia, fibrosis associated with antitumor therapy, and chronic infections including tuberculosis, aspergillosis, and other fungal infections), complications of lung transplantation, vasculitic and thrombotic disorders of the pulmonary vasculature, pulmonary hypertension (e.g., pulmonary arterial hypertension), antitussive activity, including the treatment of chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute and chronic rhinitis, including drug-induced rhinitis, and vasomotor rhinitis; neurogenic rhinitis (hay fever), perennial and seasonal allergic rhinitis, including nasal polyposis; acute viral infections, including the common cold, and respiratory viruses (e.g., respiratory syncytial virus, influenza, coronaviruses (including SARS), and adenovirus), acute lung injury, acute respiratory distress syndrome These include infections due to acute respiratory distress syndrome (ARDS), and exacerbations of the aforementioned airway disease states.

[0400] Cystic fibrosis (CF) is caused by abnormalities in the CF transmembrane conductance regulator protein, which leads to chronic lung infections (particularly by Pseudomonas aeruginosa) and excessive inflammation, resulting in bronchiectasis, decreased lung function, respiratory failure, and poor quality of life. The inflammatory process is governed by neutrophils, which produce NE, as well as other destructive NSPs, including CatG and PR3, which act directly on extracellular matrix proteins and are involved in the host response to inflammation and infection (Dittrich et al., Eur Respir J. 2018;51(3)). The methods provided herein employ reversible inhibitors of DPP1. Without being bound by theory, it is believed that compounds of Formula (I), (II), or (III) administered via the methods provided herein have beneficial effects through inhibiting NSP activation and reducing inflammation, which in turn leads to reduced pulmonary exacerbations, reduced exacerbation rates, and / or improved pulmonary function (e.g., forced expiratory volume in 1 second (FEV1)) in CF patients.

[0401] In one embodiment, a method for treating CF is provided, the method comprising administering to a CF patient in need of treatment a composition comprising an effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof.

[0402] In one method of treating CF, a composition comprising an effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, is administered to a CF patient in need of treatment for a dosing period. The method includes improving the patient's pulmonary function during the dosing period compared to the patient's pulmonary function prior to the dosing period. In one embodiment, the improvement in pulmonary function is measured by spirometry.

[0403] In one embodiment, improving the patient's pulmonary function includes increasing the patient's forced expiratory volume in one second (FEV1), increasing the patient's forced vital capacity (FVC), increasing the patient's peak expiratory flow rate (PEFR), or increasing the patient's forced expiratory flow (FEF) by 25% to 75% of the patient's FVC compared to the respective values ​​prior to the administration period. (25~75%) ) or about 5% of the respective values. In one embodiment, the increase is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%. In one embodiment, the increase is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In yet another embodiment, the increase is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20%. In yet another embodiment, the increase is about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.

[0404] In one embodiment of the methods provided herein, a composition comprising an effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, is administered to a patient with bronchiectasis in need of treatment for an administration period. Bronchiectasis is considered a pathological endpoint resulting from many disease processes and is a persistent or progressive condition characterized by dilated, thick-walled bronchi. Symptoms range from intermittent episodes of sputum and infection localized to affected lung areas to persistent daily expectoration of often copious amounts of purulent sputum. Bronchiectasis may be associated with other nonspecific respiratory symptoms. Without wishing to be bound by theory, the pathological process underlying bronchiectasis has been reported as damage to the airways resulting from an event or series of events in which inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V.65(Suppl 1), incorporated herein by reference in its entirety for all purposes).

[0405] Bronchiectasis is considered a pathological endpoint resulting from many disease processes and is a persistent or progressive condition characterized by dilated, thick-walled bronchi. Symptoms range from intermittent episodes of sputum and infection localized to affected lung areas to persistent daily expectoration, often of large amounts of purulent sputum. Bronchiectasis may be associated with other nonspecific respiratory symptoms. Without wishing to be bound by theory, the pathological process underlying bronchiectasis has been reported as damage to the airways resulting from an event or series of events in which inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, Vol. 65 (Suppl 1), incorporated herein by reference in its entirety for all purposes).

[0406] The methods provided herein use reversible inhibitors of DPP1. Without wishing to be bound by theory, it is believed that the compounds of Formula (I), (II), or (III) administered via the methods provided herein have beneficial effects through reducing inflammation and mucus hypersecretion, which in some embodiments results in reduced pulmonary exacerbations, reduced pulmonary exacerbation rates, and / or improved lung function (cough, sputum production, and forced expiratory volume in 1 second (FEV1)) in patients with bronchiectasis. Without wishing to be bound by theory, it is believed that the methods provided herein alter the progression of bronchiectasis by reducing the rate of decline in lung function or accelerated destruction of lung tissue.

[0407] In one embodiment, the bronchiectasis is non-CF bronchiectasis.

[0408] In one embodiment, the method for treating bronchiectasis comprises improving the patient's pulmonary function during the administration period compared to the patient's pulmonary function before the administration period.

[0409] In one embodiment, the pulmonary exacerbation is characterized by three or more of the following symptoms exhibited by the patient for at least 48 hours: (1) increased cough, (2) increased sputum volume or change in sputum consistency, (3) increased sputum purulence, (4) increased shortness of breath and / or decreased exercise tolerance, (5) fatigue and / or malaise, and (6) hemoptysis. In a further embodiment, the three or more symptoms result in a physician's decision to prescribe an antibiotic to the symptomatic patient.

[0410] In one embodiment of the method for treating bronchiectasis, the method comprises reducing the rate of pulmonary exacerbations in the subject compared to the rate of pulmonary exacerbations experienced by the subject prior to the administration period of the composition, or compared to a control subject with bronchiectasis who is not subjected to the treatment method. In a further embodiment, the bronchiectasis is non-CF bronchiectasis.

[0411] In another aspect, a method for treating chronic rhinosinusitis (CRS) in a subject in need thereof is provided. In one embodiment, the method comprises administering to the subject for a dosing period a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof.

[0412] The chronic sinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP) or chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, the chronic sinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP). In some embodiments, the chronic sinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, the chronic sinusitis is refractory chronic rhinosinusitis. In some embodiments, the refractory chronic sinusitis is refractory chronic rhinosinusitis without nasal polyps (CRSsNP). In some embodiments, the refractory chronic sinusitis is refractory chronic rhinosinusitis with nasal polyps (CRSwNP).

[0413] In some embodiments, the subject exhibits one or more symptoms of CRS. In some embodiments, the one or more symptoms of CRS are (a) nasal congestion, (b) nasal obstruction, (c) nasal discharge, (d) postnasal drip, (e) facial pressure, (f) facial pain, (g) facial fullness, (h) reduced odor, (i) depression, (j) mucosal edema, (k) mucopurulent secretions, (l) obstruction of the middle nasal meatus, (m) mucosal changes in the oral complex and sinuses, (n) rhinorrhea, or (o) any combination thereof. In some embodiments, the obstruction of the middle nasal meatus is mucosal obstruction, edematous obstruction, or a combination thereof.

[0414] In some embodiments, administration of the pharmaceutical composition reduces, decreases the severity of, delays the onset of, or eliminates one or more symptoms of CRS. In some embodiments, the one or more symptoms of CRS are (a) nasal congestion, (b) nasal obstruction, (c) runny nose, (d) postnasal drip, (e) facial pressure, (f) facial pain, (g) facial fullness, (h) reduced odor, (i) depression, (j) mucosal edema, (k) mucopurulent secretions, (l) obstruction of the middle nasal meatus, (m) mucosal changes in the oral cavity complex and sinuses, (n) rhinorrhea, (o), or any combination thereof. In some embodiments, administration of the pharmaceutical composition enhances sinus drainage.

[0415] In some embodiments, the method includes reducing a composite severity score of one or more symptoms of CRS. As used herein, a "composite severity score" is a quantitative measure of all symptoms of CRS experienced by a subject. In some embodiments, the composite severity score is the sum of all daily symptoms experienced by a subject. In some embodiments, the composite severity score is reduced during or after an administration period compared to the composite severity score measured before the administration period. In some embodiments, the one or more symptoms of CRS experienced by a subject can be any symptom described herein or known in the art to be associated with CRS. In some embodiments, the one or more symptoms of CRS are nasal congestion, reduced odor, rhinorrhea, or any combination thereof. In some embodiments, the rhinorrhea is anterior rhinorrhea. In some embodiments, the rhinorrhea is posterior rhinorrhea.

[0416] In some embodiments, the method includes reducing the subject's Sino-Nasal Outcome Test-22 (SNOT-22) score during or after the administration period, compared to the subject's SNOT-22 score before the administration period. As used herein, "SNOT-22" is a patient-reported outcome measure developed for use in CRS with or without nasal polyps, and includes 22 individual questions. The questions cover a wide range of health and health-related quality of life issues, including physical problems, functional limitations, and emotional consequences. The theoretical range of SNOT-22 scores is 0 to 110, with lower scores indicating better health-related quality of life. Further details of SNOT-22 are provided in Hopkins, et al., Clin. Otolaryngol. 2009, 34, 447-454, and Kennedy, et al., Ann Allergy Asthma Immunol. 2013 October;111(4):246-251, the contents of which are incorporated herein by reference in their entireties.

[0417] Hidradenitis suppurativa (HS) is a chronic, recurring inflammatory disorder. Symptoms include skin lesions, often associated with hair follicles, which may be accompanied by pain, inflammation, and / or swelling. If the skin lesions heal, they may recur, potentially resulting in subcutaneous tunnels and progressive scarring. Because HS is a chronic condition, it can persist for many years and worsen over time, significantly impacting quality of life and psychological and emotional well-being. In fact, HS patients have increased rates of anxiety and depression, with a suicide risk 2.5 times higher than that of the general population.

[0418] Patients with HS are classified as having mild (Stage I), moderate (Stage II), or severe (Stage III) disease, depending on the severity of the disease, called the Hurley stage. Although more than 200,000 cases of HS are diagnosed annually in the United States, the disease can be difficult to diagnose and requires specialized care. HS can be mistaken for infection, ingrown hairs, or other conditions. Furthermore, current treatment options are limited and lack effectiveness.

[0419] In one aspect, a method of treating HS in a subject in need thereof is provided. In one embodiment, the method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for an administration period. In a further embodiment, the method of treating HS comprises reducing neutrophilic inflammation in the subject.

[0420] In one embodiment, the HS is Hurley Stage I HS, Hurley Stage II HS, or Hurley Stage III HS. In some embodiments, the HS is Hurley Stage I HS. In some embodiments, the HS is Hurley Stage II HS. In some embodiments, the HS is Hurley Stage III HS.

[0421] The present disclosure provides a method for treating cancer in a subject in need of cancer treatment, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein. The present disclosure provides a method for treating cancer-induced pain in a subject with cancer, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein for an administration period. In some embodiments, the cancer-induced pain is cancer-induced bone pain. The present disclosure also provides a method for treating cancer-induced bone pain in a subject with cancer, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein for an administration period.

[0422] In some embodiments, the cancer comprises a primary solid tumor, hi some embodiments, the cancer is bladder cancer, lung cancer, brain cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, liver cancer, hepatocellular carcinoma, renal cancer, gastric cancer, skin cancer, fibroid cancer, lymphoma, virally induced cancer, oropharyngeal cancer, testicular cancer, thymic cancer, thyroid cancer, melanoma, or bone cancer.

[0423] In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is fibroid cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is virally induced cancer. In some embodiments, the cancer is oropharyngeal cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is thymic carcinoma. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is bone cancer. In some embodiments, the fibroid cancer is leiomyosarcoma.

[0424] In some embodiments, breast cancer comprises ductal carcinoma, lobular carcinoma, medullary carcinoma, colloid carcinoma, tubular carcinoma, or inflammatory breast cancer. In some embodiments, breast cancer comprises ductal carcinoma. In some embodiments, breast cancer comprises lobular carcinoma. In some embodiments, breast cancer comprises medullary carcinoma. In some embodiments, breast cancer comprises colloid carcinoma. In some embodiments, breast cancer comprises tubular carcinoma. In some embodiments, breast cancer comprises inflammatory breast cancer.

[0425] In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the breast cancer does not respond to hormone therapy or therapeutic agents that target the HER2 protein receptor.

[0426] In some embodiments, the lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, natural killer cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, or Kaposi's sarcoma. In some embodiments, the lymphoma is Hodgkin's lymphoma. In some embodiments, the lymphoma is non-Hodgkin's lymphoma. In some embodiments, the lymphoma is diffuse large B-cell lymphoma. In some embodiments, the lymphoma is B-cell immunoblastic lymphoma. In some embodiments, the lymphoma is natural killer cell lymphoma. In some embodiments, the lymphoma is T-cell lymphoma. In some embodiments, the lymphoma is Burkitt's lymphoma. In some embodiments, the lymphoma is Kaposi's sarcoma.

[0427] In some embodiments, the brain cancer is an astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, or medulloblastoma. In some embodiments, the brain cancer is an astrocytoma. In some embodiments, the brain cancer is an anaplastic astrocytoma. In some embodiments, the brain cancer is glioblastoma multiforme. In some embodiments, the brain cancer is an oligodendroglioma. In some embodiments, the brain cancer is an ependymoma. In some embodiments, the brain cancer is a meningioma. In some embodiments, the brain cancer is a schwannoma. In some embodiments, the brain cancer is a medulloblastoma.

[0428] In some embodiments, the cancer is a liquid tumor. In some embodiments, the liquid tumor is acute myeloid leukemia (AML), acute lymphoblastic leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myeloproliferative disorder, natural killer cell leukemia, blastic plasmacytoid dendritic cell neoplasm, chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), or myelodysplastic syndrome (MDS). In some embodiments, the liquid tumor is acute myeloid leukemia (AML). In some embodiments, the liquid tumor is acute lymphoblastic leukemia. In some embodiments, the liquid tumor is acute lymphocytic leukemia. In some embodiments, the liquid tumor is acute promyelocytic leukemia. In some embodiments, the liquid tumor is chronic myeloid leukemia. In some embodiments, the liquid tumor is hairy cell leukemia. In some embodiments, the liquid tumor is a myeloproliferative disorder. In some embodiments, the liquid tumor is natural killer cell leukemia. In some embodiments, the liquid tumor is blastic plasmacytoid dendritic cell neoplasm. In some embodiments, the liquid tumor is chronic myeloid leukemia (CML). In some embodiments, the liquid tumor is mastocytosis. In some embodiments, the liquid tumor is chronic lymphocytic leukemia (CLL). In some embodiments, the liquid tumor is multiple myeloma (MM). In some embodiments, the liquid tumor is myelodysplastic syndrome (MDS).

[0429] In some embodiments, the cancer is a pediatric cancer. In some embodiments, the pediatric cancer is neuroblastoma, Wilms' tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma, or Ewing's sarcoma. In some embodiments, the pediatric cancer is neuroblastoma. In some embodiments, the pediatric cancer is Wilms' tumor. In some embodiments, the pediatric cancer is rhabdomyosarcoma. In some embodiments, the pediatric cancer is retinoblastoma. In some embodiments, the pediatric cancer is osteosarcoma. In some embodiments, the pediatric cancer is Ewing's sarcoma.

[0430] In some embodiments, the cancer is metastatic cancer. In some embodiments, the subject is at risk of developing metastatic cancer. In some embodiments, the metastatic cancer comprises breast cancer metastasis to the brain, bone, pancreas, lymph nodes, and / or liver. In some embodiments, the metastatic cancer comprises bone cancer metastasis to the lung. In some embodiments, the metastatic cancer comprises colorectal cancer metastasis to the peritoneum, pancreas, stomach, lung, liver, kidney, and / or spleen. In some embodiments, the metastatic cancer comprises gastric cancer metastasis to the mesentery, spleen, pancreas, lung, liver, adrenal glands, and / or ovaries. In some embodiments, the metastatic cancer comprises leukemia metastasis to the lymph nodes, lung, liver, hind limb, brain, kidney, and / or spleen. In some embodiments, the metastatic cancer comprises liver cancer metastasis to the intestine, spleen, pancreas, stomach, lung, and / or kidney. In some embodiments, the metastatic cancer comprises lymphoma metastasis to the kidney, ovary, liver, bladder, and / or spleen.

[0431] In some embodiments, the metastatic cancer comprises hematopoietic cancer metastasis to the intestine, lung, liver, spleen, kidney, and / or stomach. In some embodiments, the metastatic cancer comprises melanoma metastasis to the lymph nodes and / or lung. In some embodiments, the metastatic cancer comprises pancreatic cancer metastasis to the mesentery, ovary, kidney, spleen, lymph nodes, stomach, and / or liver. In some embodiments, the metastatic cancer comprises prostate cancer metastasis to the lung, pancreas, kidney, spleen, intestine, liver, bone, and / or lymph nodes. In some embodiments, the metastatic cancer comprises ovarian cancer metastasis to the diaphragm, liver, intestine, stomach, lung, pancreas, spleen, kidney, lymph nodes, and / or uterus. In some embodiments, the metastatic cancer comprises myeloma metastasis to the bone.

[0432] In some embodiments, the metastatic cancer comprises lung cancer metastasis to bone, brain, lymph nodes, liver, ovaries, and / or intestines. In some embodiments, the metastatic cancer comprises kidney cancer metastasis to liver, lung, pancreas, stomach, brain, and / or spleen. In some embodiments, the metastatic cancer comprises bladder cancer metastasis to bone, liver, and / or lung. In some embodiments, the metastatic cancer comprises thyroid cancer metastasis to bone, liver, and / or lung.

[0433] In some embodiments, the methods disclosed herein include treating cancer-induced bone pain (CIBP) in a subject with cancer metastasis to bone. In some embodiments, the subject has prostate cancer, breast cancer, lung cancer, or myeloma metastasis to bone. In some embodiments, the subject is identified as having bone metastasis by the use of any one of the following methods: plain film radiography, computed tomography, technetium-99m bone scan, magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, fluorine positron emission tomography, and / or choline positron emission tomography, but is not yet experiencing cancer-induced bone pain. In some embodiments, the subject is suffering from cancer-induced bone pain indicative of metastasis of a previously treated or untreated primary tumor to bone. In some embodiments, the cancer has metastasized to the vertebrae, pelvis, long bones, or ribs.

[0434] In some embodiments, administration of the composition reduces the severity of the cancer, delays the onset of the cancer, or eliminates a symptom of the cancer. In some embodiments, the symptom of the cancer is cancer-induced bone pain (CIBP). In some embodiments, the CIBP is neuropathic pain. In some embodiments, the CIBP is inflammatory pain. In some embodiments, the CIBP is spontaneous pain. In some embodiments, the symptom of the cancer is nociceptive hypersensitivity. In some embodiments, the symptom of the cancer is allodynia. In some embodiments, the allodynia is tactile allodynia. In some embodiments, the tactile allodynia is static mechanical allodynia. In some embodiments, the tactile allodynia is dynamic mechanical allodynia. In some embodiments, the subject has bone cancer or metastases to bone.

[0435] In yet another embodiment of the present disclosure, there is provided a method for treating lupus nephritis (LN) in a subject in need thereof, the method comprising administering to the subject for a dosing period a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

[0436] Rheumatoid arthritis (RA) is characterized by inflammation and thickening of the joint capsule, along with effects on the underlying bone and cartilage. Currently, the cause of RA is unknown, and no satisfactory treatment for RA is available. While several therapeutic agents, such as disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs), have been developed and utilized to alleviate the pain and inflammation associated with the disease, they often result in intolerable side effects. To address this and other needs, in one embodiment, the present disclosure provides a method for treating RA using a reversible inhibitor of DPP1 of Formula (I), (II), or (III). In one embodiment, a method of treating RA in a subject in need thereof is provided, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for a dosing period. In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0437] Inflammatory bowel disease (IBD) is a group of inflammatory conditions that affect the colon and small intestine. The most common IBDs are Crohn's disease and ulcerative colitis. In one embodiment, the present disclosure addresses the need for new IBD therapies. Specifically, in one embodiment, a method is provided for treating inflammatory bowel disease (IBD) in a subject in need thereof. The method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for an administration period.

[0438] In a further embodiment, the IBD is Crohn's disease or ulcerative colitis. In yet a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0439] In any case, the length of the administration period will depend on the nature and severity of the condition being treated and / or prevented and can be determined by a physician, hi one embodiment, the administration period begins around the time of diagnosis of the condition / disease and continues for the life of the patient.

[0440] Embodiment 1 Embodiment 1. Compound of Formula (I)

[0441] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R 0 teeth

[0442] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1~6 alkyl), R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; R B is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 alkylene-heteroaryl; or R A and R B together form a heterocyclyl, L is an aryl, heterocycle, heteroaryl, or

[0443] [ka] and L is independently 0 to 4 R 10 and ring B is a carbocyclic or heterocyclic ring; R 1 teeth

[0444] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R 3 are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF2; Y is O or S; Q is CH or N; R 6 is C 1~6 alkyl, C 1~6 Alkyl is optionally substituted with 1, 2 or 3 F, or OH, OC 1~6 Alkyl, N(C 1~6 optionally substituted with one substituent selected from alkyl, cycloalkyl, or heterocyclyl; R 7 is H, F, Cl, Br, or C 1~6 is alkyl, R 8 and R 12 are independently H, OH, halogen, NH2, COOH, unsubstituted C1~6 Alkyl, C 1~6 Alkyl-OH, unsubstituted C 1~6 Alkoxy or halogenated C 1~6 is an alkoxy; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; Each R 10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1~6 Alkyl, N(C 1~6 Alkyl)2, COOH, COC 1~6 Alkyl, COOC 1~6 Alkyl, CON 1-6 Alkyl, CON(C 1~6 alkyl) 2、 NHCOC 1~6 alkyl, or heterocycle, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and COOH; W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~6 alkyl, alkylene-O-alkyl, or heterocyclyl; A compound of formula (I) or a pharmaceutically acceptable salt or deuterated form thereof, wherein i and j are each independently 1, 2 or 3, with the proviso that the sum of i+j is 2, 3 or 4.

[0445] Embodiment 2. The compound is a compound of formula (II)

[0446] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0 or 1; and R 10 is F.

[0447] Embodiment 3. R 1 teeth

[0448] [ka] and X is O, S or CF2; Y is O or S; Q is CH or N; R 6 is C 1~3 alkyl, C 1~3 Alkyl is one, two or three of F, OH, OC1-3 alkyl, N(C 1~3 optionally substituted by alkyl), cyclopropyl, or tetrahydropyran; R 7 is H, F, Cl, or CH3, or a pharmaceutically acceptable salt or deuterated form thereof.

[0449] Embodiment 4. R 1 teeth

[0450] [ka] and X is O, S or CF2; Y is O or S; R 6 is C 1~3 alkyl, C 1~3 Alkyl is one, two or three of F, OH, OC 1~3Alkyl, N(C 1~3 optionally substituted by alkyl), cyclopropyl, or tetrahydropyran; R 7 is H, F, Cl, or CH3, or a pharmaceutically acceptable salt or deuterated form thereof.

[0451] Embodiment 5.R 1 but

[0452] [ka] 3. The compound of embodiment 1 or 2, wherein:

[0453] Embodiment 6. X is O and R 6 is C 1~3 alkyl, and R 7 is H, or a pharmaceutically acceptable salt or deuterated form thereof.

[0454] Embodiment 7. R 1 teeth

[0455] [ka] and X is O, R 6 is C 1~3 alkyl, C 1~3 alkyl is optionally substituted by 1, 2 or 3 F; R 7 is H, or a pharmaceutically acceptable salt or deuterated form thereof.

[0456] Embodiment 8. R 1 teeth

[0457] [ka] and X is O, R 6 is C 1~3 is alkyl, R 7 is H, or a pharmaceutically acceptable salt or deuterated form thereof.

[0458] Embodiment 9.R 1 but

[0459] [ka] 3. The compound of embodiment 1 or 2, wherein:

[0460] Embodiment 10.R 1 but

[0461] [ka] 3. The compound of embodiment 1 or 2, wherein:

[0462] Embodiment 11.R 1 but

[0463] [ka] 3. The compound of embodiment 1 or 2, wherein:

[0464] Embodiment 12.R 1 but

[0465] [ka] 3. The compound of embodiment 1 or 2, wherein:

[0466] Embodiment 13.R 6 The compound of any one of embodiments 3-12, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

[0467] Embodiment 14.R 6 The compound of any one of embodiments 3-12, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is ethyl.

[0468] Embodiment 15.R 6 The compound of any one of embodiments 3-12, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is propyl.

[0469] Embodiment 16.R 1 but

[0470] [ka] 3. The compound of embodiment 1 or 2, wherein:

[0471] Embodiment 17.R 1 but

[0472] [ka] 3. The compound of embodiment 1 or 2, wherein:

[0473] Embodiment 18.R 1 but

[0474] [ka] 3. The compound of embodiment 1 or 2, wherein:

[0475] Embodiment 19. The compound is a compound of formula (III)

[0476] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0477] Embodiment 20. The compound is a compound of formula (III-A)

[0478] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0479] Embodiment 21. The compound is a compound of formula (III-B)

[0480] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 10 is —H or —F.

[0481] Embodiment 22. A compound according to any one of embodiments 1-2 and 16-21, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is O.

[0482] Embodiment 23.R 0 but

[0483] [ka] A compound according to any one of embodiments 1 to 22, or a pharmaceutically acceptable salt or deuterated form thereof.

[0484] Embodiment 24.R 0 but

[0485] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0486] Embodiment 25.R 0 but

[0487] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0488] Embodiment 26.R 0 but

[0489] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0490] Embodiment 27.R 0 but

[0491] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0492] Embodiment 28.R 8The compound of any one of embodiments 1-27, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methoxy.

[0493] Embodiment 29.R 8 The compound of any one of embodiments 1-27, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is ethoxy.

[0494] Embodiment 30.R 8 The compound of any one of embodiments 1-27, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is OH.

[0495] Embodiment 31.R 0 but,

[0496] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0497] Embodiment 32.R 0 but

[0498] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0499] Embodiment 33.R 0 but

[0500] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0501] Embodiment 34.R 0 but

[0502] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0503] Embodiment 35.R 0 but

[0504] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0505] Embodiment 36.R 0 but

[0506] [ka] 23. The compound of any one of embodiments 1-22, wherein:

[0507] Embodiment 37.R 0 but

[0508] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0509] Embodiment 38.R A But H or C 1~6 The compound of any one of embodiments 1-22 and 36-37, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R is alkyl.

[0510] Embodiment 39.R Ais H, or a pharmaceutically acceptable salt or deuterated form thereof.

[0511] Embodiment 40.R A The compound of embodiment 38, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

[0512] Embodiment 41.R B But C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 The compound of any one of embodiments 1-22 and 36-40, or a pharmaceutically acceptable salt or deuterated form thereof, which is alkylene-heteroaryl.

[0513] Embodiment 42.R B But C 1~6 Alkyl, C 1~6 Alkylene-aryl or -C 1~6 The compound of embodiment 41, or a pharmaceutically acceptable salt or deuterated form thereof, wherein:

[0514] Embodiment 43.R 0 but

[0515] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0516] Embodiment 44.R 0 but

[0517] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0518] Embodiment 45.R 0 but

[0519] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0520] Embodiment 46.R B The compound of any one of embodiments 43-45, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

[0521] Embodiment 47.R B The compound of any one of embodiments 43-45, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is ethyl.

[0522] Embodiment 48.R 0 but

[0523] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0524] Embodiment 49.R 0 but

[0525] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0526] Embodiment 50.R 0 but

[0527] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0528] Embodiment 51.R B The compound of any one of embodiments 48-50, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

[0529] Embodiment 52.R B The compound of any one of embodiments 48-50, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is ethyl.

[0530] Embodiment 53. A compound according to any one of embodiments 1-6 and 36-42, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X3 is O.

[0531] Embodiment 54.R 6 But C 1~3 The compound of any one of embodiments 1-2 and 23-53, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R is alkyl.

[0532] Embodiment 55.R 6 The compound of embodiment 40, or a pharmaceutically acceptable salt or deuterated form thereof, wherein

[0533] Embodiment 56.R 7 The compound of any one of embodiments 1-2 and 19-55, or a pharmaceutically acceptable salt or deuterated form thereof, wherein

[0534] Embodiment 57. The compound of embodiment 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is selected from Table 1.

[0535] Embodiment 58. A pharmaceutical composition comprising an effective amount of a compound according to any one of embodiments 1 to 57, or a pharmaceutically acceptable salt or deuterated form thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

[0536] Embodiment 59. A method for treating an obstructive airway disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of embodiments 1 to 57 or a composition of embodiment 58.

[0537] Embodiment 60. The method of embodiment 59, wherein the obstructive disease of the airways is asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis (CF), bronchiectasis, sarcoidosis, alpha-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, hypersensitivity pneumonitis, pulmonary fibrosis, complications of lung transplantation, vasculitis and thrombotic disorders of the pulmonary vasculature, pulmonary hypertension, antitussive activity, including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute and chronic rhinitis, including drug-induced rhinitis, and vasomotor rhinitis; perennial and seasonal allergic rhinitis, including neurogenic rhinitis (hay fever), nasal polyposis; acute viral infections, including the common cold, and infections with respiratory viruses, acute lung injury, or acute respiratory distress syndrome (ARDS).

[0538] Embodiment 61 The method of embodiment 60, wherein the obstructive airway disease is asthma.

[0539] Embodiment 62. The method of embodiment 60, wherein the obstructive airway disease is acute respiratory distress syndrome (ARDS).

[0540] Embodiment 63 The method of embodiment 60, wherein the obstructive airway disease is bronchitis.

[0541] Embodiment 64. The method of embodiment 60, wherein the obstructive airway disease is pulmonary fibrosis.

[0542] Embodiment 65. The method of embodiment 60, wherein the obstructive airway disease is emphysema.

[0543] Embodiment 66. The method of embodiment 60, wherein the obstructive airway disease is cystic fibrosis (CF).

[0544] Embodiment 67. The method of embodiment 60, wherein the obstructive airway disease is bronchiectasis.

[0545] Embodiment 68. The method of embodiment 60, wherein the obstructive disease of the airways is sarcoidosis.

[0546] Embodiment 69. The method of embodiment 60, wherein the obstructive airway disease is alpha-1 antitrypsin (A1AT) deficiency.

[0547] Embodiment 70. The method of embodiment 60, wherein the obstructive airway disease is farmer's lung.

[0548] Embodiment 71. The method of embodiment 60, wherein the obstructive airway disease is hypersensitivity pneumonitis.

[0549] Embodiment 72. The method of embodiment 60, wherein the obstructive airway disease is a complication of lung transplantation.

[0550] Embodiment 73. The method of embodiment 60, wherein the obstructive disease of the airways is a vasculitis or thrombotic disorder of the pulmonary vessels.

[0551] Embodiment 74. The method of embodiment 60, wherein the obstructive airway disease is pulmonary hypertension.

[0552] Embodiment 75. The method of embodiment 60, wherein the obstructive airway disease is iatrogenic cough.

[0553] Embodiment 76. The method of embodiment 60, wherein the obstructive airway disease is acute rhinitis.

[0554] Embodiment 77. The method of embodiment 60, wherein the obstructive airway disease is chronic rhinitis.

[0555] Embodiment 78. The method of embodiment 60, wherein the obstructive airway disease is rhinitis medicamentosa or vasomotor rhinitis.

[0556] Embodiment 79. The method of embodiment 60, wherein the obstructive airway disease is nasal polyposis.

[0557] Embodiment 80. The method of embodiment 60, wherein the obstructive airway disease is COPD.

[0558] Embodiment 81. The method of embodiment 61, wherein the asthma is bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, or medication-induced asthma.

[0559] Embodiment 82. The method of embodiment 63, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

[0560] Embodiment 83. The method of embodiment 64, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, fibrosing alveolitis of unknown cause, idiopathic interstitial pneumonia, or anti-tumor therapy-associated fibrosis or chronic infection.

[0561] Embodiment 84. The method of embodiment 67, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

[0562] Embodiment 85. The method of embodiment 67, wherein the bronchiectasis is associated with cystic fibrosis.

[0563] Embodiment 86. The method of embodiment 74, wherein the pulmonary hypertension is pulmonary arterial hypertension.

[0564] Embodiment 87. A method for treating cystic fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 57 or a composition according to embodiment 58.

[0565] Embodiment 88. The method of embodiment 87, wherein treating comprises improving the patient's pulmonary function compared to the patient's pulmonary function before treatment.

[0566] Embodiment 89. Improving the patient's pulmonary function includes increasing the patient's forced expiratory volume in one second (FEV1), increasing the patient's forced vital capacity (FVC), increasing the patient's peak expiratory flow rate (PEFR), or increasing the patient's forced expiratory flow rate (FEF) by 25% to 75% of the patient's FVC, compared to the patient's respective values ​​before treatment. (25-75%) 89. The method of embodiment 88, comprising increasing

[0567] Embodiment 90. The method of embodiment 88 or 89, wherein pulmonary function is measured by spirometry.

[0568] Embodiment 91. A method for treating bronchiectasis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of embodiments 1 to 57 or a composition of embodiment 58.

[0569] Embodiment 92. The method of embodiment 91, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

[0570] Embodiment 93. The method of embodiment 91, wherein the bronchiectasis is associated with cystic fibrosis.

[0571] Embodiment 94. The method of any one of embodiments 91-93, wherein treating comprises improving the patient's pulmonary function compared to the patient's pulmonary function before treatment.

[0572] Embodiment 95. Improving the patient's pulmonary function includes increasing the patient's forced expiratory volume in one second (FEV1), increasing the patient's forced vital capacity (FVC), increasing the patient's peak expiratory flow rate (PEFR), or increasing the patient's forced expiratory flow rate (FEF) by 25% to 75% of the patient's FVC, compared to the patient's respective values ​​before treatment. (25-75%) 95. The method of embodiment 94, comprising increasing

[0573] Embodiment 96. The method of embodiment 94 or 95, wherein pulmonary function is measured by spirometry.

[0574] Embodiment 97. The method of any one of embodiments 91-96, wherein treating comprises reducing the pulmonary exacerbation rate compared to the patient's pulmonary exacerbation rate before treatment.

[0575] Embodiment 98. The method of any one of embodiments 91-97, wherein treating comprises increasing the time to first pulmonary exacerbation compared to an untreated patient.

[0576] Embodiment 99. The method of embodiment 86 or 87, wherein the pulmonary exacerbation is characterized by the patient experiencing three or more of the following symptoms for at least 48 hours: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased shortness of breath and / or decreased exercise tolerance; (5) fatigue and / or malaise; and (6) hemoptysis.

[0577] Embodiment 100. A method for treating chronic rhinosinusitis (CRS) in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of embodiments 1 to 57 or a composition of embodiment 58.

[0578] Embodiment 101. The method of embodiment 100, wherein the chronic sinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP).

[0579] Embodiment 102. The method of embodiment 100, wherein the chronic sinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP).

[0580] Embodiment 103. The method of any one of embodiments 100 to 102, wherein the chronic sinusitis is refractory chronic sinusitis.

[0581] Embodiment 104. The method of any one of embodiments 100 to 103, wherein treating comprises reducing one or more symptoms of CRS, reducing its severity, delaying its onset, or eliminating it.

[0582] Embodiment 105. The method of embodiment 104, wherein one or more symptoms of CRS are nasal congestion, nasal obstruction, runny nose, postnasal drip, facial pressure, facial pain, facial fullness, reduced odor, depression, mucosal edema, mucopurulent secretions, obstruction of the middle nasal meatus, mucosal changes in the oral complex and sinuses, or rhinorrhea.

[0583] Embodiment 106. A method for treating hidradenitis suppurativa (HS) in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 57 or a composition according to embodiment 58.

[0584] Embodiment 107. The method of embodiment 106, wherein the hidradenitis suppurativa (HS) is Hurley stage I.

[0585] Embodiment 108. The method of embodiment 106, wherein the hidradenitis suppurativa (HS) is Hurley stage II.

[0586] Embodiment 109. The method of embodiment 106, wherein the hidradenitis suppurativa (HS) is Hurley stage III.

[0587] Embodiment 110. A method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 57, or a composition according to embodiment 58.

[0588] Embodiment 111. The method described in embodiment 110, wherein the cancer is metastatic cancer.

[0589] Embodiment 112. The method of embodiment 111, wherein the metastatic cancer is metastatic cancer from the breast to the lung.

[0590] Embodiment 113. The method of embodiment 111, wherein the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes, or liver.

[0591] Embodiment 114. The method of embodiment 111, wherein the metastatic cancer comprises metastasis of bone cancer to the lung.

[0592] Embodiment 115. The method of embodiment 111, wherein the metastatic cancer comprises metastasis of colorectal cancer to the peritoneum, pancreas, stomach, lung, liver, kidney, or spleen.

[0593] Embodiment 116. The method of embodiment 111, wherein the metastatic cancer comprises metastasis of gastric cancer to the mesentery, spleen, pancreas, lung, liver, adrenal gland, or ovary.

[0594] Embodiment 117. The method of embodiment 111, wherein the metastatic cancer comprises metastasis of liver cancer to the intestine, spleen, pancreas, stomach, lung, or kidney.

[0595] Embodiment 118. The method of embodiment 111, wherein the metastatic cancer comprises lymphoma metastasis to the kidney, ovary, liver, bladder, or spleen.

[0596] Embodiment 119. A method for treating lupus nephritis in a patient in need thereof, comprising administering to the patient an effective amount of a compound described in any one of embodiments 1 to 57 or a composition described in embodiment 58.

[0597] Embodiment 120. A method for treating rheumatoid arthritis in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 57 or a composition according to embodiment 58.

[0598] Embodiment 121. A method for treating inflammatory bowel disease (IBD) in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 57 or a composition according to embodiment 58.

[0599] Embodiment 122. The method of embodiment 121, wherein the inflammatory bowel disease (IBD) is Crohn's disease.

[0600] Embodiment 123. The method of embodiment 121, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

[0601] Embodiment 124. A method for treating antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in a patient in need thereof, comprising administering to the patient an effective amount of a compound described in any one of embodiments 1 to 57 or a composition described in embodiment 58, wherein the ANCA-associated disease is granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA).

[0602] Embodiment 125. A method for treating a disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 57 or a composition according to embodiment 58, wherein the disease is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpasture's disease), systemic sclerosis, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcer, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatosis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or ventilator-induced lung injury.

[0603] Embodiment 2 Embodiment 1. Compound of Formula (I)

[0604] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R 0 teeth

[0605] [ka] and X1 and X2 are independently O, S, NH, N(C 1~6 alkyl), or CR 12 R 13 and at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1~6 alkyl), R A is H, C 1~6 Alkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 alkylene-heteroaryl, heteroaryl or carbocyclyl; R B is C 1~6 Alkyl, C 2~6 Alkenyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, C 1~6 Alkylene-aryl, C 1~6 alkylene-heteroaryl, heteroaryl, or carbocyclyl; R A and R B together form a heterocyclyl, L is aryl, heterocyclyl, heteroaryl, or

[0606] [ka] and L is independently 0 to 4 R 10 and ring B is a carbocyclic or heterocyclic ring; R 1 teeth

[0607] [ka] and R 2 are H, F, Cl, Br, OSOC 1~6 Alkyl or C 1~6 is alkyl, R3 are H, F, Cl, Br, CN, and C 1~6 Haloalkyl, SO2C 1~6 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF2; Y is O or S; Q is CH or N; R 6 is C 1~6 alkyl, optionally substituted with 1, 2 or 3 F, or OH, OC 1~6 Alkyl, N(C 1~6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl; R 7 is H, F, Cl, Br, or C 1~6 is alkyl, Each R 8 and R 12 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 Alkylene-heteroaryl, halogenated C 1~6 alkoxy, heteroaryl, or carbocyclyl; Each R 13 are independently H, F, Cl, Br, I, or C1-C6 alkyl; Each R 10 are independently oxo, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, SC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C1~6 Alkyl, N(C 1~6 Alkyl)2, COOH, COC 1~6 Alkyl, COOC 1~6 Alkyl, CON 1-6 Alkyl, CON(C 1~6 alkyl) 2、 NHCOC 1~6 alkyl, or heterocycle, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxyl, NH, and COOH; W, X4 and Y2 are each independently CH or N, provided that at most one of W, X4 and Y2 may be N; DE is N(H)-C(O), N(C 1~6 alkyl)-C(O), CHCH, C(O)—O or CH—O; R 11 is H, C 1~6 alkyl, alkylene-O-alkyl, or heterocyclyl; A compound of formula (I) or a pharmaceutically acceptable salt or deuterated form thereof, wherein i and j are each independently 1, 2 or 3, with the proviso that the sum of i+j is 2, 3 or 4.

[0608] Embodiment 2. The compound is a compound of formula (II)

[0609] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0 or 1; and R 10 is a halogen.

[0610] Embodiment 3. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein halogen is F.

[0611] Embodiment 4. A compound of embodiment 2 or 3, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0612] Embodiment 5. A compound of embodiment 2 or 3, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0613] Embodiment 6. R 1 teeth

[0614] [ka] and X is O, S or CF2; Y is O or S; Q is CH or N; R 6 is C 1~3 alkyl, C 1~3 Alkyl is one, two or three of F, OH, OC1-3 alkyl, N(C 1~3 optionally substituted by alkyl), cyclopropyl, or tetrahydropyran; R 7 The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is H, F, Cl, or CH3.

[0615] Embodiment 7. R 1 teeth

[0616] [ka] and X is O, S or CF2; Y is O or S; R 6 is C 1~3 alkyl, C 1~3 Alkyl is one, two or three of F, OH, OC 1~3 Alkyl, N(C 1~3 optionally substituted by alkyl), cyclopropyl, or tetrahydropyran; R 7The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is H, F, Cl, or CH3.

[0617] Embodiment 8.R 1 but

[0618] [ka] 6. The compound of any one of embodiments 1 to 5, wherein:

[0619] Embodiment 9. X is O and R 6 is C 1~3 alkyl, and R 7 is H, or a pharmaceutically acceptable salt or deuterated form thereof.

[0620] Embodiment 10. R 1 teeth

[0621] [ka] and X is O, R 6 is C 1~3 alkyl, C 1~3 alkyl is optionally substituted by 1, 2 or 3 F; R 7 The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt or deuterated form thereof, wherein

[0622] Embodiment 11. R 1 but

[0623] [ka] and X is O, R 6 is C 1~3 is alkyl, R 7 The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt or deuterated form thereof, wherein

[0624] Embodiment 12.R 1 but

[0625] [ka] 6. The compound of any one of embodiments 1 to 5, wherein:

[0626] Embodiment 13.R 1 but

[0627] [ka] 6. The compound of any one of embodiments 1 to 5, wherein:

[0628] Embodiment 14.R 1 but

[0629] [ka] 6. The compound of any one of embodiments 1 to 5, wherein:

[0630] Embodiment 15.R 1 but

[0631] [ka] 6. The compound of any one of embodiments 1 to 5, wherein:

[0632] Embodiment 16.R 6 The compound of any one of embodiments 3-15, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

[0633] Embodiment 17.R 6 The compound of any one of embodiments 3-15, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is ethyl.

[0634] Embodiment 18.R 6 The compound of any one of embodiments 3-15, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is propyl.

[0635] Embodiment 19.R 1 but

[0636] [ka] 6. The compound of any one of embodiments 1 to 5, wherein:

[0637] Embodiment 20.R 1 but

[0638] [ka] 6. The compound of any one of embodiments 1 to 5, wherein:

[0639] Embodiment 21.R 1 but

[0640] [ka] 6. The compound of any one of embodiments 1 to 5, wherein:

[0641] Embodiment 22. The compound is a compound of formula (III)

[0642] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0643] Embodiment 23. The compound is a compound of formula (III-A)

[0644] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0645] Embodiment 24. A compound according to embodiment 22 or 23, wherein n is 0.

[0646] Embodiment 25. A compound according to embodiment 22 or 23, wherein n is 1.

[0647] Embodiment 26. The compound is a compound of formula (III-B)

[0648] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 10 is —H or —F.

[0649] Embodiment 27.R 10 The compound of any one of embodiments 22-23 and 25-26, wherein is F.

[0650] Embodiment 28. A compound according to any one of embodiments 1-5 and 16-27, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is O.

[0651] Embodiment 29.R 0 but

[0652] [ka] 29. The compound of any one of embodiments 1-28, wherein:

[0653] Embodiment 30.R 0 but

[0654] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0655] Embodiment 31.R 0 but

[0656] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0657] Embodiment 32.R 0 but

[0658] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0659] Embodiment 33.R 0 but

[0660] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0661] Embodiment 34.R 0 but

[0662] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0663] Embodiment 35.R 0 but

[0664] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0665] Embodiment 36.R 0 but

[0666] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0667] Embodiment 37.R 0 but

[0668] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0669] Embodiment 38. A compound according to embodiment 35 or 36, wherein X1 is O and X2 is NH.

[0670] Embodiment 39. A compound according to embodiment 36 or 37, wherein X1 is CH2 and X2 is NH.

[0671] Embodiment 40. One R 8 , OH, unsubstituted C 1~6 The compound of any one of embodiments 34-39, which is alkoxy, or O-cycloalkyl.

[0672] Embodiment 41.R 8 The compound of any one of embodiments 1-40, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each occurrence of is methoxy.

[0673] Embodiment 42.R 8 The compound of any one of embodiments 1-40, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each occurrence of is ethoxy.

[0674] Embodiment 43.R 8 The compound of any one of embodiments 1-40, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each occurrence of is OH.

[0675] Embodiment 44.R 0 but

[0676] [ka] 29. The compound of any one of embodiments 1-28, wherein:

[0677] Embodiment 45.R 0 but

[0678] [ka] 29. The compound of any one of embodiments 1-28, wherein:

[0679] Embodiment 46.R 0 but

[0680] [ka] 29. The compound of any one of embodiments 1-28, wherein:

[0681] Embodiment 47.R 0 but

[0682] [ka] 29. The compound of any one of embodiments 1-28, wherein:

[0683] Embodiment 48.R 0 but

[0684] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0685] Embodiment 49.R 0 but

[0686] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0687] Embodiment 50.R0 but

[0688] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0689] Embodiment 51.R 0 but

[0690] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0691] Embodiment 52. A compound according to embodiment 49 or 50, wherein X1 is O and X2 is NH.

[0692] Embodiment 53. A compound according to embodiment 50 or 51, wherein X1 is CH2 and X2 is NH.

[0693] Embodiment 54. Each R 8 are independently H, OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, or halogenated C 1~6 Alkoxy with the proviso that one R 8 The compound of any one of embodiments 1-53, wherein is not H.

[0694] Embodiment 55. Each R 8 are independently OH, halogen, NH2, COOH, C 1~6 Alkyl, C 1~6 Alkyl-OH, C 2~6 Alkenyl, C 1~6 Alkoxy, O-cycloalkyl, cycloalkyl, or halogenated C1~6 The compound of any one of embodiments 1-53, which is alkoxy.

[0695] Embodiment 56. Each R 8 are independently OH or C 1~6 The compound of any one of embodiments 1-53, which is alkoxy.

[0696] Embodiment 57. Each R 8 is C 1~6 The compound of any one of embodiments 1-53, which is alkoxy.

[0697] Embodiment 58. Each R 8 The compound of any one of embodiments 1-53, wherein is OH.

[0698] Embodiment 59.C 1~6 The compound according to any one of embodiments 55-58, wherein alkoxy is methoxy or ethoxy.

[0699] Embodiment 60.C 1~6 The compound of any one of embodiments 55-58, wherein alkoxy is methoxy.

[0700] Embodiment 61.C 1~6 The compound according to any one of embodiments 55-58, wherein alkoxy is ethoxy.

[0701] Embodiment 62. One R 8 , OH, unsubstituted C 1~6 alkoxy, or O-cycloalkyl, and the other R 8 But unsubstituted C 1~6 The compound of any one of embodiments 44-54, wherein is alkyl or cycloalkyl.

[0702] Embodiment 63.R 0 but,

[0703] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0704] Embodiment 64.R 0 but

[0705] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0706] Embodiment 65.R 0 but

[0707] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0708] Embodiment 66.R 0 but

[0709] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0710] Embodiment 67.R 0 but

[0711] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0712] Embodiment 68.R 0 but

[0713] [ka] 29. The compound of any one of embodiments 1-28, wherein:

[0714] Embodiment 69.R 0 but

[0715] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0716] Embodiment 70.R A But H or C 1~6 The compound of any one of embodiments 1-28 and 68-69, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R is alkyl.

[0717] Embodiment 71.R A is H, or a pharmaceutically acceptable salt or deuterated form thereof.

[0718] Embodiment 72.R A The compound of embodiment 70, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

[0719] Embodiment 73.R B But C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Alkylene-carbocyclyl, or C 1~6 The compound of any one of embodiments 1-28 and 68-72, or a pharmaceutically acceptable salt or deuterated form thereof, which is alkylene-heteroaryl.

[0720] Embodiment 74.R B But C 1~6 Alkyl, C 1~6Alkylene-aryl or -C 1~6 The compound of embodiment 73, or a pharmaceutically acceptable salt or deuterated form thereof, wherein: alkylene-5-6 membered heteroaryl.

[0721] Embodiment 75.R 0 but

[0722] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0723] Embodiment 76.R 0 but

[0724] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0725] Embodiment 77.R 0 but

[0726] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0727] Embodiment 78.R B The compound of any one of embodiments 75-77, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

[0728] Embodiment 79.R B The compound of any one of embodiments 75-77, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is ethyl.

[0729] Embodiment 80.R0 but

[0730] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0731] Embodiment 81.R 0 but

[0732] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0733] Embodiment 82.R 0 but

[0734] [ka] or a pharmaceutically acceptable salt or deuterated form thereof.

[0735] Embodiment 83.R B The compound of any one of embodiments 80-82, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

[0736] Embodiment 84.R B The compound of any one of embodiments 80-82, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is ethyl.

[0737] Embodiment 85.R B The compound of any one of embodiments 80-82, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is isopropyl.

[0738] Embodiment 86.R B but

[0739] [ka] 83. The compound of any one of embodiments 80-82, wherein:

[0740] Embodiment 87.R B but

[0741] [ka] 83. The compound of any one of embodiments 80-82, wherein:

[0742] Embodiment 88. A compound according to any one of embodiments 1 to 9 and 68 to 74, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X3 is O.

[0743] Embodiment 89.R 6 C 1~3 The compound of any one of embodiments 1-5 and 23-88, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R is alkyl.

[0744] Embodiment 90.R 6 The compound of embodiment 72, or a pharmaceutically acceptable salt or deuterated form thereof, wherein

[0745] Embodiment 91.R 7 The compound of any one of embodiments 1-5 and 22-90, or a pharmaceutically acceptable salt or deuterated form thereof, wherein

[0746] Embodiment 92. The compound of embodiment 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is selected from Table 1.

[0747] Embodiment 93. A pharmaceutical composition comprising an effective amount of a compound according to any one of embodiments 1 to 92, or a pharmaceutically acceptable salt or deuterated form thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

[0748] Embodiment 94. A method for treating an obstructive airway disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of embodiments 1 to 92 or a composition of embodiment 93.

[0749] Embodiment 95. The method of embodiment 94, wherein the obstructive disease of the airways is asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis (CF), bronchiectasis, sarcoidosis, alpha-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, hypersensitivity pneumonitis, pulmonary fibrosis, complications of lung transplantation, vasculitis and thrombotic disorders of the pulmonary vasculature, pulmonary hypertension, antitussive activity, including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute and chronic rhinitis, including drug-induced rhinitis, and vasomotor rhinitis; perennial and seasonal allergic rhinitis, including neurogenic rhinitis (hay fever), nasal polyposis; acute viral infections, including the common cold, and infections with respiratory viruses, acute lung injury, or acute respiratory distress syndrome (ARDS).

[0750] Embodiment 96 The method of embodiment 95, wherein the obstructive airway disease is asthma.

[0751] Embodiment 97. The method of embodiment 95, wherein the obstructive airway disease is acute respiratory distress syndrome (ARDS).

[0752] Embodiment 98. The method of embodiment 95, wherein the obstructive airway disease is bronchitis.

[0753] Embodiment 99. The method of embodiment 95, wherein the obstructive airway disease is pulmonary fibrosis.

[0754] Embodiment 100. The method of embodiment 95, wherein the obstructive airway disease is emphysema.

[0755] Embodiment 101. The method of embodiment 95, wherein the obstructive airway disease is cystic fibrosis (CF).

[0756] Embodiment 102. The method of embodiment 95, wherein the obstructive airway disease is bronchiectasis.

[0757] Embodiment 103. The method of embodiment 95, wherein the obstructive airway disease is sarcoidosis.

[0758] Embodiment 104. The method of embodiment 95, wherein the obstructive airway disease is alpha-1 antitrypsin (A1AT) deficiency.

[0759] Embodiment 105. The method of embodiment 95, wherein the obstructive airway disease is farmer's lung.

[0760] Embodiment 106. The method of embodiment 95, wherein the obstructive airway disease is hypersensitivity pneumonitis.

[0761] Embodiment 107. The method of embodiment 95, wherein the obstructive airway disease is a complication of lung transplantation.

[0762] Embodiment 108. The method of embodiment 95, wherein the obstructive disease of the airways is a vasculitic or thrombotic disorder of the pulmonary vessels.

[0763] Embodiment 109. The method of embodiment 95, wherein the obstructive airway disease is pulmonary hypertension.

[0764] Embodiment 110. The method of embodiment 95, wherein the obstructive airway disease is iatrogenic cough.

[0765] Embodiment 111. The method of embodiment 95, wherein the obstructive airway disease is acute rhinitis.

[0766] Embodiment 112. The method of embodiment 95, wherein the obstructive airway disease is chronic rhinitis.

[0767] Embodiment 113. The method of embodiment 95, wherein the obstructive airway disease is rhinitis medicamentosa or vasomotor rhinitis.

[0768] Embodiment 114. The method of embodiment 95, wherein the obstructive airway disease is nasal polyposis.

[0769] Embodiment 115. The method of embodiment 95, wherein the obstructive airway disease is COPD.

[0770] Embodiment 116. The method of embodiment 96, wherein the asthma is bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma or drug-induced asthma.

[0771] Embodiment 117. The method of embodiment 116, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

[0772] Embodiment 118. The method of embodiment 99, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, fibrosing alveolitis of unknown cause, idiopathic interstitial pneumonia, or fibrosis or chronic infection associated with antitumor therapy.

[0773] Embodiment 119. The method of embodiment 102, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

[0774] Embodiment 120. The method of embodiment 102, wherein the bronchiectasis is associated with cystic fibrosis.

[0775] Embodiment 121. The method of embodiment 109, wherein the pulmonary hypertension is pulmonary arterial hypertension.

[0776] Embodiment 122. A method for treating cystic fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 92 or a composition according to embodiment 93.

[0777] Embodiment 123. The method of embodiment 122, wherein treating includes improving the patient's pulmonary function compared to the patient's pulmonary function before treatment.

[0778] Embodiment 124. Improving the patient's pulmonary function includes increasing the patient's forced expiratory volume in one second (FEV1), increasing the patient's forced vital capacity (FVC), increasing the patient's peak expiratory flow rate (PEFR), or increasing the patient's forced expiratory flow rate (FEF) by 25% to 75% of the patient's FVC, compared to the patient's respective values ​​before treatment. (25-75%) 124. The method of embodiment 123, comprising increasing

[0779] Embodiment 125. The method of embodiment 123 or 124, wherein pulmonary function is measured by spirometry.

[0780] Embodiment 126. A method for treating bronchiectasis in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 92 or a composition according to embodiment 93.

[0781] Embodiment 127. The method of embodiment 126, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

[0782] Embodiment 128. The method of embodiment 126, wherein the bronchiectasis is associated with cystic fibrosis.

[0783] Embodiment 129. The method of any one of embodiments 126 to 128, wherein treating includes improving the patient's pulmonary function compared to the patient's pulmonary function before treatment.

[0784] Embodiment 130. Improving the patient's pulmonary function includes increasing the patient's forced expiratory volume in one second (FEV1), increasing the patient's forced vital capacity (FVC), increasing the patient's peak expiratory flow rate (PEFR), or increasing the patient's forced expiratory flow rate (FEF) by 25% to 75% of the patient's FVC, compared to the patient's respective values ​​before treatment. (25-75%)130. The method of embodiment 129, comprising increasing

[0785] Embodiment 131. The method of embodiment 129 or 130, wherein pulmonary function is measured by spirometry.

[0786] Embodiment 132. The method of any one of embodiments 126 to 131, wherein treating comprises reducing the pulmonary exacerbation rate compared to the patient's pulmonary exacerbation rate before treatment.

[0787] Embodiment 133. The method of any one of embodiments 126 to 132, wherein treating comprises increasing the time to first pulmonary exacerbation compared to untreated patients.

[0788] Embodiment 134. The method of embodiment 121 or 122, wherein the pulmonary exacerbation is characterized by the patient experiencing three or more of the following symptoms for at least 48 hours: (1) increased cough, (2) increased sputum volume or change in sputum consistency, (3) increased sputum purulence, (4) increased shortness of breath and / or decreased exercise tolerance, (5) fatigue and / or malaise, and (6) hemoptysis.

[0789] Embodiment 135. A method for treating chronic rhinosinusitis (CRS) in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 92 or a composition according to embodiment 93.

[0790] Embodiment 136. The method of embodiment 135, wherein the chronic sinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP).

[0791] Embodiment 137. The method of embodiment 135, wherein the chronic sinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP).

[0792] Embodiment 138. A method according to any one of embodiments 128 to 137, wherein the chronic sinusitis is refractory chronic sinusitis.

[0793] Embodiment 139. The method of any one of embodiments 125 to 130, wherein treating comprises reducing one or more symptoms of CRS, reducing its severity, delaying its onset, or eliminating it.

[0794] Embodiment 140. The method of embodiment 139, wherein one or more symptoms of CRS are nasal congestion, nasal obstruction, runny nose, postnasal drip, facial pressure, facial pain, facial fullness, reduced odor, depression, mucosal edema, mucopurulent secretions, obstruction of the middle nasal meatus, mucosal changes in the oral complex and sinuses, or rhinorrhea.

[0795] Embodiment 141. A method for treating hidradenitis suppurativa (HS) in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 92 or a composition according to embodiment 93.

[0796] Embodiment 142. The method of embodiment 141, wherein the hidradenitis suppurativa (HS) is Hurley stage I.

[0797] Embodiment 143. The method of embodiment 141, wherein the hidradenitis suppurativa (HS) is Hurley stage II.

[0798] Embodiment 144. The method of embodiment 141, wherein the hidradenitis suppurativa (HS) is Hurley stage III.

[0799] Embodiment 145. A method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 92, or a composition according to embodiment 93.

[0800] Embodiment 146. The method of embodiment 145, wherein the cancer is metastatic cancer.

[0801] Embodiment 147. The method of embodiment 146, wherein the metastatic cancer is metastatic cancer from the breast to the lung.

[0802] Embodiment 148. The method of embodiment 146, wherein the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes, or liver.

[0803] Embodiment 149. The method of embodiment 146, wherein the metastatic cancer comprises metastasis of bone cancer to the lung.

[0804] Embodiment 150. The method of embodiment 146, wherein the metastatic cancer comprises metastasis of colorectal cancer to the peritoneum, pancreas, stomach, lung, liver, kidney, or spleen.

[0805] Embodiment 151. The method of embodiment 146, wherein the metastatic cancer comprises metastasis of gastric cancer to the mesentery, spleen, pancreas, lung, liver, adrenal gland, or ovary.

[0806] Embodiment 152. The method of embodiment 146, wherein the metastatic cancer comprises metastasis of liver cancer to the intestine, spleen, pancreas, stomach, lung, or kidney.

[0807] Embodiment 153. The method of embodiment 146, wherein the metastatic cancer comprises lymphoma metastasis to the kidney, ovary, liver, bladder, or spleen.

[0808] Embodiment 154. A method for treating lupus nephritis in a patient in need thereof, comprising administering to the patient an effective amount of a compound described in any one of embodiments 1 to 92 or a composition described in embodiment 93.

[0809] Embodiment 155. A method for treating rheumatoid arthritis in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 92 or a composition according to embodiment 93.

[0810] Embodiment 156. A method for treating inflammatory bowel disease (IBD) in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 92 or a composition according to embodiment 93.

[0811] Embodiment 157. The method of embodiment 156, wherein the inflammatory bowel disease (IBD) is Crohn's disease.

[0812] Embodiment 158. The method of embodiment 156, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

[0813] Embodiment 159. A method for treating antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in a patient in need thereof, comprising administering to the patient an effective amount of a compound described in any one of embodiments 1 to 92 or a composition described in embodiment 93.

[0814] Embodiment 160. The method of embodiment 159, wherein the ANCA-associated disease is granulomatosis with polyangiitis (GPA).

[0815] Embodiment 161. The method described in embodiment 159, wherein the ANCA-associated disease is microscopic polyangiitis (MPA).

[0816] Embodiment 162. A method of treating a disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 92 or a composition according to embodiment 93, wherein the disease is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpasture's disease), systemic sclerosis, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcer, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatosis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or ventilator-induced lung injury. [Example]

[0817] The present disclosure is further illustrated by reference to the following examples, however, it should be noted that these examples, like the above embodiments, are illustrative and should not be construed as limiting the scope of the present disclosure in any way.

[0818] In embodiments, compounds of the present disclosure can be synthesized using the following methods: The general reaction conditions are given, and the reaction products can be purified by commonly known methods, including silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol, etc., or preparative reverse-phase high pressure liquid chromatography.

[0819] Representative Synthesis of Compounds of Formula (I) Scheme 1: Representative Synthesis of Compounds of the Disclosure

[0820] [ka] As shown in Scheme 1, L and R 1 Compounds of the present disclosure, wherein R is defined herein, can be prepared from Compound A.

[0821] Scheme 2: Representative Synthesis of Compounds of the Disclosure

[0822] [ka] As shown in Scheme 2, R A , R B , L, and R 1 Compounds of the present disclosure, wherein R is defined herein, can be prepared from Compound B.

[0823] Scheme 3: Representative Synthesis of Compounds of the Disclosure

[0824] [ka] As shown in Scheme 3, L and R 1 is defined herein, and R C C 1~6 Compounds of the present disclosure that are alkyl, haloalkyl, or cycloalkyl can be prepared from compound D.

[0825] Scheme 4: Representative Synthesis of Compounds of the Disclosure

[0826] [ka] As shown in Scheme 4, R 8 , L, and R 1 is defined herein, and R C C 1~6 Compounds of the present disclosure that are alkyl, haloalkyl, or cycloalkyl can be prepared from compound D.

[0827] Scheme 5: Representative Synthesis of Compounds of the Disclosure

[0828] [ka] As shown in Scheme 5, L and R 1 is defined herein, and R C C 1~6 Compounds of the present disclosure that are alkyl, haloalkyl, or cycloalkyl can be prepared from compound E.

[0829] Scheme 6: Representative Synthesis of Compounds of the Disclosure

[0830] [ka] As shown in Scheme 6, R 8 , L, and R 1 is defined herein, and R C C 1~6Compounds of the present disclosure that are alkyl, haloalkyl, or cycloalkyl can be prepared from compound E.

[0831] Scheme 7: Representative Synthesis of Compounds of the Disclosure

[0832] [ka] As shown in Scheme 7, R B , L, and R 1 Compounds of the present disclosure, wherein is defined herein, can be prepared from compounds B1-84-1 or B1-85-1.

[0833] General Experiment 1 H NMR analysis: 1 H-NMR spectra were recorded on a Bruker Ultrashield (400 MHz). The multiplicities of the signals are designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet.

[0834] All observed coupling constants J are reported in Hertz (Hz).

[0835] Exchangeable protons are not always observed.

[0836] LC / MS analysis: LC / MS method AN01_001_012: LC-MS data were generated using a Waters Acquity system: TUV detector, SQD2 MS detector, Sedere SEDEX 80 (light scattering detector).

[0837] LC-MS method: Reversed phase HPLC analysis Column: Agilent Cortex C18 Solvent A: Water containing formic acid (0.1% V / V) Solvent B: Acetonitrile

[0838] [Table 2]

[0839] LC / MS method AN01_001_061: LC-MS data were generated using a Waters Acquity UPLC Class I: Waters PDA eλ detector, Waters SQD2 MS detector, Sedere SEDEX 80 (light scattering detector).

[0840] LC-MS method: Reversed phase HPLC analysis Column: Waters Acquity UPLC CSH C18, length: 30 mm, inner diameter: 2.1 mm, particle size: 1.7 μm Solvent A: Water containing formic acid (0.1% V / V) Solvent B: Acetonitrile UV detection: 220 nm

[0841] [Table 3]

[0842] LC / MS method AN01_001_021: LC-MS data were generated using a Waters 2695 e system: Waters PDA 2998 detector, Waters QDA detector (ESI), Sedere SEDEX 80 (light scattering detector).

[0843] LC-MS method: Reversed phase HPLC analysis Column: Agilent: Poroshell, length: 100 mm, inner diameter: 4.6 mm, particle size: 4 μm Solvent A: Water containing TFA (0.1% V / V) Solvent B: Acetonitrile UV detection: 220 nm

[0844] [Table 4]

[0845] LC / MS method AN01_001_026: LC-MS data were generated using a Waters Acquity system: TUV detector, SQD2 MS detector, Sedere SEDEX 80 (light scattering detector).

[0846] LC-MS method: Reversed phase HPLC analysis Column: Agilent: Poroshell Solvent A: Water containing formic acid (0.1% V / V) Solvent B: Acetonitrile

[0847] [Table 5] UV detection: 220 nm

[0848] LC / MS method AN01_001_086: LC-MS data were generated using a Waters Acquity UPLC Class I: Waters PDA eλ detector, Waters SQD2 MS detector, Sedere SEDEX 80 (light scattering detector).

[0849] LC-MS method: Reversed phase HPLC analysis Column: Waters: Acquity Premier CSH C18, length: 100 mm, inner diameter: 2.1 mm, particle size: 1.7 μm Solvent A: Water containing formic acid (0.1% V / V) Solvent B: Acetonitrile UV detection: 220 nm

[0850] [Table 6]

[0851] LC / MS method AN01_001_087: LC-MS data were generated using a Waters Acquity UPLC Class I: Waters PDA eλ detector, Waters SQD2 MS detector, Sedere SEDEX 80 (light scattering detector).

[0852] LC-MS method: Reversed phase HPLC analysis Column: Waters: Acquity Premier CSH C18, length: 100 mm, inner diameter: 2.1 mm, particle size: 1.7 μm Solvent A: Water containing formic acid (0.1% V / V) Solvent B: Acetonitrile UV detection: 220 nm

[0853] [Table 7]

[0854] LC / MS method AN01_001_088: LC-MS data were generated using a Waters Acquity UPLC Class I: Waters PDA eλ detector, Waters SQD2 MS detector, Sedere SEDEX 80 (light scattering detector).

[0855] LC-MS method: Reversed phase HPLC analysis Column: Waters: Acquity Premier CSH C18, length: 100 mm, inner diameter: 2.1 mm, particle size: 1.7 μm Solvent A: Water containing TFA (0.1% V / V) Solvent B: Acetonitrile UV detection: 220 nm

[0856] [Table 8]

[0857] Chiral SFC purity analysis conditions Column details: Chiralpak OD-3 (4.6 x 100 mm) Column temperature: 35℃ Flow rate: 3.5mL / min Detector wavelength: 220 to 410 nm Injection volume: 2μL BPR: 1500 PSI Isocratic conditions: i-PrOH:CO2, 30:70

[0858] General synthetic procedure Step AO-Bn deprotection A solution of the protected alcohol (1 equiv.) in EtOH (4.78 mL / mmol of protected alcohol) was purged with argon, and 10% Pd / C (0.1 equiv.) was added at room temperature. The resulting mixture was purged with argon (3 times) and then with H2 (3 times). The reaction mixture was stirred at room temperature under atmospheric pressure of H2 for 18 hours. The reaction mixture was purged with argon, filtered through a pad of Celite, and rinsed with EtOH (3 x 5 mL). The filtrate was concentrated under reduced pressure to give the expected compound.

[0859] Step B - Oxidation of Alcohols to Carboxylic Acids To a solution of the alcohol derivative (1 equiv.) and sodium bromide (0.3 equiv.) in acetone (16.7 mL / mmol of alcohol) was added a saturated aqueous solution of NaHCO3 (2.59 mL / mmol of alcohol) at room temperature. To the resulting mixture, trichlorocyanuric acid (2.2 equiv.) and 2,2,6,6-tetramethylpiperidine-1-oxyl (0.03 equiv.) were added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 h. Isopropanol (10 mL) was added at room temperature, and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc (50 mL), and saturated aqueous NaHCO3 (50 mL) was added. The two layers were separated, and the aqueous layer was washed with EtOAc (50 mL). The aqueous layer was then acidified to pH 1 with 3 M aqueous HCl and extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the expected compound.

[0860] Procedure C-peptide coupling To a solution of the amine derivative (1 eq.) and the carboxylic acid derivative (1.05 eq.) in anhydrous DMF (7.14 mL / mmol of amine) was added DIPEA (2.5 eq.) and TBTU (1.5 eq.) at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL), and the combined organic layers were washed with brine (3 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (see conditions for each compound) on SiO2 to give the expected compound.

[0861] Steps for DN-Boc deprotection To a preheated vial (50 °C) containing the Boc-protected amine derivative (1 equiv.) was added formic acid (7.6 mL / mmol), also preheated at 50 °C. The reaction mixture was stirred at 50 °C for 15 min. The reaction mixture was cooled back to room temperature and added dropwise to a cooled (0 °C) mixture of a stirred aqueous solution of saturated NaHCO (40 mL) and DCM (40 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 × 40 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on SiO and / or by preparative HPLC (see conditions for each compound) to give the expected compound.

[0862] Procedure EO-Alkylation To a solution of the alcohol derivative (1 equivalent) and a halogen alkyl, such as iodomethane (2 equivalents), in anhydrous DMF (5.49 mL / mmol of alcohol derivative) was added 60% NaH in oil (1.1 equivalents) at 0 °C under an argon atmosphere. The resulting mixture was warmed to room temperature and stirred for 22 h. The reaction mixture was quenched with a saturated aqueous solution of NH Cl (10 mL) at room temperature. EtOAc (50 mL) and water (50 mL) were then added, and the two layers were separated. The aqueous layer was extracted with EtOAc (2 × 50 mL), and the combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (see conditions for each compound) to give the expected compound.

[0863] Step F (TBAF deprotection) To a solution of O-TBDMS-protected alcohol (1 equivalent) in anhydrous THF (6.0 mL / mmol of protected alcohol) was added 1 M TBAF solution (1.5 equivalents) in THF under an argon atmosphere at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (see conditions for each compound) on SiO2 to give the expected compound.

[0864] Procedure GN-Boc protection To a solution of the amine derivative (1 equivalent) in DCM (4 mL / mmol of amine derivative), BocO (1.2 equivalents) and EtN (2 equivalents) were added at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (40 mL) and extracted with DCM (2 x 60 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified by silica gel flash chromatography (see conditions for each compound) to give the expected compound.

[0865] Procedure H (Olefin Metathesis) To a solution of the diene (1 equiv.) in DCM (63 mL / mmol) was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.1 equiv.) at room temperature. The resulting mixture was stirred at 55° C. for 8 hours. The reaction was concentrated to dryness under reduced pressure. The crude residue was purified by silica gel flash chromatography (see conditions for each compound) to give the expected compound.

[0866] Step I (hydroboration) A solution of the alkene derivative (1 equiv.) in THF (2.5 mL / mmol) was purged with argon and a 1 M THF solution of borane tetrahydrofuran complex (1 equiv.) was added at 0 °C. The resulting mixture was stirred at 0 °C for 2.5 h. Next, 3 M aqueous NaOH (1 equiv.) and 33% aqueous HO (1 equiv.) were added sequentially, and the resulting mixture was stirred at 0 °C for 3.5 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified by silica gel flash chromatography (see conditions for each compound) to give the expected compound.

[0867] Preparation of key intermediates Intermediate B1-46-1-(S) * and B1-46-1-(R) * Preparation of

[0868] [ka]

[0869] tert-Butyl N-[(2S)-2,3-dihydroxypropyl]carbamate B1-2-2 To a solution of (2S)-3-aminopropane-1,2-diol (1 equiv., 14.4 g, 158.1 mmol) and EtN (1.01 equiv., 22.2 mL, 159.6 mmol) in anhydrous MeOH (245 mL) was added a solution of BocO (1.2 equiv., 41.4 g, 189.7 mmol) in anhydrous DCM (41 mL) at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure to give B1-2-2 as a pale yellow oil (30.2 g, quantitative). The crude product was deemed quantitative and was used as is.

[0870] LC / MS (AN01_001_012): Rt=1.69 min, non-UV active, [M+Na] + =214.1.

[0871] tert-Butyl N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]carbamate B1-2-3 To a solution of B1-2-2 (1 equiv., 1.72 g, 8.99 mmol), di(n-butyl)tin oxide (0.1 equiv., 0.224 g, 0.899 mmol), and TBAB (0.3 equiv., 0.870 g, 2.70 mmol) was added DIPEA (2 equiv., 3.13 mL, 18.0 mmol) and BnBr (2 equiv., 2.15 mL, 18.0 mmol) at room temperature under an argon atmosphere. The reaction mixture was stirred at 70 °C for 6 h. The reaction mixture was concentrated under reduced pressure, then taken up in EtOAc (50 mL), and filtered through a pad of silica gel. The latter was rinsed with EtOAc (3 × 150 mL), and the filtrate was concentrated under reduced pressure. The resulting orange oil (4.46 g) was purified by silica gel flash chromatography (120 g, gradient: 100:0 to 50:50 cyclohexane / EtOAc) to give B1-2-3 as a pale yellow oil (2.31 g, 75%), which contained the other -OBn regioisomer protected at position 2 ( 1 1 H NMR analysis revealed that the product was contaminated with 17% by weight of HCl.

[0872] LC / MS (AN01_001_012): Rt=2.28 min, 100%, [M+Na] + =304.1.

[0873] tert-Butyl (2S)-2-[(benzyloxy)methyl]-6-methylidene-1,4-oxazepane-4-carboxylate B1-2-13 To a suspension of NaH 60% in oil (2.1 equiv., 3.40 g, 85.1 mmol) in anhydrous DMF (72 mL) was added 3-chloro-2-chloromethyl-1-propene (1 equiv., 4.69 mL, 40.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, and then a solution of B1-2-3 (1 equiv., 11.4 g, 40.5 mmol) in anhydrous THF (50 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (200 mL), and the aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (330 g, gradient: 100:0 to 90:10 cyclohexane / EtOAc) to afford B1-2-13 (5.93 g, 44%) as a colorless oil.

[0874] LC / MS(AN01_001_012): Rt=2.73 min, 100%, [M-C4H8+H] + =278.1.

[0875] tert-Butyl (2S)-2-[(benzyloxy)methyl]-6-oxo-1,4-oxazepane-4-carboxylate B1-2-14 To a solution of B1-2-13 (1 eq., 2.10 g, 6.30 mmol) in a mixture of DCM (38 mL) and acetonitrile (38 mL) were added 2,6-lutidine (2 eq., 1.47 mL, 12.6 mmol), water (57 mL), and sodium periodate (4 eq., 5.39 g, 25.2 mmol) at room temperature. A solution of RuCl3.3HO (0.035 eq., 57.6 mg, 0.220 mmol) in water (6.3 mL) was added dropwise to form a brown suspension. The reaction mixture was vigorously stirred at room temperature for 2 hours. The reaction mixture was diluted with water (150 mL) and extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (120 g, gradient: 100:0 to 85:15 cyclohexane / EtOAc) to afford B1-2-14 as a colorless oil (1.88 g, 89%).

[0876] LC / MS(AN01_001_012): Rt=2.56 min, 100%, [M+H] + =336.1.

[0877] tert-Butyl (2S,6S * )-2-[(benzyloxy)methyl]-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate B1-46-1-(S) * and tert-butyl (2S,6R * )-2-[(benzyloxy)methyl]-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate B1-46-1-(R) * To a solution of B1-2-14 (1 equiv., 1.28 g, 3.82 mmol) in anhydrous THF (35 mL) was added a solution of 3 M MeMgBr in EtO (2.5 equiv., 3.18 mL, 9.54 mmol) under an argon atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with a saturated aqueous solution of NH4Cl (100 mL), and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (80 g, gradient: 100:0 to 70:30 cyclohexane / EtOAc) to give B1-46-1-(S). * (0.650g, 48%) and B1-46-1-(R) * (0.363 g, 27%) was obtained as a colorless oil. Stereochemistry (S) * is arbitrarily assigned to the first eluted product by flash chromatography, and then the second eluted product is assigned to (R) * was assigned to.

[0878] B1-46-1-(S) * :LC / MS(AN01_001_012):Rt=2.47 min, 100%, [M-C4H8+H] + =296.2.

[0879] B1-46-1-(R) * :LC / MS(AN01_001_012):Rt=2.41 min, 100%, [M-C4H8+H] + =296.2.

[0880] Preparation of Intermediates B1-84-1 and B1-85-1

[0881] [ka]

[0882] Ethyl 3-[(prop-2-en-1-yl)amino]propanoate B1-6-3 A solution of allylamine (1 equiv., 2.5 g, 3.28 mL, 43.79 mmol) in EtOH (65 mL) was purged with argon, and ethyl acrylate (1 equiv., 4.38 g, 4.76 mL, 43.79 mmol) was added, and the resulting mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated to dryness under reduced pressure to afford B1-6-3 (6.58 g, 41.85 mmol, 95.59%) as a colorless oil. The crude product was used directly in the next step without further purification.

[0883] LC / MS (AN01_001_012): Rt=1.67 min, ND, [M+H] + =258.1.

[0884] Ethyl 3-{[(tert-butoxy)carbonyl](prop-2-en-1-yl)amino}propanoate B1-6-4 A solution of B1-6-3 (1 equiv., 6.58 g, 41.85 mmol) in DCM (65 mL) was purged with argon, and diisopropylamine (1 equiv., 4.24 g, 5.92 mL, 41.85 mmol), BocO (1 equiv., 9.13 g, 8.96 mL, 41.85 mmol), and DMAP (0.1 equiv., 0.51 g, 4.19 mmol) were added at room temperature. The resulting mixture was stirred for 24 h. The reaction mixture was then diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure to afford B1-6-4 (10.6 g, 41.19 mmol, 98%) as a yellow oil. The crude product was used directly in the next step without further purification.

[0885] LC / MS (AN01_001_012): Rt=2.53 min, 100%, [M-Boc+H] + =158.1.

[0886] Ethyl 2-({[(tert-butoxy)carbonyl](prop-2-en-1-yl)amino}methyl)pent-4-enoate B1-6-6 A solution of B1-6-4 (1 equiv., 1 g, 3.89 mmol) in THF (10 mL) was purged with argon and 1 M LiHMDS in THF (1.1 equiv., 4.27 mL, 4.27 mmol) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 1 h, after which allyl iodide (1.1 equiv., 0.72 g, 0.39 mL, 4.27 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure to afford B1-6-6 (1.1 g, 95%) as an orange oil. The crude product was used directly in the next step.

[0887] LC / MS (AN01_001_012): Rt=2.76 min, 100%, [M-Boc+H] + =198.1.

[0888] 1-tert-butyl 3-ethyl 2,3,4,7-tetrahydro-1H-azepine-1,3-dicarboxylate B1-6-7 A solution of B1-6-6 (1 equiv., 1.1 g, 3.7 mmol) in DCM (200 mL) was purged with argon and benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.1 equiv., 0.305 g, 0.37 mmol) was added at room temperature, and the resulting mixture was stirred at 55° C. for 7 h.

[0889] The reaction was concentrated to dryness under reduced pressure.

[0890] Residual Ruthenium Scavenger Procedure: The crude material was dissolved in DCM (0.1 M) and 2-mercaptonicotinic acid (5 equiv.) was added. The reaction mixture was heated and stirred at 60 °C for 1 h, then warmed back to room temperature and washed with saturated NaHCO3 followed by water. The organic layer was concentrated under reduced pressure, and the crude residue was purified by ELSD flash chromatography on silica gel (amorphous SiOH, 50 μm, 80 g intercalate, dry-packed (silica), mobile phase gradient: 100 / 0 to 60 / 40 cyclohexane / EtOAc over 40 min) and coevaporated with DCM to give B1-6-7 (0.57 g, 2.098 mmol, 57%) as a black oil.

[0891] LC / MS (AN01_001_012): Rt=2.56 min, 82.71%, [M- t Bu+H] + =214.1.

[0892] 1-tert-butyl 3-ethyl 5-hydroxyazepane-1,3-dicarboxylate B1-84-1 and 1-tert-butyl 3-ethyl 6-hydroxyazepane-1,3-dicarboxylate B1-85-1 Starting with B1-6-7 (1 equiv., 673 mg, 2.5 mmol), general procedure I was used to obtain B1-84-1 (82 mg, 0.28 mmol, 11%) and B1-85-1 (319 mg, 1.11 mmol, 44%) as colorless oils after purification on silica gel by flash chromatography (amorphous SiOH, 15 μm, 40 g, dry-packed (silica), mobile phase gradient: Cyclo / EtOAc 10 / 0 to 4 / 6 over 30 min) and coevaporation with DCM. The C-6 and C-7 regioisomers were confirmed by 2D NMR analysis. SFC analysis indicated the presence of two pairs of enantiomers in B1-85-1 and one pair of enantiomers in B1-84-1 (see below).

[0893] B1-84-1 (C5 positional isomer): Chiral SFC analysis: Chiralpak (AD-3 4.6 x 100 mm, mobile phase: CO2 / (iPrOH+0.3% iPrNH2) 85 / 15): pair of enantiomers (two products), Rt = 0.76 min and 0.98 min, 48.05% and 51.95%.

[0894] LC / MS (AN01_001_026): Rt=7.97 min, 91.2%, [M- t Bu+H] + =232.1.

[0895] 1 H NMR (400MHz, DMSO) δ4.69-4.60(m, 1H), 4.16-4.01(m, 2H), 3.98-3.87(m, 1H), 3.64-3.41(m, 2H), 3.37-3.28(m, 1H), 3 .24-3.11(m, 1H), 3.07-2.91(m, 1H), 1.89-1.79(m, 1H), 1.78-1.55(m, 3H), 1.48-1.31(m, 9H), 1.19(t, J=7.1Hz, 3H).

[0896] B1-85-1 (C6 positional isomer): Chiral SFC analysis: Chiralpak (IG-3 4.6 x 100 mm, mobile phase: CO2 / (iPrOH+0.3% iPrNH2) 90 / 10): two pairs of enantiomers (four products), Rt = 1.64, 1.95, 2.46 and 2.90 min, 31.84, 32.79, 16.57 and 18.80%.

[0897] LC / MS (AN01_001_026): Rt = 8.00 and 8.14 min, 53.24 and 43.62%, [M- t Bu+H] + =232.1.

[0898] 1 H NMR (400MHz, DMSO) δ4.23-3.56(m, 5H), 3.10(dd, J=14.0, 10.7Hz, 1H), 2.85-2.74(m, 1H), 2. 50-2.35(m, 4H), 2.09-1.99(m, 1H), 1.79-1.63(m, 1H), 1.47-1.33(m, 9H), 1.27-1.12(m, 3H).

[0899] Intermediate I1-2-1-(S) as a mixture * and I1-3-1-(S) * Preparation of

[0900] [ka]

[0901] [(2S)-3-(benzyloxy)-2-hydroxypropyl](prop-2-en-1-yl)amine I1-1-11 To I1-1-2 (1 equiv., 10 g, 9.26 mL, 60.9 mmol) was added allylamine (17.55 equiv., 61.04 g, 80 mL, 1069.077 mmol), and the resulting mixture was stirred at 50 °C for 19 h. The reaction mixture was concentrated to dryness under reduced pressure to give I1-1-11 (13.5 g, 66%) as a yellow oil, contaminated with 23% I1-1-11'.

[0902] LC / MS (AN01_001_012): Rt=1.57 min, 91.2%, [M+H] + =222.1.

[0903] 1 H NMR (400MHz, DMSO) δ7.58-7.07(m, 5H), 5.83(ddt, J=17.2, 10.2, 5.7Hz, 1H), 5.14(dq, J=17.2, 1.8Hz, 1H), 5.02(ddt, J=10.3, 2.5, 1.4Hz, 1 H), 4.72(s, 1H), 4.48(s, 2H), 3.71(dt, J=11.5, 5.3Hz, 1H), 3.42-3.34(m, 2H), 3.14(dt, J=5.5, 1.2Hz, 2H), 2.61-2.42(m, 2H), 1.67(s, 1H).

[0904] tert-Butyl N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-N-(prop-2-en-1-yl)carbamate I1-1-12 Starting from I1-1-11 (1 equiv., 2.6 g, 7.52 mmol) (containing approximately 75% mol of I1-1-11 and approximately 25% mol of I1-1-11), general procedure G was used to obtain I1-1-12 as a yellowish oil (2.32 g, 96%) after purification on silica gel by flash chromatography (amorphous SiOH, 50 μm, 80 g intercalated, dry packed (silica), mobile phase gradient: DCM / MeOH 100 / 0 to 95 / 5 over 30 min) and coevaporation with DCM.

[0905] LC / MS (AN01_001_012): Rt=2.56 min, 100%, [M-Boc+H] + =222.1.

[0906] 1H NMR (400MHz, DMSO) δ7.40-7.23(m, 5H), 5.86-5.60(m, 1H), 5.14-4.98(m, 2H), 4.95-4.80(m, 1 H), 4.49(s, 2H), 3.96-3.73(m, 3H), 3.42-3.23(m, 3H), 3.04-2.88(m, 1H), 1.39-1.26(m, 9H).

[0907] tert-Butyl N-[(2S)-3-(benzyloxy)-2-(prop-2-en-1-yloxy)propyl]-N-(prop-2-en-1-yl)carbamate I1-1-13 A solution of I1-1-12 (1 equiv., 3.0 g, 9.33 mmol) in DMSO (35 mL) was purged with argon, and KOH (2 equiv., 1.047 g, 18.67 mmol) and allyl bromide (3 equiv., 3.39 g, 2.44 mL, 28.00 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel (amorphous SiOH, 50 μm, 80 g intercalant, dry-packed (silica), mobile phase gradient: 100 / 0 to 85 / 15 cyclohexane / EtOAc over 25 min). The fractions containing the compound were combined, evaporated in vacuo and co-evaporated with DCM to give I1-1-13 (2.26 g, 67%) as a yellowish oil.

[0908] LC / MS (AN01_001_012): Rt=2.90 min, 100%, [M-Boc+H] + =262.2.

[0909] 1H NMR (400MHz, DMSO) δ7.40-7.24(m, 5H), 5.93-5.79(m, 1H), 5.81-5.64(m, 1H), 5.30-5.19(m, 1H), 5.16-4.99(m, 3H), 4.50(s, 2H), 4.15-4. 05(m, 1H), 4.04-3.94(m, 1H), 3.90-3.73(m, 2H), 3.74-3.64(m, 1H), 3 .53-3.39(m, 2H), 3.31-3.22(m, 1H), 3.20-3.10(m, 1H), 1.37(s, 9H).

[0910] tert-Butyl (2S)-2-[(benzyloxy)methyl]-3,4,5,8-tetrahydro-2H-1,4-oxazocine-4-carboxylate I1-1-14 Starting from I1-1-13 (1 equiv., 2.64 g, 7.29 mmol) and using general procedure H, after purification on silica gel by flash chromatography (amorphous SiOH, 50 μm, 25 g intercalate, dry packing (silica), mobile phase gradient: 100 / 0 to 80 / 20 cyclohexane / EtOAc over 35 min) and coevaporation with DCM, I1-1-14 was obtained as a black gum (1.86 g, 76%).

[0911] LC / MS (AN01_001_012): Rt=2.72 min, 100%, [M-Boc+H] + =234.1.

[0912] 1 H NMR (400MHz, DMSO) δ7.44-7.21(m, 5H), 5.85-5.67(m, 1H), 5.61-5.44(m, 1H), 4.55-4.49(m, 2H) , 4.49-4.37(m, 1H), 4.13-3.66(m, 4H), 3.62-3.33(m, 3H), 2.95-2.70(m, 1H), 1.44-1.29(m, 9H).

[0913] Mixture of tert-butyl (2S)-2-[(benzyloxy)methyl]-7-hydroxy-1,4-oxazocane-4-carboxylate and tert-butyl (2S)-2-[(benzyloxy)methyl]-6-hydroxy-1,4-oxazocane-4-carboxylate I1-2-1-(S) * and I1-3-1-(S) * Starting from I1-1-14 (1 equiv., 1 g, 3 mmol) and using general procedure I, after purification on silica gel by ELSD flash chromatography (amorphous SiOH, 15 μm, 40 g intercalation, dry packing (silica), mobile phase gradient: 100 / 0 to 50 / 50 cyclohexane / EtOAc over 40 min) and coevaporation with DCM, a mixture of I1-2 / 3-1 (59:41 ratio from chiral SFC) was obtained as a brown oil (601 mg, 57%). (The positions of the C-6 and C-7 regioisomers were determined to be the final compounds (2S,7S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-7-methoxy-1,4-oxazocane-2-carboxamide and (2S,6S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-7-methoxy-1,4-oxazocane-2-carboxamide.) * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-1,4-oxazocane-2-carboxamide).

[0914] Chiral SFC analysis: Chiralpak (OD-3 4.6 x 100 mm, mobile phase: CO2 / (MeOH+0.2% iPrNH2) 95 / 05): two products, Rt = 5.09 and 6.31 min, 58.95 and 41.05%.

[0915] LC / MS (AN01_001_026): Rt=8.96 min, 96.3%, [M-Boc+H] + =252.5.

[0916] 1H NMR (400MHz, DMSO) δ7.40-7.24(m, 5H), 4.76-4.59(m, 1H), 4.55-4.43(m, 2H), 4.09-3.74(m, 2H) , 3.74-3.51(m, 4H), 3.51-3.33(m, 2H), 3.23-2.53(m, 2H), 2.06-1.51(m, 2H), 1.44-1.35(m, 9H).

[0917] 3.5 Intermediate I1-2-1-(R) as a mixture * and I1-3-1-(R) * Preparation of

[0918] [ka] tert-Butyl (2S,6R * )-2-[(benzyloxy)methyl]-6-(4-nitrobenzoyloxy)-1,4-oxazocane-4-carboxylate and tert-butyl (2S,7R * )-2-[(benzyloxy)methyl]-6-(4-nitrobenzoyloxy)-1,4-oxazocane-4-carboxylate I1-2-14-(R) * and I1-3-14-(R) *

[0919] I1-2-1-(S) * and I1-3-1-(S) *To a solution of DIAD (1 equiv., 4 g, 10.65 mmol), triphenylphosphine (1.25 equiv., 3.49 g, 13.32 mmol), and 4-nitrobenzoic acid (1.5 equiv., 2.67 g, 15.98 mmol) in THF (40 mL) was added a solution of DIAD (1.2 equiv., 2.58 g, 2.53 mL, 12.78 mmol) in THF (20 mL) at −78° C. The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (150 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure to give the crude product (13.7 g) as a brown oil. The crude product was purified by flash chromatography on silica gel (amorphous SiOH, 50 μm, 220 g intercalate, dry-packed (silica), mobile phase gradient: 100 / 0 to 60 / 40 cyclohexane / EtOAc over 45 min). Fractions containing compound were combined, evaporated in vacuo, and co-evaporated with DCM to give I1-2-14-(R). * and I1-3-14-(R) * was obtained as a brown gum (4.00 g, 7.99 mmol, 75%).

[0920] LC / MS (AN01_001_026, ELSD): Rt = 11.29 and 11.36 min, 11.46 and 83.91%, [M- t Bu+H] + =445.38.

[0921] 1 H NMR (400MHz, DMSO) δ8.43-8.24(m, 2H), 8.25-8.05(m, 2H), 7.43-7.19(m, 5H), 5.23-4.99(m, 1H), 4.55-4. 45(m, 2H), 4.20-3.64(m, 4H), 3.63-3.36(m, 3H), 3.21-2.81(m, 2H), 2.24-2.03(m, 2H), 1.49-1.33(m, 9H).

[0922] tert-Butyl (2S,6R *)-2-[(benzyloxy)methyl]-6-hydroxy-1,4-oxazocane-4-carboxylate and tert-butyl (2S,7R * )-2-[(benzyloxy)methyl]-6-hydroxy-1,4-oxazocane-4-carboxylate and mixture I1-2-1-(R) * and I1-3-1-(R) * .

[0923] I1-2-14-(R) in MeOH (57 mL) and HO (14 mL) * and I1-3-14-(R) * To a solution of the mixture of (1 equiv, 5.77 g, 10.098 mmol) was added lithium hydroxide hydrate (2 equiv, 0.85 g, 20.2 mmol) at room temperature and the reaction was stirred for 16 hours.

[0924] The MeOH from the reaction mixture was removed under reduced pressure. The residue was diluted with an aqueous solution of NaHCO3 (40 mL) and water (60 mL) (pH ∼10) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the crude product (3.24 g) as a yellow gum. The crude product was purified by flash chromatography on silica gel (amorphous SiOH, 50 μm, 80 g intercalant, dry-packed (silica), mobile phase gradient: 100 / 0 to 90 / 10 DCM / MeOH over 40 min). The compound-containing fractions were combined, evaporated in vacuo, and co-evaporated with DCM to give I1-2-1-(R). * and I1-3-1-(R) * was obtained as a yellow oil (2.73 g, 77%).

[0925] LC / MS (AN01_001_026): Rt = 8.79 and 9.53 min, 71.71 and 15.81%, [M-Boc+H] + =252.50

[0926] 1H NMR (400MHz, DMSO) δ7.39-7.24(m, 5H), 4.96-4.60(m, 1H), 4.54-4.42(m, 2H), 4.00-3.50(m, 5H) , 3.45-3.32(m, 2H), 3.21-3.07(m, 1H), 2.95-2.63(m, 2H), 2.07-1.59(m, 2H), 1.45-1.31(m, 9H).

[0927] Example 1: (2S,6R * )-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-6-methyl-1,4-oxazepane-2-carboxamide and (2S,6S * Synthesis of )-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-6-methyl-1,4-oxazepane-2-carboxamide (Compound 2-A and Compound 2-B)

[0928] [ka]

[0929] Part A: Intermediate B1-46-1-(S) * and B1-46-1-(R) * Synthetic scheme for the preparation of

[0930] [ka]

[0931] tert-Butyl N-[(2S)-2,3-dihydroxypropyl]carbamate (B1-2-2)

[0932] [ka]

[0933] To a solution of (2S)-3-aminopropane-1,2-diol (1 equiv., 14.4 g, 158.1 mmol) and EtN (1.01 equiv., 22.2 mL, 159.6 mmol) in anhydrous MeOH (245 mL) was added a solution of BocO (1.2 equiv., 41.4 g, 189.7 mmol) in anhydrous DCM (41 mL) at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure to give B1-2-2 as a pale yellow oil (30.2 g, quantitative). The crude product was deemed quantitative and was used as is.

[0934] LC / MS (AN01_001_012): Rt=1.69 min, non-UV active, [M+Na] + =214.1.

[0935] tert-Butyl N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]carbamate (B1-2-3)

[0936] [ka] To a solution of B1-2-2 (1 equiv., 1.72 g, 8.99 mmol), di(n-butyl)tin oxide (0.1 equiv., 0.224 g, 0.899 mmol), and TBAB (0.3 equiv., 0.870 g, 2.70 mmol) was added DIPEA (2 equiv., 3.13 mL, 18.0 mmol) and BnBr (2 equiv., 2.15 mL, 18.0 mmol) at room temperature under an argon atmosphere. The reaction mixture was stirred at 70 °C for 6 h. The reaction mixture was concentrated under reduced pressure, then taken up in EtOAc (50 mL), and filtered through a pad of silica gel. The latter was rinsed with EtOAc (3 × 150 mL), and the filtrate was concentrated under reduced pressure. The resulting orange oil (4.46 g) was purified by silica gel flash chromatography (120 g, gradient: 100:0 to 50:50 cyclohexane / EtOAc) to give B1-2-3 as a pale yellow oil (2.31 g, 75%), which was contaminated with the other -OBn regioisomer protected at the 2-position ( 1 17% by weight by H NMR analysis.

[0937] LC / MS (AN01_001_012): Rt=2.28 min, 100%, [M+Na] + =304.1.

[0938] tert-Butyl (2S)-2-[(benzyloxy)methyl]-6-methylidene-1,4-oxazepane-4-carboxylate B1-2-13

[0939] [ka] To a suspension of NaH 60% in oil (2.1 equiv., 3.40 g, 85.1 mmol) in anhydrous DMF (72 mL) was added 3-chloro-2-chloromethyl-1-propene (1 equiv., 4.69 mL, 40.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, and then a solution of B1-2-3 (1 equiv., 11.4 g, 40.5 mmol) in anhydrous THF (50 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (200 mL), and the aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (330 g, gradient: 100:0 to 90:10 cyclohexane / EtOAc) to afford B1-2-13 (5.93 g, 44%) as a colorless oil.

[0940] LC / MS(AN01_001_012): Rt=2.73 min, 100%, [M-C4H8+H] + =278.1.

[0941] tert-Butyl (2S)-2-[(benzyloxy)methyl]-6-oxo-1,4-oxazepane-4-carboxylate B1-2-14

[0942] [ka] To a solution of B1-2-13 (1 eq., 2.10 g, 6.30 mmol) in a mixture of DCM (38 mL) and acetonitrile (38 mL) were added 2,6-lutidine (2 eq., 1.47 mL, 12.6 mmol), water (57 mL), and sodium periodate (4 eq., 5.39 g, 25.2 mmol) at room temperature. A solution of RuCl3.3HO (0.035 eq., 57.6 mg, 0.220 mmol) in water (6.3 mL) was added dropwise to form a brown suspension. The reaction mixture was vigorously stirred at room temperature for 2 hours. The reaction mixture was diluted with water (150 mL) and extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (120 g, gradient: 100:0 to 85:15 cyclohexane / EtOAc) to afford B1-2-14 as a colorless oil (1.88 g, 89%).

[0943] LC / MS(AN01_001_012): Rt=2.56 min, 100%, [M+H] + =336.1.

[0944] tert-Butyl (2S,6S * )-2-[(benzyloxy)methyl]-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate B1-46-1-(S) * and tert-butyl (2S,6R * )-2-[(benzyloxy)methyl]-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate B1-46-1-(R) *

[0945] [ka] To a solution of B1-2-14 (1 equiv., 1.28 g, 3.82 mmol) in anhydrous THF (35 mL) was added a 3 M solution of MeMgBr in EtO (2.5 equiv., 3.18 mL, 9.54 mmol) under an argon atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with a saturated aqueous solution of NH4Cl (100 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (80 g, gradient: 100:0 to 70:30 cyclohexane / EtOAc) to give B1-46-1-(S). * (0.650g, 48%) and B1-46-1-(R) * (0.363 g, 27%) was obtained as a colorless oil. Stereochemistry (S) * is arbitrarily assigned to the first eluted product by flash chromatography, and then the second eluted product is assigned to (R) * was assigned to.

[0946] B1-46-1-(S) * :LC / MS(AN01_001_012):Rt=2.47 min, 100%, [M-C4H8+H] + =296.2.

[0947] B1-46-1-(R) * :LC / MS(AN01_001_012):Rt=2.41 min, 100%, [M-C4H8+H] + =296.2.

[0948] Part B: General strategy for the synthesis of compounds 2-A and 2-B

[0949] [ka]

[0950] Synthetic scheme for the preparation of compound 2-A: Protecting group-free approach (A)

[0951] [ka]

[0952] tert-Butyl (2S,6R * )-6-Hydroxy-2-(hydroxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate B1-46-2-(R) *

[0953] [ka] B1-46-1-(R) * (1 equiv., 0.160 g, 0.455 mmol) and using general procedure A, B1-46-2-(R) * was obtained as a colorless oil (0.119 g, 100%).

[0954] LC / MS (AN01_001_012): Rt=1.83 min, non-UV active, [M+Na] + =284.1.

[0955] (2S,6R * )-4-[(tert-butoxy)carbonyl]-6-hydroxy-6-methyl-1,4-oxazepane-2-carboxylic acid B1-46-3-(R) *

[0956] [ka] B1-46-2-(R) in acetone (7 mL) *To a solution of 1,2,3-trichlorocyanuric acid (1 equiv., 0.110 g, 0.421 mmol) and sodium bromide (0.3 equiv., 13.2 mg, 0.126 mmol) was added a saturated aqueous solution of NaHCO3 (2 mL) at room temperature. To the resulting mixture, trichlorocyanuric acid (2.2 equiv., 0.215 mg, 0.926 mmol) and 2,2,6,6-tetramethylpiperidine-1-oxyl (0.03 equiv., 1.97 mg, 0.0126 mmol) were added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 h. Isopropanol (10 mL) was added at room temperature, and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc (50 mL), and a saturated aqueous solution of NaHCO3 (50 mL) was added. The two layers were separated, and the aqueous layer was washed with EtOAc (50 mL). The aqueous layer was then acidified with 3 M aqueous HCl to pH 1 and extracted with DCM (2 x 50 mL). The aqueous layer was further extracted with a mixture of CHCl / isopropanol (8:2, 2 x 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give B1-46-3-(R). * was obtained as a yellowish oil (42.6 mg, 37%).

[0957] LC / MS (AN01_001_012): Rt=1.83 min, non-UV active, [M+Na] + =298.1.

[0958] tert-Butyl (2S,6R * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate B1-46-4-(R) *

[0959] [ka] BB01 (1 equivalent, 45.6 mg, 0.138 mmol) and B1-46-3-(R) *(1.05 equiv., 40.0 mg, 0.145 mmol) using general procedure C to give B1-46-4-(R) after purification by silica gel flash chromatography (12 g, gradient: 100:0 to 97:3 DCM / MeOH). * was obtained as a white solid (27.3 mg, 36%).

[0960] LC / MS (AN01_001_012), Rt=2.37 min, 100%, [M+Na] + =573.2.

[0961] (2S,6R * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-6-methyl-1,4-oxazepane-2-carboxamide (compound 2-A)

[0962] [ka] B1-46-4-(R) * Starting from (1 equiv., 25.0 mg, 0.0454 mmol), general procedure D was used to obtain compound 2-A as a white solid (9.70 mg, 47%) after purification by preparative HPLC (eluent: water + 0.1% TFA / acetonitrile, gradient: 15-30% acetonitrile in water + 0.1% TFA, column: XBridge C18 (30 × 150 (5 μm)), flow rate: 43 mL / min) and lyophilization.

[0963] LC / MS (AN01_001_026): Rt=6.40 min, 99.5%, [M+H] + =451.5.

[0964] 1H NMR (DMSO-d6, 400MHz): δppm8.68 (d, j=8.4Hz, 1H), 7.65 (d, j=8.3Hz, 2H), 7.59 -7.54(m, 1H), 7.43-7.35(m, 4H), 5.02(qJ=8.5Hz, 1H), 4.55(s, 1H), 3.99(dd, j= 7.8, 5.1Hz, 1H), 3.60(d, j=12.7Hz, 1H), 3.49(d, j=12.6Hz, 1H), 3.40(s, 3H), 3 .25-3.14(m, 2H), 3.02(dd, j=14.1, 5.1Hz, 1H), 2.62-2.45(m, 4H), 0.98(s, 3H).

[0965] Synthetic scheme for the preparation of compound 2-B: Protecting group approach (B)

[0966] [ka]

[0967] (2S,6S * )-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane B1-46-2-(S) *

[0968] [ka] B1-46-1-(S) *To a solution of TBDMSOTf (1 equiv., 0.320 g, 0.911 mmol) and 2,6-lutidine (2.5 equiv., 0.265 mL, 2.28 mmol) in anhydrous DCM (3 mL) was added TBDMSOTf (1.5 equiv., 0.310 mL, 1.37 mmol) and DMAP (0.05 equiv., 5.56 mg, 0.0455 mmol) under an argon atmosphere. The reaction mixture was stirred at room temperature for 6 h. The resulting mixture was diluted with DCM (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (40 g, gradient: 100 / 0 to 50:50 cyclohexane / EtOAc) to give B1-46-2-(S). * was obtained as a pale yellow oil (0.308 g, 93%).

[0969] LC / MS (AN01_001_012): Rt=2.30 min, 100%, [M+H] + =366.3.

[0970] tert-Butyl (2S,6S * )-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane-4-carboxylate B1-46-3-(S) *

[0971] [ka] B1-46-2-(S) in anhydrous MeOH (1.3 mL) * To a solution of BocO (1.2 equiv., 0.218 g, 1.00 mmol) in anhydrous DCM (0.25 mL) was added a solution of BocO (1.2 equiv., 0.218 g, 1.00 mmol) under an argon atmosphere. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure to give B1-46-3-S * was obtained as a colorless oil (0.389 g, quantitative). The crude mixture was deemed quantitative and used as is.

[0972] LC / MS (AN01_001_012): Rt=3.38 min, 100%, [M+Na] + =488.3.

[0973] tert-Butyl (2S,6S * )-6-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate B1-46-4-(S) *

[0974] [ka] B1-46-3-(S) * (1 equiv., 0.385 g, 0.827 mmol) and using general procedure A, B1-46-4-(S) * was obtained as a colorless oil (0.306 g, 99%).

[0975] LC / MS (AN01_001_012): Rt = 2.95 min, no UV activity, [M-C4H8+H] + =320.2.

[0976] (2S,6S * )-4-[(tert-butoxy)carbonyl]-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane-2-carboxylic acid B1-46-5-(S) *

[0977] [ka] B1-46-4-(S) * (1 equiv., 0.290 g, 0.772 mmol) and using general procedure B, B1-46-5-(S) * was obtained as a yellowish oil (0.219 g, 73%).

[0978] LC / MS (AN01_001_012): Rt=2.84 min, no UV activity, [M+Na] + =412.2.

[0979] tert-Butyl (2S,6S * )-6-[(tert-butyldimethylsilyl)oxy]-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methyl-1,4-oxazepane-4-carboxylate B1-46-6-(S) *

[0980] [ka] BB01 (1 equivalent, 0.173 g, 0.526 mmol) and B1-46-5-(S) * (1.05 equiv., 0.215 g, 0.552 mmol) using general procedure C to give B1-46-6-(S) after purification by silica gel flash chromatography (25 g, gradient: 100:0 to 70:30 cyclohexane / EtOAc). * was obtained as an orange solid (0.209 g, 60%).

[0981] LC / MS (AN01_001_012): Rt=3.08 min, 100%, [M+Na] + =687.3.

[0982] tert-Butyl (2S,6S * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate B1-46-7-(S) *

[0983] [ka] B1-46-6-(S) in anhydrous THF (1.85 mL) * To a solution of B1-46-7-(S) (1 equiv., 0.200 g, 0.301 mmol) was added a 1 M solution of TBAF in THF (1.5 equiv., 0.451 mL, 0.451 mmol) under an argon atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (12 g, gradient: 100:0 to 25:75 cyclohexane / EtOAc) to give B1-46-7-(S). * as a colorless oil (0.116 g, 70%).

[0984] LC / MS (AN01_001_012): Rt=2.38 min, 100%, [M+Na] + =573.2.

[0985] (2S,6S * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-6-methyl-1,4-oxazepane-2-carboxamide (compound 2-B)

[0986] [ka] B1-46-7-(S) * Starting with (1 equiv., 0.115 g, 0.209 mmol) and using general procedure D, compound 2B was purified by silica gel flash chromatography (4 g, gradient: 100:0 to 93:7 DCM / MeOH), followed by preparative HPLC (eluent: water + 0.1% TFA / acetonitrile, gradient: 20 to 35% acetonitrile in water + 0.1% TFA, column: XBridge C18 (30 × 150 (5 μm)), flow rate: 43 mL / min) to give compound 2B as a white solid (13.8 mg, 15%) after purification and lyophilization.

[0987] LC / MS (AN01_001_026): Rt=6.54 min, 100%, [M+H] + =451.4.

[0988] 1 H NMR (DMSO-d6, 400MHz): δppm8.56 (d, j=8.4Hz, 1H), 7.65 (d, j=8.3Hz, 2H), 7.5 8-7.53(m, 1H), 7.40-7.37(m, 4H), 5.01(q, J=8.7Hz, 1H), 4.47(s, 1H), 4.04(dd , j=8.8, 4.4Hz, 1H), 3.50-3.44(m, 2H), 3.40(s, 3H), 3.25-3.14(m, 2H), 3.07(d d, j=14.2, 4.4Hz, 1H), 2.63(d, j=13.7Hz, 1H), 2.48-2.42(m, 3H), 1.03(s, 3H).

[0989] Example 2: (2S, 6S * )-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methoxy-6-methyl-1,4-oxazepane-2-carboxamide and (2S,6R * Synthesis of )-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methoxy-6-methyl-1,4-oxazepane-2-carboxamide (Compound 3-A and Compound 3-B)

[0990] [ka]

[0991] Synthetic scheme for the preparation of compound 3-A

[0992] [ka]

[0993] tert-Butyl (2S,6S *)-2-[(benzyloxy)methyl]-6-methoxy-6-methyl-1,4-oxazepane-4-carboxylate B1-47-1-(S) *

[0994] [ka] B1-46-1-(S) * (1 equiv., 0.320 g, 0.910 mmol) using general procedure E to give B1-47-1-(S) after purification by silica gel flash chromatography (25 g, gradient: 100:0 to 80:20 cyclohexane / EtOAc). * was obtained as a colorless oil (0.268 g, 81%).

[0995] LC / MS (AN01_001_012): Rt=2.65 min, 100%, [M+Na]+=388.2.

[0996] tert-Butyl (2S,6S * )-2-(hydroxymethyl)-6-methoxy-6-methyl-1,4-oxazepane-4-carboxylate B1-47-2-(S) *

[0997] [ka] B1-47-1-(S) * (1 equiv., 0.265 g, 0.725 mmol) and using general procedure A, B1-47-2-(S) * was obtained as a colorless oil (0.181 g, 91%).

[0998] LC / MS (AN01_001_012): Rt=2.00 min, non-UV active, [M+Na] + =298.2.

[0999] (2S,6S *)-4-[(tert-butoxy)carbonyl]-6-methoxy-6-methyl-1,4-oxazepane-2-carboxylic acid B1-47-3-(S) *

[1000] [ka] B1-47-2-(S) * (1 equiv., 0.175 g, 0.636 mmol) and using general procedure B, B1-47-3-(S) * was obtained as a white solid (0.147 g, 80%).

[1001] LC / MS (AN01_001_012): Rt=1.98 min, non-UV active, [M+Na] + =312.1.

[1002] (2S,6S * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5yl)phenyl]ethyl]carbamoyl}-6-methoxy-6-methyl-1,4-oxazepane-4-carboxylate B1-47-4-(S) *

[1003] [ka] BB01 (1 equivalent, 0.157 g, 0.477 mmol) and B1-47-3-(S) * (1.05 equiv., 0.145 g, 0.501 mmol) using general procedure C to give B1-47-4-(S) after purification by silica gel flash chromatography (25 g, gradient: 100:0 to 25:75 cyclohexane / EtOAc). * was obtained as an orange solid (0.209 g, 77%).

[1004] LC / MS (AN01_001_012): Rt=2.51 min, 100%, [M+Na] + =587.3.

[1005] (2S,6S * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-6-methyl-1,4-oxazepane-2-carboxamide Compound 3-A

[1006] [ka] B1-47-4-(S) * Starting with (1 equiv., 0.100 g, 0.170 mmol), general procedure D was used to give compound 3-A as a white solid (55.3 mg, 70%) after purification by silica gel flash chromatography (4 g, gradient: 100:0 to 95:5 DCM / MeOH).

[1007] LC / MS (AN01_001_026): Rt=6.69 min, 99.8%, [M+H] + =465.5.

[1008] 1 H NMR (DMSO-d6, 400MHz): δppm8.58 (d, j=8.4Hz, 1H), 7.66 (d, j=8.2Hz, 2H), 7.59-7.52 (m, 1H), 7.45-7.33(m, 4H), 5.01(q, J=8.7Hz, 1H), 4.03(dd, J=9.3, 4.0Hz, 1H), 3.70(d, J=12.5Hz, 1H), 3.53 (d, J = 12.5 Hz, 1H), 3.40 (s, 3H), 3.26-3.16 (m, 2H), 3.14 (s, 3H), 3.08 (dd, J = 14.1, 4.3 Hz, 1H), 2.92 (d, J = 14.4 Hz, 1H), 2.38 (dt, J = 14.3, 4.8 Hz, 2H), 1.05 (s, 3H), one -NH signal missing.

[1009] Synthetic scheme for the preparation of compound 3-B

[1010] [ka]

[1011] tert-Butyl (2S,6R * )-2-[(benzyloxy)methyl]-6-methoxy-6-methyl-1,4-oxazepane-4-carboxylate B1-47-1-(R) *

[1012] [ka] B1-46-1-(R) * (1 equiv., 0.360 g, 1.02 mmol) using general procedure E to give B1-47-1-(R) after purification by silica gel flash chromatography (25 g, gradient: 100:0 to 75:25 cyclohexane / EtOAc). * was obtained as a colorless oil (0.311 g, 83%).

[1013] LC / MS (AN01_001_012): Rt=2.65 min, 100%, [M+Na] + =388.2.

[1014] tert-Butyl (2S,6R * )-2-(hydroxymethyl)-6-methoxy-6-methyl-1,4-oxazepane-4-carboxylate B1-47-2-(R) *

[1015] [ka] B1-47-1-(R) * (1 equiv., 0.310 g, 0.848 mmol) and using general procedure A, B1-47-2-(R) * was obtained as a colorless oil (0.208 g, 89%).

[1016] LC / MS (AN01_001_012): Rt=2.00 min, non-UV active, [M+Na] +=298.1.

[1017] (2S,6R * )-4-[(tert-butoxy)carbonyl]-6-methoxy-6-methyl-1,4-oxazepane-2-carboxylic acid B1-47-3-(R) *

[1018] [ka] B1-47-2-(R) * (1 equiv., 0.205 g, 0.744 mmol) and using general procedure B, B1-47-3-(R) * was obtained as a white solid (0.124 g, 58%).

[1019] LC / MS (AN01_001_012): Rt=2.00 min, non-UV active, [M+Na] + =312.1.

[1020] (2S,6R * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5yl)phenyl]ethyl]carbamoyl}-6-methoxy-6-methyl-1,4-oxazepane-4-carboxylate B1-47-4-(R) *

[1021] [ka] BB01 (1 equivalent, 0.130 g, 0.395 mmol) and B1-47-3-(R) * (1.05 equiv., 0.120 g, 0.415 mmol) using general procedure C to give B1-47-4-(R) after purification by silica gel flash chromatography (25 g, gradient: 100:0 to 25:75 cyclohexane / EtOAc). * was obtained as an orange solid (0.181 g, 81%).

[1022] LC / MS (AN01_001_012): Rt=2.53 min, 92%, [M+Na] + =587.3.

[1023] (2S,6R * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-6-methyl-1,4-oxazepane-2-carboxamide (compound 3-B)

[1024] [ka] B1-47-4-(R) * Starting with (1 equiv., 96.1 mg, 0.170 mmol), general procedure D was used to obtain compound 3-B as a white solid (60.4 mg, 76%) after purification on silica gel by flash chromatography (4 g, gradient: 100:0 to 95:5 DCM / MeOH).

[1025] LC / MS (AN01_001_026): Rt=6.64 min, 99.4%, [M+H]+=465.5.

[1026] 1 H NMR (DMSO-d6): δppm8.57 (d, J=8.5Hz, 1H), 7.65 (d, J=8.3Hz, 2H), 7.59-7.54 (m, 1H), 7 .44-7.32(m, 4H), 5.01(q, J=8.5Hz, 1H), 3.95-3.91(m, 2H), 3.43(d, J=13.3Hz, 1H), 3. 40 (s, 3H), 3.26-3.14 (m, 5H), 3.08 (dd, J = 13.6, 4.2 Hz, 1H), 2.69 (d, J = 13.5 Hz, 1H), 2.64 (d, J = 13.6 Hz, 1H), 2.36 (dd, J = 13.6, 9.8 Hz, 1H), 0.99 (s, 3H), one -NH signal missing.

[1027] Example 3: Synthesis of N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)azocane-3-carboxamide (Compound 1-A)

[1028] [ka]

[1029] Synthetic scheme for the preparation of compound 1-A

[1030] [ka]

[1031] Ethyl 3-[(but-3-en-1-yl)[(tert-butoxy)carbonyl]amino]propanoate H1-2-3

[1032] [ka] A solution of but-3-en-1-amine hydrochloride H1-2-1 (1 equiv., 1.99 g, 18.5 mmol) and triethylamine (1.05 equiv., 2.70 mL, 19.4 mmol) in EtOH (28 mL) was purged with argon and stirred at room temperature for 30 min. Ethyl acrylate (1 equiv., 2.01 mL, 18.5 mmol) was then added, and the resulting mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated under reduced pressure to give a crude mixture containing H1-2-2 (4.88 g, estimated purity: 50%) as a colorless oil.

[1033] A solution of the crude mixture containing H1-2-2 (4.88 g, estimated purity: 50%, 14.2 mmol, 1 equiv.) in DCM (30 mL) was purged with argon, and diisopropylamine (1.2 equiv., 2.42 mL, 17.1 mmol), BocO (1.2 equiv., 3.73 g, 17.1 mmol), and DMAP (0.1 equiv., 0.170 g, 1.42 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 19 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (25 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting yellow oil was purified twice by silica gel flash chromatography (first flash chromatography: 120 g, gradient: 100:0 to 80:20 cyclohexane / EtOAc; second flash chromatography: 40 g, gradient: 80:20 to 0:100 cyclohexane / DCM, then 100:0 to 80:20 DCM / EtOAC) to afford H1-2-3 as a colorless oil (1.99 g, 40% over two steps).

[1034] LC / MS (AN01_001_012): Rt=2.65 min, 100%, [M-C4H8+H] + =216.2.

[1035] Ethyl 2-{[(but-3-en-1-yl)[(tert-butoxy)carbonyl]amino]methyl}pent-4-enoate H1-2-4

[1036] [ka] A solution of H1-2-3 (1 equiv., 1.99 g, 7.33 mmol) in THF (20 mL) was purged with argon and a 1 M solution of LiHMDS in THF (1.1 equiv., 8.07 mL, 8.07 mmol) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 1 hour, after which allyl iodide (1.1 equiv., 0.740 mL, 8.07 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 15 hours. The reaction mixture was cooled to −78° C. and a 1 M solution of LiHMDS in THF (0.2 equiv., 1.47 mL, 1.47 mmol) was added dropwise at −78° C. The reaction was stirred at this temperature for 30 minutes, after which allyl iodide (0.2 equiv., 0.135 mL, 1.47 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting orange oil was purified by silica gel flash chromatography (80 g, gradient: 100:0 to 80:20 cyclohexane / EtOAc) to afford H1-2-4 (1.62 g, 71%) as a yellow oil.

[1037] LC / MS(AN01_001_012): Rt=2.85 min, 100%, [M-C5H8O2+H] + =212.2.

[1038] 1-tert-butyl 3-ethyl 1,2,3,4,7,8-hexahydroazocine-1,3-dicarboxylate H1-2-5

[1039] [ka] A solution of H1-2-4 (1 equiv., 1.20 g, 3.85 mmol) in DCM (200 mL) was purged with argon and benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.1 equiv., 0.318 g, 0.385 mmol) was added at room temperature. The resulting mixture was stirred and refluxed for 7 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting black oil was purified by silica gel flash chromatography (80 g, gradient: 100:0 to 80:20 cyclohexane / EtOAc) to give H1-2-5 as a black oil (0.613 g, 56%).

[1040] LC / MS(AN01_001_012): Rt=2.67 min, 81%, [M-C4H8+H] + =228.1.

[1041] 1-tert-butyl 3-ethylazocane-1,3-dicarboxylate H1-2-6

[1042] [ka] A solution of H1-2-5 (1 equiv., 0.350 g, 1.24 mmol) in EtOH (6 mL) was purged with argon, and 10% Pd / C (0.2 equiv., 0.263 g, 0.247 mmol) was added at room temperature. The resulting mixture was purged with argon (3 times) and then with H (3 times). The reaction mixture was stirred at room temperature under atmospheric pressure of H for 19 hours. The reaction mixture was purged with argon, filtered through a pad of Celite, and rinsed with EtOH (2 × 15 mL). The filtrate was concentrated under reduced pressure to give H1-2-6 as a yellow oil (0.323 g, 92%).

[1043] LC / MS (AN01_001_012): Rt=2.73 min, non-UV active, [M-C4H8+H] + =230.1.

[1044] 1-[(tert-butoxy)carbonyl]azocane-3-carboxylic acid H1-2-7

[1045] [ka] To a solution of H1-2-6 (1 equiv., 0.323 g, 1.13 mmol) in THF (11 mL) was added a solution of LiOH (5 equiv., 0.237 g, 5.66 mmol) in water (5.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 19 h. The reaction mixture was poured dropwise into a stirred mixture of 1 M aqueous HCl (50 mL) and DCM (100 mL) at 0 °C. The resulting mixture was stirred for 1 h (pH ∼ 1), and the layers were separated. The aqueous layer was extracted with DCM (2 × 50 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give H1-2-7 as a yellow oil (0.291 g, 100%).

[1046] LC / MS (AN01_001_012): Rt=2.29 min, non-UV active, [M+Na] + =280.2.

[1047] tert-Butyl-3-{[1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-azocane-1-carboxylate H1-2-8 (mixture of diastereomers)

[1048] [ka] Starting from BB01 (1 equiv., 0.150 g, 0.455 mmol) and H1-2-7 (1.05 equiv., 0.145 g, 0.477 mmol), general procedure C was used to afford H1-2-8 as a yellow gum (0.130 g, 54%) after purification by silica gel flash chromatography (25 g, 100:0 to 50:50 cyclohexane / EtOAc).

[1049] LC / MS(AN01_001_012): Rt=2.64 min, 100%, [M+H] + =533.3.

[1050] N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]azocane-3-carboxamide Compound 1-A (mixture of diastereomers)

[1051] [ka] Starting from H1-2-8 (1 equiv., 0.113 g, 0.212 mmol), general procedure D was used to afford compound 1-A as a white solid (35.4 mg, 39%) after purification by silica gel flash chromatography (12 g, 100:0 to 80:20 DCM / MeOH) and lyophilization.

[1052] LC / MS (AN01_001_026): Rt=7.29 min, 97.8%, [M+H] + =433.4.

[1053] 1 H NMR (DMSO-d6, 400MHz): δppm8.79-8.60(m, 1H), 7.66(dd, j=8.2, 2.9Hz, 2H), 7.58-7.55(m, 1H), 7.43-7.38(m, 4H), 5.00- 4.92(m, 1H), 3.40(s, 3H), 3.18-3.05(m, 2H), 2.92-2.67(m, 4H), 2.60-2.54(m, 1H), 2.46-2.41(m, 1H), 1.75-1.35(m, 8H).

[1054] Example 4: Synthesis of (S)—N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazocane-2-carboxamide (Compound 4)

[1055] [ka]

[1056] [(2S)-3-(benzyloxy)-2-hydroxypropyl](prop-2-en-1-yl)amine I1-1-11 To I-1-2 (1 equiv., 10 g, 9.26 mL, 60.9 mmol) was added allylamine (17.55 equiv., 61.04 g, 80 mL, 1069.077 mmol), and the resulting mixture was stirred at 50 °C for 19 h. The reaction mixture was concentrated to dryness under reduced pressure to give I1-1-11 (13.5 g, 66%) as a yellow oil, contaminated with 23% I1-1-11'.

[1057] LC / MS (AN01_001_012): Rt=1.57 min, 91.2%, [M+H] + =222.1.

[1058] 1 H NMR (400MHz, DMSO) δ7.58-7.07(m, 5H), 5.83(ddt, J=17.2, 10.2, 5.7Hz, 1H), 5.14(dq, J=17.2, 1.8Hz, 1H), 5.02(ddt, J=10.3, 2.5, 1.4Hz, 1H), 4.72(s, 1H), 4.48(s, 2H), 3.71(m, 1H), 3.47-3.25(m, 2H), 3.14(dt, J=5.7, 1.6Hz, 2 H), 2.57(dd, J=11.8, 4.5Hz, 1H), 2.45(dd, J=11.8, 7.2Hz, 1H), 1.67(s, 1H).

[1059] tert-Butyl N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-N-(prop-2-en-1-yl)carbamate I1-1-12 Starting from I1-1-11 (1 equiv., 2.6 g, 7.52 mmol) (containing approximately 75% mol of I1-1-11 and approximately 25% mol of I1-1-11), general procedure G was used to obtain I1-1-12 as a yellowish oil (2.32 g, 96%) after purification on silica gel by flash chromatography (amorphous SiOH, 50 μm, 80 g intercalated, dry packed (silica), mobile phase gradient: DCM / MeOH 100 / 0 to 95 / 5 over 30 min) and coevaporation with DCM.

[1060] LC / MS (AN01_001_012): Rt=2.56 min, 100%, [M-Boc+H] + =222.1.

[1061] 1 H NMR (400MHz, DMSO) δ7.39-7.23(m, 5H), 5.73(s, 1H), 5.21-4.95(m, 2H), 4.88(s, 1 H), 4.48(s, 2H), 4.02-3.66(m, 3H), 3.38-3.20(m, 3H), 2.97(s, 1H), 1.36(s, 9H).

[1062] tert-Butyl N-[(2S)-3-(benzyloxy)-2-(prop-2-en-1-yloxy)propyl]-N-(prop-2-en-1-yl)carbamate I1-1-13 A solution of I1-1-12 (1 equiv., 3 g, 9.33 mmol) in DMSO (12 mL) was purged with argon and added with KOH (2 equiv., 1.047 g, 18.67 mmol) and allyl bromide (3 equiv., 3.39 g, 2.44 mL, 28.001 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure to give the crude product (2.26 g) as a yellow oil. The crude product was purified by flash chromatography on silica gel (amorphous SiOH, 50 μm, 80 g intercalant, dry-packed (silica), mobile phase gradient: 100 / 0 to 85 / 15 cyclohexane / EtOAc over 25 min). The fractions containing the compound were combined, evaporated in vacuo and co-evaporated with DCM to give I1-1-13 (2.26 g, 6.25 mmol, 66.98%) as a yellowish oil.

[1063] LC / MS (AN01_001_012): Rt=2.90 min, 100%, [M-Boc+H] + =262.2.

[1064] 1 H NMR (400MHz, DMSO) δ7.47-7.18(m, 5H), 5.85(ddt, J=17.2, 10.5, 5.3Hz, 1H), 5.73(s, 1H), 5.24 (dq, J=17.3, 1.9Hz, 1H), 5.17-4.97(m, 3H), 4.49(s, 2H), 4.09(ddt, J=13.4, 5.1, 1.7Hz, 1H), 3 .99(ddt, J=13.4, 5.5, 1.6Hz, 1H), 3.75-3.85(m, 2H), 3.72-3.61(m, 1H), 3.48(dd, J=10.6, 4.0 Hz, 1H), 3.42(dd, J=10.6, 5.4Hz, 1H), 3.26(s, 1H), 3.15(dd, J=14.4, 7.0Hz, 1H), 1.37(s, 9H).

[1065] tert-Butyl (2S)-2-[(benzyloxy)methyl]-3,4,5,8-tetrahydro-2H-1,4-oxazocine-4-carboxylate I1-1-14 Starting from I1-1-13 (1 equiv., 0.58 g, 1.59 mmol) and using general procedure H, after purification on silica gel by flash chromatography (amorphous SiOH, 50 μm, 25 g intercalate, dry packing (silica), mobile phase gradient: 100 / 0 to 80 / 20 cyclohexane / EtOAc over 35 min) and coevaporation with DCM, I1-1-14 was obtained as a black gum (0.42 g, 80%).

[1066] LC / MS (AN01_001_012): Rt=2.72 min, 100%, [M-Boc+H] + =234.1.

[1067] 1 H NMR (400MHz, DMSO) δ7.60-7.08(m, 5H), 5.89-5.63(m, 1H), 5.62-5.44(m, 1H), 4.57-4.35(m, 3H), 4.12-3.67(m , 4H), 3.62-3.40(m, 2H), 3.37(dd, J=10.2, 6.0Hz, 1H), 2.81(ddd, J=64.1, 14.3, 9.4Hz, 1H), 1.45-1.32(m, 9H).

[1068] tert-Butyl (2S)-2-(hydroxymethyl)-1,4-oxazocane-4-carboxylate I1-1-15 Starting from I1-1-14 (1 equiv., 94 mg, 0.28 mmol), general procedure D was used to afford I1-1-15 as a yellowish gum (60 mg, 87%).

[1069] LC / MS (AN01_001_012): Rt=2.06 min, 100%, [M-Boc+H] + =144.0.

[1070] 1 H NMR (400MHz, DMSO) δ4.75-4.44(m, 1H), 3.97-3.56(m, 3H), 3.52-3.27(m, 3H), 3.26-3.15(m, 1H), 3.02(ddd, J=14.3, 11.1, 5.5Hz, 1H), 2.53(ddd, J=54.4, 14.4, 9.7Hz, 1H), 1.96-1.76(m, 1H), 1.69-1.42(m, 3H), 1.40(d, J=1.2Hz, 9H).

[1071] 2S-4-[(tert-butoxy)carbonyl]-1,4-oxazocane-2-carboxylic acid I1-1-16 Starting from I1-1-15 (1 equiv, 60 mg, 0.24 mmol) and using general procedure E, I1-1-16 was obtained as a white solid (60.3 mg, 95%).

[1072] LC / MS (AN01_001_012): Rt=2.08 min, 65.5%, [MH]-=258.0.

[1073] 1 H NMR (400MHz, DMSO) δ12.63(s, 1H), 4.12-3.75(m, 3H), 3.68-3.44(m, 2H), 3.12-2.73(m, 2H), 1.94-1.76(m, 1H), 1.68-1.45(m, 3H), 1.41(s, 9H).

[1074] tert-Butyl (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,4-oxazocane-4-carboxylate I1-1-17 Starting from BB01 (1 equiv., 72.67 mg, 0.22 mmol) and I1-1-16 (1.05 equiv., 60 mg, 0.23 mmol), general procedure B was used to afford I1-1-17 as an orange gum (60.2 mg, 51%) after purification on silica gel by flash chromatography (amorphous SiOH, 50 μm, 12 g intercalate, dry packing (silica), mobile phase gradient: 100 / 0 to 50 / 50 cyclohexane / EtOAc over 30 min) and coevaporation with DCM.

[1075] LC / MS (AN01_001_012): Rt=2.58 min, 92.8%, [M-Boc+H] + =435.1.

[1076] 1 H NMR (400MHz, DMSO) δ8.77(d, J=8.7Hz, 1H), 7.66(dt, J=8.5, 2.0Hz, 2H), 7.56(s, 1H), 7.44-7.32(m, 4H), 5.01(p, J=7.9Hz, 1H), 4.03-3.84(m, 3H), 3. 58(s, 2H), 3.40(s, 3H), 3.25-3.12(m, 2H), 2.98(ddd, J=42.9, 15.6, 5.2Hz , 1H), 2.59-2.38(m, 1H), 1.94-1.81(m, 1H), 1.72-1.44(m, 3H), 1.38(s, 9H)

[1077] (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazocane-2-carboxamide Starting from I1-1-17 (1 equiv., 73.3 mg, 0.11 mmol) and using general procedure C, purification on silica gel by flash chromatography (amorphous SiOH, 15 μm, 12 g intercalation, dry packing (silica), mobile phase gradient: DCM / MeOH 100 / 0 to 90 / 10 over 40 min), coevaporation with DCM, and lyophilization using a mixture of ACN / water (1:10) gave (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazocane-2-carboxamide as a white solid (28.6 mg, 58%).

[1078] LC / MS(AN_01_001_021_DEDL): Rt=7.07 min, 99.6%, [M+H] + =435.4.

[1079] 1 H NMR (400MHz, DMSO) δ8.64(d, J=8.6Hz, 1H), 7.72-7.60(m, 2H), 7.57(dd, J=1.6, 0.8Hz, 1H), 7.45-7.30(m, 4H), 5. 00(td, J=8.6, 7.3Hz, 1H), 3.95(td, J=9.1, 4.9Hz, 1H), 3.89(dd, J=9.6, 3.0Hz, 1H), 3.65(ddd, J=11.7, 6.2, 3.9H z, 1H), 3.40 (s, 3H), 3.25-3.12 (m, 2H), 2.98 (dd, J = 14.0, 3.1 Hz, 1H), 2.93 (dt, J = 5.0, 4.5 Hz, 1H), 2.62 (ddd, J = 13.5, 8.5, 4.7 Hz, 1H), 2.27 (dd, J = 14.0, 9.7 Hz, 1H), 1.94-1.80 (m, 1H), 1.64-1.45 (m, 3H), one proton (NH) missing.

[1080] Example 5: Synthesis of (7S)—N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,6-dioxa-9-azaspiro[3.6]decane-7-carboxamide (Compound 5)

[1081] [ka]

[1082] tert-Butyl (7S)-7-[(benzyloxy)methyl]-1,6-dioxa-9-azaspiro[3.6]decane-9-carboxylate B1-70-2 To a solution of potassium tert-butoxide (2 equiv., 162.6 mg, 1.45 mmol) in tert-butanol (2.43 mL) was added trimethylsulfoxonium iodide (2 equiv., 318.88 mg, 1.45 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 30 minutes. B1-2-14 (previous preparation) (1 equiv., 243 mg, 0.72 mmol) in tert-butanol (1.46 mL) was added, and the reaction mixture was stirred for 18 hours. The reaction mixture was quenched with water (25 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by flash chromatography (50 μm, 12 g, 100 / 0 to 70 / 30 cyclohexane / EtOAc over 35 min) to afford B1-70-2 (92 mg, 35%) as a colorless oil.

[1083] LC / MS (AN01_001_012): Rt=2.61 min, 90.5%, [M-Boc+H] + =264.6.

[1084] 1 H NMR (400MHz, DMSO) δ7.40-7.24(m, 5H), 4.48(s, 2H), 4.41-4.29(m, 2H), 4.30-3.89(m, 2H), 3.79-3.57(m, 2H), 3.49-3.44 (m, 1H), 3.46-3.40(m, 1H), 3.36(ddd, J=10.4, 7.6, 5.1Hz, 1H), 3.14-2.56(m, 2H), 2.47-2.17(m, 2H), 1.46-1.31(m, 9H).

[1085] tert-Butyl (7S)-7-(hydroxymethyl)-1,6-dioxa-9-azaspiro[3.6]decane-9-carboxylate B1-70-3 Starting from B1-70-2 (1 equiv., 130 mg, 0.36 mmol) and using general procedure D, B1-70-3 was obtained as a colorless oil (88 mg, 90%).

[1086] LC / MS (AN01_001_012): Rt=1.93 min, ND, [M-Boc+H] + =174.2.

[1087] 1 H NMR (400MHz, DMSO) δ4.74-4.67(m, 1H), 4.39-4.27(m, 2H), 4.27-3.93(m, 2H), 3.89-3.55(m, 2H) , 3.50-3.33(m, 2H), 3.30-3.21(m, 1H), 3.13-2.58(m, 2H), 2.46-2.20(m, 2H), 1.59-1.21(m, 9H).

[1088] (7S)-9-[(tert-butoxy)carbonyl]-1,6-dioxa-9-azaspiro[3.6]decane-7-carboxylic acid B1-70-4 Starting from B1-70-3 (1 equiv, 130 mg, 0.36 mmol) and using general procedure E, B1-70-4 was obtained as a white solid (74.4 mg, 88%).

[1089] LC / MS (AN01_001_012): Rt=1.90 min, ND, [M-Boc+H] + =188.1.

[1090] 1 H NMR (400MHz, DMSO) δ12.77(s, 1H), 4.35(t, J=7.8Hz, 2H), 4.28-3.91(m, 4H), 3.83-3.44(m, 2H), 3.24-2.96(m, 1H), 2.70-2.26(m, 2H), 1.49-1.29(m, 9H).

[1091] tert-Butyl (7S)-7-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-1,6-dioxa-9-azaspiro[3.6]decane-9-carboxylate B1-70-57.

[1092] Starting with BB01 (1 equiv., 71.055 mg, 0.22 mmol) and B1-70-4 (1.05 equiv., 65 mg, 0.23 mmol), general procedure B was used to afford B1-70-5 as an orange solid (59 mg, 49%) after purification on silica gel by flash chromatography (50 μm, 12 g, 80:20 to 20:80 cyclohexane / EtOAc over 45 min). A 65:35 diastereomeric ratio was confirmed by LC / MS and HPLC. 1 Determined by 1 H NMR.

[1093] LC / MS(AN01_001_021_DEDL): Rt=9.33 min, 90.9%, [M- t Bu+H] + =507.4.

[1094] 1 H NMR (400MHz, DMSO) δ8.81(dd, J=21.1, 8.4Hz, 1H), 7.74-7.61(m, 2H), 7.62-7.52(m, 1H), 7.47-7.30(m, 4H), 5.02(q, J=8.1Hz, 1H), 4.4 6-4.27(m, 2H), 4.33-3.74(m, 5H), 3.67-3.34(m, 4H), 3.27-2.95(m, 3H), 2.91-2.58(m, 1H), 2.42(t, J=7.9Hz, 1H), 1.50-1.28(m, 9H).

[1095] (7S)-N-[(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,6-dioxa-9-azaspiro[3.6]decane-7-carboxamide Starting with B1-70-5 (1 equiv., 50 mg, 0.089 mmol), general procedure C was used to give, after purification on silica gel by flash chromatography (15 μm, 4 g, 100:0 to 95:05 DCM / MeOH over 40 min), (7S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,6-dioxa-9-azaspiro[3.6]decane-7-carboxamide as a white solid (15.6 mg, 38%). A diastereomeric ratio of 65:35 was confirmed by LC / MS and HPLC. 1 Determined by 1 H NMR.

[1096] LC / MS (AN_01_001_021_DEDL): Rt = 6.98 and 7.07 min, 98.7%, [M+H] + =463.4.

[1097] 1 H NMR (400MHz, DMSO) δ8.63(dd, J=11.2, 8.5Hz, 1H), 7.71-7.61(m, 2H), 7.57(s, 1H), 7. 46-7.32(m, 4H), 5.08-4.94(m, 1H), 4.39-4.25(m, 2H), 4.09(dd, J=75.9, 13.2Hz, 1H) , 3.92(ddd, J=10.3, 6.3, 3.7Hz, 1H), 3.75(dd, J=34.9, 13.2Hz, 1H), 3.40(s, 3H), 3.2 6-3.13(m, 3H), 3.14-3.00(m, 1H), 2.74(dd, J=15.6, 14.0Hz, 1H), 2.48-2.21(m, 4H).

[1098] Example 6 Preparation of (2S,6R)—N—((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-ethyl-6-hydroxy-1,4-oxazepane-2-carboxamide (Compound 6)

[1099] [ka]

[1100] tert-Butyl (2S,6R * )-2-[(benzyloxy)methyl]-6-ethyl-6-hydroxy-1,4-oxazepane-4-carboxylate B1-71-1-(R) * To a solution of B1-2-14 (described above) (1 equiv., 992 mg, 2.96 mmol) in THF (28 mL) was added 3 M ethylmagnesium bromide in EtO (2.5 equiv., 2.46 mL, 7.39 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2.5 h. The reaction mixture was cooled to 0 °C, and additional 3 M ethylmagnesium bromide in EtO (0.8 equiv., 0.79 mL, 2.37 mmol) was introduced dropwise. The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NHCl (75 mL) and diluted with EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 75 mL). The combined organic layers were washed with brine (150 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (15 μm, 40 g, 100:0 to 70:30 cyclohexane / EtOAc over 50 min, PMA exposure) to give impure B1-71-1-(R) * This was repurified on silica gel by flash chromatography (15 μm, 40 g, 100:0 to 60:40 cyclohexane / EtOAc over 55 min, exposure with PMA) to give B1-71-1-(R) * was obtained as a colorless oil (160 mg, 15%).

[1101] LC / MS (AN01_001_012): Rt=2.51 min, 100%, [M-Boc+H] + =266.2.

[1102] 1H NMR (400MHz, DMSO) δ7.39-7.23(m, 5H), 4.48(s, 2H), 4.34(d, J=30.5Hz, 1H), 3.76(s, 1H), 3.60-3.33(m , 5H), 3.25(dd, J=15.5, 4.1Hz, 2H), 3.19(d, J=14.2Hz, 1H), 1.47-1.33(m, 11H), 0.85(t, J=7.4Hz, 3H).

[1103] tert-Butyl (2S,6R * )-6-Ethyl-6-hydroxy-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate B1-71-2-(R) * B1-71-1-(R) * (1 equiv., 212 mg, 0.58 mmol) and using general procedure D, B1-71-2-(R) * was obtained as a colorless oil (135 mg, 85%).

[1104] LC / MS (AN01_001_012): Rt=1.93 min, ND, [M- t Bu+H] + =220.1.

[1105] 1 H NMR (400MHz, DMSO) δ4.69(d, J=5.5Hz, 1H), 4.40(d, J=15.9Hz, 1H), 4.01(d, J=13.9Hz, 1H), 3.79(d, J=13.9Hz, 1H), 3.65(d, J=12.9Hz, 1H), 3.5 6-3.37(m, 2H), 3.35-3.27(m, 1H), 3.23(d, J=12.9Hz, 1H), 3.17(d, J=4. 8Hz, 1H), 2.99-2.70(m, 2H), 1.42-1.20(m, 10H), 0.85(t, J=7.3Hz, 3H).

[1106] (2S,6R * )-4-[(tert-butoxy)carbonyl]-6-ethyl-6-hydroxy-1,4-oxazepane-2-carboxylic acid B1-71-3-(R) * B1-71-2-(R)* (1 equiv., 129 mg, 0.47 mmol) and using general procedure E, B1-71-3-(R) * was obtained as a white solid (129 mg, 95%).

[1107] LC / MS (AN01_001_012): Rt=2.35 min, ND, [M- t Bu+H] + =234.0.

[1108] 1 H NMR (400MHz, DMSO) δ12.79(s, 1H), 4.52(s, 1H), 4.23-4.14(m, 1H), 4.11(dd, J=14.1, 5.1Hz, 1H), 3.77(dd, J=20.0, 13.6Hz , 1H), 3.64(t, J=13.1Hz, 1H), 3.42-3.04(m, 2H), 2.74(dd, J=17.7, 13.8Hz, 1H), 1.40(d, J=6.1Hz, 11H), 0.92-0.77(m, 3H).

[1109] tert-Butyl (2S,6R * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-ethyl-6-hydroxy-1,4-oxazepane-4-carboxylate B1-71-4-(R) * BB01 (1 equivalent, 135.69 mg, 0.41 mmol) and B1-71-3-(R) * Starting from (1.05 equiv., 125 mg, 0.43 mmol) and using general procedure B, after purification on silica gel by flash chromatography (amorphous SiOH, 50 μm, 25 g, dry packing (silica), mobile phase gradient: 70 / 30 to 30 / 70 cyclo / EtOAc over 45 min) and coevaporation with DCM, B1-71-4-(R) * was obtained as a pale yellow solid (134 mg, 58%).

[1110] LC / MS (AN01_001_012): Rt=2.51 min, 76.8%, [M- t Bu+H] + =509.7.

[1111] 1 H NMR (400MHz, DMSO) δ8.88(d, J=8.4Hz, 1H), 7.70-7.62(m, 2H), 7.57(s, 1H), 7.45-7. 35(m, 4H), 5.03(q, J=8.1Hz, 1H), 4.58(s, 1H), 4.18-4.10(m, 1H), 4.06-3.87(m, 1H), 3.74(d, J=14.4Hz, 1H), 3.61-3.42(m, 2H), 3.40(s, 3H), 3.18(t, J=6.6Hz, 2H), 2.99- 2.85(m, 1H), 2.74(d, J=14.0Hz, 1H), 1.38(d, J=10.9Hz, 11H), 0.87(t, J=7.3Hz, 3H).

[1112] (2S,6R * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-ethyl-6-hydroxy-1,4-oxazepane-2-carboxamide.

[1113] B1-71-4-(R) * Starting from (1 equiv., 130 mg, 0.23 mmol), general procedure C was used to obtain (2S,6R) after purification on silica gel by flash chromatography (amorphous SiOH, 50 μm, 12 g intercalated, dry packed (silica), mobile phase gradient: DCM / MeOH 100 / 00 to 90 / 10 over 30 min), coevaporation with DCM, and drying in vacuo at 40 °C for 24 h. * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-ethyl-6-hydroxy-1,4-oxazepane-2-carboxamide as a white solid (52 mg, 49%).

[1114] LC / MS(AN_01_001_021_DEDL): Rt=7.00 min, 99.1%, [M+H] + =465.4.

[1115] 1 H NMR (400MHz, DMSO) δ8.68(d, J=8.5Hz, 1H), 7.72-7.61(m, 2H), 7.60-7.54(m, 1H), 7.49-7.30(m , 4H), 5.07-4.96(m, 1H), 4.36(s, 1H), 3.97(dd, J=8.1, 5.0Hz, 1H), 3.60(d, J=12.7Hz, 1H), 3.52 (d, J=12.7Hz, 1H), 3.40(s, 3H), 3.26-3.13(m, 2H), 3.03(dd, J=13.9, 5.1Hz, 1H), 2.65(d, J=13 .5Hz, 1H), 2.58-2.51(m, 2H), 2.45(d, J=13.5Hz, 1H), 1.43-1.26(m, 2H), 0.82(t, J=7.5Hz, 3H).

[1116] Example 7: Preparation of (S)—N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)azocane-3-carboxamide (Compound 7-A) and (R)—N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)azocane-3-carboxamide (Compound 7-B)

[1117] [ka]

[1118] Ethyl 3-[(but-3-en-1-yl)amino]propanoate H1-2-2 A solution of but-3-en-1-amine hydrochloride (1 equiv., 1.99 g, 18.5 mmol) and triethylamine (1.05 equiv., 1.97 g, 2.7 mL, 19.42 mmol) in EtOH (28 mL) was stirred at room temperature for 30 min in an argon-purged container. Ethyl acrylate (1 equiv., 1.85 g, 2.013 mL, 18.5 mmol) was then added, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure to give a 50:50 mixture of H1-2-2 and H1-2-2' as a colorless oil (4.88 g, 18.5 mmol, quantitative yield). The crude product was used directly in the next step without further purification.

[1119] LC / MS (AN01_001_012): Rt=0.53 min, ND, [M+H] + =172.1 Ethyl 3-[(but-3-en-1-yl)[(tert-butoxy)carbonyl]amino]propanoate H1-2-3 A solution of H1-2-2 (1 equiv., 4.88 g, 14.25 mmol) (containing approximately 50% mol of H1-2-2') in DCM (30 mL) was purged with argon, and diisopropylamine (1.2 equiv., 1.73 g, 2.42 mL, 17.099 mmol), BocO (1.2 equiv., 3.73 g, 3.66 mL, 17.099 mmol), and DMAP (0.1 equiv., 0.17 g, 1.42 mmol) were added at room temperature. The resulting mixture was stirred for 19 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (25 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified on silica gel by ELSD flash chromatography (1: amorphous SiOH, 50 μm, 120 g intercalant, dry-packed (silica), mobile phase gradient: 100 / 0 to 80 / 20 cyclohexane / EtOAc over 45 min; 2: amorphous SiOH, 50 μm, 40 g intercalant, dry-packed (silica), mobile phase gradient: 80 / 20 to 0 / 100 cyclohexane / DCM over 30 min, then 100 / 0 to 80 / 20 DCM / EtOAc over 20 min). Fractions containing the compound were combined, evaporated in vacuo, and co-evaporated with DCM to give H1-2-3 (1.99 g, 7.33 mmol, 51% over two steps) as a colorless oil.

[1120] LC / MS(AN_01_001_012): Rt=2.64 min, 100%, [M-Boc+H] + =172.1.

[1121] Ethyl 2-{[(but-3-en-1-yl)[(tert-butoxy)carbonyl]amino]methyl}pent-4-enoate H1-2-4 A solution of H1-2-3 (1 equiv., 1.99 g, 7.33 mmol) in THF (20 mL) was purged with argon and 1 M LiHMDS in THF (1.1 equiv., 8.067 mL, 8.067 mmol) was added dropwise at −78°C. The resulting mixture was stirred at −78°C for 1 hour, after which allyl iodide (1.1 equiv., 1.36 g, 0.74 mL, 8.067 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 18 hours. The reaction was cooled to −78°C and 1 M LiHMDS in THF (0.2 equiv., 1.47 mL, 1.47 mmol) was added dropwise at −78°C. The reaction was stirred at this temperature for 30 minutes, after which allyl iodide (0.2 equiv., 0.25 g, 0.13 mL, 1.47 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified on silica gel by ELSD flash chromatography (amorphous SiOH, 15 μm, 80 g intercalant, dry-packed (silica), mobile phase gradient: 100 / 0 to 80 / 20 cyclohexane / EtOAc over 50 min). The compound-containing fractions were combined, evaporated in vacuo, and co-evaporated with DCM to give H1-2-4 (1.62 g, 5.20 mmol, 71%) as a yellow oil.

[1122] LC / MS(AN_01_001_012): Rt=2.86 min, 100%, [M-Boc+H] + =212.

[1123] 1-tert-butyl 3-ethyl 1,2,3,4,7,8-hexahydroazocine-1,3-dicarboxylate H1-2-5 Starting from H1-2-4 (1 equiv., 1.2 g, 3.85 mmol) in DCM (200 mL) and using general procedure H, after purification on silica gel by flash chromatography (amorphous SiOH, 50 μm, 80 g intercalate, dry packing (silica), mobile phase gradient: 100 / 0 to 80 / 20 cyclohexane / EtOAc over 45 min) and co-evaporation with DCM, H1-2-5 was obtained as a black oil (613 mg, 56%).

[1124] LC / MS (AN_01_001_012): Rt=2.67 min, 100%, [M-Boc+H] + =184.11 1-tert-butyl 3-ethylazocane-1,3-dicarboxylate H1-2-6 Starting from H1-2-5 (1 equiv, 350 mg, 1.24 mmol) and using general procedure D, H1-2-6 was obtained as a yellow oil (323 mg, 92%).

[1125] LC / MS (AN_01_001_012): Rt=2.73 min, ND, [M- t Bu+H] + =230.15 1-[(tert-butoxy)carbonyl]azocane-3-carboxylic acid H1-2-7 A solution of H1-2-6 (1 equiv., 0.32 g, 1.13 mmol) in THF (11 mL) was purged with argon, and a solution of LiOH (5 equiv., 0.24 g, 5.66 mmol) in water (5.5 mL) was added, and the reaction mixture was stirred at room temperature for 19 h. The reaction was poured dropwise into a stirred solution of 1 M HCl (50 mL) and DCM (100 mL) cooled to 0 °C. The mixture was stirred for 1 h (pH ∼ 1). The layers were separated, and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness under reduced pressure to give crude H1-2-7 (0.29 g, 1.13 mmol, 100%) as a yellow oil.

[1126] LC / MS (AN01_001_012): Rt=2.29 min, ND, [MH]-=256.1.

[1127] tert-Butyl 3-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}azocane-1-carboxylate H1-2-8 Starting from BB01 (1 equiv., 150 mg, 0.45 mmol) and mixture H1-2-7 (1 equiv., 138.4 mg, 0.45 mmol), general procedure B was used to obtain H1-2-8 (225 mg, 80%) as a yellow gum after purification on silica gel by flash chromatography (amorphous SiOH, 50 μm, 25 g intercalation, dry packing (silica), mobile phase gradient: 90 / 10 to 50 / 50 cyclohexane / EtOAc over 25 min) and coevaporation with DCM.

[1128] LC / MS (AN01_001_012): Rt=2.63 min, 100%, [M- t Bu+H] + =477.2.

[1129] (3S * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]azocane-3-carboxamide and (3R * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]azocane-3-carboxamide.

[1130] Starting with H1-2-8 (1 equiv., 230 mg, 0.36 mmol), general procedure C was used to obtain H1-2-8. After purification on silica gel by flash chromatography (amorphous SiOH, 15 μm, 12 g intercalated, dry packed (silica), mobile phase gradient: 100 / 0 to 80 / 20 DCM / MeOH over 60 min), (3S * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]azocane-3-carboxamide and (3R *)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]azocane-3-carboxamide (134 mg, 85%) as a yellow gum.

[1131] SFC purification (Chiralpak OJ-3 (4.6 × 100 mm), 35 °C, 35:65 MeOH:CO (0.3% v / v iPrNH, 80 mL / min, 100 bar) was used to obtain the 3S * )-N-[(1S)-1-cyano 2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]azocane-3-carboxamide (37.1 mg, 24%) and (3R * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]azocane-3-carboxamide (36.2 mg, 23%) as a white solid.

[1132] (3S * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]azocane-3-carboxamide: LC / MS(AN01_001_026_DEDL): Rt=7.26 min, 98.80%, [M+H] + =433.4.

[1133] 1 H NMR (400MHz, DMSO) δ8.87-8.59(m, 1H), 7.72-7.62(m, 2H), 7.62-7.53(m, 1H), 7.47-7.33(m, 4H), 4.96 (q, J=7.7Hz, 1H), 3.41(s, 3H), 3.21-3.06(m, 2H), 2.95-2.76(m, 3H), 2.45(s, 2H), 1.83-1.42(m, 8H).

[1134] (3R *)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]azocane-3-carboxamide: LC / MS(AN01_001_026_DEDL): Rt=7.29 min, 97.74%, [M+H] + =433.4.

[1135] 1 H NMR (400MHz, DMSO) δ8.73(d, J=7.9Hz, 1H), 7.72-7.62(m, 2H), 7.60-7.54(m, 1H), 7.47-7.35(m, 4H), 5.03-4.92 (m, 1H), 3.40(d, J=3.5Hz, 3H), 3.22-3.04(m, 2H), 2.96-2.72(m, 3H), 2.46(t, J=1.9Hz, 2H), 1.65-1.32(m, 8H).

[1136] Example 8 Preparation of (2S,6S)—N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-6-propyl-1,4-oxazepane-2-carboxamide (Compound 8)

[1137] [ka]

[1138] tert-Butyl (2S,6S * )-2-[(benzyloxy)methyl]-6-hydroxy-6-(prop-2-en-1-yl)-1,4-oxazepane-4-carboxylate B1-80-1-(S) * To a solution of B1-2-14) (1.0 equiv., 500 mg, 1.49 mmol) (previously described) in THF (13.5 mL) was added 1 M allylmagnesium bromide in EtO (3.0 equiv., 4.47 mL, 4.47 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and diluted with EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by flash chromatography (15 μm, 25 g, 100:0 to 75:25 cyclohexane / EA, PMA exposure over 40 min) to give impure B1-71-1-(R). * This was repurified on silica gel by flash chromatography (15 μm, 40 g, 100:0 to 6:4 cyclohexane / EA over 55 min) to give B1-80-1-(S). * was obtained as a colorless oil (237 mg, 42%), B1-80-1-(R) * was obtained as a colorless oil (186 mg, 33%).

[1139] LC / MS (AN01_001_012): Rt=2.67 min, 100%, [M-Boc+H] + =278.2.

[1140] 1 H NMR (400MHz, DMSO) δ7.41-7.21(m, 5H), 5.94-5.78(m, 1H), 5.11-4.96(m, 2H), 4.59-4.41(m, 3H), 3.82-3. 71(m, 1H), 3.65-3.50(m, 2H), 3.49-3.33(m, 3H), 3.31-3.15(m, 3H), 2.24-2.09(m, 2H), 1.47-1.29(m, 9H).

[1141] tert-Butyl (2S,6S * )-6-Hydroxy-2-(hydroxymethyl)-6-propyl-1,4-oxazepane-4-carboxylate B1-81-1-(S) * B1-80-1-(S) * (1 equiv., 210 mg, 0.56 mmol) and using general procedure D, B1-81-1-(S) * was obtained as a colorless oil (140 mg, 87%).

[1142] LC / MS (AN01_001_012): Rt=2.07 min, ND, [M- t Bu+H] + =234.1.

[1143] 1 H NMR (400MHz, DMSO) δ4.71-4.55(m, 1H), 4.41-4.22(m, 2H), 3.62-3.50(m, 2H), 3.50-3.34(m, 2H), 3.30-3.12(m, 4H), 1.57-1.19(m, 13H), 0.94-0.74(m, 3H).

[1144] (2S,6S * )-4-[(tert-butoxy)carbonyl]-6-hydroxy-6-propyl-1,4-oxazepane-2-carboxylic acid B1-81-2-(S) * B1-81-1-(S) * (1 equiv., 130 mg, 0.45 mmol) and using general procedure E, B1-81-2-(S) * was obtained as a white solid (95 mg, 70%).

[1145] LC / MS (AN01_001_012): Rt=2.07 min, ND, [MH]-=302.1.

[1146] 1 H NMR (400MHz, DMSO) δ12.59(s, 1H), 4.40-4.23(m, 1H), 4.23-3.99(m, 1H), 3.84-3.68(m, 1H), 3.67-3.54( m, 1H), 3.53-3.38(m, 1H), 3.37-3.25(m, 2H), 3.20-3.12(m, 2H), 1.46-1.19(m, 13H), 0.93-0.79(m, 3H).

[1147] tert-Butyl (2S,6S * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-6-propyl-1,4-oxazepane-4-carboxylate B1-81-3-(S) * .

[1148] BB01 (1 equivalent, 93.2 mg, 0.28 mmol) and B1-81-2-(S) * Starting from (1.05 equiv., 90.0 mg, 0.30 mmol) using general procedure B, after purification on silica gel by flash chromatography (amorphous SiOH, 50 μm, 25 g, dry packing (silica), mobile phase gradient: 100:0 to 40:60 cyclo / EtOAc) gave B1-81-3-(S). * was obtained as an orange solid (90 mg, 53%).

[1149] LC / MS (AN01_001_012): Rt=2.56 min, 96%, [M- t Bu+H] + =523.2.

[1150] 1 H NMR (400MHz, DMSO, presence of rotamers) δ8.65 (m, 1H), 7.66 (d, J=7.8Hz, 2H), 7.57 (s, 1H) , 7.46-7.29(m, 4H), 5.10-4.92(m, 1H), 4.36(d, J=15.8Hz, 1H), 4.18(dd, J=8.9 , 4.7Hz, 1H), 3.76(dd, J=14.5, 4.8Hz, 1H), 3.58(t, J=12.0Hz, 1H), 3.41(s, 3H) , 3.38-3.29(m, 2H), 3.30-3.09(m, 4H), 1.49-1.21(m, 13H), 0.94-0.78(m, 3H).

[1151] (2S,6S *)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-6-propyl-1,4-oxazepane-2-carboxamide.

[1152] B1-81-3-(S) * Starting from (1 equiv., 80.0 mg, 0.14 mmol), using general procedure C, after purification on silica gel by flash chromatography (amorphous SiOH, 15 μm, 4 g intercalate, dry packing (silica), mobile phase gradient: 100:0 to 90:10 DCM / MeOH) and drying in vacuo at 40 °C for 24 h, (2S,6S * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-6-propyl-1,4-oxazepane-2-carboxamide as a white solid (52 mg, 49%).

[1153] LC / MS(AN_01_001_021_DEDL): Rt=7.43 min, 99.90%, [M+H] + =479.44.

[1154] 1 H NMR (400MHz, DMSO) δ8.53(d, J=8.5Hz, 1H), 7.71-7.61(m, 2H), 7.56(t, J=1.2Hz, 1H), 7.44-7 .29(m, 4H), 5.01(td, J=8.7, 7.2Hz, 1H), 4.31(s, 1H), 4.01(dd, J=9.4, 4.2Hz, 1H), 3.50(dd, J=44.7, 12.4Hz, 2H), 3.40(s, 3H), 3.27-3.13(m, 2H), 3.09(dd, J=14.0, 4.3Hz, 1H), 2.63(d, J=13.7Hz, 1H), 2.49-2.44(m, 2H), 2.39-2.32(m, 1H), 1.36-1.23(m, 4H), 0.90-0.77(m, 3H).

[1155] Example 9 Preparation of (2S,6R)—N—((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-6-propyl-1,4-oxazepane-2-carboxamide (Compound 9)

[1156] [ka]

[1157] tert-Butyl (2S,6R * )-2-[(benzyloxy)methyl]-6-hydroxy-6-(prop-2-en-1-yl)-1,4-oxazepane-4-carboxylate B1-80-1-(R) * To a solution of B1-2-14 (1.0 equiv., 500 mg, 1.49 mmol) (previously described) in THF (13.5 mL) was added 1 M allylmagnesium bromide in EtO (3.0 equiv., 4.47 mL, 4.47 mmol) at −78 °C. The reaction mixture was stirred at −78 °C for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and diluted with EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel by flash chromatography (15 μm, 25 g, 100:0 to 75:25 cyclohexane / EA, PMA exposure over 40 min) to give impure B1-71-1-(R). * This was repurified on silica gel by flash chromatography (15 μm, 40 g, 100:0 to 6:4 cyclohexane / EA over 55 min) to give B1-80-1-(S). * was obtained as a colorless oil (237 mg, 42%), B1-80-1-(R) * was obtained as a colorless oil (186 mg, 33%).

[1158] LC / MS (AN01_001_012): Rt=2.58 min, 100%, [M- t Bu+H]+ =322.1 1 H NMR (400MHz, DMSO) δ7.40-7.24(m, 5H), 5.95-5.80(m, 1H), 5.11-4.99(m, 2H), 4.62(d, J=16.8Hz, 1H), 4.50(s, 2H), 3.99- 3.60(m, 4H), 3.52-3.44(m, 1H), 3.44-3.36(m, 1H), 3.30-3.25(m, 1H), 3.10-2.85(m, 2H), 2.19-2.09(m, 2H), 1.40(s, 9H).

[1159] tert-Butyl (2S,6R * )-6-Hydroxy-2-(hydroxymethyl)-6-propyl-1,4-oxazepane-4-carboxylate B1-81-1-(R) * B1-80-1-(R) * (1 equiv., 210 mg, 0.56 mmol) and using general procedure D, B1-81-1-(R) * was obtained as a colorless oil (145 mg, 90%).

[1160] LC / MS (AN01_001_012): Rt=2.05 min, ND, [M- t Bu+H] + =234.1.

[1161] 1 H NMR (400MHz, DMSO) δ4.68(t, J=5.6Hz, 1H), 4.51-4.36(m, 1H), 4.34(t, J=5.1Hz, 1H), 4.04-3.56(m, 3H) , 3.55-3.32(m, 2H), 3.23(d, J=12.9Hz, 1H), 3.02-2.70(m, 2H), 1.52-1.18(m, 13H), 0.97-0.76(m, 3H).

[1162] (2S,6R * )-4-[(tert-butoxy)carbonyl]-6-hydroxy-6-propyl-1,4-oxazepane-2-carboxylic acid B1-81-2-(R) * B1-81-1-(R) * (1 equiv., 145 mg, 0.50 mmol) and using general procedure E, B1-81-2-(R) * was obtained as a white solid (127 mg, 84%).

[1163] LC / MS (AN01_001_012): Rt=2.08 min, ND, [MH]-=302.1.

[1164] tert-Butyl (2S,6R * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-6-propyl-1,4-oxazepane-4-carboxylate B1-81-3-(R) * BB01 (1 equivalent, 133 mg, 0.40 mmol) and B1-81-2-(S) * Starting from (1.05 equiv., 128 mg, 0.42 mmol) and using general procedure B, B1-81-3-(R) was obtained after purification on silica gel by flash chromatography (amorphous SiOH, 15 μm, 12 g, dry packing (silica), mobile phase gradient: 100:0 to 0:100 cyclo / EtOAc). * was obtained as a pale yellow solid (81 mg, 35%).

[1165] LC / MS (AN01_001_012): Rt=2.53 min, 100%, [M- t Bu+H] + =523.15.

[1166] 1H NMR (400MHz, DMSO, presence of rotamers) δ8.87(d, J=8.4Hz, 1H), 7.72-7.63(m, 2H), 7.61-7.53(m, 1H) ), 7.49-7.34(m, 4H), 5.03(q,J=8.1Hz, 1H), 4.65-4.52(m, 1H), 4.20-4.09(m, 1H), 4.08-3 .98(m, 1H), 3.95-3.74(m, 1H), 3.76-3.68(m, 1H), 3.62-3.46(m, 1H), 3.40(s, 3H), 3.26-3 .12(m, 2H), 3.07-2.85(m, 1H), 2.82-2.71(m, 1H), 1.52-1.27(m, 13H), 0.94-0.76(m, 3H).

[1167] (2S,6R * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-6-propyl-1,4-oxazepane-2-carboxamide B1-81-3-(R) * Starting with (1 equiv., 87.0 mg, 0.15 mmol), general procedure C was used to obtain (2S,6R) as a white solid after purification on silica gel by flash chromatography (amorphous SiOH, 50 μm, 4 g intercalate, dry packing (silica), mobile phase gradient: 100:0 to 90:10 DCM / MeOH) and drying in vacuo at 40 °C for 24 h. * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-6-propyl-1,4-oxazepane-2-carboxamide (36 mg, 50%).

[1168] LC / MS(AN_01_001_021_DEDL): Rt=7.28 min, 97.98%, [M+H] + =479.38.

[1169] 1H NMR (400MHz, DMSO) δ8.68(d, J=8.5Hz, 1H), 7.69-7.61(m, 2H), 7.59-7.54(m, 1H), 7 .44-7.36(m, 4H), 5.02(td, J=8.5, 7.3Hz, 1H), 4.38(s, 1H), 3.97(dd, J=8.0, 5.0Hz, 1H), 3.64-3.49(m, 2H), 3.40(s, 3H), 3.25-3.13(m, 2H), 3.02(dd, J=14.0, 5.1Hz, 1H ), 2.64(d, J=13.2Hz, 1H), 2.58-2.51(m, 3H), 1.39-1.20(m, 4H), 0.91-0.80(m, 3H).

[1170] Example 10: Preparation of (2S,6R)—N—((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-isobutoxy-6-methyl-1,4-oxazepane-2-carboxamide (Compound 10)

[1171] [ka]

[1172] tert-Butyl (2S,6R * )-2-[(benzyloxy)methyl]-6-methyl-6-[(2-methylprop-2-en-1-yl)oxy]-1,4-oxazepane-4-carboxylate B1-79-1-(R) * B1-79-1-(R) * Starting with (1 equiv., 273 mg, 0.780 mmol) (as described above) and 3-bromo-2-methylpropene (2.5 equiv., 262.18 mg, 0.2 mL, 1.94 mmol), using general procedure F, after purification by silica gel flash chromatography (50 μm, 25 g, exposure to 100:0 to 8:2 cyclohexane / EtOAc, PMA over 32 min), B1-79-1-(R) * was obtained as a colorless oil (235 mg, 75%).

[1173] LC / MS (AN01_001_012): Rt=2.95 min, 100%, [M- t Bu+H]+=350.1.

[1174] tert-Butyl (2S,6R * )-2-(hydroxymethyl)-6-methyl-6-(2-methylpropoxy)-1,4-oxazepane-4-carboxylate B1-79-2-(R) * B1-47-1-(S) * (1 equiv., 235 mg, 0.58 mmol) and using general procedure D, B1-79-2-(R) * was obtained as a colorless oil (174 g, 95%).

[1175] LC / MS (AN01_001_012): Rt=2.00 min, non-UV active, [M+H] + =262.1.

[1176] (2S,6R * )-4-[(tert-butoxy)carbonyl]-6-methyl-6-(2-methylpropoxy)-1,4-oxazepane-2-carboxylic acid B1-79-3-(R) * B1-79-2-(R) * (1 equiv., 176 mg, 0.55 mmol) and using general procedure E, B1-79-3-(R) * was obtained as a colorless gum (184 mg, 100%).

[1177] LC / MS (AN01_001_012): Rt=2.46 min, non-UV active, [MH]-=330.1.

[1178] tert-Butyl (2S,6R * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methyl-6-(2-methylpropoxy)-1,4-oxazepane-4-carboxylate B1-79-4-(R) * BB01 (1 equivalent, 172.5 mg, 0.52 mmol) and B1-79-3-(R) * Starting with (1.05 equiv., 0.182 mg, 0.55 mmol), using general procedure B, B1-79-4-(R) was obtained after purification by silica gel flash chromatography ((amorphous SiOH, 50 μm, 24 g, dry packed (silica), mobile phase gradient: 10 / 0 to 5 / 5 cyclohexane / EtOAc over 50 min). * was obtained as a pale yellow solid (220 mg, 70%).

[1179] LC / MS (AN01_001_012): Rt=2.80 min, 100%, [M- t Bu+H] + =551.2.

[1180] (2S,6R * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methyl-6-(2-methylpropoxy)-1,4-oxazepane-2-carboxamide.

[1181] B1-79-4-(R) * Starting from (1 equiv., 100 mg, 0.16 mmol), using general procedure C, after purification by silica gel flash chromatography (amorphous SiOH, 50 μm, 12 g intercalated, dry packed (silica), mobile phase gradient: DCM / MeOH 10 / 0 to 9 / 1 over 30 min) gave (2S,6R) as a white solid. * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methyl-6-(2-methylpropoxy)-1,4-oxazepane-2-carboxamide (59.0 mg, 71%).

[1182] LC / MS (AN01_001_026): Rt=8.11 min, 98.3%, [M+H] + =507.5.

[1183] 1 H NMR (400MHz, DMSO) δ8.55(d, J=8.5Hz, 1H), 7.66-7.60(m, 2H), 7.57-7.54(m, 1H) , 7.42-7.35(m, 4H), 5.05-4.95(m, 1H), 3.96-3.86(m, 2H), 3.43(d, J=13.3Hz, 1H) , 3.40(s, 3H), 3.24-3.16(m, 3H), 3.15-3.05(m, 2H), 2.75-2.60(m, 2H), 2.36-2.2 6(m, 1H), 1.69(dt, J=13.2, 6.6Hz, 1H), 1.00(s, 3H), 0.88(dd, J=6.7,1.7Hz, 7H).

[1184] Example 11: Preparation of a mixture of N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-5-hydroxyazocane-3-carboxamide and N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxyazocane-3-carboxamide (Compound 11)

[1185] [ka]

[1186] Mixture of 1-tert-butyl 3-ethyl 5-hydroxyazocane-1,3-dicarboxylate and 1-tert-butyl 3-ethyl 6-hydroxyazocane-1,3-dicarboxylate H1-3 / 4-1 Starting from H1-2-5 (1 equiv., 1.41 g, 4.98 mmol), general procedure I was used to give, after purification on silica gel by flash chromatography (amorphous SiOH, 15 μm, 40 g, dry-packed (silica), mobile phase gradient: Cyclo / EtOAc from 10 / 0 to 0 / 10 over 50 min) and co-evaporation with DCM, a mixture of H1-3 / 4-1 (780 mg, 2.62 mmol, 53%) was obtained as a yellow gum.

[1187] Chiral SFC analysis: Chiralpak (AD-3 4.6 x 100 mm, mobile phase: CO2 / (iPrOH + 0.3% iPrNH2) 90 / 10): (8 products) Rt = 0.84, 1.07, 1.23, 1.34, 1.44, 1.71, 2.36 and 5.37 min, 21.6, 21.0, 2.14, 8.37, 3.54, 21.09, 1.88 and 20.33%.

[1188] LC / MS (AN01_001_026, ELSD): Rt = 8.09 and 8.18 min, 52.4 and 47.4%, [M- t Bu+H] + =246.2 Mixture of 1-tert-butyl 3-lithio 5-hydroxyazocane-1,3-dicarboxylate and 1-tert-butyl 3-lithio 6-hydroxyazocane-1,3-dicarboxylate H1-3 / 4-3 A solution of H1-3 / 4-1 (1 equiv., 75.1 mg, 0.25 mmol) in THF (2.5 mL) was purged with argon, and a solution of LiOH (1 equiv., 10.46 mg, 0.25 mmol) in HO (0.3 mL) was added, and the reaction mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated to dryness under reduced pressure and coevaporated with THF to give crude H1-3 / 4-3 as an off-white solid (76.3 mg, 100%), which was used directly without further purification.

[1189] LC / MS (AN01_001_012): No UV activity, Rt=1.88 min, ND, [M-Li+H] + =272.1.

[1190] Mixture of tert-butyl 3-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-5-hydroxyazocane-1-carboxylate and tert-butyl 3-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxyazocane-1-carboxylate H1-3 / 4-4 After purification by silica gel flash chromatography ((amorphous SiOH, 15 μm, 12 g, dry-packed (silica), mobile phase gradient: 80 / 20 to 0 / 100 DCM / EtOAc over 40 min) using general procedure B starting from BB01 (1 equiv., 78.0 mg, 0.24 mmol) and H1-3 / 4-3 (1.05 equiv., 69.4 mg, 0.25 mmol), H1-3 / 4-4 was obtained as a yellowish solid (69.0 mg, 53%).

[1191] LC / MS (AN01_001_026): Rt = 8.73 and 9.06 min, 48.9 and 47.0%, [M- t Bu+H] + =493.39.

[1192] A mixture of N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-5-hydroxyazocane-3-carboxamide and N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxyazocane-3-carboxamide.

[1193] Starting from H1-3 / 4-4 (1 equiv., 62.7 mg, 0.11 mmol) and using general procedure C, a mixture of regioisomers and diastereomers of N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-5-hydroxyazocane-3-carboxamide and N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxyazocane-3-carboxamide was obtained by preparative HPLC (eluent: water + 0.1% TFA / acetonitrile, gradient: 20-35% acetonitrile in water + 0.1% TFA, column: XBridge After purification on C18 (30 × 150 (5 μm)), flow rate: 43 mL / min), it was obtained as a white solid (18.5 mg, 36%). The fractions containing the compound were combined, and the ACN was evaporated in vacuo. The resulting solution containing water was basified and extracted with DCM (3 × 200 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to dryness under reduced pressure, and the resulting solid was lyophilized.

[1194] Chiral SFC analysis: Chiralpak (AD-3 4.6 x 100 mm, mobile phase: CO2 / (iPrOH + 0.3% iPrNH2) 90 / 10): (7 products) Rt = 4.15, 4.93, 5.31, 5.61, 6.19, 6.84 and 7.46 min, 14.35, 16.49, 2.52, 1.30, 30.38, 4.25 and 29.9%.

[1195] LC / MS (AN01_001_026): Rt = 6.82 and 6.95 min, 36.49 and 59.94%, [M+H] + =449.45.

[1196] 1H NMR (400MHz, DMSO) δ8.85-8.54(m, 1H), 7.72-7.50(m, 3H), 7.48-7.24(m, 4H), 5.06-4.82(m, 1H), 3.95- 3.53(m, 1H), 3.40(s, 3H), 3.19-3.02(m, 2H), 2.92-2.54(m, 5H), 2.45-2.34(m, 1H), 1.92-1.25(m, 7H).

[1197] Example 12: Preparation of (2S,6S)—N—((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-isobutoxy-6-methyl-1,4-oxazepane-2-carboxamide (Compound 12)

[1198] [ka]

[1199] tert-Butyl (2S,6S * )-2-[(benzyloxy)methyl]-6-methyl-6-[(2-methylprop-2-en-1-yl)oxy]-1,4-oxazepane-4-carboxylate B1-79-2-(S) * B1-46-1-(S) * Starting with (1 equiv., 164 mg, 0.47 mmol) (as described above) and 3-bromo-2-methylpropene (2.5 equiv., 157.5 mg, 0.12 mL, 1.17 mmol), using general procedure F, B1-79-2-(S) was obtained after purification by silica gel flash chromatography (50 μm, 25 g, 100:0 to 8:2 cyclohexane / EtOAC, PMA exposure over 32 min). * was obtained as a colorless oil (151.4 mg, 80%).

[1200] LC / MS (AN01_001_012): Rt=2.95 min, 100%, [M-Boc+H]+=306.17.

[1201] tert-Butyl (2S,6S *)-2-(hydroxymethyl)-6-methyl-6-(2-methylpropoxy)-1,4-oxazepane-4-carboxylate B1-79-3-(S) * B1-79-2-(S) * (1 equiv., 194 Mg, 0.48 mmol) and using general procedure D, B1-79-3-(S) * was obtained as a colorless oil (149 mg, 98%).

[1202] LC / MS (AN01_001_012): Rt=2.46 min, non-UV active, [M- t Bu+H] + =262.1.

[1203] (2S,6S * )-4-[(tert-butoxy)carbonyl]-6-methyl-6-(2-methylpropoxy)-1,4-oxazepane-2-carboxylic acid B1-79-4-(S) * B1-79-3-(S) * (1 equiv., 141 mg, 0.44 mmol) and using general procedure E, B1-79-4-(S) * was obtained as a colorless gum (131 mg, 89%).

[1204] LC / MS (AN01_001_012): Rt=2.42 min, 100%, [MH]-=330.1.

[1205] tert-Butyl (2S,6S * )-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5- {6-methyl-6-(2-methylpropoxy)-1,4-oxazepane-4-carboxylate B1-79-5-(S) * BB01 (1 equivalent, 120.4 mg, 0.36 mmol) and B1-79-4-(S) *Starting with (1.05 equiv., 127 mg, 0.38 mmol), B1-79-5-(S) was obtained using general procedure B. After purification by silica gel flash chromatography (50 μm, 40 g, 100:0 to 20:80 cyclohexane / EtOAc over 42 min), B1-79-5-(S) * was obtained as a yellow solid (167 mg, 75%).

[1206] LC / MS (AN01_001_012): Rt=2.81 min, 100%, [M-Boc+H] + =507.2.

[1207] (2S,6S * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methyl-6-(2-methylpropoxy)-1,4-oxazepane-2-carboxamide.

[1208] B1-79-5-(S) * (1 equiv., 80 mg, 0.13 mmol) using general procedure C to prepare (2S,6S * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methyl-6-(2-methylpropoxy)-1,4-oxazepane-2-carboxamide was obtained as a white solid (55 mg, 70%) after purification by silica gel flash chromatography (50 μm, 12 g, gradient: 100:0 to 80:20 DCM / MeOH over 42 min).

[1209] LC / MS (AN01_001_026): Rt=8.08 min, 99.72%, [M+H] + =507.5.

[1210] 1H NMR (400MHz, DMSO) δ8.56(d, J=8.5Hz, 1H), 7.69-7.61(m, 2H), 7.59-7.53(m, 1H), 7 .44-7.32(m, 4H), 5.05-4.96(m, 1H), 4.02(dd, J=9.2, 4.0Hz, 1H), 3.70(d, J=12.3Hz , 1H), 3.53(d, J=12.3Hz, 1H), 3.40(s, 3H), 3.26-3.03(m, 5H), 2.90(d, J=14.2Hz, 1H) ), 2.44-2.27(m, 3H), 1.65(hept, J=6.7Hz, 1H), 1.07(s, 3H), 0.84(d, J=6.7Hz, 6H).

[1211] Example 13 Preparation of (2S,6S)—N—((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-6-(hydroxymethyl)-1,4-oxazepane-2-carboxamide (Compound 13)

[1212] [ka] tert-Butyl (2S,6R * )-2-[(benzyloxy)methyl]-6-hydroxy-6-(hydroxylmethyl)-1,4-oxazepane-4-carboxylate B1-78-1-(R) * and tert-butyl (2S,6S * )-2-[(benzyloxy)methyl]-6-hydroxy-6-(hydroxylmethyl)-1,4-oxazepane-4-carboxylate B1-78-1-(S) * .

[1213] To a solution of B1-2-13 (1 equiv., 820 mg, 2.46 mmol) (prepared) in a mixture of THF (13.67 mL) and water (4.56 mL) was added potassium osmate(VI) dihydrate (0.1 equiv., 90.61 mg, 0.25 mmol) and NMO (1.5 equiv., 432.15 mg, 3.69 mmol) sequentially at room temperature. The resulting mixture was stirred at room temperature for 18 h.

[1214] The reaction mixture was diluted with water (40 mL) and EtOAc (75 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 75 mL). The combined organic layers were washed with NaSO solution (2 × 100 mL), then brine (75 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting crude product was purified on silica gel by flash chromatography (15 μm, 25 g, 100:0 to 2:8 cyclohexane / EtOAc over 36 min, exposed with PMA) to give B1-78-1-(S * ) (124 mg, 24%) and B1-78-1-(R * ) (156 mg, 36%) was obtained as a colorless oil. The stereochemistry of both diastereomers was arbitrarily assigned.

[1215] LC / MS(AN01_001_021): Rt=9.19 min, 79.3%, [M-Boc+H]+=268.08

[1216] [ka]

[1217] tert-Butyl (2S,6R * )-2-[(benzyloxy)methyl]-6-{[(tert-butyldimethylsilyl)oxy]methyl}-6-hydroxy-1,4-oxazepane-4-carboxylate B1-78-3-(R) * B1-78-(S) *To a solution of (1 equiv., 238 mg, 0.65 mmol) in DCM (5 mL) was added imidazole (2 equiv., 88.19 mg, 1.3 mmol) and DMAP (0.1 equiv., 7.91 mg, 0.065 mmol) at room temperature. The resulting mixture was stirred at room temperature for 5 minutes and then cooled to 0 °C, after which a solution of TBDMSCl (2 equiv., 195.25 mg, 0.22 mL, 1.3 mmol) in DCM (1 mL) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and then diluted with water (30 mL) and EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified on silica gel by flash chromatography (15 μm, 40 g, 100:0 to 8:2 cyclohexane / EtOAc over 42 min, exposure with PMA) to give B1-78-3-(R) * (243 mg, 78%) was obtained as a colorless oil.

[1218] LC / MS (AN01_001_012): Rt=3.26 min, 72.5%, [M-Boc+H] + =382.6.

[1219] tert-Butyl (2S,6R * )-6-{[(tert-butyldimethylsilyl)oxy]methyl}-6-hydroxy-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate B1-78-4-(R) * B1-78-3-(R) * (1 equiv., 365 mg, 0.76 mmol) and using general procedure D, B1-78-4-(R) * was obtained as a colorless oil (296 g, 100%).

[1220] LC / MS (AN01_001_021): Rt=11.11 min, non-UV active, [M-Boc+H] + =292.13 (2S,6R *)-4-[(tert-butoxy)carbonyl]-6-{[(tert-butyldimethylsilyl)oxy]methyl}-6-hydroxy-1,4-oxazepane-2-carboxylic acid B1-78-5-(R) * B1-78-4-(R) * (1 equiv., 211.0 mg, 0.54 mmol) and using general procedure E, B1-78-5-(R) * was obtained as a colorless gum (218 mg, 100%).

[1221] LC / MS (AN01_001_021): Rt=10.84 min, 91%, [M-Boc+H] + =306.1 tert-Butyl (2S,6R * )-6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-1,4-oxazepane-4-carboxylate B1-78-7-(R) * BB01 (1 equivalent, 167.1 mg, 0.51 mmol) and B1-78-5-(R) * Starting with (1.05 equiv., 260 mg, 0.51 mmol), using general procedure B, B1-78-7-(R) was obtained after purification by silica gel flash chromatography (amorphous SiOH, 50 μm, 40 g, 100:0 to 20:80 cyclohexane / EtOAc over 42 min). * was obtained as a pale yellow solid (220 mg, 70%).

[1222] LC / MS (AN01_001_021): Rt=12.38 min, 99.14%, [M-Boc+H] + =581.32 tert-Butyl (2S,6S *)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate B1-78-10-(S) * B1-78-7-(R) in a mixture of THF (0.65 mL) and water (0.65 mL) * To a solution of (1 equiv., 130 mg, 0.19 mmol) was added AcOH (178.23 equiv., 2043.6 mg, 1.95 mL, 34.031 mmol) dropwise at room temperature. The resulting solution was stirred at room temperature for 63 h. The reaction mixture was poured dropwise into a saturated aqueous solution of NaHCO3 (50 mL) at 0 °C (if foaming / effervescent, diluted with approximately 15 mL of EtOAc). The mixture was stirred at 0 °C for 10 min (pH approximately 8) and then diluted with water (25 mL) and EtOAc (60 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (75 mL), then brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified on silica gel by flash chromatography (50 μm, 12 g, 8:2 to 0:100 cyclohexane / EtOAc over 42 min) to give B1-78-10-(S). * (97 mg, 90%) was obtained as a white solid.

[1223] LC / MS (AN01_001_012): Rt=2.27 min, 100%, [M-tBu+H] + =511.2.

[1224] (2S,6S * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-6-(hydroxymethyl)-1,4-oxazepane-2-carboxamide.

[1225] B1-78-10-(S) *Starting with (1 equiv., 71 mg, 0.13 mmol), general procedure C was used to obtain (2S,6S) as a white solid after purification by silica gel flash chromatography (50 μm, 12 g, gradient: 100:0 to 80:20 DCM / MeOH over 42 min). * )-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-6-(hydroxymethyl)-1,4-oxazepane-2-carboxamide (26 mg, 45%).

[1226] LC / MS (AN01_001_026): Rt=6.38 min, 100%, [M+H] + =467.39.

[1227] 1 H NMR (400MHz, DMSO) δ8.55(d, J=8.5Hz, 1H), 7.67-7.63(m, 2H), 7.58-7.55(m, 1H), 7 .43-7.36(m, 4H), 5.04-4.96(m, 1H), 4.60-4.50(m, 1H), 4.44(s, 1H), 4.00(dd, J=8. 8, 3.8Hz, 1H), 3.78(d, J=12.4Hz, 1H), 3.44(d, J=12.4Hz, 1H), 3.40(s, 3H), 3.33-3. 12(m, 4H), 3.05(dd, J=14.0, 3.8Hz, 1H), 2.62(s, 2H), 2.37(dd, J=14.0, 8.8Hz, 1H).

[1228] Example 14: Preparation of (2S)-6-allyl-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-1,4-oxazepane-2-carboxamide (Compound 14)

[1229] [ka]

[1230] tert-Butyl (2S,6S* )-6-Hydroxy-2-(hydroxymethyl)-6-(prop-2-en-1-yl)-1,4-oxazepane-4-carboxylate B1-80-2-(S) * B1-80-1-(S) in DCM (2.91 mL) at −78° C. * To a solution of (1 equiv., 220 mg, 0.58 mmol) was added 1 M BCl in DCM (5 equiv., 2.91 mL, 2.91 mmol). The reaction mixture was stirred at −78° C. for 6 h. The RM was quenched with MeOH (10 mL) and then concentrated under reduced pressure to give the crude material (131 mg) as a colorless gum.

[1231] To a solution of the crude material (1 equiv., 131 mg, 0.53 mmol) and EtN (3 equiv., 160 mg, 0.22 mL, 1.58 mmol) in DCM (0.6 mL) and MeOH (0.6 mL) was added a solution of BocO (1 equiv., 115.027 mg, 0.11 mL, 0.53 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure to give the crude product (120 mg) as a yellowish oil. The crude product was purified by flash chromatography on silica gel (50 μm, 12 g intercalate, dry packed (silica), mobile phase gradient: 100 / 0 to 60 / 40 cyclohexane / EtOAc over 45 min) to give B1-80-2-(S). * was obtained as a colorless oil (105 mg, 43% over two steps).

[1232] LC / MS (AN_01_001_012): No UV activity, Rt=2.02 min, ND, [M- t Bu+H] + =232.1 (2S,6S * )-4-[(tert-butoxy)carbonyl]-6-hydroxy-6-(prop-2-en-1-yl)-1,4-oxazepane-2-carboxylic acid B1-80-3-(S) * B1-80-2-(S) in acetone (2.78 mL) * To a solution of (1 equiv., 80 mg, 0.28 mmol) was added Jones reagent (2.5 equiv., 0.35 mL, 0.7 mmol) at 0° C. The solution was st...

Claims

1. Compounds of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R ０ teeth 【Chemistry 2】 and X １ and X ２ are independently O, S, NH, N(C １～６ alkyl), or CR １２ R １３ and X １ and X ２ At least one of the following is CR １２ R １３ Instead, X ３ are O, S, NH, N(C １～６ alkyl), CH ２ O, R Ａ is H, C １～６ Alkyl, C １～６ Alkylene-carbocyclyl, C １～６ alkylene-heteroaryl, heteroaryl or carbocyclyl; R Ｂ is C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkyl-OH, C ２～６ Alkenyl, cycloalkyl, C １～６ Alkylene-carbocyclyl, C １～６ Alkylene-aryl, C １～６ alkylene-heteroaryl, heteroaryl, or carbocyclyl; R Ａ and R Ｂ together form a heterocyclyl, L is aryl, heterocyclyl, heteroaryl, or 【Transformation 3】 and L is independently 0 to 4 R １０ and Ring B is a carbocycle or a heterocycle; R １ teeth 【Chemistry 4】 and R ２ are H, F, Cl, Br, OSO ２ C １～６ Alkyl, or C １～６ is alkyl, R ３ are H, F, Cl, Br, CN, C １～６ Haloalkyl, SO ２ C １～６ Alkyl, CONH ２ or SO ２ NR ４ R ５ wherein R ４ and R ５ together with the nitrogen atom to which they are attached form a heterocyclyl, X is O, S, CHF, or CF ２ and Y is O, S, or CH ２ and Q is CH or N; R ６ is C １～６ alkyl, optionally substituted with 1, 2 or 3 F, or OH, OC １～６ Alkyl, N(C １～６ alkyl) ２ , N(C １～６ alkyl) (C １～６ Alkylene -O-C １～６ optionally substituted with alkyl), cycloalkyl, or heterocyclyl; R ７ is H, F, Cl, Br, or C １～６ is alkyl, Each R ８ and R １２ are independently H, OH, halogen, NH ２ , COOH, C １～６ Alkyl, C １～６ Alkyl-OH, C ２～６ Alkenyl, C １～６ Alkoxy, O-cycloalkyl, cycloalkyl, C １～６ Alkylene-carbocyclyl, C １～６ Alkylene-heteroaryl, halogenated C １～６ Alkyl, halogenated C １～６ alkoxy, heteroaryl, or carbocyclyl; Each R １３ are independently H, F, Cl, Br, I or C １ ~C ６ is alkyl, Each R １０ are independently oxo, halogen, C １～６ Alkyl, C １～６ Alkoxy, S-C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ Cycloalkyl, cyano, hydroxy, NH ２ , —NH—C １～６ Alkyl, N(C １～６ alkyl) ２ , COOH, COC １～６ Alkyl, COOC １～６ Alkyl, CON １－６ Alkyl, CON(C １～６ alkyl) ２、 NHCOC １～６ alkyl, or heterocycle, and each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle independently may be selected from the group consisting of halogen, cyano, hydroxyl, NH ２ and COOH, W, X ４ and Y ２ are each independently CH or N, provided that W, X ４ and Y ２ at most one of may be N, DE is N(H)-C(O), N(C １～６ alkyl)-C(O), CH ２ CH ２ , C(O)—O or CH ２ -O, R １１ is H, C １～６ alkyl, alkylene-O-alkyl, or heterocyclyl; A compound of formula (I) or a pharmaceutically acceptable salt or deuterated form thereof, wherein i and j are each independently 1, 2 or 3, with the proviso that the sum of i+j is 2, 3 or 4.

2. L is phenyl, and L independently represents 0, 1, or 2 R １０ 10. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, substituted with:

3. The compound is a compound of formula (II) 【Transformation 5】 or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, 1, or 2; １０ The compound of claim 1 , wherein is a halogen.

4. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, or a deuterated form thereof, wherein the halogen is F.

5. 5. The compound of claim 3 or 4, wherein n is 0, or a pharmaceutically acceptable salt thereof or a deuterated form thereof.

6. 5. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof or a deuterated form thereof, wherein n is 1.

7. R １ teeth 【Transformation 6】 and X is O, S or CF ２ and Y is O or S; Q is CH or N; R ６ is C １～３ alkyl, １～３ Alkyl is one, two or three of F, OH, OC １ ~ ３ Alkyl, N(C １～３ alkyl) ２ , N(C １～３ alkyl) (C １～３ Alkylene -O-C １～３ optionally substituted by alkyl), cyclopropyl, or tetrahydropyran; R ７ is H, F, Cl or CH ３ and R １１ is H, C １～６ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or deuterated form thereof, which is alkyl, alkylene-O-alkyl, or heterocyclyl.

8. R １ teeth 【Transformation 7】 and X is O, S or CF ２ and Y is O or S; R ６ is C １～３ alkyl, １～３ Alkyl is one, two or three of F, OH, OC １～３ Alkyl, N(C １～３ alkyl) ２ , cyclopropyl, or tetrahydropyran; R ７ is H, F, Cl or CH ３ 7. The compound of any one of claims 1 to 6, wherein:

9. R １ teeth 【Transformation 8】 7. The compound of any one of claims 1 to 6, wherein:

10. X is O and R ６ is C １～３ alkyl, and R ７ is H, or a pharmaceutically acceptable salt or deuterated form thereof.

11. R １ teeth 【Chemistry 9】 and X is O, R ６ is C １～３ alkyl, １～３ alkyl is optionally substituted by 1, 2 or 3 F; R ７ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or deuterated form thereof, wherein

12. R １ teeth 【Chemistry 10】 and X is O, R ６ is C １～３ is alkyl, R ７ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or deuterated form thereof, wherein

13. R １ but 【Chemistry 11】 7. The compound of any one of claims 1 to 6, wherein:

14. R １ but 【Chemistry 12】 7. The compound of any one of claims 1 to 6, wherein:

15. R １ but 【Chemistry 13】 7. The compound of any one of claims 1 to 6, wherein:

16. R １ but 【Chemistry 14】 7. The compound of any one of claims 1 to 6, wherein:

17. R ６ 17. The compound of any one of claims 4 to 16, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

18. R ６ 17. The compound of any one of claims 4 to 16, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is ethyl.

19. R ６ 17. The compound of any one of claims 4 to 16, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is propyl.

20. R １ but 【Chemistry 15】 7. The compound of any one of claims 1 to 6, wherein:

21. R １ but 【Chemistry 16】 7. The compound of any one of claims 1 to 6, wherein:

22. R １ but 【Chemistry 17】 7. The compound of any one of claims 1 to 6, wherein:

23. R １ but [Chemistry 18] 7. The compound of any one of claims 1 to 6, wherein:

24. R １ but 【Chemistry 19】 7. The compound of any one of claims 1 to 6, wherein:

25. The compound is a compound of formula (III) 【Chemistry 20】 or a pharmaceutically acceptable salt or deuterated form thereof.

26. The compound is a compound of formula (III-A) 【Chemistry 21】 or a pharmaceutically acceptable salt or deuterated form thereof.

27. 27. The compound of claim 25 or 26, wherein n is 0.

28. 27. The compound of claim 25 or 26, wherein n is 1.

29. The compound is a compound of formula (III-B) 【Chemistry 22】 or a pharmaceutically acceptable salt or deuterated form thereof, wherein R １０ The compound of claim 1, wherein is —H or —F.

30. R １０ The compound according to any one of claims 25 to 26 and 28 to 29, wherein is F.

31. 31. The compound of any one of claims 1 to 6 and 17 to 30, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is O.

32. R ０ but 【Chemistry 23】 32. The compound of any one of claims 1 to 31, wherein:

33. R ０ but 【Chemistry 24】 33. The compound of claim 32, wherein:

34. R ０ but 【Chemistry 25】 33. The compound of claim 32, wherein:

35. R ０ but 【Chemistry 26】 33. The compound of claim 32, wherein:

36. R ０ but 【Chemistry 27】 33. The compound of claim 32, wherein:

37. R ０ but 【Chemistry 28】 34. The compound of claim 33, wherein:

38. R ０ but 【Chemistry 29】 38. The compound of claim 37, wherein:

39. R ０ but 【Transformation 30】 38. The compound of claim 37, wherein:

40. R ０ but 【Chemistry 31】 38. The compound of claim 37, wherein:

41. X １ is O and X ２ 40. The compound of claim 38 or 39, wherein is NH.

42. X １ is CH ２ and X ２ 41. The compound of claim 39 or 40, wherein is NH.

43. One R ８ OH, unsubstituted C １～６ The compound of any one of claims 37 to 42, which is alkoxy or O-cycloalkyl.

44. R ８ 44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each occurrence of is methoxy.

45. R ８ 44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each occurrence of is ethoxy.

46. R ８ 44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each occurrence of is OH.

47. R ８ The compound of any one of claims 37 to 42, wherein is H.

48. R ０ but 【Chemistry 32】 32. The compound of any one of claims 1 to 31, wherein:

49. R ０ but 【Transformation 33】 32. The compound of any one of claims 1 to 31, wherein:

50. R ０ but 【Transformation 34】 32. The compound of any one of claims 1 to 31, wherein:

51. R ０ but 【Chemistry 35】 32. The compound of any one of claims 1 to 31, wherein:

52. R ０ but 【Transformation 36】 49. The compound of claim 48, wherein:

53. R ０ but 【Chemistry 37】 53. The compound of claim 52, wherein:

54. R ０ but 【Transformation 38】 53. The compound of claim 52, wherein:

55. R ０ but 【Chemistry 39】 53. The compound of claim 52, wherein:

56. X １ is O and X ２ 55. The compound of claim 53 or 54, wherein is NH.

57. X １ is CH ２ and X ２ 56. The compound of claim 54 or 55, wherein is NH.

58. Each R ８ are independently H, OH, halogen, NH ２ , COOH, C １～６ Alkyl, C １～６ Alkyl-OH, C ２～６ Alkenyl, C １～６ Alkoxy, O-cycloalkyl, cycloalkyl, C １～６ Alkylene-heteroaryl, halogenated C １～６ Alkyl or halogenated C １～６ Alkoxy, provided that one R ８ The compound of any one of claims 1 to 57, wherein is not H.

59. Each R ８ are independently OH, halogen, NH ２ , COOH, C １～６ Alkyl, C １～６ Alkyl-OH, C ２～６ Alkenyl, C １～６ Alkoxy, O-cycloalkyl, cycloalkyl, C １～６ Alkylene-heteroaryl, halogenated C １～６ Alkyl or halogenated C １～６ 58. The compound of any one of claims 1 to 57, which is alkoxy.

60. Each R ８ are independently OH or C １～６ 58. The compound of any one of claims 1 to 57, which is alkoxy.

61. Each R ８ is C １～６ 58. The compound of any one of claims 1 to 57, which is alkoxy.

62. Each R ８ The compound of any one of claims 1 to 57, wherein is OH.

63. Said C １～６ 63. The compound of any one of claims 59 to 62, wherein alkoxy is methoxy or ethoxy.

64. Said C １～６ 63. The compound of any one of claims 59 to 62, wherein the alkoxy is methoxy.

65. Said C １～６ 63. The compound of any one of claims 59 to 62, wherein the alkoxy is ethoxy.

66. On the other hand, R ８ is OH, and the other R ８ is unsubstituted C １～６ Alkyl, halogenated C １～６ Alkyl, C １～６ Alkyl-OH, C ２～６ Alkenyl, or C １～６ The compound of any one of claims 48 to 58, which is alkylene-heteroaryl.

67. R ０ but, 【Chemistry 40】 33. The compound of claim 32, wherein:

68. R ０ but 【Chemistry 41】 68. The compound of claim 67, wherein:

69. R ０ but 【Chemistry 42】 68. The compound of claim 67, wherein:

70. R ０ but 【Chemistry 43】 68. The compound of claim 67, wherein:

71. R ０ but 【Chemistry 44】 68. The compound of claim 67, wherein:

72. R ０ but 【Chemistry 45】 32. The compound of any one of claims 1 to 31, wherein:

73. R ０ but 【Chemistry 46】 73. The compound of claim 72, wherein:

74. R Ａ is H or C １～６ 74. The compound of any one of claims 1 to 31 and 72 to 73, or a pharmaceutically acceptable salt or deuterated form thereof, wherein:

75. R Ａ is H, or a pharmaceutically acceptable salt or deuterated form thereof.

76. R Ａ 75. The compound of claim 74, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

77. R Ａ 75. The compound of claim 74, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is butyl.

78. R Ａ 75. The compound of claim 74, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is isopropyl.

79. R Ｂ But C １～６ Alkyl, C ２～６ Alkenyl, C １～６ alkylene-carbocyclyl, or C １～６ 80. The compound of any one of claims 1 to 31 and 72 to 78, or a pharmaceutically acceptable salt or deuterated form thereof, which is alkylene-heteroaryl.

80. R Ａ and R Ｂ 74. The compound of any one of claims 1 to 31 and 72 to 73, or a pharmaceutically acceptable salt or deuterated form thereof, wherein:

81. R Ｂ But C １～６ Alkyl, C １～６ Alkylene-aryl or -C １～６ 80. The compound of claim 79, or a pharmaceutically acceptable salt or deuterated form thereof, which is alkylene-5 to 6 membered heteroaryl.

82. R ０ but 【Chemistry 47】 73. The compound of claim 72, wherein:

83. R ０ but 【Chemistry 48】 73. The compound of claim 72, wherein:

84. R ０ but 【Chemistry 49】 73. The compound of claim 72, wherein:

85. R Ｂ 85. The compound of any one of claims 82 to 84, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

86. R Ｂ 85. The compound of any one of claims 82 to 84, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is ethyl.

87. R ０ but [Transformation 50] 74. The compound of claim 73, wherein:

88. R ０ but 【Chemistry 51】 74. The compound of claim 73, wherein:

89. R ０ but 【Chemistry 52】 74. The compound of claim 73, wherein:

90. R Ｂ 90. The compound of any one of claims 87 to 89, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is methyl.

91. R Ｂ 90. The compound of any one of claims 87 to 89, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is ethyl.

92. R Ｂ 90. The compound of any one of claims 87-89, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is isopropyl.

93. R Ｂ but 【Chemistry 53】 90. The compound of any one of claims 87 to 89, wherein:

94. R Ｂ but 【Chemistry 54】 90. The compound of any one of claims 87 to 89, wherein:

95. R Ｂ is CF ３ 90. The compound of any one of claims 87 to 89, wherein:

96. R Ｂ 90. The compound of any one of claims 87-89, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is isopropyl.

97. R Ｂ -CH=CH ２ 90. The compound of any one of claims 87 to 89, wherein:

98. R Ｂ is CH ２ 90. The compound of any one of claims 87 to 89, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R is OH.

99. R Ｂ Ga-CH ２ -CH=CH ２ 90. The compound of any one of claims 87 to 89, wherein:

100. R Ｂ 90. The compound of any one of claims 87 to 89, or a pharmaceutically acceptable salt or deuterated form thereof, wherein is n-propyl.

101. X ３ 82. The compound of any one of claims 1 to 10 and 72 to 81, or a pharmaceutically acceptable salt or deuterated form thereof, wherein

102. R ６ is C １～３ 102. The compound of any one of claims 1 to 6 and 26 to 101, or a pharmaceutically acceptable salt or deuterated form thereof, wherein:

103. R ６ is CH ２ CH ３ or CH ３ 77. The compound of claim 76, wherein:

104. R ７ is H, or a pharmaceutically acceptable salt or deuterated form thereof.

105. 2. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is selected from Table 1.

106. 106. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 105, or a pharmaceutically acceptable salt or deuterated form thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier.

107. 107. A method for treating an obstructive airway disease in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 105 or a composition of claim 106.

108. 108. The method of claim 107, wherein the obstructive disease of the airways is asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis (CF), bronchiectasis, sarcoidosis, alpha-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, hypersensitivity pneumonitis, pulmonary fibrosis, complications of lung transplantation, vasculitis and thrombotic disorders of the pulmonary vasculature, pulmonary hypertension, antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute and chronic rhinitis including drug-induced rhinitis, and vasomotor rhinitis: perennial and seasonal allergic rhinitis including neurogenic rhinitis (hay fever), nasal polyposis; acute viral infections including the common cold, and infections with respiratory viruses, acute lung injury, or acute respiratory distress syndrome (ARDS).

109. 109. The method of claim 108, wherein the obstructive disease of the airways is asthma.

110. 109. The method of claim 108, wherein the obstructive disease of the airways is acute respiratory distress syndrome (ARDS).

111. 109. The method of claim 108, wherein the obstructive disease of the airways is bronchitis.

112. 109. The method of claim 108, wherein the obstructive disease of the airways is pulmonary fibrosis.

113. 109. The method of claim 108, wherein the obstructive disease of the airways is emphysema.

114. 109. The method of claim 108, wherein the obstructive disease of the airways is cystic fibrosis (CF).

115. 109. The method of claim 108, wherein the obstructive disease of the airways is bronchiectasis.

116. 109. The method of claim 108, wherein the obstructive disease of the airways is sarcoidosis.

117. 109. The method of claim 108, wherein the obstructive disease of the airways is alpha-1 antitrypsin (A1AT) deficiency.

118. 109. The method of claim 108, wherein the obstructive disease of the airways is farmer's lung.

119. 109. The method of claim 108, wherein the obstructive disease of the airways is hypersensitivity pneumonitis.

120. 109. The method of claim 108, wherein the obstructive disease of the airways is a complication of lung transplantation.

121. 109. The method of claim 108, wherein the obstructive disease of the airways is a vasculitis or thrombotic disorder of the pulmonary vessels.

122. 109. The method of claim 108, wherein the obstructive disease of the airways is pulmonary hypertension.

123. 109. The method of claim 108, wherein the obstructive disease of the airways is iatrogenic cough.

124. 109. The method of claim 108, wherein the obstructive disease of the airways is acute rhinitis.

125. 109. The method of claim 108, wherein the obstructive disease of the airways is chronic rhinitis.

126. 109. The method of claim 108, wherein the obstructive disease of the airways is rhinitis medicamentosa or vasomotor rhinitis.

127. 109. The method of claim 108, wherein the obstructive disease of the airways is nasal polyposis.

128. 109. The method of claim 108, wherein the obstructive disease of the airways is COPD.

129. 110. The method of claim 109, wherein the asthma is bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, or drug-induced asthma.

130. 112. The method of claim 111, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

131. 113. The method of claim 112, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, fibrosing alveolitis of unknown cause, idiopathic interstitial pneumonia, or anti-tumor therapy-associated fibrosis or chronic infection.

132. 116. The method of claim 115, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

133. 116. The method of claim 115, wherein the bronchiectasis is associated with cystic fibrosis.

134. 123. The method of claim 122, wherein the pulmonary hypertension is pulmonary arterial hypertension.

135. 107. A method for treating cystic fibrosis in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 105 or a composition of claim 106.

136. 136. The method of claim 135, wherein said treating comprises improving pulmonary function of said patient compared to said patient's pulmonary function before treatment.

137. Improving the patient's pulmonary function may include increasing the patient's forced expiratory volume in one second (FEV) compared to the patient's respective value before treatment. １ increasing the patient's forced vital capacity (FVC); increasing the patient's peak expiratory flow rate (PEFR); or increasing the patient's forced expiratory flow rate (FEF) by 25% to 75% of the patient's FVC. （２５－７５％） 137. The method of claim 136, comprising increasing

138. 138. The method of claim 136 or 137, wherein pulmonary function is measured by spirometry.

139. 107. A method for treating bronchiectasis in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 105 or a composition of claim 106.

140. 140. The method of claim 139, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

141. 140. The method of claim 139, wherein the bronchiectasis is associated with cystic fibrosis.

142. 142. The method of any one of claims 139-141, wherein treating comprises improving pulmonary function of the patient compared to pulmonary function of the patient before treatment.

143. Improving the patient's pulmonary function may include increasing the patient's forced expiratory volume in one second (FEV) compared to the patient's respective value before treatment. １ increasing the patient's forced vital capacity (FVC); increasing the patient's peak expiratory flow rate (PEFR); or increasing the patient's forced expiratory flow rate (FEF) by 25% to 75% of the patient's FVC. （２５－７５％） 143. The method of claim 142, comprising increasing

144. 144. The method of claim 142 or 143, wherein pulmonary function is measured by spirometry.

145. 145. The method of any one of claims 139-144, wherein treating comprises reducing the pulmonary exacerbation rate compared to the patient's pulmonary exacerbation rate before treatment.

146. 146. The method of any one of claims 139-145, wherein treating comprises increasing the time to first pulmonary exacerbation compared to an untreated patient.

147. 136. The method of any one of claims 134 or 135, wherein the pulmonary exacerbation is characterized by three or more of the following symptoms exhibited by the patient for at least 48 hours: (1) increased coughing; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased shortness of breath and / or decreased exercise tolerance; (5) fatigue and / or malaise; and (6) hemoptysis.

148. 107. A method for treating chronic rhinosinusitis (CRS) in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 105 or a composition of claim 106.

149. The method of claim 148, wherein the chronic sinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP).

150. 149. The method of claim 148, wherein the chronic sinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP).

151. The method of any one of claims 141 to 150, wherein the chronic sinusitis is intractable chronic sinusitis.

152. 152. The method of any one of claims 138-151, wherein treating comprises reducing one or more symptoms of CRS, reducing its severity, delaying its onset, or eliminating it.

153. 153. The method of claim 152, wherein one or more symptoms of CRS are nasal congestion, nasal obstruction, runny nose, postnasal drip, facial pressure, facial pain, facial fullness, reduced odor, depression, mucosal edema, mucopurulent secretions, obstruction of the middle nasal meatus, mucosal changes in the oral complex and sinuses, and rhinorrhea.

154. 107. A method for treating hidradenitis suppurativa (HS) in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 105 or a composition of claim 106.

155. 155. The method of claim 154, wherein the hidradenitis suppurativa (HS) is Hurley Stage I.

156. 155. The method of claim 154, wherein the hidradenitis suppurativa (HS) is Hurley stage II.

157. 155. The method of claim 154, wherein the hidradenitis suppurativa (HS) is Hurley stage III.

158. 107. A method for treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 105 or a composition of claim 106.

159. 159. The method of claim 158, wherein the cancer is a metastatic cancer.

160. 160. The method of claim 159, wherein the metastatic cancer is metastatic cancer from the breast to the lung.

161. 160. The method of claim 159, wherein the metastatic cancer comprises breast cancer metastasis to the brain, bone, pancreas, lymph nodes, or liver.

162. 160. The method of claim 159, wherein the metastatic cancer comprises metastasis of bone cancer to the lung.

163. 160. The method of claim 159, wherein the metastatic cancer comprises colorectal cancer metastasis to the peritoneum, pancreas, stomach, lung, liver, kidney, or spleen.

164. 160. The method of claim 159, wherein the metastatic cancer comprises metastasis of gastric cancer to the mesentery, spleen, pancreas, lung, liver, adrenal gland, or ovary.

165. 160. The method of claim 159, wherein the metastatic cancer comprises liver cancer metastasis to the intestine, spleen, pancreas, stomach, lung, or kidney.

166. 160. The method of claim 159, wherein the metastatic cancer comprises lymphoma metastasis to the kidney, ovary, liver, bladder, or spleen.

167. 107. A method for treating lupus nephritis in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 105 or a composition of claim 106.

168. 107. A method for treating rheumatoid arthritis in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 105 or a composition of claim 106.

169. 107. A method for treating inflammatory bowel disease (IBD) in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 105 or a composition of claim 106.

170. 170. The method of claim 169, wherein the inflammatory bowel disease (IBD) is Crohn's disease.

171. 170. The method of claim 169, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

172. 107. A method for treating antineutrophil cytoplasmic antibody (ANCA) associated vasculitis in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 105 or a composition of claim 106.

173. 172. The method of claim 171, wherein the ANCA-associated disease is granulomatosis with polyangiitis (GPA).

174. 174. The method of claim 173, wherein the ANCA-associated disease is microscopic polyangiitis (MPA).

175. 107. A method for treating a disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1 to 105 or a composition of claim 106, wherein the disease is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpasture's disease), systemic sclerosis, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcer, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatosis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or ventilator-induced lung injury.

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