Dipeptidyl peptidase-1 inhibitors and their uses

Abstract

This article provides compounds of formula (I) or their pharmaceutically acceptable salts, stereoisomers, or deuterated forms, wherein rings A, R... 1 、 R 2 、 R 3 、 R 4 、 R 9 、 m and n are defined herein. This document also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of formula (I) or a pharmaceutically acceptable salt or deuterated form thereof, for example, in treating diseases treatable by administration of a DPP1 inhibitor. (I)

Description

[0001] Cross-references to related applications

[0002] This application claims priority to International Patent Application No. PCT / CN2023 / 119032, filed on September 15, 2023; International Patent Application No. PCT / CN2024 / 081928, filed on March 15, 2024; and International Patent Application No. PCT / CN2024 / 087534, filed on April 12, 2024, the disclosure of each of which is incorporated herein by reference in its entirety. Background Technology

[0003] 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 human enzyme's cDNA was first described in 1995 (Paris et al. 1995, FEBS Lett, 369, 326-330). DPP1 is the only member of the papain family to function as a tetramer, composed 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).

[0004] DPP1 is constitutively expressed in many tissues, with the highest expression levels in the lung, kidney, 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 an important enzyme in lysosomal protein degradation, DPP1 also functions as a key enzyme in activating granular serine proteases in cytotoxic T lymphocytes and natural killer cells (granulases A and B), mast cells (chymotrypsin and trypsin-like proteins), and neutrophils (cathepsin G, neutrophil elastase, and protease-3).

[0005] Mast cells are present in many tissues, but are most abundant in the epithelial lining of the human body, such as the skin, respiratory tract, and gastrointestinal tract. In humans, two types of mast cells have been identified: the T-type, which expresses only trypsin, and the MC-type, which expresses both trypsin and chymotrypsin. In humans, T-type mast cells are mainly located in alveolar tissue and intestinal mucosa, while TC-type cells are mainly found in the skin and conjunctiva. Trypsin and chymotrypsin appear to be important mediators of allergic diseases, involved in processes such as inflammation, bronchoconstriction, and mucus secretion.

[0006] Neutrophils play a crucial role in the host's defense against invading pathogens. Neutrophils are produced in the bone marrow and fully mature upon release into the bloodstream to function as the first line of cellular defense. Pro-inflammatory mediators and chemotactic attractors activate neutrophils and pull them to the site of infection, where they engulf bacteria through phagocytosis and attack them using a library of antimicrobial compounds employing oxidative and non-oxidative attack methods. Neutrophil elastase, a potent serine protease, is one of the antimicrobial compounds significantly involved in bacterial elimination. Neutrophil elastase is released into phagolysosomes surrounding microorganisms, thereby eliminating them. Neutrophil elastase can attack the outer membrane protein OmpA in Gram-negative bacteria, thereby facilitating the direct killing of pathogens by degrading their membranes and enabling other antimicrobial compounds to penetrate the pathogen. Furthermore, neutrophil elastase can aid in the processing of other antimicrobial compounds, converting them from inactive propeptides to their active state, such as in the case of cathelicidin.

[0007] However, neutrophil elastase can also cause problems for its host. Neutrophil elastase is one of the most destructive enzymes in the human body, capable of degrading extracellular matrix proteins (including collagen, proteoglycans, fibronectin, platelet receptors, complement receptors, thrombomodulin, lung surfactant, and cadherin) and key plasma proteins (including coagulation factors and complement factors, immunoglobulins, several proteases, and protease inhibitors). Under physiological conditions, endogenous protease inhibitors, such as α1-antitrypsin, strictly regulate neutrophil elastase activity. However, at sites of inflammation, neutrophil elastase can evade regulation, and once unregulated, it can induce the release of pro-inflammatory cytokines such as interleukin-6 and interleukin-8, leading to acute lung injury. Neutrophil elastase can even impair the host's defenses against infection by degrading phagocyte surface receptors and opsonins. The negative effects of the neutrophil elastase are illustrated by its involvement in tissue destruction and inflammation, which are characteristic of a variety of diseases including hereditary emphysema, chronic obstructive pulmonary disease, cystic fibrosis, adult respiratory distress syndrome, ischemia-reperfusion injury, and rheumatoid arthritis.

[0008] 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

[0009] In an embodiment, this disclosure provides a compound of formula (I):

[0010] (I),

[0011] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0012] Ring A is a carbocyclic, aryl, heterocyclic, or heteroaryl ring;

[0013] R 1 Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0014] R 2 It is a carbocyclic, aryl, heterocyclic, or heteroaryl ring, wherein each R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace;

[0015] R 3 It is H, halogen, -OH, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), or -SO2 (C1-C6 alkyl); or R 3 Can be used with R 6 Together, they form a tricyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tricyclic ring is optionally connected by 1, 2, 3, or 4 R atoms. 5 replace;

[0016] Each R 4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0017] R 5 and R 6 Each of these can be independently a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkylene)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0018] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0019] R 9 It is -OH, -O (C1-C6 alkyl), -O (C1-C6 haloalkyl) or -O (C1-C6 deuterated alkyl);

[0020] m is 0, 1, 2, or 3; and

[0021] n is 0, 1, 2, or 3;

[0022] Where ring A is or And when n is 0, then R 2 no or .

[0023] In an embodiment, this disclosure provides a compound of formula (IA):

[0024] (IA),

[0025] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0026] R 1 Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0027] R 3 It is H;

[0028] Each R 4It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0029] R 6 It is a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0030] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0031] R 9 It is -OH, -O (C1-C6 alkyl), -O (C1-C6 haloalkyl) or -O (C1-C6 deuterated alkyl);

[0032] m is 0, 1, 2, or 3; and

[0033] n can be 0, 1, 2, or 3.

[0034] In an embodiment, this disclosure provides a compound of formula (IB):

[0035] (IB),

[0036] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0037] R 1 Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0038] R 3 It is H;

[0039] Each R 4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0040] R 10 It is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic;

[0041] R 9 It is -O (C1-C6 alkyl), -O (C1-C6 haloalkyl), or -O (C1-C6 deuterated alkyl);

[0042] m is 0, 1, 2, or 3; and

[0043] n can be 0, 1, 2, or 3.

[0044] In an embodiment, this disclosure provides a compound of formula (IC):

[0045] (IC),

[0046] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0047] Ring B is a 5- to 8-membered ring that optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O;

[0048] R 1 Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0049] Each R4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0050] R 5 and R 6 Each of these can be independently a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, or -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0051] R 9 It is -O (C1-C6 alkyl), -O (C1-C6 haloalkyl), or -O (C1-C6 deuterated alkyl);

[0052] m is 0, 1, 2, or 3;

[0053] n is 0, 1, 2, or 3;

[0054] p is 0, 1, 2, or 3; and

[0055] q can be 0, 1, 2 or 3.

[0056] In an embodiment, this disclosure provides a compound of formula (ID):

[0057] (ID),

[0058] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0059] Ring A is a monocyclic or bicyclic heteroaryl ring;

[0060] R 1Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0061] R 3 It is H;

[0062] Each R 4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0063] R 9 It is -O (C1-C6 alkyl), -O (C1-C6 haloalkyl), or -O (C1-C6 deuterated alkyl);

[0064] R 10 It is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic;

[0065] m is 0, 1, 2, or 3; and

[0066] n can be 0, 1, 2, or 3.

[0067] In an embodiment, this disclosure provides a compound of formula (IE):

[0068] (IE),

[0069] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0070] R 1Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0071] R 2 It is a tricyclic carbocyclic ring, a tricyclic aryl ring, a tricyclic heterocyclic ring, or a tricyclic heteroaryl ring, wherein each R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace;

[0072] R 3 It is H;

[0073] Each R 4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0074] R 6 Each of these can be independently a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, or -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0075] R 9 It is -O (C1-C6 alkyl), -O (C1-C6 haloalkyl), or -O (C1-C6 deuterated alkyl);

[0076] m is 0, 1, 2, or 3; and

[0077] n can be 0, 1, 2, or 3.

[0078] In the embodiments, this disclosure provides the compounds of Table A or their pharmaceutically acceptable salts, stereoisomers or deuterated forms.

[0079] In embodiments, this disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or a compound of Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof) and a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0080] In an embodiment, this disclosure provides a method for treating airway obstructive disease in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0081] In an embodiment, this disclosure provides a method for treating cystic fibrosis in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0082] In an embodiment, this disclosure provides a method for treating chronic sinusitis in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0083] In an embodiment, this disclosure provides a method for treating hidradenitis suppurativa in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0084] In an embodiment, this disclosure provides a method for treating cancer in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0085] In an embodiment, this disclosure provides a method for treating lupus nephritis in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0086] In an embodiment, this disclosure provides a method for treating rheumatoid arthritis in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0087] In an embodiment, this disclosure provides a method for treating inflammatory bowel disease in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0088] In an embodiment, this disclosure provides a method for treating antineutrophil cytoplasmic antibody-associated vasculitis in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof).

[0089] In embodiments, this disclosure provides a method for treating a disease in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof), wherein the disease is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpassuia), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcer, Duchenne muscular dystrophy, obstructive bronchiolitis, atopic dermatitis, pyoderma gangrenosa, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatitis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or ventilator-induced lung injury.

[0090] In an embodiment, this disclosure provides a method for treating heart failure in a patient in need, the method comprising administering to the patient an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof). Detailed Implementation

[0091] Throughout this disclosure, various patents, patent applications, and publications are cited. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety for all purposes in order to provide a more comprehensive description of the state of the prior art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0092] definition

[0093] The following lists the definitions of various terms used in the specification and claims to describe the contents of this disclosure.

[0094] 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 pertains.

[0095] When immediately preceding a numerical value, the term "about" means a range covering the numerical value ± an amount of variation acceptable in the art (e.g., the value ± 10%). For example, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc., unless the context of this disclosure otherwise indicates or is inconsistent with such interpretation. For example, in a list of numerical values ​​such as "about 49, about 50, about 55, ...", "about 50" means a range extending to less than half the interval between a previous value and a subsequent value, such as greater than 49.5 to less than 50.5. Furthermore, given the definition of the term "about" provided herein, the phrases "less than about" or "greater than about" should be understood. Similarly, when preceding a series of numerical values ​​or a range of values ​​(e.g., "about 10, 20, 30" or "about 10-30"), the term "about" refers to the endpoints of all values ​​or ranges in the series, respectively.

[0096] Unless otherwise stated, the following terms as used herein have the following meanings:

[0097] "Cyano" refers to the -CN group.

[0098] "Hydroxyl" or "hydroxyl" refers to the -OH group.

[0099] "Oxyto" refers to the =O substituent.

[0100] "alkyl" or "alkyl group" refers to a fully saturated straight-chain or branched hydrocarbon chain group having one to twelve carbon atoms, and which is connected to the rest of the molecule by a single bond. This includes alkyl groups containing any number of carbon atoms from 1 to 12. Alkyl groups containing up to 12 carbon atoms are C1-C1. 12 Alkyl groups, which contain up to 10 carbon atoms, are C1-C6. 10 Alkyl groups, specifically those containing up to six carbon atoms (C1-C6 alkyl groups) and those containing up to five carbon atoms (C1-C5 alkyl groups), are further categorized. C1-C5 alkyl groups include C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl groups encompass all the portions described above for C1-C5 alkyl groups, but also include C6 alkyl groups. C1-C 10 Alkyl groups include all the portions described above regarding C1-C5 and C1-C6 alkyl groups, but also include C7, C8, C9, and C6 alkyl groups. 10 Alkyl group. Similarly, C1-C 12 Alkyl groups include all of the above-mentioned portions, but also include C4 groups. 11 and C 12 Alkyl group. C1-C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specified in the specification, the alkyl group may optionally be substituted.

[0101] "alkylene" or "alkylene chain" refers to a fully saturated, straight-chain or branched divalent hydrocarbon chain group having one to twelve carbon atoms. C1-C 12 Non-limiting examples of alkylene groups include methylene, ethylene, propylene, n-butene, vinylene, propenylene, n-butenylene, propynylene, n-butynylene, etc. The alkylene chain is connected to the rest of the molecule by single bonds and to functional groups by single bonds. The connection points of the alkylene chain to the rest of the molecule and to functional groups can be one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the alkylene chain may optionally be substituted.

[0102] "Alkenyl" or "alkenyl group" refers to a straight-chain or branched hydrocarbon chain group having two to twelve carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is connected to the rest of the molecule by a single bond. This includes alkenyl groups containing any number of carbon atoms from 2 to 12. Alkenyl groups containing up to 12 carbon atoms are C2-C. 12 Alkenyl groups, which contain up to 10 carbon atoms, are C2-C. 10Alkenyl groups, specifically C2-C6 alkenyl groups containing up to six carbon atoms, and C2-C5 alkenyl groups containing up to five carbon atoms, are also included. C2-C5 alkenyl groups include C5, C4, C3, and C2 alkenyl groups. C2-C6 alkenyl groups include all the portions described above for C2-C5 alkenyl groups, but also include C6 alkenyl groups. C2-C 10 Alkenyl groups include all the parts described above regarding C2-C5 and C2-C6 alkenyl groups, but also include C7, C8, C9, and C6 alkenyl groups. 10 Alkenyl. Similarly, C2-C 12 Alkenyl groups include all the aforementioned portions, but also include C. 11 and C 12 Alkenyl. C2-C 12 Non-limiting examples of alkenyl groups include ethenyl, 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, 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, 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 otherwise specified in the specification, the alkenyl group may be optionally substituted.

[0103] "Alkenyl" or "alkenyl chain" refers to a straight-chain or branched divalent hydrocarbon chain group having two to twelve carbon atoms and one or more carbon-carbon double bonds. (C2-C) 12 Non-limiting examples of alkenyl groups include ethylene, propylene, butene, etc. The alkenyl chain is connected to the remainder of the molecule by a single bond and to a group by a single bond. The connection points between the alkenyl chain and the remainder of the molecule and to the group can be through one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the alkenyl chain may optionally be substituted.

[0104] "Alkynyl" or "alkynyl group" refers to a straight-chain or branched hydrocarbon chain having two to twelve carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is connected to the rest of the molecule by a single bond. This includes alkynyl groups containing any number of carbon atoms from 2 to 12. Alkynyl groups containing up to 12 carbon atoms are C2-C. 12 The alkynyl group, which contains up to 10 carbon atoms, is C2-C. 10 The alkynyl group, containing up to 6 carbon atoms, is C2-C6 alkynyl, and containing up to 5 carbon atoms, is C2-C5 alkynyl. C2-C5 alkynyl groups include C5, C4, C3, and C2 alkynyl groups. C2-C6 alkynyl groups include all the parts described above regarding C2-C5 alkynyl groups, but also include C6 alkynyl groups. C2-C 10 The alkynyl group includes all the parts described above regarding C2-C5 and C2-C6 alkynyl groups, but also includes C7, C8, C9, and C6 alkynyl groups. 10 Alkyne group. Similarly, C2-C 12 The alkynyl group includes all the aforementioned parts, but also includes C. 11 and C 12 Alkyne group. C2-C 12 Non-limiting examples of alkenyl groups include ethynyl, propynyl, butynyl, and pentyynyl. Unless otherwise specified in the specification, the ethynyl group may optionally be substituted.

[0105] "Imyynyl" or "Imyynyl chain" refers to a straight-chain or branched divalent hydrocarbon chain group having two to twelve carbon atoms and one or more carbon-carbon triple bonds. (C2-C) 12 Non-limiting examples of ynylenes include ethynylenes, propynylenes, etc. The ynylene chain is connected to the rest of the molecule by a single bond and to a group by a single bond. The connection points between the ynylene chain and the rest of the molecule and to the group can be through one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the ynylene chain may optionally be substituted.

[0106] "Alkoxy" refers to the formula -OR a The group, wherein R a It is an alkyl, alkenyl, or alkynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in the specification, the alkoxy group may optionally be substituted.

[0107] "alkylamino" refers to the formula -NHR a or -NR a R a The groups, wherein each R aIndependently, it is an alkyl, alkenyl, or ynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in the specification, the alkylamino group may optionally be substituted.

[0108] "Aryl" refers to a hydrocarbon cyclic group comprising hydrogen, 6 to 18 carbon ring atoms, and at least one aromatic ring. For the purposes of this disclosure, the aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may include fused, bridged, or spirocyclic systems. Aryl groups include, but are not limited to, aryl groups derived from anthracene, acenaphthene, phenanthrene, anthracene, azulene, benzene, chrysoprase, fluorene, asymmetric indarene, symmetric indarene, indene, indene, naphthalene, phenanthracene, heptamethrin, pyrene, and benzo[a]phenanthrene. In embodiments where "L" is aryl, the aryl group is bimethyl. Unless otherwise specifically stated in the specification, the term "aryl" means including optionally substituted aryl groups.

[0109] "Arylalkyl" or "arylalkyl" refers to the formula -R b -R c The group, wherein R b It is an alkylene group as defined above and R c It is one or more aryl groups as defined above, such as benzyl, diphenylmethyl, etc. Unless otherwise specified in the specification, the aryl group may optionally be substituted.

[0110] "Carbocyclic group," "carbocyclic ring," or "carbocycle" refers to a ring structure in which each atom forming the ring is carbon. A carbocyclic ring can contain 3 to 20 carbon atoms. Carbocyclic rings include cycloalkyl, cycloalkenyl, and cycloynyl groups as defined herein. Unless otherwise specified in the specification, the carbocyclic group may optionally be substituted.

[0111] "Cycloalkyl" refers to a stable, non-aromatic, fully saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms. It may include fused, bridged, or spirocyclic systems, having three to twenty carbon atoms (e.g., three to ten carbon atoms), and is connected to the rest 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, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specified in the specification, cycloalkyl groups may optionally be substituted.

[0112] "Cycloalkenyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having one or more carbon-carbon double bonds. It may include fused, bridged, or spirocyclic systems, having three to twenty carbon atoms (e.g., three to ten carbon atoms), and is connected to the rest of the molecule by single bonds. Monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyl groups include, for example, bicyclic [2.2.1]hept-2-enyl, etc. Unless otherwise specifically stated in the specification, cycloalkenyl groups may optionally be substituted.

[0113] "Cycloynyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds. It can include fused, bridged, or spirocyclic systems, having three to twenty carbon atoms (e.g., three to ten carbon atoms), and is connected to the rest of the molecule by single bonds. Monocyclic cycloynyl groups include, for example, cycloheptynyl, cyclooctyynyl, etc. Unless otherwise specified in the specification, the cycloynyl group may optionally be substituted.

[0114] "Cycloalkylalkyl" refers to the formula -R b -R d The group, wherein R b It is an alkylene, alkenylene, or ynylene group as defined above, and R d These are cycloalkyl, cycloalkenyl, and cycloynyl groups as defined above. Unless otherwise specified in the specification, cycloalkyl groups may optionally be substituted.

[0115] "Haloalkyl" refers to an alkyl group as defined above that has been substituted with one or more halogenated groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specified in the specification, haloalkyl may optionally be substituted.

[0116] "Haloalkenyl" refers to an alkenyl group as defined above that has been substituted with one or more halogenated groups as defined above, such as 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless otherwise specified in the specification, the haloalkenyl group may optionally be substituted.

[0117] "Haloalkynyl" refers to an alkynyl group as defined above that has been substituted with one or more halogenated groups as defined above, such as 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless otherwise specified in the specification, the haloalkynyl group may optionally be substituted.

[0118] "Heterocyclic group," "heterocyclic ring," or "heterocycle" refers to a stable 3- to 20-membered non-aromatic, saturated, or partially unsaturated cyclic group consisting of two to twelve carbon ring atoms and one to six heteroatoms selected from nitrogen, oxygen, or sulfur as ring atoms, wherein at least one non-aromatic, saturated, or partially unsaturated ring contains at least one heteroatom as a ring atom. Unless otherwise specified in the specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, bridged, or spirocyclic systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolane, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecyclo, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In examples where "L" is a heterocyclic group, the heterocyclic group is a bimolecular group. Unless otherwise specifically stated in the specification, the heterocyclic group may optionally be substituted.

[0119] "Heterocyclic alkyl" refers to the formula -R b -R e The group, wherein R b It is an alkylene group as defined above, and R e It is a heterocyclic group as defined above. Unless otherwise specified in the specification, the heterocyclic alkyl group may optionally be substituted.

[0120] "N-Heterocyclic group" refers to a heterocyclic group as defined above containing at least one nitrogen atom, wherein the connection point between the heterocyclic group and the rest of the molecule is through a nitrogen atom in the heterocyclic group. Unless otherwise specified in the specification, the N-heterocyclic group may optionally be substituted.

[0121] "Heteroaryl" refers to a 5- to 20-membered ring group comprising one to thirteen carbon ring atoms, one to six heteroatoms selected from nitrogen, oxygen, and sulfur ring atoms, and at least one aromatic ring containing at least one heteroatom as a ring atom. For the purposes of this disclosure, the heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, bridged, or spirocyclic systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Examples include, but are not limited to, acrylonitrile, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptyl, 1,4-benzodioxyl, benzonaphthuryl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiophene (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenyl, dibenzofuranyl, dibenzophenylthio, furanyl, furanoneyl, isothiazolyl, Imidazolyl, indazole, indolyl, indazole, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, indazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoacetyl, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and phenylthioyl (i.e., thiophene). In examples where "L" is a heteroaryl group, the heteroaryl group is a dimethyl group. Unless otherwise specified in the specification, heteroaryl groups may optionally be substituted.

[0122] "N-Heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen atom, wherein the connection point between the heteroaryl group and the rest of the molecule is through a nitrogen atom in the heteroaryl group. Unless otherwise specified in the specification, the N-heteroaryl group may optionally be substituted.

[0123] "Heteroarylalkyl" refers to the formula -R b -R f The group, wherein R b It is an alkylene chain as defined above, and R f It is a heteroaryl group as defined above. Unless otherwise specified in the specification, the heteroaryl alkyl group may optionally be substituted.

[0124] "Thioalkyl" refers to the formula -SR a The group, wherein Ra It is an alkyl, alkenyl, or ynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in the specification, thioalkyl groups may optionally be substituted.

[0125] As used herein, the term "substituted" means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkyne, alkyne, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl) in which at least one hydrogen atom is replaced by a bond with a non-hydrogen atom, such as, but not limited to: halogen atoms, such as F, Cl, Br and I; such as Oxygen atoms in hydroxyl, alkoxy, and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups.

[0126] "Substituted" also means that one or more hydrogen atoms in any of the above groups are replaced by a higher-order bond (e.g., a double or triple bond) with a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile groups. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are 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 -OR g -SR g -SOR g -SO2R g -OSO2R g -SO2OR g =NSO2R g and -SO2NR g R hSubstitution. "Substituted also means any of the above groups in which one or more hydrogen atoms are replaced by -C(=O)R g -C(=O)OR g -C(=O)NR g R h -CH2SO2R g -CH2SO2NR g R h Replace. In the above text, R g and R h The groups may be identical or different, and independently comprise hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further includes any of the above groups in which one or more hydrogen atoms are replaced by the following bonds: amino, cyano, hydroxyl, imino, nitro, oxo, thiooxy, halogen, alkyl, alkenyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. Additionally, each of the above substituents may optionally be substituted by one or more of the above substituents.

[0127] As used in this article, the symbol " "or" "(Hereinafter referred to as a "connection point bond")" indicates a bond that serves as a connection point between two chemical entities, one of which is depicted as being connected to the connection point bond, and the other is not depicted as being connected to the connection point bond. For example, " "or" The symbol “XY” indicates that chemical entity “XY” is bonded to another chemical entity via a tie point bond. In addition, the specific tie point with a chemical entity that is not depicted can be specified by inference.

[0128] Unless otherwise stated, in this specification, the term "pharmaceuticalally acceptable" is used to characterize a portion (e.g., salt, dosage form, or excipient) suitable for use based on reasonable medical judgment. Generally, a pharmaceutically acceptable portion has one or more benefits that outweigh any potentially harmful effects that portion may have. Harmful effects may include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0129] The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as 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, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid using any of a variety of known methods.

[0130] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomers, which may be defined according to absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. This disclosure is intended to include all such possible isomers as well as their racemic and optically pure forms, whether or not specifically described herein. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, and unless otherwise stated, it is intended that these compounds include both E-geometric isomers and Z-geometric isomers. Similarly, it aims to include all tautomer forms.

[0131] "Stereoisomers" are compounds formed by identical atoms bonded by identical bonds but having different, non-interchangeable, three-dimensional structures. This disclosure covers various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0132] As used herein, the term "treatment" in relation to a patient refers to the improvement of at least one symptom of the patient's condition. Treatment may be the improvement or at least partial improvement of the condition or related symptoms.

[0133] "Effective amount" means the amount of compound or pharmaceutical formulation that is sufficient to affect such treatment when administered to a patient in a therapeutic state, condition or symptom.

[0134] The term "therapeuticly effective" applied to dosage or amount refers to an amount of compound or pharmaceutical formulation sufficient to produce the desired clinical benefit when administered to a patient in need. In some embodiments, "therapeuticly effective amount" is a dose or amount of compound or pharmaceutical formulation sufficient to achieve a preventive effect when administered to a patient in need.

[0135] The terms “subject,” “individual,” and “patient” are used interchangeably in this document to refer to vertebrates, such as mammals. Mammals can be, for example, mice, rats, rabbits, cats, dogs, pigs, sheep, horses, non-human primates (e.g., cynomolgus monkeys, chimpanzees), or humans.

[0136] compound

[0137] In one aspect of this disclosure, a DPP1 inhibitor is provided, and the DPP1 inhibitor is a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof.

[0138] In an embodiment, this disclosure provides a compound of formula (I):

[0139] (I),

[0140] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0141] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0142] Ring A is a carbocyclic, aryl, heterocyclic, or heteroaryl ring;

[0143] R 1 Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0144] R 2 It is a carbocyclic, aryl, heterocyclic, or heteroaryl ring, wherein each R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace;

[0145] R 3 It is H, halogen, -OH, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), or -SO2 (C1-C6 alkyl); or R3 Can be used with R 6 Together, they form a tricyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tricyclic ring is optionally connected by 1, 2, 3, or 4 R atoms. 5 replace;

[0146] Each R 4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0147] R 5 and R 6 Each of these can be independently a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkylene)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0148] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0149] R 9 It is -OH, -O (C1-C6 alkyl), -O (C1-C6 haloalkyl) or -O (C1-C6 deuterated alkyl);

[0150] m is 0, 1, 2, or 3; and

[0151] n is 0, 1, 2, or 3;

[0152] Where ring A is or And when n is 0, then R 2 no or .

[0153] In one embodiment of the compound of formula (I), ring A is aryl or heteroaryl. In one embodiment, ring A is monocyclic or bicyclic. In one embodiment, ring A is phenyl.

[0154] In one embodiment of the compound of formula (I), R 2 It is a single ring, double ring, or triple ring, where R 2 Choose any route via 1, 2, 3, or 4 R's. 6 Replacement. In one embodiment, R 2 It is a monocyclic carbocyclic, monocyclic aryl, monocyclic heterocyclic, or monocyclic heteroaryl, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 Replacement. In one embodiment, R 2 It can be chosen to pass through 1, 2, 3 or 4 Rs. 6 Substituted phenyl groups.

[0155] In one embodiment of the compound of formula (I), R 2 It is a bicyclic carbocyclic ring, a bicyclic aryl ring, a bicyclic heterocyclic ring, or a bicyclic heteroaryl ring, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 Replacement. In one embodiment, R 2 It is a fused ring or a spiro ring.

[0156] In one embodiment of the compound of formula (I),

[0157] R 2 yes , , or ;

[0158] Each X 1a Independently is -NR 10 -、-O-、-CR 11 R 12 -、-C(O)-、-S-、-S(O)- or -S(O)2-;

[0159] Each R 10Independently, it is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic;

[0160] R 11 and R 12 Each is independently selected from H, deuterium, halogen, or -C1-C6 alkyl; and

[0161] p is 0, 1, 2 or 3.

[0162] In one embodiment of the compound of formula (I), R 2 yes , , or And p is 0 or 1. In one embodiment, R 2 yes , , or .

[0163] In an embodiment, this disclosure provides a compound of formula (IA):

[0164] (IA),

[0165] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0166] R 1 Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0167] R 3 It is H;

[0168] Each R4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0169] R 6 It is a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic, wherein the carbocyclic and heterocyclic are substituted or unsubstituted;

[0170] Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups;

[0171] R 9 It is -OH, -O (C1-C6 alkyl), -O (C1-C6 haloalkyl) or -O (C1-C6 deuterated alkyl);

[0172] m is 0, 1, 2, or 3; and

[0173] n can be 0, 1, 2, or 3.

[0174] In one embodiment of the compound of formula (I) or formula (IA), R 4 It is halogen and R 6 It is -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), or -SO2NR. 7 R 8 In one embodiment, m is 0 or 1; R 4 It is a halogen; and R 6 It is -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), or -SO2NR. 7 R8 .

[0175] In one embodiment of the compound of formula (I) or formula (IA), m is 0 or 1; R 4 It is a halogen; and R 6 It is a -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic, or heterocyclic ring, wherein the carbocyclic or heterocyclic ring is optionally substituted. In one embodiment, m is 0 or 1; R 4 It is a halogen; and R 6 It is -(C1-C3 alkylene)-(5- to 6-membered carbide ring), -(C1-C3 alkylene)-(5- to 6-membered heterocyclic ring), 5- to 6-membered carbide ring, or 5- to 6-membered heterocyclic ring, wherein the carbide ring and heterocyclic ring are optionally substituted. In one embodiment, m is 0 or 1; R 4 It is a halogen; and R 6 It is -(C1-C3 alkylene)-(6-membered carbide ring) or -(C1-C3 alkylene)-(6-membered heterocycle), wherein the carbide ring and heterocycle are optionally substituted. In one embodiment, m is 0 or 1; R 4 It is a halogen; and R 6 It is -(C1-C3 alkylene)-(6-membered carbon ring) or -(C1-C3 alkylene)-(6-membered heterocycle), wherein the carbon ring and heterocycle are optionally substituted with halogen, -C1-C6 alkyl, -OH or -C1-C6 alkoxy.

[0176] In some embodiments, R 6 yes or In some embodiments, R 6 for In one embodiment, m is 0 or 1; R 4 It is a halogen; and R 6 yes or .

[0177] In one embodiment of the compound of formula (I) or formula (IA), m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0178] In an embodiment, this disclosure provides a compound of formula (IB):

[0179] (IB),

[0180] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0181] R 1Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0182] R 3 It is H;

[0183] Each R 4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0184] R 10 It is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic;

[0185] R 9 It is -OH, -O (C1-C6 alkyl), -O (C1-C6 haloalkyl) or -O (C1-C6 deuterated alkyl);

[0186] m is 0, 1, 2, or 3; and

[0187] n can be 0, 1, 2, or 3.

[0188] In one embodiment of the compound of formula (I), formula (IA) or formula (IB), at least one R 4 It is halogen.

[0189] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 10 It is -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10Halogenated alkyl-OH, -(C1-C3 alkylene)-O-(C1-C4 alkyl), -(C1-C3 alkylene)-O-(C1-C4 alkyl)-OH, -(C1-C3 alkylene)-O-(C1-C3 alkylene)-O-(C1-C4 alkyl), -(C1-C3 alkylene)-O-(C1-C3 alkylene)-O-(C1-C4 alkyl)-OH, -C1-C3 alkyl-NR 7 R 8 Or –(C1-C3 alkylene)-heterocyclic. In some embodiments, R 10 It is -C1-C6 alkyl, -(C1-C3 alkylene)-O-(C1-C4 alkyl), -(C1-C3 alkylene)-O-(C1-C3 alkyl)-OH, -(C1-C3 alkylene)-O-(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-O-(C1-C3 alkylene)-O-(C1-C3 alkyl)-OH, -C1-C3 alkyl-N(C1-C3 alkyl)2 or –(C1-C3 alkylene)-(6-membered heterocyclic group).

[0190] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 10 It is a -C1-C6 alkyl group, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2CH2OCH3, -CH2CH2N(CH3)2 or .

[0191] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), n is 0 or 1. In one embodiment, n is 1 and R 1 It is methyl or halogen. In one embodiment, n is 1; R 1 It is methyl or halogen; and R 9 It is -OH or -OCH3.

[0192] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 9 It is -OH or -OCH3.

[0193] In one embodiment of a compound of formula (I) or formula (IB) or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0194] R 1 It is a halogen or a -C1-C6 alkyl group;

[0195] R 3 It is H;

[0196] R 4 It is halogen;

[0197] R 10 It is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic;

[0198] R 9 It is -OH or -OCH3;

[0199] m is 0 or 1; and

[0200] n is 0 or 1.

[0201] In one embodiment of a compound of formula (I) or formula (IB) or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0202] R 1 It is a halogen or a -C1-C6 alkyl group;

[0203] R 3 It is H;

[0204] R 4 It is halogen;

[0205] R 10 It is a -C1-C6 alkyl group, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2CH2OCH3, -CH2CH2N(CH3)2 or ;

[0206] R 9 It is -OH or -OCH3;

[0207] m is 0 or 1; and

[0208] n is 0 or 1.

[0209] In one embodiment of the compound of formula (I), formula (IA), or formula (IB), R 10 It is a methyl group.

[0210] In one embodiment of the compound of formula (I), R 2 It is phenyl and R 3 With R 6 One of them, together with ring A, forms a tricycle, wherein the tricycle optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O, and the tricycle optionally passes through 1, 2, 3, or 4 R atoms. 10 replace.

[0211] In an embodiment, this disclosure provides a compound of formula (IC):

[0212] (IC),

[0213] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0214] Ring B is a 5- to 8-membered ring that optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O;

[0215] R 1 Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0216] Each R 4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0217] R 5 and R 6 Each of these can be independently a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, or -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0218] R 9 It is -OH, -O (C1-C6 alkyl), -O (C1-C6 haloalkyl) or -O (C1-C6 deuterated alkyl);

[0219] m is 0, 1, 2, or 3;

[0220] n is 0, 1, 2, or 3;

[0221] p is 0, 1, 2, or 3; and

[0222] q can be 0, 1, 2 or 3.

[0223] In one embodiment of the compound of formula (IC), the tricyclic ring containing ring B is... , , or ;X 1a Yes -NR 10 -、-O-、-CR 11 R 12 -、-C(O)-、-S-、-S(O)– or -S(O)2-; and R 11 and R 12 Each is independently selected from H, deuterium, halogen, or -C1-C6 alkyl. In some embodiments, X 1a It is -NH-, -NCH3-, -O-, or -CH2-.

[0224] In one embodiment of the compound of formula (IC), the tricyclic ring containing ring B is... , , , , , , , or Where m is 0 or 1 and p is 0, 1 or 2.

[0225] In one embodiment of the compound of formula (IC), each R 4 It is independently a halogen, -C1-C3 alkyl, or -CN.

[0226] In one embodiment of the compound of formula (IC), each R 6Independently, it is a halogen, -OH, -CN, -C1-C3 alkyl, -C1-C3 haloalkyl, -S (C1-C3 alkyl), -SO (C1-C3 alkyl), -SO2 (C1-C3 alkyl), -SO2N (C1-C3 alkyl), -SO2NR 7 R 8 Or a 4-6 membered heterocyclic ring. In some embodiments, R 6 Independently, it is a halogen, -OH, -CN, -SO2CH3, , or In some embodiments, R 6 Independently, it is a halogen, -OH, -CN, -SO2CH3, , , or .

[0227] In one embodiment of the compound of formula (IC), the tricyclic ring containing ring B is... , , , , , , , , , , , , or .

[0228] In one embodiment of a compound of formula (I), formula (IA), formula (IB), or formula (IC), n is 0 or 1. In one embodiment, n is 1 and R 1 It is methyl or halogen. In one embodiment, n is 1; R 1 It is methyl or halogen; and R 9 It is -OH or -OCH3.

[0229] In one embodiment of a compound of formula (I), formula (IA), formula (IB), or formula (IC), R 9 It is -OH or -OCH3.

[0230] In an embodiment, this disclosure provides a compound of formula (ID):

[0231] (ID),

[0232] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0233] Ring A is a monocyclic or bicyclic heteroaryl ring;

[0234] R 1 Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0235] R 3 It is H;

[0236] Each R 4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0237] R 9 It is -OH, -O (C1-C6 alkyl), -O (C1-C6 haloalkyl) or -O (C1-C6 deuterated alkyl);

[0238] R 10 It is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic;

[0239] m is 0, 1, 2, or 3; and

[0240] n can be 0, 1, 2, or 3.

[0241] In one embodiment of the compound of formula (ID), ring A is a 5-membered heteroaryl, a 6-membered heteroaryl, a 5,6-fused heteroaryl, a 6,5-fused heteroaryl, or a 6,6-fused heteroaryl. In some embodiments, ring A contains one or two heteroatoms selected from N, S, or O. In some embodiments, ring A is , , or In some embodiments, ring A is , , or In some embodiments, ring A is or , where * indicates the linkage with benzoxazolone.

[0242] In one embodiment of the compound of formula (ID), each R 4 It is independently a halogen, -C1-C3 alkyl, or -CN.

[0243] In one embodiment of the compound of formula (ID), m is 0 or 1.

[0244] In one embodiment of the compound of formula (ID), R 10 It is -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -(C1-C3 alkylene)-O-(C1-C4 alkyl), -(C1-C3 alkylene)-O-(C1-C4 alkyl)-OH, -(C1-C3 alkylene)-O-(C1-C3 alkylene)-O-(C1-C4 alkyl), -(C1-C3 alkylene)-O-(C1-C3 alkylene)-O-(C1-C4 alkyl)-OH, -C1-C3 alkyl-NR 7 R 8 Or -(C1-C3 alkylene)-heterocyclic. In some embodiments, R 10 It is -C1-C6 alkyl, -(C1-C3 alkylene)-O-(C1-C4 alkyl), -(C1-C3 alkylene)-O-(C1-C3 alkyl)-OH, -(C1-C3 alkylene)-O-(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-O-(C1-C3 alkylene)-O-(C1-C3 alkyl)-OH, -C1-C3 alkyl-N(C1-C3 alkyl)2 or -(C1-C3 alkylene)-(6-membered heterocyclic group).

[0245] In one embodiment of the compound of formula (ID), R 10 - is a C1-C6 alkyl group, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2CH2OCH3, -CH2CH2N(CH3)2 or In some embodiments, R 10 It is a -C1-C3 alkyl group.

[0246] In an embodiment, this disclosure provides a compound of formula (IE):

[0247] (IE),

[0248] Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein:

[0249] R 1 Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl;

[0250] R 2 It is a tricyclic carbocyclic ring, a tricyclic aryl ring, a tricyclic heterocyclic ring, or a tricyclic heteroaryl ring, wherein each R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace;

[0251] R 3 It is H;

[0252] Each R 4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently;

[0253] R 6 Each of these can be independently a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, or -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic;

[0254] R 9 It is -OH, -O (C1-C6 alkyl), -O (C1-C6 haloalkyl) or -O (C1-C6 deuterated alkyl);

[0255] m is 0, 1, 2, or 3; and

[0256] n can be 0, 1, 2, or 3.

[0257] In one embodiment of the compound of formula (IE),

[0258] R 2 yes or , where R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace;

[0259] -DE-is-N(R 10 -C(O)-, -CH2CH2-, -C(O)-O-, or -CH2-O-;

[0260] W, Y, and Z are each independently CH or N, provided that at most two of W, Y, and Z can be N;

[0261] X 1a Yes -NR 13 -、-O-、-CR 11 R 12 -、-C(O)-、-S-、-S(O)- or -S(O)2-;

[0262] R 10 It is an H or -C1-C6 alkyl group;

[0263] R 13 It is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 Heterocyclic or -(C1-C6 alkylene)-heterocyclic;

[0264] R 11 and R 12 Each is independently selected from H, deuterium, halogen, or -C1-C6 alkyl;

[0265] s is 1, 2, or 3; and

[0266] t is 1, 2, or 3;

[0267] The condition is that the sum of s = t is 2, 3, or 4.

[0268] In one embodiment of the compound of formula (IE), R 2 yes , , , , , , or , where R 2 Choose either 1 or 2 R 6 Replacement. In one embodiment, W and Z are both CH, or W is CH and Z is N. In one embodiment, X 1a Yes -NR 13 - In one embodiment, R 13 It is H, -C1-C6 alkyl, or a 4-6 membered heterocyclic ring. In one embodiment, R 13 Is it H, methyl or In one embodiment, a) s is 2 and t is 2; b) s is 1 and t is 3 or s is 3 and t is 1; c) s is 1 and t is 2 or s is 2 and t is 1; or d) s is 1 and t is 1.

[0269] In one embodiment of the compound of formula (IE), R 2 yes , , , , , , , , , , , , , , or , where R 2 Choose either 1 or 2 R 6 replace.

[0270] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 9 It is -OH, -OCH3, -OCH2CH3, -OCD3, -OCF3, or -OCHF2. In one embodiment, R 9 It is -OH. In one embodiment, R 9 It is -OH; n is 1; and R 1 It is a halogen or a -C1-C3 alkyl group. In one embodiment, R 9 It is -OH; n is 1; and R 1 It is a halogen or a methyl group.

[0271] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), having R 9 The substituents of the oxazine heterocyclic heptane ring are , , or .

[0272] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 9 It is -OCH3, -OCH2CH3, -OCD3, -OCF3, or -OCHF2. In one embodiment, R 9 It is -OCH3.

[0273] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 9 It is -OCH3 and n is 0. In one embodiment, it has R 9 The substituents of the oxazine heterocyclic heptane ring are (R) 9 It is -OCH3).

[0274] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), n is 1, 2, or 3. In one embodiment, n is 1. In one embodiment, R 1 It is a -C1-C6 alkyl group. In one embodiment, R 1 It is methyl. In one embodiment, R 1 It is halogen.

[0275] In one embodiment of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE), R 9 It is -OCH3; n is 1; and R 1 It is methyl. In one embodiment, it has R 9 The substituents of the oxazine heterocyclic heptane ring are yes (R) 9 It is -OCH3 and R 1 (It is methyl).

[0276] Another embodiment is the product that can be obtained by any of the methods or examples disclosed herein.

[0277] In the embodiments, this document provides compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or their stereoisomers or pharmaceutically acceptable salts thereof.

[0278] In the embodiments, pharmaceutically acceptable salts of compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) are provided herein. Further embodiments of this disclosure relate to deuterated compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), or pharmaceutically acceptable salts thereof.

[0279] In the examples, this document provides the compounds in Table A or their pharmaceutically acceptable salts, their racemic forms or their stereoisomers.

[0280] In the embodiments, this document provides the compounds in Table A or their pharmaceutically acceptable salts or stereoisomers.

[0281] In the examples, the compounds in Table A or their pharmaceutically acceptable salts are provided herein.

[0282] In one embodiment, the compounds listed in Table A are provided herein.

[0283] In some embodiments, pharmaceutically acceptable salts of the compounds in Table A are provided herein.

[0284] In some embodiments, this document provides compounds selected from compounds 1-145 or pharmaceutically acceptable salts thereof, their racemic forms or their stereoisomers.

[0285] Unless otherwise stated herein (such as compounds 54-56), the names of the diastereomers of the compounds in Table A may be assumed.

[0286] Table A. Various compounds of the present invention

[0287]

[0288] Composition

[0289] Compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or their pharmaceutically acceptable salts or the aforementioned deuterated forms, may be used alone, but are usually administered as pharmaceutical compositions in which a compound / salt (active ingredient) of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A is combined with a pharmaceutically acceptable adjuvant, diluent, or carrier. Standard procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in “Pharmaceuticals - The Science of Dosage Form Designs”, ME Aulton, Churchill Livingstone, 2nd edition, 2002.

[0290] Depending on the administration method, the pharmaceutical composition will preferably contain 0.05 to 99% w (weight percentage), more preferably 0.05 to 80% w, even more preferably 0.10 to 70% w, and even more preferably 0.10 to 50% w of the active ingredient, all weight percentages being based on the total composition.

[0291] In the embodiments, this disclosure provides pharmaceutical compositions comprising a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0292] This disclosure further provides a method for preparing the pharmaceutical composition of this disclosure, comprising mixing a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A as defined above, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0293] The pharmaceutical composition may be administered topically (e.g., to the skin or lungs and / or airways) in the form of creams, solutions, suspensions, sevoflurane (HFA) aerosols, and dry powder formulations (e.g., formulations in inhalation devices called Turbuhaler®); or systemically, for example, by oral administration 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 sterile solutions, suspensions, or emulsions for injection; or by rectal administration in the form of suppositories.

[0294] For oral administration, the compounds of this disclosure can be mixed with adjuvants, diluents, or carriers, such as lactose, sucrose, 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, waxes, paraffin, etc., and then compressed into tablets. If coated tablets are required, the tablet core prepared as described above can be coated with a suitable polymer dissolved or dispersed in water or a volatile organic solvent. Alternatively, the tablets can be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, and titanium dioxide.

[0295] For the preparation of soft gelatin capsules, the compounds of this disclosure can be mixed with, for example, vegetable oils or polyethylene glycol. Hard gelatin capsules can contain particles of compounds using pharmaceutical excipients (such as the excipients used in tablets described above). Additionally, liquid or semi-solid formulations of the compounds of this disclosure can be filled into hard gelatin capsules.

[0296] Liquid formulations for oral administration may be in the form of syrups, solutions, or suspensions. Solutions may, for example, contain compounds disclosed herein, with the remainder being sugar and a mixture of ethanol, water, glycerol, and propylene glycol. Optionally, such liquid formulations may contain colorants, flavoring agents, saccharin, and / or carboxymethyl cellulose as thickeners. Furthermore, other excipients known to those skilled in the art may be used when preparing formulations for oral use.

[0297] Therapeutic uses

[0298] In the embodiments, compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, and their pharmaceutically acceptable salts, are DPP1 inhibitors and are therefore applicable to any disease area where DPP1 is active. Therefore, in one aspect of this disclosure, a treatment method is provided. In one embodiment, the treatment method comprises administering to a subject in need a composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt of (I), (IA), (IB), (IC), (ID), or (IE) or Table A. In the embodiments, the composition is administered to the patient for a continuous period.

[0299] In embodiments, in methods for treating the following diseases, the compound or composition of this disclosure is administered to a patient: obstructive airway disease; chronic sinusitis (CRS); hidradenitis suppurativa (HS); cancer (e.g., metastatic cancer); granulomatous polyangiitis (GPA); microscopic polyangiitis (MPA); giant cell arteritis; polyarteritis nodosa; anti-GBM disease (Goodpassuia disease); rheumatoid arthritis; lupus nephritis; systemic lupus erythematosus; systemic scleroderma; inflammatory bowel disease (IBD) (e.g., ulcerative colitis; Crohn's disease); diabetic nephropathy; diabetic neuropathy; diabetic retinopathy; diabetic ulcer; Duchenne muscular dystrophy; bronchiolitis obliterans; long-term COVID-19) – Prevention of ILD; atopic dermatitis; pyoderma gangrenosa; Sweet's syndrome; dermatomyositis / polymyositis; neutrophilic dermatitis; uveitis; Behçet's disease; thrombosis; bronchopulmonary dysplasia; amyotrophic lateral sclerosis; sickle cell anemia; psoriasis; ventilator-associated lung injury.

[0300] In an embodiment, the compound or composition of this disclosure is administered to a patient in a method for treating an airway obstructive disease. In one embodiment, the airway obstructive disease is asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced asthma (including aspirin and NSAID-induced asthma and dust-induced asthma, intermittent and persistent and of all severity), 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; α-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, allergic pneumonia, interstitial lung disease, pulmonary fibrosis (including idiopathic pulmonary fibrosis, cryptogenic pulmonary fibrosis) Fibrosis, idiopathic interstitial pneumonia, fibrosis associated with antitumor therapy or chronic infections, including tuberculosis and aspergillosis as well as other fungal infections, complications of lung transplantation, vasculitis and thrombotic conditions of the pulmonary vasculature, pulmonary hypertension (e.g., pulmonary hypertension); cough suppression activities, including treatment of chronic cough associated with inflammatory and secretory symptoms 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 caused by respiratory viruses (e.g., respiratory syncytial virus, influenza, coronaviruses (including SARS) and adenovirus), acute lung injury, acute respiratory distress syndrome (ARDS), and exacerbations of each of the aforementioned respiratory disease states.

[0301] In embodiments, in a method for treating pulmonary hypertension, a compound or composition of the present disclosure is administered to a patient. In some embodiments, pulmonary hypertension is pulmonary arterial hypertension. In some embodiments, pulmonary hypertension is pulmonary hypertension caused by left ventricular disease. In some embodiments, pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

[0302] Cystic fibrosis (CF) is caused by abnormalities in CF transmembrane transport regulators, leading to chronic lung infections (especially those caused by Pseudomonas aeruginosa) and excessive inflammation, resulting in bronchiectasis, decreased lung function, respiratory failure, and reduced quality of life. The inflammatory process is dominated by neutrophils, which produce NE and other disruptive NSPs, including CatG and PR3, which act directly on extracellular matrix proteins and play a role in the host's response to inflammation and infection (Dittrich et al., *Eur Respir J*. 2018;51(3)). The method presented in this paper utilizes a reversible inhibitor of DPP1. It is not intended to be theoretically construed that compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or their pharmaceutically acceptable salts, stereoisomers, or deuterated forms, administered via the methods provided herein, have beneficial effects by inhibiting NSP activation and reducing inflammation, which in turn leads to a reduction in lung deterioration, a lower rate of lung deterioration, and / or an improvement in lung function (e.g., forced expiratory volume in one second [FEV1]) in patients with CF.

[0303] In one embodiment, a method for treating CF is provided, comprising administering to a CF patient requiring treatment a composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof.

[0304] In one treatment method for CF, a continuous administration period is provided to a CF patient requiring treatment, comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof. The method comprises improving the patient's lung function during the administration period compared to lung function prior to the administration period. In one embodiment, the improvement in lung function is measured by spirometry.

[0305] In one embodiment, improving the patient's lung 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 FVC, compared to the corresponding values ​​before the administration cycle. (25-75%)In one embodiment, the increase is an increase of approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, or approximately 50% in the corresponding value. In one embodiment, the increase is an increase of at least approximately 5%, at least approximately 10%, at least approximately 15%, at least approximately 20%, at least approximately 25%, at least approximately 30%, at least approximately 35%, at least approximately 40%, at least approximately 45%, or at least approximately 50%. In yet another embodiment, the increase is an increase of approximately 5% to approximately 50%, approximately 5% to approximately 40%, approximately 5% to approximately 30%, or approximately 5% to approximately 20%. In even another embodiment, the increase is an increase of approximately 10% to approximately 50%, approximately 15% to approximately 50%, approximately 20% to approximately 50%, or approximately 25% to approximately 50%.

[0306] In one embodiment of the method provided herein, a continuous administration of a composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, is administered to a patient requiring treatment for bronchiectasis. Bronchiectasis is considered a pathological endpoint resulting from a variety of disease processes and is a persistent or progressive disease characterized by dilated, thick-walled bronchi. Symptoms range from intermittent expectoration and localized lung infection to persistent, copious amounts of purulent sputum daily. Bronchiectasis may be accompanied by other nonspecific respiratory symptoms. Without wishing to be bound by theory, it has been reported that the basic pathological process of bronchiectasis is airway damage resulting from one or more events centered on inflammation (Guideline for non-CF Bronchiectasis, Thorax, July 2010, Vol. 65 (Supplement 1), which is incorporated herein by reference in its entirety for all purposes).

[0307] Bronchiectasis is considered a pathological endpoint resulting from a variety of disease processes and is a persistent or progressive disease characterized by dilated, thick-walled bronchi. Symptoms range from intermittent expectoration and localized lung infection to persistent, copious amounts of purulent sputum daily. Bronchiectasis may be accompanied by other nonspecific respiratory symptoms. Without wishing to be bound by theory, it has been reported that the basic pathological process of bronchiectasis is airway damage resulting from one or more events centered on inflammation (Guideline for non-CF Bronchiectasis, Thorax, July 2010, Vol. 65 (Supplement 1), which is incorporated herein by reference in its entirety for all purposes).

[0308] The methods described herein employ reversible inhibitors of DPP1. It is not intended to be theoretically binding, but it is believed that compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or their pharmaceutically acceptable salts, stereoisomers, or deuterated forms, administered via the methods described herein, have beneficial effects by reducing inflammation and excessive mucus secretion, which in some embodiments resulted in reduced lung deterioration, a lower rate of lung deterioration, and / or improved lung function (cough, sputum secretion, and forced expiratory volume in one second [FEV1]) in patients with bronchiectasis. It is not intended to be theoretically binding, but it is believed that the methods described herein alter the course of bronchiectasis by slowing the rate of decline in lung function or lung tissue destruction.

[0309] In one embodiment, the bronchodilator is a non-CF bronchodilator.

[0310] In one embodiment, a method for treating bronchiectasis includes improving the patient's lung function during the administration cycle compared to the patient's lung function before the administration cycle.

[0311] In one embodiment, lung deterioration is characterized by the patient exhibiting three or more of the following symptoms for at least 48 hours: (1) increased cough; (2) increased sputum volume or altered sputum consistency; (3) increased purulent sputum; (4) worsening dyspnea and / or decreased exercise tolerance; (5) fatigue and / or lethargy; (6) hemoptysis. In another embodiment, the three or more symptoms lead the physician to decide to prescribe antibiotics to the patient exhibiting the symptoms.

[0312] In one embodiment of a method for treating bronchiectasis, the method includes reducing the rate of lung deterioration experienced by the subject compared to a rate of lung deterioration prior to a period of administration of the composition, or compared to a control subject with bronchiectasis who did not receive the treatment. In another embodiment, the bronchiectasis is non-CF bronchiectasis.

[0313] On the other hand, a method is provided for treating chronic sinusitis (CRS) in a subject of need. In one embodiment, the method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, for a period of time.

[0314] Chronic sinusitis refers to chronic sinusitis without nasal polyps (CRSsNP) or chronic sinusitis with nasal polyps (CRSwNP). In some embodiments, chronic sinusitis is chronic sinusitis without nasal polyps (CRSsNP). In some embodiments, chronic sinusitis is chronic sinusitis with nasal polyps (CRSwNP). In some embodiments, chronic sinusitis is refractory chronic sinusitis. In some embodiments, refractory chronic sinusitis is refractory chronic sinusitis without nasal polyps (CRSsNP). In some embodiments, refractory chronic sinusitis is refractory chronic sinusitis with nasal polyps (CRSwNP).

[0315] In some embodiments, the subject exhibits one or more symptoms of CRS. In some embodiments, 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) decreased sense of smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (l) middle meatus obstruction; (m) mucosal changes in the ostiomeatal complex and sinuses; (n) nasal discharge; or (o) any combination thereof. In some embodiments, middle meatus obstruction is mucosal obstruction, edematous obstruction, or a combination thereof.

[0316] In some embodiments, the pharmaceutical composition is administered to alleviate CRS, reduce its severity, delay its onset, or eliminate one or more of its symptoms. In some embodiments, 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) decreased sense of smell; (i) depression; (j) mucosal edema; (k) mucopurulent discharge; (l) middle nasal meatus obstruction; (m) mucosal changes in the ostiomeatal complex and within the sinuses; (n) nasal discharge; (o) or any combination thereof. In some embodiments, the pharmaceutical composition is administered to enhance sinus drainage.

[0317] In some embodiments, the method includes a comprehensive severity score that reduces one or more symptoms of CRS. As used herein, a “comprehensive severity score” is a quantitative measure of all CRS symptoms exhibited by the subject. In some embodiments, the comprehensive severity score is the sum of all daily symptoms exhibited by the subject. In some embodiments, the comprehensive severity score decreases during or after the administration period compared to a comprehensive severity score measured before the administration period. In some embodiments, one or more symptoms of CRS exhibited by the subject can be any CRS-related symptom described herein or known in the art. In some embodiments, the one or more symptoms of CRS are: nasal congestion, decreased sense of smell, nasal discharge, or any combination thereof. In some embodiments, the nasal discharge is anterior nasal discharge. In some embodiments, the nasal discharge is posterior nasal discharge.

[0318] In some embodiments, the method includes reducing the subject's SNOT-22 score during or after the application cycle, compared to the subject's SNOT-22 score before the application cycle. As used herein, "SNOT-22" is a patient-reported measure of CRS outcomes for patients with or without nasal polyps and comprises 22 separate questions. These 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 for SNOT-22 scores is 0-110, with lower scores indicating higher health-related quality of life. Further details of SNOT-22 are provided in Hopkins et al., Clinical Otorhinolaryngol. Otolaryngol. 2009, 34, 447–454, and Kennedy et al., Ann Allergy Asthma Immunol. Oct. 2013; 111(4): 246–251, the contents of which are incorporated herein by reference in their entirety.

[0319] Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory condition. Symptoms include skin lesions that are typically associated with hair follicles and may be painful, inflamed, and / or swollen. In some cases, recurrences may occur as the lesions heal, potentially leading to subcutaneous tunneling and progressive scarring. Because HS is a chronic condition that can last for years and worsen over time, it significantly impacts quality of life, mental and emotional health. In fact, people with HS have a higher incidence of anxiety and depression, and their suicide risk is two and a half times that of the general population.

[0320] Patients with hepatitis B (HS) are classified into mild (Stage I), moderate (Stage II), or severe (Stage III) based on the severity of the disease, known as the Hurley classification. 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 misdiagnosed as an infection, ingrown hairs, or other conditions. Furthermore, current treatment options are limited and often ineffective.

[0321] On one hand, a method for treating HS in a subject in need 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), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, for a sustained period. In another embodiment, the method of treating HS comprises reducing neutrophil inflammation in the subject.

[0322] In one embodiment, HS is a Hurley Phase I HS, a Hurley Phase II HS, or a Hurley Phase III HS. In some embodiments, HS is a Hurley Phase I HS. In some embodiments, HS is a Hurley Phase II HS. In some embodiments, HS is a Hurley Phase III HS.

[0323] This disclosure provides a method for treating cancer in a subject of need, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of any of the compounds disclosed herein. This disclosure also 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 of the compounds disclosed herein for a continuous administration period. In some embodiments, the cancer-induced pain is cancer-induced bone pain. This disclosure further 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 of the compounds disclosed herein for a continuous administration period.

[0324] In some embodiments, cancer includes primary solid tumors. In some embodiments, cancer is bladder cancer, lung cancer, brain cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, liver cancer, hepatocellular carcinoma, kidney cancer, stomach cancer, skin cancer, fibrous carcinoma, lymphoma, viral cancer, oropharyngeal cancer, testicular cancer, thymic cancer, thyroid cancer, melanoma, or bone cancer.

[0325] 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 kidney cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is fibrocarcinoma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is a virus-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, fibrocarcinoma is leiomyosarcoma.

[0326] In some embodiments, breast cancer includes ductal carcinoma, lobular carcinoma, medullary carcinoma, colloidal carcinoma, tubular carcinoma, or inflammatory breast cancer. In some embodiments, breast cancer includes ductal carcinoma. In some embodiments, breast cancer includes lobular carcinoma. In some embodiments, breast cancer includes medullary carcinoma. In some embodiments, breast cancer includes colloidal carcinoma. In some embodiments, breast cancer includes tubular carcinoma. In some embodiments, breast cancer includes inflammatory breast cancer.

[0327] In some embodiments, the breast cancer is inflammatory breast cancer. In some embodiments, the breast cancer does not respond to hormone therapy or treatment targeting the HER2 protein receptor.

[0328] 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 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 lymphoma. In some embodiments, the lymphoma is Kaposi's sarcoma.

[0329] In some embodiments, brain cancer is an astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, or medulloblastoma. In some embodiments, brain cancer is an astrocytoma. In some embodiments, brain cancer is an anaplastic astrocytoma. In some embodiments, brain cancer is a glioblastoma multiforme. In some embodiments, brain cancer is an oligodendroglioma. In some embodiments, brain cancer is an ependymoma. In some embodiments, brain cancer is a meningioma. In some embodiments, brain cancer is a schwannoma. In some embodiments, brain cancer is a medulloblastoma.

[0330] In some embodiments, the cancer is a liquid tumor. In some embodiments, the liquid tumor is acute myeloid leukemia (AML), acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myeloproliferative disorder, natural killer cell leukemia, blastic plasmacytoid dendritic cell vegetations, chronic myeloid 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 lymphoblastic 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 myeloproliferative disorder. In some embodiments, the liquid tumor is natural killer cell leukemia. In some embodiments, the liquid tumor is a blastic plasmacytoid dendritic cell proliferation. 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).

[0331] 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.

[0332] In some embodiments, the cancer is a metastatic cancer. In some embodiments, the subject is at risk of having metastatic cancer. In some embodiments, metastatic cancer includes breast cancer metastasized to the brain, bone, pancreas, lymph nodes, and / or liver. In some embodiments, metastatic cancer includes bone cancer metastasized to the lungs. In some embodiments, metastatic cancer includes colorectal cancer metastasized to the peritoneum, pancreas, stomach, lungs, liver, kidneys, and / or spleen. In some embodiments, metastatic cancer includes gastric cancer metastasized to the mesentery, spleen, pancreas, lungs, liver, adrenal glands, and / or ovaries. In some embodiments, metastatic cancer includes leukemia metastasized to lymph nodes, lungs, liver, hind limbs, brain, kidneys, and / or spleen. In some embodiments, metastatic cancer includes liver cancer metastasized to the intestines, spleen, pancreas, stomach, lungs, and / or kidneys. In some embodiments, metastatic cancer includes lymphoma metastasized to the kidneys, ovaries, liver, bladder, and / or spleen.

[0333] In some embodiments, metastatic cancer includes hematopoietic cancer metastasized to the intestine, lung, liver, spleen, kidney, and / or stomach. In some embodiments, metastatic cancer includes melanoma metastasized to lymph nodes and / or lung. In some embodiments, metastatic cancer includes pancreatic cancer metastasized to the mesentery, ovary, kidney, spleen, lymph nodes, stomach, and / or liver. In some embodiments, metastatic cancer includes prostate cancer metastasized to the lung, pancreas, kidney, spleen, intestine, liver, bone, and / or lymph nodes. In some embodiments, metastatic cancer includes ovarian cancer metastasized to the diaphragm, liver, intestine, stomach, lung, pancreas, spleen, kidney, lymph nodes, and / or uterus. In some embodiments, metastatic cancer includes myeloma metastasized to bone.

[0334] In some embodiments, metastatic cancer includes lung cancer metastasized to bone, brain, lymph nodes, liver, ovary, and / or intestine. In some embodiments, metastatic cancer includes kidney cancer metastasized to liver, lung, pancreas, stomach, brain, and / or spleen. In some embodiments, metastatic cancer includes bladder cancer metastasized to bone, liver, and / or lung. In some embodiments, metastatic cancer includes thyroid cancer metastasized to bone, liver, and / or lung.

[0335] In some embodiments, the methods disclosed herein include treating cancer-induced bone pain (CIBP) in a subject with cancer metastasized to the bone. In some embodiments, the subject has prostate cancer, breast cancer, lung cancer, or myeloma that has metastasized to the bone. In some embodiments, the subject is determined to have metastases to the bone by using any of the following methods: plain 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 has not yet experienced cancer-induced bone pain. In some embodiments, the subject experiences cancer-induced bone pain, indicating that a previously treated or untreated primary tumor has metastasized to the bone. In some embodiments, the cancer has metastasized to the vertebrae, pelvis, long bones, or ribs.

[0336] In some embodiments, the composition is applied to reduce the severity of cancer, delay the onset of cancer, or eliminate cancer symptoms. In some embodiments, the symptom of cancer is cancer-induced bone pain (CIBP). In some embodiments, CIBP is neuropathic pain. In some embodiments, CIBP is inflammatory pain. In some embodiments, CIBP is spontaneous pain. In some embodiments, the symptom of cancer is hyperalgesia. In some embodiments, the symptom of cancer is anomalous pain. In some embodiments, anomalous pain is tactile anomalous pain. In some embodiments, tactile anomalous pain is static mechanical anomalous pain. In some embodiments, hyperalgesia is dynamic mechanical anomalous pain. In some embodiments, the subject has bone cancer or metastasis to the bone.

[0337] In yet another embodiment of this disclosure, a method for treating lupus nephritis (LN) in a subject of need is provided. The method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, for a period of time.

[0338] Rheumatoid arthritis (RA) is characterized by inflammation and thickening of the joint capsule, and its impact on the underlying bone and cartilage. Currently, the etiology of RA is unknown, and there is no satisfactory treatment. While many therapeutic agents have been developed and used to relieve pain and inflammation associated with the disease, such as disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs), these agents often produce intolerable side effects. To address this and other needs, in one embodiment, this disclosure provides a method for treating RA using a reversible inhibitor of DPP1 of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof. In one embodiment, a method for treating RA in a subject of need is provided, and the method includes administering to the subject a continuous administration cycle of a pharmaceutical composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof. In another embodiment, the method includes reducing neutrophil inflammation in the subject.

[0339] Inflammatory bowel disease (IBD) is a group of inflammatory conditions affecting the colon and small intestine. The most common IBDs are Crohn's disease and ulcerative colitis. In one embodiment, this disclosure addresses the need for novel IBD therapies. Specifically, in one embodiment, a method of treating an IBD patient in need is provided. The method comprises administering to the patient a pharmaceutical composition comprising an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof.

[0340] In another embodiment, IBD is Crohn's disease or ulcerative colitis. In even further embodiments, the method includes reducing neutrophil inflammation in the subject.

[0341] In embodiments, in a method for treating heart failure, the compounds or compositions of this disclosure are administered to a patient. In some embodiments, heart failure is heart failure with a reduced ejection fraction. In some embodiments, heart failure is heart failure with a preserved ejection fraction.

[0342] The length of the administration cycle in any given case can depend on the nature and severity of the symptoms to be treated and / or prevented, and is determined by the physician. In one embodiment, the administration cycle begins approximately at the time of diagnosis of the symptoms / disease and continues for the patient's entire life.

[0343] In some embodiments, the application period is about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 30 months, about 36 months, about 4 years, about 5 years, about 10 years, about 15 years, or about 20 years. In some embodiments, the compounds or compositions disclosed herein may be applied for a period of about 24 weeks. In some embodiments, the compounds or compositions disclosed herein may be applied for a period of about 52 weeks. In yet another embodiment, the application period is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years, or at least about 20 years.

[0344] In some embodiments, the application period of the methods provided herein is at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 2 months, at least about 3 months, at least about 4 months, or at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years. In another embodiment, the application period of the methods provided herein is from about 30 days to about 180 days. In another embodiment, the application period is from about 30 days to about 36 months, or from about 30 days to about 30 months, or from about 30 days to about 24 months, or from about 30 days to about 18 months, or from about 30 days to about 12 months, or from about 30 days to about 6 months, or from about 6 months to about 30 months, or from about 6 months to about 24 months, or from about 6 months to about 18 months, or from about 12 months to about 36 months, or from about 12 months to about 24 months.

[0345] In one embodiment, the application period is from about 1 year to about 30 years. For example, in one embodiment, the application period is from about 1 year to about 25 years, from 1 year to about 20 years, from about 1 year to about 15 years, from about 1 year to about 10 years, from about 1 year to about 5 years, from about 1 year to about 3 years, from about 1 year to about 2 years, from about 2 years to about 15 years, from about 2 years to about 10 years, from about 2 years to about 8 years, from about 2 years to about 5 years, from about 2 years to about 4 years, or from about 2 years to about 3 years.

[0346] In one embodiment of the method, the composition is administered to the subject once daily during the administration period. In another embodiment, the composition is administered to the patient twice daily, every other day, or once weekly during the administration period. In yet another embodiment, the composition is administered every other day, every three days, three times a week, or four times a week during the administration period.

[0347] In one embodiment, the oral dosage form is administered once daily during the administration period. In a further embodiment, the oral dosage form is administered at approximately the same time each day, for example, before breakfast. In another embodiment, during the administration period, a composition comprising an effective amount of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, is administered once daily or twice daily. In yet another embodiment, during the administration period, a composition comprising an effective amount of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, is administered once weekly, every other day, every three days, twice weekly, three times weekly, four times weekly, or five times weekly.

[0348] In one embodiment, administration is via oral route. In a further embodiment, the composition is administered once daily.

[0349] The administered dose will vary depending on the compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, the administration method, and the desired therapeutic outcome. For example, in one embodiment, if inhaled, the daily dose of a compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, may range from 0.05 μg / kg body weight (μg / kg) to 100 μg / kg body weight (μg / kg). Alternatively, in one embodiment, if the compound of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A or its pharmaceutically acceptable salt, stereoisomer, or deuterated form is administered orally, the daily dose of the compound disclosed herein may be in the range of 0.01 μg / kg body weight (μg / kg) to 100 mg / kg body weight (mg / kg).

[0350] Compounds of formula (I), (IA), (IB), (IC), (ID), or (IE) or Table A, or their pharmaceutically acceptable salts, stereoisomers, or deuterated forms, may be used alone, but are usually administered in the form of pharmaceutical compositions in combination with pharmaceutically acceptable adjuvants, diluents, or carriers. Routine procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in “Pharmaceuticals - The Science of Dosage Form Designs”, ME Aulton, Churchill Livingstone, 2nd edition, 2002.

[0351] Example

[0352] The present disclosure is further illustrated by reference to the following examples. However, it should be noted that, similar to the embodiments described above, these examples are illustrative and should not be construed as limiting the scope of the present disclosure in any way.

[0353] In the embodiments, the compounds of this disclosure can be synthesized using the following methods. General reaction conditions are given, and the reaction products can be purified by generally known methods, including silica gel chromatography or preparative reversed-phase high-performance liquid chromatography using various organic solvents (such as hexane, dichloromethane, ethyl acetate, methanol, etc.).

[0354] Example 1: Synthesis of (2S,6R)-N-[(1S)-2-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]-1-cyanoethyl]-6-methoxy-1,4-oxazacycloheptane-2-carboxamide (Compound 1)

[0355] Step 1. Synthesis of N-[(1S)-2-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]-1-cyanoethyl] tert-butyl carbamate

[0356]

[0357] Under a nitrogen atmosphere at room temperature, tert-butyl carbamate (350 mg, 0.89 mmol, 1.0 equivalent) and 1-(4-bromobenzenesulfonyl)azacyclobutane (272 mg, 0.98 mmol, 1.1 equivalent) were added in portions to a stirred solution of N-[(1S)-1-cyano-2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl]ethyl]carbamate (350 mg, 0.89 mmol, 1.0 equivalent) and 1-(4-bromobenzenesulfonyl)azacyclobutane (272 mg, 0.98 mmol, 1.1 equivalent) in 1,4-dioxane (8 mL) and H2O (1 mL) to be added in portions. The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (3:1) to give N-[(1S)-2-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]-1-cyanoethyl] tert-butyl carbamate (280 mg, 67.94%) as a white solid. LCMS (ES, m / z): [M+H] + : 460.

[0358] Step 2. Synthesis of (2S)-2-amino-3-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]propionitrile

[0359]

[0360] At room temperature, TsOH·H₂O (579 mg, 3.04 mmol, 5.0 equivalent) was added in portions to a stirred solution of N-[(1S)-2-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]-1-cyanoethyl]carbamate (280 mg, 0.61 mmol, 1.0 equivalent) in ACN (9.0 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (5 mL). The mixture was alkalized to pH 8 with saturated NaHCO₃ (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S)-2-amino-3-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]propionitrile (100 mg, 45.66%) as a white solid. LCMS (ES, m / z): [M+H] + 360.

[0361] Step 3. Synthesis of (2S,6R)-2-{[(1S)-2-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]-1-cyanoethyl]carbamoyl}-6-methoxy-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester

[0362]

[0363] DIEA (70 mg, 0.20 mmol, 1.1 equivalence) and HATU (83 mg, 0.22 mmol, 1.2 equivalence) were added in portions to a stirred solution of (2S)-2-amino-3-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]propionitrile (71 mg, 0.20 mmol, 1.1 equivalence) and (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (50 mg, 0.18 mmol, 1.0 equivalence) in DCM (1 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 hours under a nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give (2S,6R)-2-{[(1S)-2-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]-1-cyanoethyl]carbamoyl}-6-methoxy-1,4-oxozycycloheptane-4-carboxylic acid tert-butyl ester (90 mg, 80.35%) as a white solid. LCMS (ES, m / z): [M+H] + : 617.

[0364] Step 4. Synthesis of (2S,6R)-N-[(1S)-2-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]-1-cyanoethyl]-6-methoxy-1,4-oxazacycloheptane-2-carboxamide

[0365]

[0366] At room temperature, TsOH·H₂O (111 mg, 0.58 mmol, 4.0 equivalent) was added fractionally to a stirred solution of (2S,6R)-2-{[(1S)-2-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]-1-cyanoethyl]carbamoyl}-6-methoxy-1,4-oxozycycloheptane-4-carboxylic acid tert-butyl ester (90 mg, 0.14 mmol, 1.0 equivalent) in ACN (2 mL). The resulting mixture was stirred at room temperature for 3 h. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH₃·H₂O) in a 10% to 70% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-2-[4'-(azacyclobutane-1-sulfonyl)-3-fluoro-[1,1'-biphenyl]-4-yl]-1-cyanoethyl]-6-methoxy-1,4-oxazacycloheptane-2-carboxamide (20 mg, 26.53%) as a white solid. LCMS (ES, m / z): [M+H] + : 517. 1 H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J = 8.6 Hz,1H), 8.04 (d, J = 8.4 Hz, 2H), 7.92 – 7.84 (m, 2H), 7.75 – 7.60 (m, 2H), 7.52(m, 1H), 5.07 (m, 1H), 4.07 – 3.93 (m, 2H), 3.71 (m, 4H), 3.57 (dd, J = 12.5,7.0 Hz, 1H), 3.45 (d, J = 5.1 Hz, 1H), 3.32 – 3.18 (m, 5H), 3.06 (dd, J =14.1, 3.5 Hz, 1H), 2.89 (dd, J = 14.2, 4.6 Hz, 1H), 2.74 (dd, J = 14.0, 3.5Hz, 1H), 2.49 – 2.38 (m, 1H), 2.10 – 1.95 (m, 2H).

[0367] Example 2: Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-1,4-oxazheptan-2-carboxamide (compound 2)

[0368] Step 1. Synthesis of 5-bromo-3-(2-ethoxyethyl)-1,3-benzoxazol-2-one

[0369]

[0370] At 0 °C under a nitrogen atmosphere, PPh3 (3.67 g, 14.01 mmol, 1.5 equivalent) and DIAD (2.83 g, 14.01 mmol, 1.5 equivalent) were added dropwise to a stirred solution of 2-benzoxazolinone, 5-bromo- (2 g, 9.345 mmol, 1.0 equivalent), and 2-ethoxyethanol (1.01 g, 11.21 mmol, 1.2 equivalent) in DCM (30 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (8:1), to give 5-bromo-3-(2-ethoxyethyl)-1,3-benzoxazolinone (2 g, 74.8%) as a pale yellow solid. LCMS (ES) [M+1] + m / z:286.

[0371] Step 2.3-(2-ethoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3-benzoxazol-2-one Synthesis

[0372] AcOK (1.37 g, 13.98 mmol, 1.0 equivalent) and XPhos (0.66 g, 1.39 mmol, 0.2 equivalent) were added to a stirred solution of 5-bromo-3-(2-ethoxyethyl)-1,3-benzoxazol-2-one (2 g, 6.99 mmol, 1.0 equivalent) and bis(pinacol)diborone (2.13 g, 8.38 mmol, 1.2 equivalent) in dioxane (30 mL). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (12:1) to give a brown solid, 3-(2-ethoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3-benzoxazol-2-one (2 g, 85.8%). LCMS (ES) [M+1] + m / z: 334.

[0373] Step 3. Synthesis of N-[(1S)-1-cyano-2-{4-[3-(2-ethoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]tert-butyl carbamate

[0374]

[0375] K₂CO₃ (1.65 g, 12.00 mmol, 1.0 equivalent) and Pd(dppf)Cl₂ (0.43 g, 0.60 mmol, 0.1 equivalent) were added to a stirred solution of 3-(2-ethoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3-benzoxazol-2-one (2 g, 6.00 mmol, 1.0 equivalent) and N-[(1S)-1-cyano-2-(4-iodophenyl)ethyl]carbamate tert-butyl (2.45 g, 6.60 mmol, 1.1 equivalent) in dioxane (30 mL) and H₂O (3 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (4:1) to give N-[(1S)-1-cyano-2-{4-[3-(2-ethoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]tert-butyl carbamate (2 g, 73.7%) as a pale yellow solid. LCMS (ES) [M+1] + m / z: 452.

[0376] Step 4. Synthesis of (2S)-2-amino-3-{4-[3-(2-ethoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl}propionitrile

[0377]

[0378] TsOH (2.28 g, 13.28 mmol, 3.0 equivalent) was added to a stirred solution of N-[(1S)-1-cyano-2-{4-[3-(2-ethoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamate (2 g, 4.42 mmol, 1.0 equivalent) in ACN (30 mL). The resulting mixture was stirred at room temperature for 4 h. The residue was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S)-2-amino-3-{4-[3-(2-ethoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl}propionitrile (1.2 g, 77.0%), a pale yellow oil. LCMS (ES) [M+1] + m / z:352.

[0379] Step 5. Synthesis of (2S)-2-{[(1S)-1-cyano-2-{4-[3-(2-ethoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0380]

[0381] DIEA (1.10 g, 8.53 mmol, 3.0 equivalent) and HATU (1.29 g, 3.41 mmol, 1.2 equivalent) were added in portions to a stirred solution of (2S)-2-amino-3-{4-[3-(2-ethoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl}propionitrile (1 g, 2.84 mmol, 1.0 equivalent) and (2S)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (0.86 g, 3.13 mmol, 1.1 equivalent) in DCM (15 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1) to give (2S)-2-{[(1S)-1-cyano-2-{4-[3-(2-ethoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (1.4 g, 80.8%) as a white solid. LCMS (ES) [M+1]+ m / z: 609.

[0382] Step 6. Synthesis of (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-ethoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]-6-methoxy-1,4-oxazheptan-2-carboxamide

[0383]

[0384] TsOH (0.85 g, 4.92 mmol, 3.0 equivalent) was added to a stirred solution of (2S)-2-{[(1S)-1-cyano-2-{4-[3-(2-ethoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (1 g, 1.64 mmol, 1.0 equivalent) in ACN (30 mL). The resulting mixture was stirred at room temperature for 3 h. The crude product was purified by preparative HPLC under the following conditions: column, XBridge PrepC18 OBD column, 19*150 mm 5 μm; mobile phase, water (0.1% NH4+). 3• H2O) and ACN (10% phase B, reaching 80% within 20 min); detector, UV 254 nm. This yielded (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-ethoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (0.4 g, 47.8%) as a white solid. LCMS (ES) [M+1] + m / z: 509. 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (dd,J = 8.6, 3.5 Hz, 1H), 7.65 – 7.63 (m, 3H), 7.40 – 7.37 (m, 4H), 5.02 (q, J =8.1 Hz, 1H), 4.13 – 3.87 (m, 4H), 3.81 – 3.53 (m, 3H), 3.50 – 3.36 (m, 3H), 3.25 (s, 3H), 3.22 – 2.97 (m, 4H), 2.46 – 2.29 (m, 2H), 1.03 (t, J = 7.0 Hz, 3H).

[0385] Example 3: Synthesis of ((2S,6R)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazol-5-yl]phenyl}ethyl]-6-methoxy-1,4-oxazheptan-2-carboxamide (compound 6)

[0386] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0387]

[0388] DIEA (70 mg, 0.546 mmol, 3.0 equivalent) was added to a stirred solution of (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (50 mg, 0.182 mmol, 1.0 equivalent) and (2S)-2-amino-3-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazol-5-yl]phenyl}propionitrile (73 mg, 0.200 mmol, 1.1 equivalent) in DCM (2 mL). HATU (82 mg, 0.218 mmol, 1.2 equivalent) was added in portions to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for another 1 h. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,6R)-2-{[(1S)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 88.42%) as a white solid. LCMS (ES) [M+H] + m / z:623.

[0389] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazol-5-yl]phenyl}ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide

[0390]

[0391] TsOH (82 mg, 0.483 mmol, 3.0 equivalent) was added to a stirred solution of (2S,6R)-2-{[(1S)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 0.161 mmol, 1.0 equivalent) in ACN (1.0 mL), and the resulting mixture was stirred at room temperature for 3 h. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O), gradient from 10% to 50% over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2-propoxyethyl)-1,3-benzoxazol-5-yl]phenyl}ethyl]-6-methoxy-1,4-oxazheptan-2-carboxamide (45 mg, 53.62%) as a white solid. 1 HNMR (300 MHz, DMSO-d6) δ 8.64 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.0 Hz, 3H), 7.44 – 7.34 (m, 4H), 5.09 – 4.95 (m, 1H), 4.06 (t, J = 5.2 Hz, 2H), 4.05 –3.93 (m, 2H), 3.71 (t, J = 5.2 Hz, 2H), 3.57 (dd, J = 12.5, 7.0 Hz, 1H), 3.51– 3.36 (m, 1H), 3.33 (d, J = 2.6 Hz, 2H), 3.25 (s, 3H), 3.20 (dd, J = 8.0,4.3 Hz, 2H), 3.04 (dd, J = 14.1, 3.6 Hz, 1H), 2.87 (dd, J = 14.2, 4.7 Hz,1H), 2.72 (dd, J = 14.2, 3.5 Hz, 1H), 2.42 (dd, J = 14.1, 8.3 Hz, 1H), 1.41(h, J = 7.0 Hz, 2H), 0.74 (t, J = 7.4 Hz, 3H). LCMS (ES) [M+H] + m / z:523.

[0392] Example 4: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (compound 7)

[0393] Step 1. Synthesis of N-[(1S)-1-cyano-2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]ethyl]carbamate tert-butyl

[0394]

[0395] A solution of N-[(1S)-2-(4-bromo-2-fluorophenyl)-1-cyanoethyl] tert-butyl carbamate (4.0 g, 11.65 mmol, 1.0 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (5.94 g, 23.31 mmol, 2.0 equivalent) and KOAc (2.3 g, 23.31 mmol, 2.0 equivalent) in dioxane (50 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (5:1) to give N-[(1S)-1-cyano-2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]ethyl]carbamate tert-butyl (4.0 g, 87.9%) as a yellow solid. LCMS (ES, m / z): [M+H] + : 391.

[0396] Step 2. Synthesis of N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl] tert-butyl carbamate

[0397]

[0398] A solution of N-[(1S)-1-cyano-2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]ethyl]carbamate tert-butyl ester (1.0 g, 2.56 mmol, 1.0 equivalent), 5-bromo-3-[2-(2-methoxyethoxy)ethyl]-1,3-benzoxazol-2-one (1.1 g, 3.33 mmol, 1.3 equivalent), K2CO3 (0.7 g, 5.12 mmol, 2.0 equivalent), and Pd(dppf)Cl2 (94 mg, 0.12 mmol, 0.10 equivalent) in dioxane (20 mL) and H2O (2 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl] tert-butyl carbamate (1.2 g, 93.7%), a pale yellow oil. LCMS (ES, m / z): [M+H] + : 500.

[0399] Step 3. Synthesis of (2S)-2-amino-3-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)propionitrile

[0400] At room temperature, tert-butyl N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamate (1.2 g, 2.40 mmol, 1.0 equivalent), ACN (30 mL), and TsOH·H₂O (1 g, 7.206 mmol, 3.0 equivalent) were added to a 100 mL round-bottom flask. The resulting mixture was stirred at room temperature for another 3 hours. The mixture was alkalized to pH 8 with saturated NaHCO₃ (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:2) to give (2S)-2-amino-3-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)propionitrile (800 mg, 83.3%), a pale yellow oil. LCMS (ES, m / z): [M+H] + : 400.

[0401] Step 4. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0402]

[0403] At room temperature, HATU (685 mg, 1.80 mmol, 1.2 equivalent) was added in portions to (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (414 mg, 1.50 mmol, 1.0 equivalent); (2S)-2-amino-3-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)propionitrile (600 mg, 1.50 mmol, 1.0 equivalent) and DIEA (582 mg, 4.50 mmol, 3.0 equivalent) in a stirred solution of DCM (15 mL). The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give a pale yellow oil, (2S,6R)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (700 mg, 70.9%). LCMS (ES, m / z): [M+H] + : 657.

[0404] Step 5. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide

[0405]

[0406] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazolidinyl-heptane-4-carboxylic acid tert-butyl ester (650 mg, 0.99 mmol, 1.0 equivalent) and TsOH (511 mg, 2.97 mmol, 3.0 equivalent) in ACN (20 mL) were added. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10-min gradient from 10% to 80%; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-methoxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (300 mg, 54.46%) as a white solid. LCMS (ES, m / z): [M+H] + :557.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 1.8Hz, 1H), 7.62 – 7.51 (m, 2H), 7.51 – 7.45 (m, 2H), 7.45 – 7.39 (m, 1H), 5.04(q, J = 8.2 Hz, 1H), 4.06 (t, J = 5.3 Hz, 2H), 4.04 – 3.95 (m, 2H), 3.76 (t,J = 5.3 Hz, 2H), 3.62 – 3.51 (m, 3H), 3.47 – 3.41 (m, 1H), 3.39 – 3.34 (m,2H), 3.34 – 3.25 (m, 1H), 3.25 (s, 3H), 3.18 (dd, J = 13.7, 8.5 Hz, 1H), 3.11(s, 3H), 3.07 (dd, J = 14.2, 3.6 Hz, 1H), 2.89 (dd, J = 14.2, 4.8 Hz, 1H), 2.74 (dd, J = 14.2, 3.6 Hz, 1H), 2.46 (dd, J = 14.0, 8.3 Hz, 1H), 2.16 (br,1H).

[0407] Example 5: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazheptan-2-carboxamide (compound 8)

[0408] Step 1. Synthesis of N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl] tert-butyl carbamate

[0409]

[0410] Under a nitrogen atmosphere at room temperature, tert-butyl carbamate (470 mg, 1.20 mmol, 1.0 equivalent) and 5-bromo-3-[2-(morpholin-4-yl)ethyl]-1,3-benzoxazol-2-one (472 mg, 1.44 mmol, 1.2 equivalent) were added in portions to a stirred solution of N-[(1S)-1-cyano-2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxane (10 mL) and H2O (1.0 mL)] containing 1,4-dioxane (332 mg, 2.41 mmol, 2.0 equivalent) and Pd(dppf)Cl2 (88 mg, 0.12 mmol, 0.1 equivalent) were added in portions to the mixture. The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1), to give N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl] tert-butyl carbamate (500 mg, 81.32%) as a yellow solid. LCMS (ES, m / z): [M+H] + : 511.

[0411] Step 2. Synthesis of (2S)-2-amino-3-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)propionitrile

[0412]

[0413] TsOH·H₂O (558 mg, 2.94 mmol, 3.0 equivalent) was added in portions to a stirred solution of N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamate (500 mg, 0.98 mmol, 1.0 equivalent) in ACN (20 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 6 hours. The resulting mixture was diluted with water (30 mL). The residue was alkalized to pH 8 with saturated NaHCO₃ (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:3) to give a yellow oily substance (2S)-2-amino-3-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)propionitrile (300 mg, 74.64%). LCMS (ES, m / z): [M+H] + : 411.

[0414] Step 3. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0415]

[0416] DIEA (63 mg, 0.49 mmol, 3.0 equivalent) and HATU (74 mg, 0.19 mmol, 1.2 equivalent) were added in portions to a stirred solution of (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (45 mg, 0.16 mmol, 1.0 equivalent) and (2S)-2-amino-3-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)propionitrile (80 mg, 0.19 mmol, 1.2 equivalent) in DCM (1.0 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 hours under a nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,6R)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 91.62%) as a white solid. LCMS (ES, m / z): [M+H] + : 668.

[0417] Step 4. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide

[0418]

[0419] At room temperature, TsOH·H₂O (113 mg, 0.60 mmol, 4.0 equivalent) was added fractionally to a stirred solution of (2S,6R)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-heptane-4-carboxylic acid tert-butyl ester (100 mg, 0.15 mmol, 1.0 equivalent) in ACN (3 mL). The resulting mixture was stirred at room temperature for 6 h. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18Silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O), gradient from 10% to 70% over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(morpholin-4-yl)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (20.0 mg, 23.53%) as a white solid. LCMS (ES, m / z): [M+H] + : 568. 1 H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 1.7 Hz, 1H), 7.66 – 7.53(m, 2H), 7.53 – 7.38 (m, 3H), 5.05 (m, 1H), 4.00 (m, 4H), 3.64 – 3.45 (m,6H), 3.34 – 3.14 (m, 5H), 3.18 (m, 1H), 3.06 (m, 1H), 2.80 – 2.62 (m, 3H), 2.48 – 2.42 (m, 5H), 2.17 (br, 1H).

[0420] Example 6: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (compound 9)

[0421] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0422]

[0423] A solution of (2S,6R)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazolidinyl heptane-4-carboxylic acid tert-butyl ester (110 mg, 0.20 mmol, 1.0 equivalent), 5-bromo-3-[2-(dimethylamino)ethyl]-1,3-benzoxazol-2-one (59 mg, 0.20 mmol, 1.0 equivalent), K2CO3 (57 mg, 0.41 mmol, 2.0 equivalent), and Pd(dppf)Cl2 (15 mg, 0.02 mmol, 0.1 equivalent) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give a yellow oily substance: (2S,6R)-2-{[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (80 mg, 63.3%). LCMS (ES, m / z): [M+H] + 608.

[0424] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazheptan-2-carboxamide

[0425]

[0426] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazolidinyl-heptane-4-carboxylic acid tert-butyl ester (80 mg, 0.13 mmol, 1.0 equivalent) and TsOH (68 mg, 0.39 mmol, 3.0 equivalent) in ACN (3 mL) were added. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10-80% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (17.3 mg, 25.89%) as a white solid. LCMS (ES, m / z): [M+H] + : 508.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.62 (d, J =1.3 Hz, 1H), 7.43 – 7.36 (m, 4H), 5.02 (q, J = 8.5 Hz, 1H), 4.03 – 3.94 (m,4H), 3.57 (dd, J = 12.6, 6.9 Hz, 1H), 3.48 – 3.38 (m, 1H), 3.25 (s, 3H), 3.25– 3.12 (m, 2H), 3.04 (dd, J = 14.1, 3.6 Hz, 1H), 2.87 (dd, J = 14.2, 4.8 Hz, 1H), 2.73 (dd, J = 14.1, 3.5 Hz, 1H), 2.62 (t, J = 6.2 Hz, 2H), 2.43 (dd, J =14.1, 8.3 Hz, 1H), 2.19 (s, 6H).

[0427] Example 7: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (compound 10)

[0428] Step 1. Synthesis of N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl] tert-butyl carbamate

[0429]

[0430] A solution of N-[(1S)-1-cyano-2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]ethyl]carbamate tert-butyl ester (500 mg, 1.28 mmol, 1.0 equivalent), 5-bromo-3-[2-(2-hydroxyethoxy)ethyl]-1,3-benzoxazol-2-one (426 mg, 1.40 mmol, 1.1 equivalent), K2CO3 (354 mg, 2.56 mmol, 2.0 equivalent), and Pd(dppf)Cl2 (934 mg, 0.12 mmol, 0.1 equivalent) in dioxane (10 mL) and H2O (1 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl] tert-butyl carbamate (470 mg, 75.5%), a yellow oil. LCMS (ES, m / z): [M+H] + : 486.

[0431] Step 2. Synthesis of (2S)-2-amino-3-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)propionitrile

[0432]

[0433] At room temperature, N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamate (500 mg, 1.03 mmol, 1.0 equivalent) and TsOH (532 mg, 3.09 mmol, 3.0 equivalent) in ACN (15 mL) were added to a 100 mL round-bottom flask. The resulting mixture was stirred at room temperature for another 3 hours. The mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:2) to give (2S)-2-amino-3-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)propionitrile (320 mg, 80.6%) as a white solid. LCMS (ES, m / z): [M+H] + : 386.

[0434] Step 3. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0435]

[0436] At room temperature, HATU (141 mg, 0.30 mmol, 1.2 equivalent) was added in portions to a stirred solution of (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (85 mg, 0.30 mmol, 1.0 equivalent), (2S)-2-amino-3-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)propionitrile (119 mg, 0.30 mmol, 1.0 equivalent) and DIEA (119 mg, 0.92 mmol, 3.0 equivalent) in DCM (10 mL). The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,6R)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 50.4%) as a white solid. LCMS (ES, m / z): [M+H] + : 643.

[0437] Step 4. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide

[0438]

[0439] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazolidinyl-heptane-4-carboxylic acid tert-butyl ester (100 mg, 0.15 mmol, 1.0 equivalent) and TsOH (80 mg, 0.46 mmol, 3.0 equivalent) in ACN (3 mL) were added. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-(2-fluoro-4-{3-[2-(2-hydroxyethoxy)ethyl]-2-oxo-1,3-benzoxazol-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (17.3 mg, 20.49%) as a white solid. LCMS (ES, m / z): [M+H] + : 543.2. 1 HNMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.59 – 7.52 (m, 1H), 7.51 – 7.39 (m, 3H), 5.05 (q,J = 8.2 Hz, 1H), 4.58 (s, 1H), 4.10 – 3.95 (m, 4H), 3.77 (t, J = 5.4 Hz, 2H), 3.57 (dd, J = 12.6, 7.0 Hz, 1H), 3.49 – 3.41(m, 5H), 3.31 – 3.26 (m, 1H), 3.25 (s, 3H), 3.18 (dd, J = 13.7, 8.4 Hz, 1H), 3.06 (dd, J = 14.0, 3.6 Hz, 1H), 2.89 (dd, J = 14.2, 4.7 Hz, 1H), 2.74 (dd, J = 14.1, 3.6 Hz, 1H), 2.49 –2.41 (m, 1H).

[0440] Example 8: Synthesis of (2S,6R)-N-[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}-1-cyanoethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (compound 11)

[0441] Step 1. Synthesis of N-[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}-1-cyanoethyl]tert-butyl carbamate

[0442]

[0443] A solution of N-[(1S)-1-cyano-2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]ethyl]carbamate tert-butyl (500 mg, 1.28 mmol, 1.0 equivalent), 5-bromo-3-(2-butoxyethyl)-1,3-benzoxazol-2-one (483 mg, 1.53 mmol, 1.2 equivalent), K2CO3 (354 mg, 2.56 mmol, 2.0 equivalent) and Pd(dppf)Cl2 (94 mg, 0.12 mmol, 0.1 equivalent) in 1,4-dioxane (10 mL) and H2O (1 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give N-[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}-1-cyanoethyl]tert-butyl carbamate (520 mg, 81.5%) as a yellow oil. LCMS (ES, m / z): [M+H] + : 498.

[0444] Step 2. Synthesis of (2S)-2-amino-3-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}propionitrile

[0445]

[0446] At room temperature, N-[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}-1-cyanoethyl] tert-butyl carbamate (520 mg, 1.04 mmol, 1.0 equivalent) and TsOH (539 mg, 3.13 mmol, 3.0 equivalent) in ACN (15 mL) were added. The resulting mixture was stirred at room temperature for another 3 hours. The mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S)-2-amino-3-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}propionitrile (320 mg, 77.0%) as a white solid. LCMS (ES, m / z): [M+H] + : 398.

[0447] Step 3. Synthesis of (2S,6R)-2-{[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}-1-cyanoethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0448]

[0449] At 0 °C, HATU (98 mg, 0.21 mmol, 1.2 equivalent) was added dropwise to a stirred mixture of (2S)-2-amino-3-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}propionitrile (85 mg, 0.21 mmol, 1.0 equivalent), (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (59 mg, 0.21 mmol, 1.0 equivalent) and DIEA (83 mg, 0.64 mmol, 3.0 equivalent) in a DCM (5 mL). The resulting mixture was stirred at room temperature for an additional 3 hours. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,6R)-2-{[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}-1-cyanoethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 71.4%) as a white solid. LCMS (ES, m / z): [M+H] + : 655.

[0450] Step 4. Synthesis of (2S,6R)-N-[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}-1-cyanoethyl]-6-methoxy-1,4-oxazetane-2-carboxamide

[0451]

[0452] At room temperature, (2S,6R)-2-{[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}-1-cyanoethyl]carbamoyl}-6-methoxy-1,4-oxazolidinyl-heptane-4-carboxylic acid tert-butyl ester (100 mg, 0.15 mmol, 1.0 equivalent) and TsOH (79 mg, 0.45 mmol, 3.0 equivalent) in ACN (3 mL) were added. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-2-{4-[3-(2-butoxyethyl)-2-oxo-1,3-benzoxazol-5-yl]-2-fluorophenyl}-1-cyanoethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (17.3 mg, 20.42%) as a white solid. LCMS (ES, m / z): [M+H] + : 555. 1 H NMR (400 MHz, DMSO-d6)δ 8.73 (d, J = 8.6 Hz, 1H), 7.70 (dd, J = 4.6, 1.7 Hz, 1H), 7.60 – 7.50 (m,2H), 7.53 – 7.39 (m, 3H), 5.04 (q, J = 8.2 Hz, 1H), 4.10 – 3.92 (m, 4H), 3.71 (t, J = 5.2 Hz, 2H), 3.57 (dd, J = 12.5, 7.0 Hz, 1H), 3.48 – 3.35 (m, 3H), 3.32 – 3.29 (m, 1H), 3.25 (s, 3H), 3.18 (dd, J = 13.7, 8.5 Hz, 1H), 3.14 –3.02 (m, 1H), 2.89 (dd, J = 14.2, 4.7 Hz, 1H), 2.74 (dd, J = 14.2, 3.5 Hz,1H), 2.49 – 2.41 (m, 1H), 1.43 – 1.32 (m, 2H), 1.28 – 1.09 (m, 2H), 0.74 (t,J = 7.4 Hz, 3H).

[0453] Example 9: Synthesis of (2S,6R)-N-(1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide (compound 13)

[0454] Step 1. Synthesis of tert-butyl (2S,6R)-2-(((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)carbamoyl)-6-methoxy-1,4-oxazetane-4-carboxylic acid ester

[0455]

[0456] HATU (82 mg, 0.21 mmol, 1.2 equivalent) was added in portions to a stirred solution of (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (50 mg, 0.18 mmol, 1.0 equivalent), 3-(2-amino-2-cyanoethyl)-2-fluoro-6H-benzo[c]chromene-8-carboxynitrile (69 mg, 0.23 mmol, 1.3 equivalent), and DIEA (46 mg, 0.36 mmol, 2.0 equivalent) in DCM (1 mL) at 0 °C. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,6R)-2-(((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)carbamoyl)-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (93 mg, 93%) as a white solid. LCMS (ES) [M+1] + m / z: 551.

[0457] Step 2. Synthesis of (2S,6R)-N-(1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide

[0458]

[0459] A solution of (2S,6R)-2-[(1-cyano-2-{8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl}ethyl)carbamoyl]-6-methoxy-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (93 mg, 0.17 mmol, 1.0 equivalent) and TsOH (101 mg, 0.59 mmol, 3.5 equivalent) in ACN (1.5 mL) was stirred at room temperature for 2 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g, MeCN aqueous solution (0.1% NH3·H2O), 10% to 60% gradient over 20 min; detector, UV 254 nm. This yielded (2S,6R)-N-(1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide (25 mg, 32.9%) as a white solid. LCMS (ES) [M+1] + m / z: 451.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J =8.6 Hz, 1H), 8.09 – 8.03 (m, 1H), 7.91 – 7.88 (m, 2H), 7.81 (s, 1H), 7.07 –7.01 (m, 1H), 5.21 – 5.13 (m, 2H), 5.08 – 4.95 (m, 1H), 4.06 – 3.87 (m, 2H), 3.61 – 3.50 (m, 1H), 3.47 – 3.42 (m, 1H), 3.29 – 3.15 (m, 5H), 3.14 – 2.99(m, 1H), 2.94 – 2.84 (m, 1H), 2.79 – 2.70 (m, 1H), 2.64 – 2.56 (m, 1H).

[0460] Example 10: Synthesis of (2S,6R)-N-(1-cyano-2-{2,8-difluoro-6H-benzo[c]chromen-3-yl}ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide (compound 14)

[0461] Step 1. Synthesis of tert-butyl (2S,6R)-2-[(1-cyano-2-{2,8-difluoro-6H-benzo[c]chromen-3-yl}ethyl)carbamoyl]-6-methoxy-1,4-oxazetane-4-carboxylate]

[0462]

[0463] DIEA (81 mg, 0.63 mmol, 3.0 equivalent) and HATU (95 mg, 0.25 mmol, 1.2 equivalent) were added in portions to a stirred solution of 2-amino-3-{2,8-difluoro-6H-benzo[c]chromen-3-yl}propionitrile (60 mg, 0.21 mmol, 1.0 equivalent) and (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (63 mg, 0.23 mmol, 1.1 equivalent) in DCM (2 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1) to give a colorless oil, (2S,6R)-2-[(1-cyano-2-{2,8-difluoro-6H-benzo[c]chromen-3-yl}ethyl)carbamoyl]-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 87.7%). LCMS (ES) [M+1] + m / z:544.

[0464] Step 2. Synthesis of (2S,6R)-N-(1-cyano-2-{2,8-difluoro-6H-benzo[c]chromen-3-yl}ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide

[0465]

[0466] TsOH (95 mg, 0.55 mmol, 3.0 equivalent) was added to a stirred solution of (2S,6R)-2-[(1-cyano-2-{2,8-difluoro-6H-benzo[c]chromen-3-yl}ethyl)carbamoyl]-6-methoxy-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol, 1.0 equivalent) in ACN (3 mL). The resulting mixture was stirred at room temperature for 6 h. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 19*150mm 5µm; mobile phase, water (0.1% NH3H2O) and ACN (10% phase B, reaching 80% within 20 min); detector, UV 254 nm. This yielded (2S,6R)-N-(1-cyano-2-{2,8-difluoro-6H-benzo[c]chromen-3-yl}ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide (25 mg, 30.6%) as a white solid. LCMS (ES) [M+1] + m / z: 444. 1H NMR (300MHz, DMSO-d6) δ 8.69 (dd, J = 8.4, 6.1 Hz, 1H), 7.92 (ddd, J = 8.5, 5.4, 1.7Hz, 1H), 7.76 (dd, J = 10.7, 2.4 Hz, 1H), 7.32–7.16 (m, 2H), 6.98 (d, J = 6.5Hz, 1H), 5.12 (d, J = 3.0 Hz, 2H), 4.99 (dq, J = 20.2, 8.0 Hz, 1H), 4.07–3.86(m, 2H), 3.56 (dt, J = 12.8, 6.9 Hz, 1H), 3.44 – 3.34 (m, 1H), 3.24 (d, J =3.2 Hz, 3H), 3.22–2.99 (m, 3H), 2.89 (td, J = 14.3, 4.6 Hz, 1H), 2.81–2.68(m, 1H), 2.59 (q, J = 8.3, 7.4 Hz, 1H).

[0467] Example 11: Synthesis of (2S,6R)-N-(1-cyano-2-{9-cyano-2-fluoro-6H-benzo[c]chromen-3-yl}ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide (compound 16)

[0468] Step 1. Synthesis of 3-bromo-4-(bromomethyl)benzonitrile

[0469]

[0470] NBS (49.93 g, 280.54 mmol, 2.5 equivalents) and BPO (14.38 g, 56.11 mmol, 0.5 equivalents) were added in portions to a stirred solution of 3-bromo-4-methylbenzonitrile (22 g, 112.21 mmol, 1.0 equivalent) in a DCE (440 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with CH2Cl2 (3 x 150 mL). The combined organic layers were washed with brine (1 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (10:1) to give 3-bromo-4-(bromomethyl)benzonitrile (10.8 g, 35.00%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.25 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 4.78 (s, 2H).

[0471] Step 2. Synthesis of methyl 2-[(2-bromo-4-cyanophenyl)methoxy]-2-fluorobenzoate

[0472]

[0473] At room temperature, K₂CO₃ (10.86 g, 78.56 mmol, 2.0 equivalent) was added in portions to a stirred mixture of 3-bromo-4-(bromomethyl)benzonitrile (10.8 g, 39.28 mmol, 1.0 equivalent) and methyl 2-fluoro-5-hydroxybenzoate (6.68 g, 39.28 mmol, 1.0 equivalent) in DMF (160 mL). The resulting mixture was stirred at 40 °C for 12 hours. The mixture was then cooled to room temperature. The resulting mixture was slowly poured into ice water (800 mL). The product precipitated. This gave methyl 5-[(2-bromo-4-cyanophenyl)methoxy]-2-fluorobenzoate (8 g, 55.92%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ8.28 (d, J = 1.6 Hz, 1H), 7.94 (dd, J = 8.0, 1.6 Hz, 1H), 7.79 (d, J = 8.0Hz, 1H), 7.51 – 7.42 (m, 1H), 7.42 – 7.27 (m, 2H), 5.23 (s, 2H), 3.86 (s, 3H).

[0474] Step 3. Synthesis of methyl 9-cyano-2-fluoro-6H-benzo[c]chromene-3-carboxylate

[0475]

[0476] Pd(OAc)₂ (0.49 g, 2.19 mmol, 0.1 equivalent) and PCy₃HBF₄ (0.81 g, 2.19 mmol, 0.1 equivalent) were added in portions to a stirred mixture of methyl 5-[(2-bromo-4-cyanophenyl)methoxy]-2-fluorobenzoate (8.0 g, 21.968 mmol, 1.0 equivalent) and K₂CO₃ (6.07 g, 43.93 mmol, 2.0 equivalent) in DMF (100 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 1.5 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give methyl 9-cyano-2-fluoro-6H-benzo[c]chromene-3-carboxylate (3.5 g, 56.25%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 11.5 Hz, 1H), 7.90 (dd, J = 7.8, 1.5 Hz, 1H), 7.55 (d, J = 7.9Hz, 1H), 7.42 (d, J = 6.2 Hz, 1H), 5.28 (s, 2H), 3.87 (s, 3H).

[0477] Step 4.2 Synthesis of fluoro-3-(hydroxymethyl)-6H-benzo[c]chromene-9-carboxynitrile

[0478]

[0479] Under a nitrogen atmosphere, methyl 9-cyano-2-fluoro-6H-benzo[c]chromene-3-carboxylate (3.5 g, 12.35 mmol, 1.0 equivalent) was added dropwise to a stirred solution of methyl 9-cyano-2-fluoro-6H-benzo[c]chromene-3-carboxylate (60 mL) in THF (18 mL, 37.06 mmol, 3.0 equivalent). The resulting mixture was stirred at 40 °C for 4 h under a nitrogen atmosphere. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN solution (0.1% FA), gradient from 0% to 50% over 3 min, gradient from 50% to 70% over 8 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. The residue was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded 2-fluoro-3-(hydroxymethyl)-6H-benzo[c]chromene-9-carboxynitrile (1.6 g, 50.73%) as a white solid. LCMS (ES, m / z): [M-OH] + :238. 1 H NMR (300 MHz, DMSO-d6) δ 8.38 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 10.8Hz, 1H), 7.81 (dd, J = 7.8, 1.6 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 6.4 Hz, 1H), 5.36 (t, J = 5.8 Hz, 1H), 5.21 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H).

[0480] Step 5. Synthesis of 3-(bromomethyl)-2-fluoro-6H-benzo[c]chromene-9-carboxynitrile

[0481]

[0482] Under a nitrogen atmosphere, at 0 °C, a solution of PBr3 (1.19 g, 4.38 mmol, 0.7 equivalent) in DCM (2 mL) was added dropwise to a stirred solution of 2-fluoro-3-(hydroxymethyl)-6H-benzo[c]chromene-9-carboxynitrile (1.6 g, 6.26 mmol, 1.0 equivalent) in DCM (30 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (3 x 40 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 3-(bromomethyl)-2-fluoro-6H-benzo[c]chromene-9-carboxynitrile (1.2 g) could be used directly in the next step without further purification. 1 H NMR (300MHz, DMSO-d6) δ 8.41 (d, J = 1.5 Hz, 1H), 7.96 (d, J = 10.7 Hz, 1H), 7.84 (dd, J = 7.9, 1.6 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 6.5 Hz,1H), 5.23 (s, 2H), 4.68 (s, 2H).

[0483] Step 6.3 Synthesis of {2-cyano-2-[(diphenylmethylene)amino]ethyl}-2-fluoro-6H-benzo[c]chromene-9-carboxynitrile

[0484]

[0485] At room temperature, benzyltrimethylammonium chloride (70 mg, 0.37 mmol, 0.1 equivalent) was added dropwise to a stirred mixture of 3-(bromomethyl)-2-fluoro-6H-benzo[c]chromene-9-carboxynitrile (1.2 g, 3.77 mmol, 1.0 equivalent) and 2-[(diphenylmethylene)amino]acetonitrile (830 mg, 3.77 mmol, 1.0 equivalent) in DCM (15 mL). At room temperature, a solution of NaOH (301 mg, 7.54 mmol, 2.0 equivalent) in H₂O (1.5 mL) was added dropwise to the above mixture. The resulting mixture was stirred at 40 °C for an additional 16 hours. The mixture was then cooled to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH₂Cl₂ (3 x 20 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give 3-{2-cyano-2-[(diphenylmethylene)amino]ethyl}-2-fluoro-6H-benzo[c]chromene-9-carboxynitrile (1.0 g, 57.95%) as a white solid. LCMS (ES, m / z): [M+H] + : 458.

[0486] Step 7.3 Synthesis of (2-amino-2-cyanoethyl)-2-fluoro-6H-benzo[c]chromene-9-carboxynitrile

[0487] At room temperature, HCl (2.5 mL, 1 M) was added dropwise to a stirred solution of 3-{2-cyano-2-[(diphenylmethylene)amino]ethyl}-2-fluoro-6H-benzo[c]chromene-9-carboxynitrile (1.0 g, 2.18 mmol, 1.0 equivalent) in THF (50 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOEt (2 x 30 mL). The combined organic layers were washed with brine (1 x 50 mL). The combined aqueous layers were alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded a white oily substance, 3-(2-amino-2-cyanoethyl)-2-fluoro-6H-benzo[c]chromene-9-carboxynitrile (350 mg, 54.60%). LCMS (ES, m / z): [M+H] + : 294.

[0488] Step 8. Synthesis of (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propionitrile

[0489]

[0490] DIEA (84 mg, 0.65 mmol, 3.0 equivalent) and HATU (99 mg, 0.26 mmol, 1.2 equivalent) were added in portions to a stirred solution of (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (60 mg, 0.21 mmol, 1.0 equivalent) and 3-(2-amino-2-cyanoethyl)-2-fluoro-6H-benzo[c]chromene-9-carboxynitrile (70 mg, 0.24 mmol, 1.1 equivalent) in DCM (1 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours under a nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,6R)-2-[(1-cyano-2-{9-cyano-2-fluoro-6H-benzo[c]chromen-3-yl}ethyl)carbamoyl]-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (80 mg, 66.67%) as a white solid. LCMS (ES, m / z): [M+H] + :551.

[0491] Step 9. Synthesis of (2S,6R)-N-(1-cyano-2-{9-cyano-2-fluoro-6H-benzo[c]chromen-3-yl}ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide

[0492]

[0493] At room temperature, TsOH·H₂O (93 mg, 0.49 mmol, 3.0 equivalent) was added fractionally to a stirred solution of (2S,6R)-2-[(1-cyano-2-{9-cyano-2-fluoro-6H-benzo[c]chromen-3-yl}ethyl)carbamoyl]-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (90 mg, 0.16 mmol, 1.0 equivalent) in ACN (2 mL). The resulting mixture was stirred at room temperature for 3 h. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH₃·H₂O) in a 10-70% gradient over 10 min; detector, UV 254 nm. LCMS (ES, m / z): [M+H] + : 451.2.1 H NMR (300 MHz, DMSO-d6) δ 8.68 (m, 1H), 8.38 (s, 1H), 7.90 (dd, J = 10.6, 2.0 Hz, 1H), 7.81 (dd, J = 7.9, 1.5 Hz, 1H), 7.49 (d, J = 7.9Hz, 1H), 7.00 (d, J = 6.4 Hz, 1H),5.19 (d, J = 3.6 Hz, 2H), 4.97 (m, 1H),4.05 – 3.84 (m, 2H), 3.53 (m, 1H), 3.49 – 3.42 (s, 1H), 3.22 (d, J = 3.4 Hz,3H), 3.19 – 2.96 (m, 3H), 2.96 – 2.74 (m, 1H),2.70 (d, J = 10.7 Hz, 1H), 2.46– 2.35 (m, 1H), 2,21 (br, 1H).

[0494] Example 12: Synthesis of (2S,6R)-N-(1-cyano-2-(2-fluoro-8-(methanesulfonyl)-6H-benzo[c]chromen-3-yl)ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide (compound 18)

[0495] Step 1. Synthesis of {2-fluoro-8-methanesulfonyl-6H-benzo[c]chromen-3-yl}methanol

[0496]

[0497] At 0 °C, LiBH4 (10 mL) was added in portions to a stirred solution of methyl 2-fluoro-8-methanesulfonyl-6H-benzo[c]chromene-3-carboxylate (2.4 g, 7.13 mmol, 1.0 equivalent) in THF (30 mL). The resulting mixture was stirred at 40 °C for 16 h. The reaction was quenched at room temperature with saturated sodium hyposulfite (aqueous solution). The resulting mixture was filtered, and the filter cake was washed with THF (3 x 30 mL). The filtrate was concentrated under reduced pressure. This gave 1.4 g crude {2-fluoro-8-methanesulfonyl-6H-benzo[c]chromene-3-yl}methanol as a yellow solid. LCMS (ES, m / z): [M+H] + :309.

[0498] Step 2. Synthesis of 3-(bromomethyl)-2-fluoro-8-methanesulfonyl-6H-benzo[c]chromene

[0499]

[0500] At 0 °C, PBr3 (0.6 g, 2.27 mmol, 0.5 equivalent) was added dropwise to a stirred solution of {2-fluoro-8-methanesulfonyl-6H-benzo[c]chromene-3-yl}methanol (1.4 g, 4.54 mmol, 1.0 equivalent) in DCM (10 mL). The resulting mixture was stirred at room temperature for another 3 h. The mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 1.4 g crude 3-(bromomethyl)-2-fluoro-8-methanesulfonyl-6H-benzo[c]chromene as a yellow solid. LCMS (ES, m / z): [M+H] + :371.

[0501] Step 3.2 Synthesis of 2-[(diphenylmethylene)amino]-3-{2-fluoro-8-methanesulfonyl-6H-benzo[c]chromen-3-yl}propionitrile

[0502]

[0503] Add 1.4 g (1.4 g, 3.77 mmol, 1.0 equivalent) of 3-(bromomethyl)-2-fluoro-8-methanesulfonyl-6H-benzo[c]chromene (1.4 g, 3.77 mmol, 1.0 equivalent) to a solution of 3-(bromomethyl)-2-fluoro-8-methanesulfonyl-6H-benzo[c]chromene in DCM (10 mL), and stir at 40 °C for 2 h with a solution of benzyltrimethylammonium chloride (0.1 g, 0.37 mmol, 0.1 equivalent) in H2O (1 mL). Extract the resulting mixture with CH2Cl2 (3 x 100 mL). Wash the combined organic layers with brine (3 x 30 mL) and dry to anhydrous Na2SO4. Filter and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (5:1) to give 2-[(diphenylmethylene)amino]-3-{2-fluoro-8-methanesulfonyl-6H-benzo[c]chromen-3-yl}propionitrile (550 mg, 28.5%) as a white solid. LCMS (ES, m / z): [M+H] + :511.

[0504] Step 4. Synthesis of 2-amino-3-{2-fluoro-8-methanesulfonyl-6H-benzo[c]chromen-3-yl}propionitrile

[0505]

[0506] At room temperature, 2-[(diphenylmethylene)amino]-3-{2-fluoro-8-methanesulfonyl-6H-benzo[c]chromen-3-yl}propionitrile (550 mg, 1.07 mmol, 1.0 equivalent) and HCl (1 M) (1.2 mL), THF (30 mL), and H2O (3 mL) were added to a 100 mL round-bottom flask. The resulting mixture was stirred at room temperature for another 3 hours. The resulting mixture was extracted with Et2O (1 x 50 mL). The mixture was alkalized to pH 5 with NaOH. The aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 2-amino-3-{2-fluoro-8-methanesulfonyl-6H-benzo[c]chromen-3-yl}propionitrile (220 mg, 58.9%) as a white solid. LCMS (ES, m / z): [M+H] + :347.

[0507] Step 5. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-{2-fluoro-8-methanesulfonyl-6H-benzo[c]chromen-3-yl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0508]

[0509] A solution of (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (50 mg, 0.18 mmol, 1.0 equivalent) in DMF (5 mL) was treated with 2-amino-3-{2-fluoro-8-methanesulfonyl-6H-benzo[c]chromen-3-yl}propionitrile (69 mg, 0.20 mmol, 1.1 equivalent) and DIEA (70 mg, 0.54 mmol, 3.0 equivalent), followed by dropwise addition of HATU (83 mg, 0.21 mmol, 1.2 equivalent) at 0 °C. The resulting mixture was then stirred at 0 °C for 3 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give a white oily substance, (2S,6R)-2-{[(1S)-1-cyano-2-{2-fluoro-8-methanesulfonyl-6H-benzo[c]chromen-3-yl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (90 mg, 82.0%). LCMS (ES, m / z): [M+H] + :604.

[0510] Step 6. Synthesis of (2S,6R)-N-(1-cyano-2-(2-fluoro-8-(methanesulfonyl)-6H-benzo[c]chromen-3-yl)ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide

[0511]

[0512] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-{2-fluoro-8-methanesulfonyl-6H-benzo[c]chromen-3-yl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (90 mg, 0.14 mmol, 1.0 equivalent) and TsOH·H2O (89 mg, 0.47 mmol, 3.0 equivalent) were added to a 50 mL round-bottom flask. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-(1-cyano-2-(2-fluoro-8-(methanesulfonyl)-6H-benzo[c]chromen-3-yl)ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide (17.3 mg, 23.0%) as a white solid. LCMS (ES, m / z): [M+H] + : 504.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J = 8.6 Hz, 1H), 8.13 (dd, J = 8.4, 1.9Hz, 1H), 7.97 – 7.86 (m, 3H), 7.05 (dd, J = 6.6, 1.9 Hz, 1H), 5.24 (d, J =5.4 Hz, 2H), 5.11-4.96 (m, 1H), 4.10-3.85 (m, 2H), 3.62 – 3.50 (m, 1H), 3.46-3.38 (m, 1H), 3.36-3.30 (m, 7H), 3.17-3.01 (m, 2H), 2.95-2.80 (m, 1H), 2.77(d, J = 15.9 Hz, 1H), 2.53-2.50 (m, 1H).

[0513] Example 13: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (compound 19)

[0514] Step 1. Synthesis of 2-bromo-9,10-dihydrophenanthrene

[0515]

[0516] At room temperature, 9,10-dihydrophenanthrene (3.0 g, 16.64 mmol, 1.0 equivalent), NBS (3.3 g, 18.30 mmol, 1.1 equivalent), acetonitrile (20 mL), and TsOH (859 mg, 4.99 mmol, 0.3 equivalent) were added to a 100 mL round-bottom flask. The resulting mixture was then incubated at 60 °C. o The mixture was stirred at C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel - 120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O), 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded 2-bromo-9,10-dihydrophenanthrene (2.2 g, 51%) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.77 – 7.70 (m, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.49 – 7.39 (m, 2H), 7.38 – 7.30 (m, 1H), 7.33 – 7.23 (m, 2H), 2.91 – 2.86 (m, 4H).

[0517] Step 2. Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(9,10-dihydrophenanthrene-2-yl)propionate

[0518]

[0519] I₂ (0.29 g, 1.16 mmol, 0.15 equivalent) was added to a stirred mixture of Zn dust (1.51 g, 23.15 mmol, 3.0 equivalent) and DMF (10 mL) under a nitrogen atmosphere at room temperature. Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropionate (2.54 g, 7.72 mmol, 1.0 equivalent) was added to the mixture. The resulting mixture was stirred for 10 min under a nitrogen atmosphere at room temperature. 2-Bromo-9,10-dihydrophenanthrene (2 g, 7.72 mmol, 1.0 equivalent) and Pd₂(dba)₃ in DMF (10 mL) were added to the mixture under a nitrogen atmosphere at room temperature. . CHCl3 (0.40 g, 0.39 mmol, 0.05 equivalents) and SPhos (0.32 g, 0.77 mmol, 0.1 equivalents) were used. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(9,10-dihydrophenanthrene-2-yl)propionate (2 g, 68%) as a pale yellow oil. LCMS (ES, m / z): [M+H] + : 382.

[0520] Step 3. Synthesis of N-[(1S)-1-carbamoyl-2-(9,10-dihydrophenanthrene-2-yl)ethyl] tert-butyl carbamate

[0521]

[0522] NH3 (g) in MeOH (30 mL) was added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for another 36 h. The mixture was concentrated to remove the solvent. This yielded N-[(1S)-1-carbamoyl-2-(9,10-dihydrophenanthrene-2-yl)ethyl]carbamate tert-butyl ester (2.8 g, crude) as a white solid, which could be used in the next step without purification. LCMS (ES, m / z): [M+H] + : 367.

[0523] Step 4. Synthesis of N-[(1S)-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl]carbamate tert-butyl ester

[0524]

[0525] TFAA (4.6 g, 22.10 mmol, 3.0 equivalent) was added dropwise to a solution of N-[(1S)-1-carbamoyl-2-(9,10-dihydrophenanthrene-2-yl)ethyl]carbamate (2.7 g, 7.36 mmol, 1.0 equivalent) and TEA (2.2 g, 22.10 mmol, 3.0 equivalent) in DCM (30 mL). The mixture was stirred at room temperature for 3 h. The mixture was alkalized to pH 8 with K2CO3 (aqueous solution) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give N-[(1S)-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl]carbamate tert-butyl ester (1.4 g, 54.5%) as a yellow oil. LCMS (ES, m / z): [M+H] + : 349.

[0526] Step 5. Synthesis of (2S)-2-amino-3-(9,10-dihydrophenanthrene-2-yl)propionitrile

[0527]

[0528] At room temperature, N-[(1S)-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl]carbamate tert-butyl ester (700 mg, 2.00 mmol, 1.0 equivalent), ACN (21 mL), and TsOH (1.0 g, 6.00 mmol, 3.0 equivalent) were added sequentially to a 50 mL round-bottom flask. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded (2S)-2-amino-3-(9,10-dihydrophenanthrene-2-yl)propionitrile (300 mg, 60%) as a white solid. LCMS (ES, m / z): [M+H] + : 249.

[0529] Step 6. Synthesis of tert-butyl (2S,6R)-2-{[(1S)-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylate

[0530]

[0531] HATU (83 mg, 0.21 mmol, 1.2 equivalent) was added in portions to a stirred solution of (2S)-2-amino-3-(9,10-dihydrophenanthrene-2-yl)propionitrile (50 mg, 0.20 mmol, 1.1 equivalent), (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (50 mg, 0.18 mmol, 1.0 equivalent), and DIEA (70 mg, 0.54 mmol, 3.0 equivalent) in DCM (5 mL) at 0 °C. The resulting mixture was then heated in 0 °C. o The mixture was stirred at C for 3 hours. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give a yellow oil, (2S,6R)-2-{[(1S)-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (80 mg, 87%). LCMS (ES, m / z): [M+H] + : 506.

[0532] Step 7. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl]-6-methoxy-1,4-oxazacycloheptane-2-carboxamide

[0533]

[0534] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (80 mg, 0.15 mmol, 1.0 equivalent) and TsOH (82 mg, 0.47 mmol, 3.0 equivalent) in ACN (3 mL) were added. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (17.3 mg, 27%) as a white solid. LCMS (ES, m / z): [M+H] + : 406.3. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.2 Hz, 1H), 7.84 – 7.79 (m, 1H), 7.77 (d, J = 8.0 Hz,1H), 7.35 – 7.16 (m, 5H), 4.93 (q, J = 8.0 Hz, 1H), 4.02 (dd, J = 12.4, 5.2Hz, 1H), 3.90 (dd, J = 8.6, 3.5 Hz, 1H), 3.54 (dd, J = 12.4, 6.9 Hz, 1H), 3.50 – 3.41 (m, 1H), 3.24 (s, 3H), 3.18 – 3.09 (m, 3H), 2.92 (dd, J = 14.2, 4.6 Hz, 1H), 2.85 – 2.73 (m, 5H), 2.58 (dd, J = 14.0, 8.6 Hz, 1H).

[0535] Example 14: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (compound 26)

[0536] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0537]

[0538] At 0 °C, a solution of 2-amino-3-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-2-yl]propionitrile (96 mg, 0.26 mmol, 1.2 equivalence) in DMF (2 mL) was treated with (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (60 mg, 0.21 mmol, 1.0 equivalence), DIEA (84 mg, 0.65 mmol, 3.0 equivalence), followed by fractional addition of HATU (99 mg, 0.26 mmol, 1.2 equivalence). oThe resulting mixture was stirred at C for another 2 hours. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give a colorless oil of (2S,6R)-2-{[(1S)-1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 73.4%). LCMS (ES, m / z): [M+H] + : 625.

[0539] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide

[0540]

[0541] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol, 1.0 equivalent) and TsOH·H2O (91 mg, 0.48 mmol, 3.0 equivalent) in ACN (3 mL) were added. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (17.3 mg, 20.6%) as a white solid. LCMS (ES, m / z): [M+H] + : 525.4. 1HNMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H), 7.83 (t, J =1.2 Hz, 2H), 7.72 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 8.4, 1.9 Hz, 1H), 7.44(d, J = 8.3 Hz, 1H), 5.14 – 5.00 (m, 1H), 4.08 – 3.92 (m, 2H), 3.63 – 3.50(m, 2H), 3.51 – 3.42 (m, 2H), 3.43 (s, 3H), 3.25 (d, J = 2.0 Hz, 3H), 3.12(ddd, J = 35.3, 14.1, 3.6 Hz, 1H), 2.91 (td, J = 13.5, 13.1, 4.6 Hz, 1H), 2.82 – 2.58 (m, 2H), 2.25 (br, 1H).

[0542] Example 15: Synthesis of (2S,6R)-N-{1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl}-6-methoxy-1,4-oxazetane-2-carboxamide (compound 28)

[0543] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-2-oxo-1H-spiro[indol-3,4'-piperidin]-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0544]

[0545] HATU (124 mg, 0.32 mmol, 1.2 equivalents) was added in portions to a stirred solution of 2-amino-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-2-yl]propionitrile (110 mg, 0.29 mmol, 1.1 equivalents), (2S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxypropionic acid (329 mg, 1.60 mmol, 5.0 equivalents), and DIEA (106 mg, 0.81 mmol, 3.0 equivalents) in DCM (5 mL) at 0 °C. The resulting mixture was stirred at 0 °C for another 3 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,6R)-2-({1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl}carbamoyl)-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 58.7%) as a white solid. LCMS (ES, m / z): [M+H] + : 625.

[0546] Step 2. Synthesis of (2S,6R)-N-{1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl}-6-methoxy-1,4-oxazetane-2-carboxamide

[0547] At room temperature, (2S,6R)-2-({1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl}carbamoyl)-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol, 1.0 equivalent) and TsOH (82 mg, 0.48 mmol, 3.0 equivalent) in ACN (3 mL) were added. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-{1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl}-6-methoxy-1,4-oxazetane-2-carboxamide (17.3 mg, 20.60%) as a white solid. LCMS (ES, m / z): [M+H] +:525.2. 1 H NMR (400 MHz, DMSO-d6) δ8.81 (dd, J = 8.5, 1.6 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 2.2Hz, 1H), 7.80 (dt, J = 8.5, 1.7 Hz, 1H), 7.73 (t, J = 2.1 Hz, 1H), 7.53 (dt,J = 8.5, 1.5 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.13 – 5.00 (m, 1H), 4.08 –3.92 (m, 2H), 3.62 – 3.51 (m, 2H), 3.46 –3.40 (m, 2H), 3.43 (s, 3H), 3.24 (d,J = 1.0 Hz, 3H), 3.20 – 3.03 (m, 1H), 2.89 (td, J = 14.0, 4.7 Hz, 1H), 2.82 –2.58 (m, 2H), 2.23 (br, 1H).

[0548] Example 16: Synthesis of (2S,6R)-N-{1-cyano-2-[6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl}-6-methoxy-1,4-oxazetane-2-carboxamide (compound 32)

[0549] Step 1. Synthesis of (2S,6R)-2-({1-cyano-2-[6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl}carbamoyl)-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0550]

[0551] HATU (99 mg, 0.21 mmol, 1.2 equivalent) was added in portions to a stirred solution of 2-amino-3-[6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-2-yl]propionitrile (76 mg, 0.21 mmol, 1.0 equivalent), (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (60 mg, 0.21 mmol, 1.0 equivalent), and DIEA (85 mg, 0.65 mmol, 3.0 equivalent) in DMF (5 mL). The resulting mixture was stirred at 0 °C for another 3 h. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1) to give (2S,6R)-2-({1-cyano-2-[6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl}carbamoyl)-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 75.6%) as a white solid. LCMS (ES, m / z): [M+H] + : 607.

[0552] Step 2. Synthesis of (2S,6R)-N-{1-cyano-2-[6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl}-6-methoxy-1,4-oxazetane-2-carboxamide

[0553]

[0554] At room temperature, (2S,6R)-2-({1-cyano-2-[6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl}carbamoyl)-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol, 1.0 equivalent) and TsOH (85 mg, 0.49 mmol, 3.0 equivalent) in ACN (3 mL) were added. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-{1-cyano-2-[6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-2-yl]ethyl}-6-methoxy-1,4-oxazetane-2-carboxamide (17.3 mg, 20.72%) as a white solid. LCMS (ES, m / z): [M+H] + : 507.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (d,J = 8.4 Hz, 1H), 8.29 (dd, J = 1.9, 1.0 Hz, 1H), 7.88 (dd, J = 8.3, 1.8 Hz,1H), 7.75 – 7.67 (m, 2H), 7.51 (dd, J = 8.4, 1.9 Hz, 1H), 7.42 (d, J = 8.3Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 5.16 – 5.01 (m, 1H), 4.08 – 3.91 (m, 2H), 3.62 – 3.41 (m, 4H), 3.43 (s, 3H), 3.25 (d, J = 2.0 Hz, 3H), 3.20 – 3.02 (m,1H), 2.96 – 2.59 (m, 3H).

[0555] Example 17: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pyrrolo-3-yl]ethyl]-6-methoxy-1,4-oxazheptan-2-carboxamide (compound 33)

[0556] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pyrrolo-3-yl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0557]

[0558] At 0 °C, HATU (161 mg, 0.42 mmol, 1.2 equivalent) was added in portions to a stirred solution of 2-amino-3-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pyrrolo-3-yl]propionitrile (100 mg, 0.35 mmol, 1.0 equivalent), (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (70 mg, 0.25 mmol, 0.7 equivalent) and DIEA (137 mg, 1.06 mmol, 3.0 equivalent) in DCM (1 mL). The resulting mixture was then heated at 0 °C. o Stirred at C for 2 hours. Concentrate under reduced pressure to remove solvent, and purify the residue by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,6R)-2-{[(1S)-1-cyano-2-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pyrrolo-3-yl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (110 mg, 57.6%) as a white solid. LCMS (ES) [M+1] + m / z: 540.

[0559] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pyrrolo-3-yl]ethyl]-6-methoxy-1,4-oxazheptan-2-carboxamide

[0560]

[0561] A solution of (2S,6R)-2-{[(1S)-1-cyano-2-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pyrrolo-3-yl]ethyl]carbamoyl}-6-methoxy-1,4-oxazolidinyl heptane-4-carboxylic acid tert-butyl ester (110 mg, 0.20 mmol, 1.0 equivalent) and TsOH (105 mg, 0.61 mmol, 3.0 equivalent) in ACN (1.5 mL) was stirred at room temperature for 2 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 70% gradient over 10 min; detector, UV 254 nm. The target fraction was freeze-dried to give a colored solid of (2S,6R)-N-[(1S)-1-cyano-2-[1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)pyrrolo-3-yl]ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (30 mg, 33.5%). LCMS (ES) [M+1] + m / z: 440. 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 8.2 Hz, 1H), 7.53 (dd, J= 2.3, 1.1 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.35 – 7.28 (m, 2H), 7.28 –7.23 (m, 1H), 6.24 (t, J = 2.4 Hz, 1H), 4.92 – 4.82 (m, 1H), 4.05 – 3.95 (m,2H), 3.60 – 3.53 (m, 1H), 3.50 – 3.41 (m, 1H), 3.38 (s, 3H), 3.23 (d, J = 2.8Hz, 3H), 3.14 (td, J = 14.3, 3.6 Hz, 1H), 3.08 – 3.00 (m, 1H), 2.99 – 2.91(m, 1H), 2.91 – 2.83 (m, 1H), 2.81 – 2.71 (m, 1H), 2.67 – 2.54 (m, 1H), 2.25(brs, 1H).

[0562] Example 18: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{1'-methyl-2-oxo-1H-spiro[indol-3,4'-piperidin]-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazacycloheptane-2-carboxamide (compound 39)

[0563] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-2-oxo-1H-spiro[indol-3,4'-piperidin]-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0564]

[0565] (2S,6R)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (120 mg, 0.22 mmol, 1.0 equivalent), 5-bromo-1'-methyl-1H-spiro[indol-3,4'-piperidin]-2-one (67 mg, 0.22 mmol, 1.0 equivalent), K2CO3 (63 mg, 0.45 mmol, 2.0 equivalent), and Pd(dppf)Cl2 (17 mg, 0.02 mmol, 0.1 equivalent) were dissolved in 1,4-dioxane (5 mL) and H2O (0.5 mL). The solution in mL was stirred at 80 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give a yellow oily substance (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-2-oxo-1H-spiro[indol-3,4'-piperidin]-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (80 mg, 57.1%). LCMS (ES, m / z): [M+H] + :618.

[0566] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{1'-methyl-2-oxo-1H-spiro[indol-3,4'-piperidin]-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide

[0567]

[0568] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-2-oxo-1H-spiro[indol-3,4'-piperidin]-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (80 mg, 0.13 mmol, 1.0 equivalent) and TsOH (67 mg, 0.39 mmol, 3.0 equivalent) in ACN (3 mL) were added. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-(4-{1'-methyl-2-oxo-1H-spiro[indol-3,4'-piperidin]-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (15 mg, 22.38%) as a white solid. LCMS (ES, m / z): [M+H] + :518.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s,1H), 8.62 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.2 Hz,2H), 7.47 (dd, J = 8.1, 1.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 6.92 (d, J =8.0 Hz, 1H), 5.01 (q, J = 8.2 Hz, 1H), 4.03 – 3.94 (m, 2H), 3.57 (dd, J =12.6, 7.0 Hz, 1H), 3.49 – 3.39 (m, 1H), 3.25 (s, 3H), 3.18 (t, J = 7.5 Hz,2H), 3.04 (dd, J = 14.2, 3.6 Hz, 1H), 2.92 – 2.62 (m, 4H), 2.61 – 2.50 (m,2H), 2.44 (dd, J = 14.1, 8.2 Hz, 1H), 2.31 (s, 3H), 1.99 (br, 1H), 1.84 –1.76 (m, 4H).

[0569] Example 19: Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-3-oxospiro[2-benzofuran-1,4'-piperidin]-6-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (compound 40)

[0570]

[0571] Step 1. Synthesis

[0572] A solution of (2S,6R)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (120 mg, 0.22 mmol, 1.0 equivalent), 6-bromo-1'-methylspiro[2-benzofuran-1,4'-piperidin]-3-one (67 mg, 0.22 mmol, 1.0 equivalent), K2CO3 (63 mg, 0.45 mmol, 2.0 equivalent), and Pd(dppf)Cl2 (16 mg, 0.02 mmol, 0.1 equivalent) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 seconds. h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:2) to give a yellow oily substance (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-3-oxospiro[2-benzofuran-1,4'-piperidin]-6-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (80 mg, 57.05%). LCMS (ES, m / z): [M+H] + : 619.

[0573] Step 2. Synthesis of (2S,6R)-N-((S)-1-cyano-2-(4-(1'-methyl-3-oxo-3H-spiro[isobenzofuran-1,4'-piperidin]-6-yl)phenyl)ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide

[0574]

[0575] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-3-oxospiro[2-benzofuran-1,4'-piperidin]-6-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol, 1.0 equivalent) and TsOH (83 mg, 0.48 mmol, 3.0 equivalent) in ACN (3 mL) were added. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-((S)-1-cyano-2-(4-(1'-methyl-3-oxo-3H-spiro[isobenzofuran-1,4'-piperidin]-6-yl)phenyl)ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide as a white solid (17.3 mg, 21.82%). LCMS (ES, m / z): [M+H + : 519.3. 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 1.3 Hz, 1H), 7.88 (s, 2H), 7.82– 7.75 (m, 2H), 7.47 – 7.41 (m, 2H), 5.05 (td, J = 8.7, 7.2 Hz, 1H), 3.98 (dt, J = 11.9, 4.4 Hz, 2H), 3.56 (dd, J = 12.6, 7.0 Hz, 1H), 3.43 (dt, J =5.6, 4.0 Hz, 1H), 3.30 – 3.15 (m, 5H), 3.04 (dd, J = 14.1, 3.6 Hz, 1H), 2.91– 2.80 (m, 3H), 2.73 (dd, J = 14.1, 3.6 Hz, 1H), 2.47 – 2.23 (m, 8H), 2.09(br, 1H), 1.65 (d, J = 13.0 Hz, 2H).

[0576] Example 20: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{1,1'-dimethyl-2-oxospiro[indol-3,3'-piperidin]-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (compound 41)

[0577] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1,1'-dimethyl-2-oxospiro[indol-3,3'-piperidin]-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0578]

[0579] Add K2CO3 (53 mg, 0.38 mmol, 2.0 equivalent) and Pd(dppf)Cl2 (14 mg, 0.01 mmol, 0.1 equivalent) to a stirred solution of 5-bromo-1,1'-dimethylspiro[indol-3,3'-piperidin]-2-one (60 mg, 0.19 mmol, 1.0 equivalent) and (2S,6R)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-heptane-4-carboxylic acid tert-butyl ester (102 mg, 0.19 mmol, 1.0 equivalent) in dioxane (1 mL) and H2O (0.1 mL) to a stirred solution. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was then cooled to room temperature. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1,1'-dimethyl-2-oxospiro[indol-3,3'-piperidin]-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (90 mg, 73.41%) as a grayish-white solid. LCMS (ES) [M+1] + m / z:632.

[0580] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{1,1'-dimethyl-2-oxospiro[indol-3,3'-piperidin]-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide

[0581]

[0582] TsOH (73 mg, 0.42 mmol, 3.0 equivalent) was added to a stirred solution of (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1,1'-dimethyl-2-oxospiro[indol-3,3'-piperidin]-5-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (90 mg, 0.14 mmol, 1.0 equivalent) in ACN (2 mL). The resulting mixture was stirred at room temperature for 3 h. The crude product was purified by preparative HPLC under the following conditions (column, XBridge Prep C10). 18 OBD column, 19*150mm 5µm; mobile phase, water (0.1% NH3H2O) and ACN (10% phase B, reaching 80% within 20 min); detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-(4-{1,1'-dimethyl-2-oxospiro[indol-3,3'-piperidin]-5-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (30 mg, 39.6%) as a grayish-white solid. LCMS (ES) [M+1] + m / z: 532. 1H NMR (300 MHz, DMSO-d6) δ 8.63 (dd, J =8.5, 2.3 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.62–7.50 (m, 3H), 7.37 (d, J =8.1 Hz, 2H), 7.12 (d, J = 8.2 Hz, 1H), 5.01 (qd, J = 8.0, 3.0 Hz, 1H), 3.98(ddt, J = 8.8, 4.9, 2.6 Hz, 2H), 3.57 (ddd, J = 12.5, 7.1, 1.7 Hz, 1H), 3.43(d, J = 5.4 Hz, 1H), 3.26 (d, J = 1.9 Hz, 3H), 3.21–3.12 (m, 5H), 3.12–3.01(m, 1H), 2.99 – 2.90 (m, 1H), 2.85 (dd, J = 14.2, 4.8 Hz, 1H), 2.74 (dd, J =14.0, 3.7 Hz, 1H), 2.50–2.38 (m, 1H), 2.24 (d, J = 11.0 Hz, 1H), 2.17 (s,3H), 2.10 –1.95 (m, 2H), 1.79 – 1.64 (m, 2H), 1.47 (d, J = 12.5 Hz, 1H).

[0583] Example 21: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-{4-[1'-(oxacyclobutane-3-yl)-3H-spiro[2-benzofuran-1,4'-piperidin]-6-yl]phenyl}ethyl]-6-methoxy-1,4-oxazacyclobutane-2-carboxamide (compound 42)

[0584] Step 1. Synthesis of tert-butyl (2S,6R)-2-{[(1S)-2-(4-bromophenyl)-1-cyanoethyl]carbamoyl}-6-methoxy-1,4-oxazacycloheptane-4-carboxylate

[0585]

[0586] HATU (1.66 g, 4.36 mmol, 1.2 equivalent) was added in portions to a stirred solution of (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (1 g, 3.632 mmol, 1 equivalent); (2S)-2-amino-3-(4-bromophenyl)propionitrile (0.98 g, 4.36 mmol, 1.2 equivalent) and DIEA (1.41 g, 10.90 mmol, 3 equivalent) in DCM (20 mL) at room temperature. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1) to give (2S,6R)-2-{[(1S)-2-(4-bromophenyl)-1-cyanoethyl]carbamoyl}-6-methoxy-1,4-oxazacycloheptan-4-carboxylic acid tert-butyl ester (1.4 g, 67.92%), a pale yellow oil. LCMS (ES, m / z): [M+H] + : 482.

[0587] Step 2. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborheptan-2-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0588]

[0589] KOAc (0.48 g, 4.93 mmol, 2 equivalents) and Pd(dppf)Cl2CH2Cl2 (0.20 g, 0.25 mmol, 0.1 equivalents) were added to a solution of (2S,6R)-2-{[(1S)-2-(4-bromophenyl)-1-cyanoethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (1.4 g, 2.47 mmol, 1 equivalent) and bis(pinacol)diboron (0.94 g, 3.70 mmol, 1.5 equivalents) in dioxane (20 mL). After stirring at 80 °C under nitrogen atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1) to give (2S,6R)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (1.4 g, 91.11%). LCMS (ES, m / z): [M+H + : 530.

[0590] Step 3. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-{4-[1'-(oxetane-3-yl)-3H-spiro[2-benzofuran-1,4'-piperidin]-6-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0591]

[0592] (2S,6R)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (127 mg, 0.24 mmol, 1.2 equivalents), 6-bromo-1'-(oxazetane-3-yl)-3H-spiro[2-benzofuran-1,4'-piperidine] (65 mg, 0.20 mmol, 1.00 equivalents), K2CO3 (55 mg, 0.40 mmol, 2 equivalents) and Pd(dppf)Cl2CH2Cl2 (16 mg, 0.02 mmol, 0.1 equivalents) were placed in dioxane (5 mL) and H2O (0.5 mL). The solution in mL was stirred at 80 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:2) to give a pale yellow oil (90 mg, 69.41%) of (2S,6R)-2-{[(1S)-1-cyano-2-{4-[1'-(oxetane-3-yl)-3H-spiro[2-benzofuran-1,4'-piperidin]-6-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester. LCMS (ES, m / z): [M+H] + : 647.

[0593] Step 4. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-{4-[1'-(oxetane-3-yl)-3H-spiro[2-benzofuran-1,4'-piperidin]-6-yl]phenyl}ethyl]-6-methoxy-1,4-oxetane-2-carboxamide

[0594]

[0595] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-{4-[1'-(oxecyclobutane-3-yl)-3H-spiro[2-benzofuran-1,4'-piperidin]-6-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (90 mg, 0.14 mmol, 1 equivalent), TsOH·H2O (79 mg, 0.42 mmol, 3 equivalent), and ACN (3 mL) were added to a 50 mL round-bottom flask. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-{4-[1'-(oxetane-3-yl)-3H-spiro[2-benzofuran-1,4'-piperidin]-6-yl]phenyl}ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (20 mg, 26.29%) as a white solid. LCMS (ES, m / z): [M+H] + : 547. 1 H NMR (400MHz, DMSO-d6) δ 8.63 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.61 –7.54 (m, 2H), 7.41 – 7.31 (m, 3H), 5.07 – 4.97 (m, 3H), 4.57 (t, J = 6.4 Hz,2H), 4.46 (t, J = 6.1 Hz, 2H), 4.03 – 3.94 (m, 2H), 3.57 (dd, J = 12.7, 7.0Hz, 1H), 3.50 – 3.42 (m, 2H), 3.25 (s, 3H), 3.25 – 3.12 (m, 2H), 3.04 (dd, J= 14.2, 3.6 Hz, 1H), 2.86 (dd, J = 14.1, 4.9 Hz, 1H), 2.73 (dd, J = 14.1, 3.5Hz, 1H), 2.68 – 2.60 (m, 2H), 2.44 (dd, J = 14.1, 8.2 Hz, 1H), 2.16 (t, J =11.5 Hz, 2H), 2.09 – 1.99 (m, 2H), 1.67 (d, J = 12.7 Hz, 2H).

[0596] Example 22: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{1'-methyl-2,3-dihydrospiro[indene-1,4'-piperidin]-6-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (compound 43)

[0597] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-2,3-dihydrospiro[indene-1,4'-piperidine]-6-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0598]

[0599] A solution of (2S,6R)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (121 mg, 0.23 mmol, 1.2 equivalents), 6-chloro-1'-methyl-2,3-dihydrospiro[indene-1,4'-piperidine] (45 mg, 0.19 mmol, 1.00 equivalents), K2CO3 (53 mg, 0.38 mmol, 2 equivalents) and second-generation XPhos precatalyst (15 mg, 0.02 mmol, 0.1 equivalents) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give a pale yellow oil, (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-2,3-dihydrospiro[indene-1,4'-piperidin]-6-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (80 mg, 55.63%). LCMS (ES, m / z): [M+H] + : 603.

[0600] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{1'-methyl-2,3-dihydrospiro[indene-1,4'-piperidin]-6-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide

[0601]

[0602] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-2,3-dihydrospiro[indene-1,4'-piperidin]-6-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (80 mg, 0.11 mmol, 1 equivalent, 80%), TsOH·H2O (61 mg, 0.32 mmol, 3 equivalents), and ACN (3 mL) were added to a 50 mL round-bottom flask. The resulting mixture was stirred at room temperature for another 2 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-(4-{1'-methyl-2,3-dihydrospiro[indene-1,4'-piperidin]-6-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (13.4 mg, 25.11%) as a white solid. LCMS (ES, m / z): [M+H] + : 503. 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J =8.5 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.45 – 7.38 (m, 2H), 7.35 (d, J = 8.0Hz, 2H), 7.27 (d, J = 7.7 Hz, 1H), 5.01 (q, J = 8.2 Hz, 1H), 4.02 – 3.94 (m,2H), 3.56 (dd, J = 12.6, 7.0 Hz, 1H), 3.47 – 3.39 (m, 1H), 3.25 (s, 3H), 3.26– 3.14 (m, 2H), 3.04 (dd, J = 14.1, 3.7 Hz, 1H), 2.93 – 2.81 (m, 3H), 2.77 –2.70 (m, 3H), 2.44 (dd, J = 14.1, 8.2 Hz, 1H), 2.22 (s, 3H), 2.08 (t, J =11.5 Hz, 2H), 2.03 – 1.87 (m, 4H), 1.46 (d, J = 12.6 Hz, 2H).

[0603] Example 23: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{1-methyl-3'-oxospiro[azacyclobutane-3,1'-[2]benzofuran]-6'-yl}phenyl)ethyl]-6-methoxy-1,4-oxazacycloheptane-2-carboxamide (compound 44)

[0604] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1-methyl-3'-oxospiro[azacyclobutane-3,1'-[2]benzofuran]-6'-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester

[0605] (2S,6R)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (140 mg, 0.26 mmol, 1.0 equivalent), 6'-bromo-1-methylspiro[azetane-3,1'-[2]benzofuran]-3'-one (71 mg, 0.26 mmol, 1.0 equivalent), NaHCO3 (44 mg, 0.52 mmol, 2.0 equivalent) and Pd(dppf)Cl2 (19 mg, 0.02 mmol, 0.1 equivalent) were placed in 1,4-dioxane (10 mL) and H2O (1 The solution in mL was stirred at 80 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:2) to give a yellow oily substance (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1-methyl-3'-oxospiro[azacyclobutane-3,1'-[2]benzofuran]-6'-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (90 mg, 57.6%). LCMS (ES, m / z): [M+H + : 591.

[0606] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{1-methyl-3'-oxospiro[azacyclobutane-3,1'-[2]benzofuran]-6'-yl}phenyl)ethyl]-6-methoxy-1,4-oxazacycloheptane-2-carboxamide

[0607]

[0608] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1-methyl-3'-oxospiro[azacyclobutane-3,1'-[2]benzofuran]-6'-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (90 mg, 0.15 mmol, 1.0 equivalent) and TsOH (79 mg, 0.45 mmol, 3.0 equivalent) in ACN (3 mL) were added to a 50 mL round-bottom flask. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-(4-{1-methyl-3'-oxospiro[azacyclobutane-3,1'-[2]benzofuran]-6'-yl}phenyl)ethyl]-6-methoxy-1,4-oxazacycloheptane-2-carboxamide (17.3 mg, 23.15%) as a white solid. LCMS (ES, m / z): [M+H] + : 491.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 8.5 Hz,1H), 8.16 (s, 1H), 7.95 – 7.85 (m, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.47 (d, J= 8.2 Hz, 2H), 5.06 (q, J = 8.2 Hz, 1H), 4.03 – 3.94 (m, 2H), 3.73 (d, J =8.2 Hz, 2H), 3.64 (d, J = 8.1 Hz, 2H), 3.57 (dd, J = 12.5, 7.0 Hz, 1H), 3.48– 3.39 (m, 1H), 3.30–3.20 (m, 5H), 3.03 (dd, J = 14.1, 3.7 Hz, 1H), 2.87 (dd,J = 14.2, 4.8 Hz, 1H), 2.73 (dd, J = 14.2, 3.5 Hz, 1H), 2.45 (s, 3H), 2.44 –2.36 (m, 1H).

[0609] Example 24: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{1'-methyl-3-oxospiro[2-benzofuran-1,3'-pyrrolidine]-6-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (compound 45)

[0610] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-3-oxospiro[2-benzofuran-1,3'-pyrrolidine]-6-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0611]

[0612] A solution of (2S,6R)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (120 mg, 0.22 mmol, 1.3 equivalents), 6-bromo-1'-methylspiro[2-benzofuran-1,3'-pyrrolidine]-3-one (50 mg, 0.175 mmol, 1.0 equivalents), NaHCO3 (29 mg, 0.34 mmol, 2.0 equivalents), and Pd(dppf)Cl2 (13 mg, 0.01 mmol, 0.1 equivalents) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 seconds. h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give a white oily substance (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-3-oxospiro[2-benzofuran-1,3'-pyrrolidine]-6-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (90 mg, 85.3%). LCMS (ES, m / z): [M+H + : 605.

[0613] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-(4-{1'-methyl-3-oxospiro[2-benzofuran-1,3'-pyrrolidine]-6-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide

[0614]

[0615] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-(4-{1'-methyl-3-oxospiro[2-benzofuran-1,3'-pyrrolidine]-6-yl}phenyl)ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (90 mg, 0.14 mmol, 1.0 equivalent) and TsOH (77 mg, 0.44 mmol, 3.0 equivalent) in ACN (3 mL) were added. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-(4-{1'-methyl-3-oxospiro[2-benzofuran-1,3'-pyrrolidine]-6-yl}phenyl)ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide as a white solid (17.3 mg, 23.04%). LCMS (ES, m / z): [M+H + : 505.3. 1 H NMR (400 MHz, DMSO-d6)δ8.65 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7.92 – 7.83 (m, 2H), 7.79 (d, J =8.3 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 5.05 (q, J = 8.4 Hz, 1H), 3.98 (dq, J= 8.5, 4.3, 3.7 Hz, 2H), 3.57 (dd, J = 12.5, 7.0 Hz, 1H), 3.49 – 3.38 (m,1H), 3.25 (s, 3H), 3.27 – 3.15 (m, 2H), 3.08 – 2.91 (m, 4H), 2.87 (dd, J =14.1, 4.8 Hz, 1H), 2.77 – 2.68 (m, 2H), 2.46 – 2.39 (m, 2H), 2.37 (s, 3H), 2.34 – 2.26 (m, 1H).

[0616] Example 25: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-{4-[1'-(oxacyclobutane-3-yl)-5H-spiro[furano[3,4-b]pyridin-7,4'-piperidin]-2-yl]phenyl}ethyl]-6-methoxy-1,4-oxazacyclobutane-2-carboxamide (compound 46)

[0617] Step 1. Synthesis of (2S,6R)-2-{[(1S)-1-cyano-2-{4-[1'-(oxetane-3-yl)-5H-spiro[furano[3,4-b]pyridin-7,4'-piperidin]-2-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0618]

[0619] (2S,6R)-2-{[(1S)-1-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (120 mg, 0.22 mmol, 1.0 equivalent), 2-chloro-1'-(oxazetane-3-yl)-5H-spiro[furano[3,4-b]pyridine-7,4'-piperidine] (64 mg, 0.22 mmol, 1.0 equivalent), K2CO3 (63 mg, 0.45 mmol, 2.0 equivalent), and Pd-2G-Xphos (18 mg, 0.1 equivalent) and H2O (0.5 mL) were added to 1,4-dioxane (5 The solution in mL was stirred at 80 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,6R)-2-{[(1S)-1-cyano-2-{4-[1'-(oxetane-3-yl)-5H-spiro[furano[3,4-b]pyridin-7,4'-piperidin]-2-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (80 mg, 54.4%) as a white solid. LCMS (ES, m / z): [M+H] + : 648.

[0620] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-{4-[1'-(oxecyclobutane-3-yl)-5H-spiro[furano[3,4-b]pyridin-7,4'-piperidin]-2-yl]phenyl}ethyl]-6-methoxy-1,4-oxecyclobutane-2-carboxamide]

[0621]

[0622] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-{4-[1'-(oxecyclobutane-3-yl)-5H-spiro[furano[3,4-b]pyridin-7,4'-piperidin]-2-yl]phenyl}ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (80 mg, 0.12 mmol, 1.0 equivalent) and TsOH (64 mg, 0.37 mmol, 3.0 equivalent) in ACN (3 mL) were added. The resulting mixture was stirred at room temperature for another 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 80% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-{4-[1'-(oxecyclobutane-3-yl)-5H-spiro[furano[3,4-b]pyridin-7,4'-piperidin]-2-yl]phenyl}ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (17.3 mg, 25.58%) as a white solid. LCMS (ES, m / z): [M+H] + : 548.3. 1 H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J = 8.5 Hz, 1H), 8.07 (d, J =8.1 Hz, 2H), 7.84 (q, J = 8.1 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 5.06 – 4.99(m, 3H), 4.58 (t, J = 6.4 Hz, 2H), 4.47 (t, J = 6.1 Hz, 2H), 4.04 – 3.92 (m,2H), 3.63 – 3.38 (m, 3H), 3.26 (s, 3H), 3.27 – 3.17 (m, 2H), 3.03 (dd, J =14.1, 3.6 Hz, 1H), 2.91 – 2.64 (m, 5H), 2.50 – 2.36 (m, 1H), 2.18 (t, J =11.3 Hz, 2H), 2.12 – 1.96 (m, 2H), 1.69 (d, J = 12.8 Hz, 2H).

[0623] Example 26: Synthesis of (2S,6R)-N-(1-cyano-2-{13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadecan-1(11),2,4,6,12,14-hexen-5-yl}ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide (compound 20)

[0624] Step 1. Synthesis of methyl 4'-fluoro-2,2'-dicarboxylo-[1,1'-biphenyl]-4-carboxylate

[0625]

[0626] Pd(dppf)Cl2 (1.51 g, 2.05 mmol, 0.1 equivalent) and K2CO3 (5.69 g, 41.14 mmol, 2.0 equivalent) were added to a stirred solution of 4-fluoro-2-carboxyphenylboronic acid (4.49 g, 26.74 mmol, 1.3 equivalent) and 4-bromo-3-carboxybenzoate (5 g, 20.57 mmol, 1.0 equivalent) in dioxane (70 mL) and H2O (7 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (7:1), to give methyl 4'-fluoro-2,2'-dicarboxy-[1,1'-biphenyl]-4-carboxylate (5 g, 84.9%) as a pale yellow solid. LCMS (ES) [M+1] + m / z:287.

[0627] Step 2. Synthesis of methyl 4'-fluoro-2,2'-bis(hydroxymethyl)-[1,1'-biphenyl]-4-carboxylate

[0628]

[0629] NaBH4 (1.78 g, 47.16 mmol, 3.0 equivalent) was added in portions to a stirred solution of methyl 4'-fluoro-2,2'-dicarboxy-[1,1'-biphenyl]-4-carboxylate (4.5 g, 15.72 mmol, 1.0 equivalent) in THF (60 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 2 h. The reaction was quenched at 0 °C with water / ice. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave methyl 4'-fluoro-2,2'-bis(hydroxymethyl)-[1,1'-biphenyl]-4-carboxylate (4 g, 87.6%) as a pale yellow oil. LCMS (ES) [M+1] + m / z: 291.

[0630] Step 3.1 Synthesis of 3-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadecan-1(11),2,4,6,12,14-hexen-5-carboxylic acid

[0631]

[0632] Methyl 4'-fluoro-2,2'-bis(hydroxymethyl)-[1,1'-biphenyl]-4-carboxylate (4 g, 13.77 mmol, 1.0 equivalent) was added to a stirred H3PO4 solution (60 mL). The resulting mixture was stirred at 150 °C for 1 h. The mixture was then cooled to room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadecan-1(11),2,4,6,12,14-hexene-5-carboxylic acid (3.1 g, 87.1%) as a pale yellow solid. LCMS (ES)[M+1] + m / z: 259.

[0633] Step 4.1 Synthesis of 3-fluoro-9-oxatricyclo[9.4.0.0-{2,7}]pentadecan-1(11),2,4,6,12,14-hexen-5-yl}methanol

[0634]

[0635] BH3-THF (3.09 g, 36.01 mmol, 3.0 equivalent) was added dropwise to a stirred solution of 13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadeca-1(11),2,4,6,12,14-hexen-5-carboxylic acid (3.1 g, 12.00 mmol, 1.0 equivalent) in THF (45 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 3 h. The mixture was then cooled to room temperature. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 2.7 g (92.0%) of a pale yellow solid {13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadecan-1(11),2,4,6,12,14-hexen-5-yl}methanol. LCMS (ES) [M+1] + m / z: 245.

[0636] Step 5. Synthesis of 5-(bromomethyl)-13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadecan-1(11),2,4,6,12,14-hexene

[0637]

[0638] PBr3 (1.66 g, 6.14 mmol, 0.5 equivalent) was added dropwise to a stirred solution of {13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadeca-1(11),2,4,6,12,14-hexen-5-yl}methanol (3 g, 12.28 mmol, 1.0 equivalent) in DCM (50 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 3.3 g (87.4%) of 5-(bromomethyl)-13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadeca-1(11),2,4,6,12,14-hexene as a pale yellow solid. LCMS (ES) [M+1] + m / z: 307.

[0639] Step 6.2 Synthesis of 3-[(diphenylmethylene)amino]-3-{13-fluoro-9-oxatricyclo[9.4.0.0-{2,7}]pentadecano-1(11),2,4,6,12,14-hexen-5-yl}propionitrile

[0640]

[0641] Add benzyltrimethylammonium chloride (0.20 g, 1.07 mmol, 0.1 equivalent) and NaOH (0.86 g, 21.48 mmol, 2.0 equivalent) to a stirred solution of 5-(bromomethyl)-13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadeca-1(11),2,4,6,12,14-hexene (3.3 g, 10.74 mmol, 1.0 equivalent) and 2-[(diphenylmethylene)amino]acetonitrile (2.37 g, 10.74 mmol, 1.0 equivalent) in DCM (50 mL) and H2O (5 mL). Stir the resulting mixture at 40 °C for 4 h. Allow the mixture to cool to room temperature. Dilute the resulting mixture with water (50 mL). Extract the resulting mixture with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded 3.4 g, 70.8%, of 2-[(diphenylmethylene)amino]-3-{13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadecan-1(11),2,4,6,12,14-hexen-5-yl}propionitrile (a pale yellow solid). LCMS (ES) [M+1] + m / z: 447.

[0642] Step 7.2 Synthesis of 2-amino-3-{13-fluoro-9-oxatricyclo[9.4.0.0-{2,7}]pentadecan-1(11),2,4,6,12,14-hexen-5-yl}propionitrile

[0643]

[0644] HCl (1M) (2 mL) was added to a stirred solution of 2-[(diphenylmethylene)amino]-3-{13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadecano-1(11),2,4,6,12,14-hexen-5-yl}propionitrile (800 mg, 1.79 mmol, 1.0 equivalent) in THF (40 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (30 mL). The aqueous layer was extracted with EtOEt (2 x 10 mL). The aqueous layer was alkalized to pH 10 with NaOH (1 M) (aqueous solution). The resulting mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 2-amino-3-{13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadecano-1(11),2,4,6,12,14-hexen-5-yl}propionitrile (400 mg, 79.0%) as a pale yellow solid. LCMS (ES) [M+1] + m / z: 283.

[0645] Step 8. Synthesis of (2S,6R)-2-[(1-cyano-2-{13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadecan-1(11),2,4,6,12,14-hexen-5-yl}ethyl)carbamoyl]-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0646]

[0647] DIEA (98 mg, 0.27 mmol, 1.1 equivalents) and HATU (116 mg, 0.30 mmol, 1.2 equivalents) were added in portions to a stirred solution of 2-amino-3-{13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadeca-1(11),2,4,6,12,14-hexen-5-yl}propionitrile (78 mg, 0.27 mmol, 1.1 equivalents) and (2S,6R)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (60 mg, 0.34 mmol, 1.0 equivalents) in DCM (2 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / THF (3:1) to give (2S,6R)-2-[(1-cyano-2-{13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadecan-1(11),2,4,6,12,14-hexen-5-yl}ethyl)carbamoyl]-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (120 mg, 87.4%) as a white solid. LCMS (ES) [M+1] + m / z: 540.

[0648] Step 9. Synthesis of (2S,6R)-N-(1-cyano-2-{13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadecan-1(11),2,4,6,12,14-hexen-5-yl}ethyl)-6-methoxy-1,4-oxazetane-2-carboxamide

[0649]

[0650] TsOH (95 mg, 0.55 mmol, 3.0 equivalent) was added to a stirred solution of (2S,6R)-2-[(1-cyano-2-{13-fluoro-9-oxatricyclo[9.4.0.0^{2,7}]pentadeca-1(11),2,4,6,12,14-hexen-5-yl}ethyl)carbamoyl]-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol, 1.0 equivalent) in ACN (2 mL). The resulting mixture was stirred at room temperature for 3 h. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 19*150mm 5µm; mobile phase, water (0.1% NH3H2O) and ACN (10% phase B, reaching 80% within 20 min); detector, UV 254 nm. This yielded compound 20 (30 mg, 36.8%) as a white solid. LCMS (ES) [M+1] + m / z: 440. 1 H NMR (300 MHz, DMSO-d6) δ 8.65 (t, J = 8.0 Hz, 1H), 7.64 (dt, J = 8.5, 5.3 Hz, 1H), 7.55 (dd, J = 7.9, 2.6 Hz, 1H), 7.50 – 7.32(m, 4H), 5.03 (dq, J = 27.5, 8.3 Hz, 1H), 4.29-4.17 (m, 4H), 4.08 – 3.84 (m,2H), 3.63 – 3.48 (m, 1H), 3.24 (d, J = 1.9 Hz, 5H), 3.20 – 2.52 (m, 4H), 2.36(dd, J = 14.1, 8.3 Hz, 1H).

[0651] Example 27: Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-[7-fluoro-2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-6-yl]ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (compound 37)

[0652] Step 1. Synthesis of (2S,6R)-2-({1-cyano-2-[7-fluoro-2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-6-yl]ethyl}carbamoyl)-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0653]

[0654] HATU (99 mg, 0.26 mmol, 1.2 equivalents) was added in portions to a stirred mixture of 2-amino-3-[7-fluoro-2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-6-yl]propionitrile (96 mg, 0.26 mmol, 1.2 equivalents), (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazacycloheptane-2-carboxylic acid (60 mg, 0.22 mmol, 1.0 equivalents), and DIEA (84 mg, 0.65 mmol, 3.0 equivalents) in DMF (5 mL) at 0 °C. The resulting mixture was stirred at 0 °C for another 2 h. The reaction was quenched with water (15 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with brine (20 mL x 2) and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,6R)-2-({1-cyano-2-[7-fluoro-2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-6-yl]ethyl}carbamoyl)-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (110 mg, 80.8%) as a white semi-solid. LCMS (ES, m / z): [M+H] + :625.

[0655] Step 2. Synthesis of (2S,6R)-N-[(1S)-1-cyano-2-[7-fluoro-2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-6-yl]ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide

[0656]

[0657] At room temperature, (2S,6R)-2-{[(1S)-1-cyano-2-[7-fluoro-2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-6-yl]ethyl]carbamoyl}-6-methoxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (110 mg, 0.17 mmol, 1.0 equivalent), TsOH (112 mg, 0.65 mmol, 3.0 equivalent), and ACN (3 mL) were added to a 25 mL round-bottom flask. The resulting mixture was stirred at room temperature for 2 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 10 min; detector, UV 254 nm. This yielded (2S,6R)-N-[(1S)-1-cyano-2-[7-fluoro-2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-6-yl]ethyl]-6-methoxy-1,4-oxazetane-2-carboxamide (20 mg, 21.7%) as a white solid. LCMS (ES, m / z): [M+H] + : 525.4. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (dd, J = 8.4, 6.9 Hz, 1H), 7.96 (dd, J = 3.8, 2.0 Hz, 1H), 7.78 (d,J = 1.9 Hz, 1H), 7.67 (dd, J = 8.1, 2.7 Hz, 1H), 7.56 (dt, J = 8.3, 1.9 Hz,1H), 7.45 (d, J = 8.3 Hz, 1H), 7.40 (ddd, J = 8.4, 7.1, 2.3 Hz, 1H), 5.14 –4.97 (m, 1H), 4.16 – 3.83 (m, 2H), 3.56 (ddd, J = 12.4, 8.7, 6.9 Hz, 1H), 3.48 – 3.41 (m, 4H), 3.40 – 3.36 (m, 1H), 3.31 – 3.26 (m, 1H), 3.25 (d, J =3.8 Hz, 3H), 3.07 (ddd, J = 49.6, 14.0, 3.6 Hz, 1H), 2.90 (ddd, J = 18.7,14.1, 4.6 Hz, 1H), 2.74 (ddd, J = 20.1, 14.2, 3.5 Hz, 1H), 2.58 – 2.40 (m,1H), 2,20 (br, 1H).

[0658] Example 28: (2S,5S,6S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazolidinyl-heptane-2-carboxamide, (2S,5R,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazolidinyl-2-carboxamide, (2S,5R,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazolidinyl-2-yl]-2-carboxamide Synthesis of (2S,5S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazolyl heptane-2-carboxamide (compounds 49-51)

[0659] Step 1. Synthesis of tert-butyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methyl-6-oxo-1,4-oxazetane-4-carboxylate

[0660]

[0661] Under a nitrogen atmosphere at -78°C, a solution of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-oxo-1,4-oxazacycloheptan-4-carboxylic acid tert-butyl ester (3 g, 8.34 mmol, 1.0 equivalent) in THF (5 mL) was added dropwise to a stirred solution of KHMDS (1 M in THF) (10.0 mL, 10.013 mmol, 1.2 equivalent) in THF (30 mL). The resulting mixture was stirred at -78°C for 1 h under a nitrogen atmosphere. MeI (1.78 g, 12.52 mmol, 1.5 equivalent) was added dropwise to the above mixture at -78°C. The resulting mixture was stirred again at room temperature for 1 h. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (20 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give a colorless oil, (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methyl-6-oxo-1,4-oxazacycloheptan-4-carboxylic acid tert-butyl ester (360 mg, 11.6%). LCMS (ES) [M+H-100] + m / z: 274.

[0662] Step 2. Synthesis of tert-butyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-hydroxy-5-methyl-1,4-oxazacycloheptane-4-carboxylate

[0663]

[0664] At 0 °C, tert-butyl (360 mg, 0.96 mmol, 1.0 equivalent) of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methyl-6-oxo-1,4-oxazacycloheptan-4-carboxylate (5 mL) was added in portions to a stirred solution of the compound in THF (72 mg, 1.93 mmol, 2.0 equivalent). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by adding water (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (8:1) to give a colorless oil, (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-hydroxy-5-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester (300 mg, 83%). LCMS (ES) [M+H-100] + m / z: 276.

[0665] Step 3. Synthesis of tert-butyl (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-methoxy-5-methyl-1,4-oxazacycloheptan-4-carboxylate

[0666]

[0667] Under a nitrogen atmosphere, at 0 °C, NaH (60% in mineral oil) (39 mg, 0.96 mmol, 1.2 equivalent) was added dropwise to a stirred solution of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-hydroxy-5-methyl-1,4-oxazacycloheptan-4-carboxylate (300 mg, 0.80 mmol, 1.0 equivalent) in dimethylformamide (5 mL). The resulting mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. MeI (170 mg, 1.20 mmol, 1.5 equivalent) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at room temperature for another 2 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give a colorless oil, (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-methoxy-5-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester (200 mg, 64.3%). LCMS (ES) [M+H-56] + m / z: 334.

[0668] Step 4. Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-6-methoxy-5-methyl-1,4-oxazetane-4-carboxylate

[0669]

[0670] TBAF (134 mg, 0.51 mmol, 1.0 equivalent) was added to a stirred solution of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-methoxy-5-methyl-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (200 mg, 0.51 mmol, 1.0 equivalent) in THF (3 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (20 mL), and the resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give tert-butyl (2S)-2-(hydroxymethyl)-6-methoxy-5-methyl-1,4-oxazetane-4-carboxylate (120 mg, 84.9%) as a colorless oil. LCMS (ES) [M+H] + m / z: 276.

[0671] Step 5. Synthesis of (2S)-4-(tert-butoxycarbonyl)-6-methoxy-5-methyl-1,4-oxazacycloheptane-2-carboxylic acid

[0672]

[0673] At 0 °C, an aqueous solution of NaBr (9 mg, 0.09 mmol, 0.2 equivalents), TEMPO (7 mg, 0.05 mmol, 0.1 equivalents), and NaHCO3 (73 mg, 0.87 mmol, 2.0 equivalents) in H2O (1 mL) was added to a stirred solution of (2S)-2-(hydroxymethyl)-6-methoxy-5-methyl-1,4-oxazine-2,4,6-trione (202 mg, 0.87 mmol, 2.0 equivalents) in acetone (3 mL). At 0 °C, 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (202 mg, 0.87 mmol, 2.0 equivalents) was added in portions to the mixture. The resulting mixture was stirred at room temperature for another 5 h. The reaction was quenched by adding NaHCO3 (10 mL). The resulting mixture was filtered, and the filter cake was washed with H₂O (5 mL). The mixture was acidified with citric acid to pH 5. The resulting mixture was extracted with CH₂Cl₂ (6 x 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded (2S)-4-(tert-butoxycarbonyl)-6-methoxy-5-methyl-1,4-oxazetane-2-carboxylic acid (90 mg, 71.4%) as a colorless oil. LCMS (ES) [MH] - m / z: 288.

[0674] Step 6. Synthesis of (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-5-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0675]

[0676] DIEA (120 mg, 0.93 mmol, 1.0 equivalent) and HATU (177 mg, 0.47 mmol, 1.5 equivalent) were added in portions to a stirred solution of (2S)-4-(tert-butoxycarbonyl)-6-methoxy-5-methyl-1,4-oxazacycloheptane-2-carboxylic acid (90 mg, 0.31 mmol, 1.0 equivalent) in DCM (2 mL) under a nitrogen atmosphere at 0 °C. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give (2S)-2-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-5-methyl-1,4-oxazolidinyl-heptane-4-carboxylic acid tert-butyl ester (150 mg, 85.4%) as a grayish-white solid. LCMS (ES) [M+H] + m / z: 565.

[0677] Step 6. Synthesis of (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazheptan-2-carboxamide

[0678]

[0679] TsOH (137 mg, 0.80 mmol, 3.0 equivalent) was added to a stirred solution of (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-5-methyl-1,4-oxazolidinyl-heptane-4-carboxylic acid tert-butyl ester (150 mg, 0.26 mmol, 1.0 equivalent) in ACN (2 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 15 min; detector, UV 254 nm. This yielded (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazetane-2-carboxamide (80 mg, 64.8%) as a white solid. LCMS (ES) [M+H] + m / z: 465.

[0680] Step 7. (2S,5S,6S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazolidinyl-heptane-2-carboxamide (compound 50, hypothetical), (2S,5R,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazolyl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazolidinyl ...yl]-2-yl]-2-yl]-2-yl]-6-methoxy-5-methyl-1,4-oxazolidinyl-2-yl]-2-yl]-2-yl]-2-yl]-2-yl]-6-methoxy-5-methyl-1,4-oxazolidinyl-2-yl]-2-yl]-2-yl]-2-yl]-2-yl]-6-methoxy-5-methyl-1,4-oxazolidinyl-2-yl]-2-yl]-2-yl]-2-yl]-2-yl]-6-methoxy-5-methyl-1,4-oxazolidinyl-2-yl]-2-yl]-2-yl]-2-yl]-6-methoxy-5-methyl-1,4-oxazolidinyl-2-yl]-2-yl]-2-yl]-2-yl]-6-methoxy-5-methyl-1,4-oxazolidinyl- Synthesis of (5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazazole-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazazole-2-carboxamide (compound 49, hypothetical) and (2S,5S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazazole-2-carboxamide (compound 51, hypothetical)

[0681]

[0682] (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazetane-2-carboxamide (80 mg, 0.17 mmol, 1.0 equivalent) was purified by preparative chiral HPLC under the following conditions: column: XA-CHIRALPAK IH, 3*25 cm, 5 μm; mobile phase A: HEX:DCM=3:1 (HPLC); mobile phase B: ETOH (0.1% 2M NH3-MEOH); flow rate: 35 mL / min; gradient: isocratic 30; wavelength: 254 nm; RT1 (min): 5.2; RT2 (min): 8.9; sample solvent: EtOH:DCM=1:1 (HPLC); injection volume: 2 mL; Number of runs: 3), yielding (2S,5S,6S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazolyl-heptane-2-carboxamide (16 mg, 20.0%) as a white solid and (2S,5R,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazolyl-heptane-2-carboxamide (45 mg, 20.0%) as a white solid. 56.2%) and (2S,5S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-methoxy-5-methyl-1,4-oxazheptan-2-carboxamide (12 mg, 15.0%), which is a white solid.

[0683] Compound 49: 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 8.4 Hz, 1H),7.65 (d, J = 7.9 Hz, 2H), 7.56 (d, J = 1.6 Hz, 1H), 7.45 – 7.35 (m, 4H), 5.05(q, J = 8.0 Hz, 1H), 4.14 – 4.05 (m, 2H), 3.60 (dd, J = 13.4, 1.6 Hz, 1H),3.40 (s, 3H), 3.36 (s, 3H), 3.25 – 3.17 (m, 3H), 2.99 – 2.84 (m, 2H), 2.66(dd, J = 14.6, 6.8 Hz, 1H), 1.91 (s, 1H), 1.01 (d, J = 6.7 Hz, 3H). LCMS (ES)[M+H] + m / z:465。

[0684] Compound 50 : 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 8.6 Hz, 1H),7.70 – 7.63 (m, 2H), 7.59 – 7.54 (m, 1H), 7.45 – 7.35 (m, 4H), 5.02 (td, J =8.7, 7.2 Hz, 1H), 4.04 (dd, J = 9.8, 3.0 Hz, 1H), 3.83 (d, J = 4.1 Hz, 2H),3.40 (s, 3H), 3.31 (s, 3H), 3.32 – 3.26 (m, 1H), 3.30 – 3.12 (m, 2H), 3.03(dd, J = 14.5, 3.1 Hz, 1H), 2.83 (qd, J = 6.7, 2.2 Hz, 1H), 2.35 (dd, J =14.5, 9.8 Hz, 1H), 1.91 (s, 1H), 1.02 (d, J = 6.8 Hz, 3H). LCMS (ES) [M+H] + m / z:465。

[0685] Compound 51 : 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.58 – 7.53 (m, 1H), 7.45 – 7.36 (m, 4H), 5.05 (q,J = 7.9 Hz, 1H), 3.99 (t, J = 3.9 Hz, 1H), 3.86 (dd, J = 12.7, 3.2 Hz, 1H), 3.54 (dd, J = 12.7, 8.9 Hz, 1H), 3.40 (s, 3H), 3.33 (s, 3H), 3.22 (d, J = 7.8Hz, 2H), 3.05 – 2.89 LCMS (ES) [M+H] + m / z:465.

[0686] Example 29: (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-5-methyl-1,4-oxazolylheptane-2-carboxamide (compound 53), (2S,5S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-5-methyl-1,4-oxazolylheptane-2-carboxamide (compound 54), ( Synthesis of (2S,5R,6S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-5-methyl-1,4-oxazolylheptane-2-carboxamide (compound 55) and (2S,5R,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-5-methyl-1,4-oxazolylheptane-2-carboxamide (compound 56)

[0687] Step 1. Synthesis of tert-butyl (2S)-6-(benzyloxy)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methyl-1,4-oxazacycloheptane-4-carboxylate

[0688]

[0689] Under a nitrogen atmosphere, at 0 °C, NaH (25 mg, 0.639 mmol, 1.5 equivalent, 60%) was added dropwise to a stirred solution of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-hydroxy-5-methyl-1,4-oxazacycloheptan-4-carboxylate (160 mg, 0.426 mmol, 1 equivalent) in DMF (5 mL). The resulting mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. BnBr (87 mg, 0.511 mmol, 1.2 equivalent) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at room temperature for another 2 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1 to 10:1) to give (2S)-6-(benzyloxy)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methyl-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (155 mg, 78.13%), a pale yellow oil. LCMS (ES) [M+H] + m / z:466.

[0690] Step 2. Synthesis of tert-butyl (2S)-6-(benzyloxy)-2-(hydroxymethyl)-5-methyl-1,4-oxazetane-4-carboxylate

[0691]

[0692] TBAF (0.77 mL, 0.773 mmol, 1.2 equivalent, 1 M) was added to a stirred solution of (2S)-6-(benzyloxy)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methyl-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (300 mg, 0.644 mmol, 1 equivalent) in THF (5 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was quenched with NH4Cl (aqueous solution) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give tert-butyl (2S)-6-(benzyloxy)-2-(hydroxymethyl)-5-methyl-1,4-oxazine-heptane-4-carboxylate (200 mg, 88.34%), a pale yellow oil. LCMS (ES) [M+H] + m / z:352.

[0693] Step 3. Synthesis of (2S)-6-(benzyloxy)-4-(tert-butoxycarbonyl)-5-methyl-1,4-oxazacycloheptane-2-carboxylic acid

[0694]

[0695] At 0 °C, tert-butyl (2S)-6-(benzyloxy)-2-(hydroxymethyl)-5-methyl-1,4-oxazetane-4-carboxylate (230 mg, 0.654 mmol, 1.0 equivalent) was added in portions to a stirred solution of acetone (3 mL) containing NaHCO3 (109 mg, 1.308 mmol, 2.0 equivalent), NaBr (13 mg, 0.131 mmol, 0.2 equivalent), and TEMPO (10 mg, 0.065 mmol, 0.1 equivalent) in H2O (1 mL). At 0 °C, 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (304.20 mg, 1.308 mmol, 2.0 equivalent) was added in portions to the above mixture. The resulting mixture was stirred at room temperature for another 5 h. The resulting mixture was then diluted with NaHCO3 (aqueous solution). The resulting mixture was filtered, and the filter cake was washed with H₂O (2 mL). The mixture / residue was acidified to pH 6 with citric acid. The resulting mixture was extracted with CH₂Cl₂ (5 x 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded (2S)-6-(benzyloxy)-4-(tert-butoxycarbonyl)-5-methyl-1,4-oxazetane-2-carboxylic acid (220 mg, 91.99%) as a colorless oil. LCMS(ES) [M+H] + m / z:366.

[0696] Step 4. Synthesis of (2S)-4-(tert-butoxycarbonyl)-6-hydroxy-5-methyl-1,4-oxazacycloheptane-2-carboxylic acid

[0697]

[0698] At room temperature, Pd / C (50 mg) and Pd(OH)₂ / C (50 mg) were added in portions to a stirred solution of (2S)-6-(benzyloxy)-4-(tert-butoxycarbonyl)-5-methyl-1,4-oxazetane-2-carboxylic acid (250 mg, 0.684 mmol, 1.0 equivalent) in MeOH (8 mL). The resulting mixture was stirred at 50 °C under a hydrogen atmosphere (10 atm) for 16 h. The mixture was filtered, and the filter cake was washed with MeOH (8 mL). The filtrate was concentrated under reduced pressure. This gave (2S)-4-(tert-butoxycarbonyl)-6-hydroxy-5-methyl-1,4-oxazetane-2-carboxylic acid (160 mg, 84.95%) as a colorless oil. LCMS (ES) [M+H] + m / z:276.

[0699] Step 5. Synthesis of (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-5-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0700]

[0701] At 0 °C, DIEA (140 mg, 1.089 mmol, 3.0 equivalent) and HATU (165 mg, 0.436 mmol, 1.2 equivalent) were added in portions to a stirred solution of (2S)-4-(tert-butoxycarbonyl)-6-hydroxy-5-methyl-1,4-oxazacycloheptane-2-carboxylic acid (100 mg, 0.363 mmol, 1.0 equivalent) in DCM (2 mL). The resulting mixture was stirred at 0 °C for 1 h. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-5-methyl-1,4-oxazolidinyl-heptane-4-carboxylic acid tert-butyl ester (100 mg, 50.00%) as a white solid. LCMS (ES) [M+H] + m / z:551.

[0702] Step 5. Synthesis of Compound 53

[0703]

[0704] TsOH (93 mg, 0.546 mmol, 3.0 equivalent) was added to a stirred solution of (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-5-methyl-1,4-oxazolidinyl-heptane-4-carboxylic acid tert-butyl ester (100 mg, 0.182 mmol, 1.0 equivalent) in ACN (1 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 15 min; detector, UV 254 nm. This yielded (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-5-methyl-1,4-oxazetane-2-carboxamide (55 mg, 67.22%) as a white solid. LCMS (ES) [M+H] + m / z:451.

[0705] Step 6. Synthesis of compounds 54-56

[0706] (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-5-methyl-1,4-oxazacycloheptane-2-carboxamide (55 mg, 0.122 mmol, 1.0 equivalence) was purified by chiral-HPLC under the following conditions (column: XA CHIRALPAK IA, 2*25 cm, 5 μm; mobile phase A: Hex-HPLC, mobile phase B: ETOH (0.1% 2M NH3-MEOH); flow rate: 25 mL / min; gradient: isocratic 30; wavelength: 254 nm; RT1 (min): 12; RT2 (min): 14.1; sample solvent: EtOH-HPLC; injection volume: 1.2 mL; number of runs: 4), yielding compound 54 (12 mg, 1 mmol) as a white solid. Compound 54 (21.82%), compound 55 (16 mg, 29.09%), and compound 56 (7 mg, 12.73%), which are white solids, were also present. The structures of compounds 54-56 were confirmed by the chiral synthesis of Example 30.

[0707] Compound 54: 1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, J = 8.5 Hz, 1H),7.64 (d, J = 8.1 Hz, 2H), 7.55 (s, 1H), 7.45 – 7.32 (m, 4H), 4.99 (q, J = 8.1Hz, 1H), 4.47 (s, 1H), 4.03 (dd, J = 10.3, 3.2 Hz, 1H), 3.91 – 3.79 (m, 1H),3.55 (s, 2H), 3.39 (s, 3H), 3.27 – 3.07 (m, 2H), 3.05 (dd, J = 14.2, 3.3 Hz,1H), 2.71 (q, J = 7.3, 6.6 Hz, 1H), 2.30 (dd, J = 14.2, 10.3 Hz, 1H), 2.08(brs, 1H), 0.97 (d, J = 6.7 Hz, 3H). LCMS (ES) [M+H] + m / z:451。

[0708] Compound 55: 1 H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J = 8.3 Hz, 1H),7.63 (d, J = 7.9 Hz, 2H), 7.55 (s, 1H), 7.44 – 7.36 (m, 4H), 5.03 (q, J = 7.9Hz, 1H), 4.49 (d, J = 7.4 Hz, 1H), 4.07 (t, J = 5.0 Hz, 1H), 3.80 (dd, J =12.8, 3.5 Hz, 1H), 3.71 (d, J = 12.8 Hz, 1H), 3.45 – 3.40 (m, 1H), 3.39 (s,3H), 3.17 (d, J = 7.9 Hz, 2H), 2.93 (dd, J = 14.4, 5.3 Hz, 1H), 2.80 (dd, J =14.7, 4.5 Hz, 1H), 2.67 (d, J = 7.1 Hz, 1H), 1.77 (brs, 1H), 0.98 (d, J = 6.6Hz, 3H). LCMS (ES) [M+H] + m / z:451。

[0709] Compound 56:1 H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.9 Hz, 2H), 7.54 (s, 1H), 7.43 – 7.34 (m, 4H), 5.00 (q, J = 7.8Hz, 1H), 4.77 (d, J = 5.7 Hz, 1H), 3.94 (dd, J = 5.1, 2.8 Hz, 1H), 3.70 (dd,J = 12.2, 3.7 Hz, 1H), 3.48 (dd, J = 12.4, 9.6 Hz, 1H), 3.38 (s, 3H), 3.19(d, J = 7.8 Hz, 2H), 3.12 – 2.96 (m, 2H), 2.97 – 2.85 (m, 1H), 2.30 – 2.17(m, 1H), 1.61 (brs, 1H), 1.00 (d, J = 6.3 Hz, 3H). LCMS (ES) [M+H] + m / z:451.

[0710] Example 30: Synthesis of (2S,5S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-5-methyl-1,4-oxazetane-2-carboxamide (compound 54)

[0711] Step 1. Synthesis of (E)-benzyl({[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methylene})amine

[0712]

[0713] MgSO4 (69.36 g, 576.289 mmol, 1.5 equivalent) was added in portions to a stirred solution of (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (50 g, 384.193 mmol, 1.0 equivalent) and benzylamine (41.17 g, 384.193 mmol, 1.0 equivalent) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was filtered, and the filter cake was washed with DCM (500 mL). The filtrate was concentrated under reduced pressure. This gave (E)-benzyl({[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methylene})amine (80.5 g, 95.55% yield) as a pale yellow oil. LCMS (ES) [M+H] +m / z:220.

[0714] Step 2. Synthesis of benzyl[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]amine

[0715]

[0716] Boron trifluoride diethyl ether (52.10 g, 367.104 mmol, 1.0 equivalent) was added dropwise to a stirred solution of (E)-benzyl({[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methylene})amine (80.5 g, 367.104 mmol, 1.0 equivalent) in THF (800 mL) at -20 °C under a nitrogen atmosphere. The resulting mixture was stirred at -20 °C under a nitrogen atmosphere for 30 min. MeMgBr (305.92 mL, 917.760 mmol, 2.5 equivalent, 3M in Et2O solution) was added dropwise to the above mixture at -20 °C. The resulting mixture was stirred at -20 °C for another 3 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (4:1) to give benzyl[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]amine (50 g, 57.88% yield), a light brown oil. LCMS (ES) [M+H] + m / z:336.

[0717] Step 3. Synthesis of benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl][(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]amine

[0718]

[0719] (2S)-2-[(benzyloxy)methyl]ethylene oxide (87.22 g, 531.175 mmol, 2.5 equivalents) was added dropwise to a stirred solution of benzyl[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]amine (50 g, 212.470 mmol, 1.0 equivalent) in dioxane (500 mL). The resulting mixture was stirred at 100 °C for 72 h. The mixture was then cooled to room temperature. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1), to give benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl][(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]amine (42 g, 49.48% yield) as a light brown oil. LCMS (ES) [M+H] + m / z:400.

[0720] Step 4. Synthesis of (2S,3S)-3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}but-1,2-diol

[0721]

[0722] At room temperature, TSOH (51.72 g, 300.351 mmol, 3.0 equivalent) was added in portions to a stirred solution of benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl][(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]amine (40 g, 100.117 mmol, 1.0 equivalent) in MeOH (600 mL). The resulting mixture was stirred at 60 °C for 16 h. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The mixture / residue was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give (2S,3S)-3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}but-1,2-diol (35 g, 97.25% yield), a pale yellow oil. LCMS (ES) [M+H] + m / z:360.

[0723] Step 5. Synthesis of benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl][(1S)-1-[(2S)-ethyleneoxy-2-yl]ethyl]amine and (2S,5S,6S)-4-benzyl-2-[(benzyloxy)methyl]-5-methyl-1,4-oxazacycloheptane-6-ol

[0724]

[0725] CMBP (35.25 g, 146.050 mmol, 1.5 equivalent) was added dropwise to a stirred solution of (2S,3S)-3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}butane-1,2-diol (35 g, 97.367 mmol, 1.0 equivalent) in toluene (400 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (6:1) to give benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl][(1S)-1-[(2S)-ethyleneoxy-2-yl]ethyl]amine (9 g, 27.07% yield, 90% purity), which was a light yellow oil, and (2S,5S,6S)-4-benzyl-2-[(benzyloxy)methyl]-5-methyl-1,4-oxazetane-6-ol (6 g, 18.05% yield), which was a light yellow oil.

[0726] Step 6. Synthesis of (2S,5S,6S)-4-benzyl-2-[(benzyloxy)methyl]-5-methyl-1,4-oxazacycloheptane-6-ol

[0727]

[0728] K₂CO₃ (18.21 g, 131.790 mmol, 5.0 equivalent) was added fractionally to a stirred solution of benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl][(1S)-1-[(2S)-ethyleneoxy-2-yl]ethyl]amine (9 g, 26.358 mmol, 1.0 equivalent) in MeOH (100 mL). The resulting mixture was stirred at room temperature for 16 h. The mixture was filtered, and the filter cake was washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (6:1), to give (2S,5S,6S)-4-benzyl-2-[(benzyloxy)methyl]-5-methyl-1,4-oxazacycloheptane-6-ol (6 g, 66.67% yield) as a pale yellow oil. LCMS (ES) [M+H] +m / z:342.

[0729] Step 7. Synthesis of (2S,5S)-4-benzyl-2-[(benzyloxy)methyl]-5-methyl-1,4-oxazacycloheptane-6-one

[0730]

[0731] DMSO (3.57 g, 45.688 mmol, 1.2 equivalents) was added dropwise to a stirred solution of oxaloyl chloride (6.77 g, 53.302 mmol, 1.4 equivalents) in 150 mL of DCM at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 30 min. At -78 °C, (2S,5S,6S)-4-benzyl-2-[(benzyloxy)methyl]-5-methyl-1,4-oxazacycloheptan-6-ol (13 g, 38.073 mmol, 1.0 equivalents) in 10 mL of DCM was added dropwise to the above mixture. The resulting mixture was stirred at -78 °C for another 1 h. The reaction was quenched with TEA (19.26 g, 190.365 mmol, 5.0 equivalents) at -78 °C. The resulting mixture was extracted with CH₂Cl₂ (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1), to give (2S,5S)-4-benzyl-2-[(benzyloxy)methyl]-5-methyl-1,4-oxazacycloheptan-6-one (8.1 g, 62.68% yield) as a colorless oil. LCMS (ES) [M+H] + m / z:340.

[0732] Step 8. Synthesis of (2S,5S,6R)-4-benzyl-2-[(benzyloxy)methyl]-5-methyl-1,4-oxazacycloheptane-6-ol

[0733]

[0734] LAH (23.86 mL, 47.726 mmol, 2.0 equivalent, 2M in THF) was added dropwise to a stirred solution of (2S,5S)-4-benzyl-2-[(benzyloxy)methyl]-5-methyl-1,4-oxazacycloheptan-6-one (8.1 g, 23.863 mmol, 1.0 equivalent) in 100 mL of THF at -40 °C under a nitrogen atmosphere. The resulting mixture was stirred at -40 °C under a nitrogen atmosphere for 30 min. The reaction was quenched by adding Na₂SO₄·10H₂. The resulting mixture was filtered, and the filter cake was washed with THF (200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (3:1) to give (2S,5S,6R)-4-benzyl-2-[(benzyloxy)methyl]-5-methyl-1,4-oxazacycloheptane-6-ol (7.5 g, 92.05% yield) as a colorless oil. LCMS (ES) [M+H + m / z:342.

[0735] Step 9. Synthesis of (2S,5S,6R)-4-benzyl-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-5-methyl-1,4-oxazacycloheptane

[0736]

[0737] Under a nitrogen atmosphere, at 0 °C, imidazole (2.99 g, 43.930 mmol, 2.0 equivalent) and TBSCl (4.97 g, 32.947 mmol, 1.5 equivalent) were added in portions to a stirred solution of (2S,5S,6R)-4-benzyl-2-[(benzyloxy)methyl]-5-methyl-1,4-oxazacycloheptan-6-ol (7.5 g, 21.965 mmol, 1.0 equivalent) and DMAP (0.27 g, 2.196 mmol, 0.1 equivalent) in DCM (80 mL). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (8:1) to give (2S,5S,6R)-4-benzyl-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-5-methyl-1,4-oxazacycloheptane (8.0 g, 79.92% yield) as a colorless oil. LCMS (ES) [M+H] + m / z:456.

[0738] Step 10. Synthesis of tert-butyl (2S,5S,6R)-6-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)-5-methyl-1,4-oxazetane-4-carboxylate

[0739]

[0740] Pd / C (2.0 g) was added to a stirred solution of (2S,5S,6R)-4-benzyl-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-5-methyl-1,4-oxazacycloheptane (8.0 g, 17.555 mmol, 1.0 equivalent) and Boc₂O (5.75 g, 26.332 mmol, 1.5 equivalent) in MeOH (100 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The mixture was filtered, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (10:1) to give tert-butyl (2S,5S,6R)-6-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)-5-methyl-1,4-oxazetane-4-carboxylate (6.2 g, 94.04% yield) as a colorless oil. LCMS (ES) [M+H] + m / z:376.

[0741] Step 11. Synthesis of (2S,5S,6R)-4-(tert-butoxycarbonyl)-6-[(tert-butyldimethylsilyl)oxy]-5-methyl-1,4-oxazacycloheptane-2-carboxylic acid

[0742]

[0743] At 0 °C under a nitrogen atmosphere, tert-butyl ester (6.2 g, 16.508 mmol, 1.0 equivalent) of (2S,5S,6R)-6-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)-5-methyl-1,4-oxazetane-4-carboxylic acid (0.34 g, 3.302 mmol, 0.2 equivalent) and NaBr (0.34 g, 3.302 mmol, 0.2 equivalent) and 2,2,6,6-tetramethylpiperidin-1-ol (0.26 g, 1.651 mmol, 0.1 equivalent) in acetone (90 mL) were added to a stirred solution of (2S,5S,6R)-6-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)-5-methyl-1,4-oxazetane-4-carboxylic acid (0.26 g, 1.651 mmol, 0.1 equivalent) in H2O (30 mL) in H2O (2.77 g, 33.016 mmol, 2.0 equivalent). Trichloro-1,3,5-triazinane-2,4,6-trione (7.67 g, 33.016 mmol, 2.0 equivalents) was added in portions to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for another 16 h. The mixture was alkalized to pH 9 with saturated NaHCO3 (aqueous solution). The resulting mixture was filtered, and the filter cake was washed with H2O (5 mL). The resulting mixture was extracted with EtOAc (4 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave (2S,5S,6R)-4-(tert-butoxycarbonyl)-6-[(tert-butyldimethylsilyl)oxy]-5-methyl-1,4-oxazetane-2-carboxylic acid (5.2 g, 80.86% yield) as a grayish-white oil. LCMS (ES) [M+H] + m / z:390.

[0744] Step 12. Synthesis of (2S,5S,6R)-6-[(tert-butyldimethylsilyl)oxy]-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-5-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0745]

[0746] DIEA (646 mg, 5.007 mmol, 3.0 equivalent) and HATU (761 mg, 2.003 mmol, 1.2 equivalent) were added in portions to a stirred solution of (2S,5S,6R)-4-(tert-butoxycarbonyl)-6-[(tert-butyldimethylsilyl)oxy]-5-methyl-1,4-oxazacycloheptane-2-carboxylic acid (650 mg, 1.669 mmol, 1.0 equivalent) and (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]propionitrile (489 mg, 1.669 mmol, 1.0 equivalent) in DCM (8 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h. The resulting mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1) to give (2S,5S,6R)-6-[(tert-butyldimethylsilyl)oxy]-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-5-methyl-1,4-oxazolidinyl heptane-4-carboxylate (920 mg, 82.93% yield) as a pale yellow solid. LCMS (ES) [M+H] + m / z:665.

[0747] Step 13. Synthesis of Compound 54

[0748]

[0749] At room temperature, TsOH (714 mg, 4.152 mmol, 3.0 equivalent) was added fractionally to a stirred solution of (2S,5S,6R)-6-[(tert-butyldimethylsilyl)oxy]-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-5-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester (920 mg, 1.384 mmol, 1.0 equivalent) in ACN (15 mL). The resulting mixture was stirred at room temperature for 3 h. The mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 60% gradient over 15 min; detector, UV 254 nm. This yielded (2S,5S,6R)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-5-methyl-1,4-oxazetane-2-carboxamide as a white solid (410 mg, 65.77% yield). LCMS (ES) [M+H + m / z:451. 1 H NMR (300 MHz, DMSO-d6) δ 8.66 (d, J = 8.5 Hz, 1H), 7.70 – 7.61 (m, 2H), 7.57 (t, J = 1.2 Hz,1H), 7.46 – 7.33 (m, 4H), 5.01 (td, J = 8.6, 7.2 Hz, 1H), 4.50 (s, 1H), 4.05(dd, J = 10.3, 3.3 Hz, 1H), 3.93 – 3.80 (m, 1H), 3.64 – 3.47 (m, 2H), 3.40(s, 3H), 3.27 – 3.13 (m, 2H), 3.07 (dd, J = 14.2, 3.3 Hz, 1H), 2.79 – 2.66(m, 1H), 2.31 (dd, J = 14.2, 10.3 Hz, 1H), 2.07 (s, 1H), 0.99 (d, J = 6.7 Hz,3H).

[0750] Example 31: Synthesis of (2S,6R,7S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-7-fluoro-6-hydroxy-1,4-oxazetane-2-carboxamide (compound 57)

[0751] Step 1. Synthesis of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]-4-(triphenylmethyl)-3,5-dihydro-2H-1,4-oxazapyridine

[0752]

[0753] DBU (9.59 g, 62.980 mmol, 2.0 equivalent) was added dropwise to a stirred solution of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-one (15.8 g, 31.490 mmol, 1.0 equivalent) and trichloromethylsilane (5.13 g, 47.235 mmol, 1.5 equivalent) in DCM (200 mL). The resulting mixture was stirred at 40 °C for 16 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (20:1) to give a colorless oil (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]-4-(triphenylmethyl)-3,5-dihydro-2H-1,4-oxazapyrrolizidine (13.8 g, 76.36% yield). LCMS (ES, m / z): [M+H] + : 574.

[0754] Step 2. Synthesis of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-fluoro-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-one

[0755]

[0756] Add 4-(chloromethyl)-1-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-dioxazonium (13.8 g, 24.045 mmol, 1.0 equivalent) to a stirred solution of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]-4-(triphenylmethyl)-3,5-dihydro-2H-1,4-oxazonium (13.8 g, 24.045 mmol, 1.0 equivalent) in DMF (150 mL); and add dropwise bis(tetrafluoroboride) (12.78 g, 36.068 mmol, 1.5 equivalent) to DMF (30 mL) under a nitrogen atmosphere at 0 °C. Stir the resulting mixture at 0 °C under a nitrogen atmosphere for 1 h. Extract the resulting mixture with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (20:1), to give a colorless oily substance (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-fluoro-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-one (6.3 g, 50.41% yield). LCMS (ES, m / z): [M+H] + : 520.

[0757] Step 3. Synthesis of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-fluoro-4-(triphenylmethyl)-1,4-oxazetane-6-ol

[0758]

[0759] Under a nitrogen atmosphere, at -50 °C, lithium aluminum hydride (1.0 M in THF) (11.26 mL, 11.256 mmol, 1.5 equivalent) was added dropwise to a stirred solution of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-fluoro-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-one (3.9 g, 7.504 mmol, 1.0 equivalent) in 50 mL of THF. The resulting mixture was stirred at -50 °C under a nitrogen atmosphere for 1 h. The reaction was quenched with Na₂SO₄·10H₂O at -50 °C. The resulting mixture was filtered, and the filter cake was washed with THF (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-fluoro-4-(triphenylmethyl)-1,4-oxazine-6-ol (2.1 g, 53.64% yield) as a colorless oil. LCMS (ES, m / z): [M+H]+ : 522.

[0760] Step 4. Synthesis of (2S)-6-(benzyloxy)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-fluoro-4-(triphenylmethyl)-1,4-oxazacycloheptane

[0761]

[0762] Under a nitrogen atmosphere, at 0 °C, NaH (0.24 g, 6.038 mmol, 1.5 equivalent, 60%) was added dropwise to a stirred solution of (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-fluoro-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-ol (2.1 g, 4.025 mmol, 1.0 equivalent) in DMF (30 mL). The resulting mixture was stirred at 0 °C for 30 min. Benzyl bromide (1.03 g, 6.038 mmol, 1.5 equivalent) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at room temperature for another 3 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (20:1) to give (2S)-6-(benzyloxy)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-fluoro-4-(triphenylmethyl)-1,4-oxazacycloheptane (2 g, 81.21% yield) as a colorless oil. LCMS (ES, m / z): [M+H] + : 612.

[0763] Step 5. Synthesis of tert-butyl (2S)-6-(benzyloxy)-7-fluoro-2-(hydroxymethyl)-1,4-oxazetane-4-carboxylate

[0764]

[0765] HCl in 1,4-dioxane (4.0 M) (10 mL) was added to a stirred solution of (2S)-6-(benzyloxy)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-fluoro-4-(triphenylmethyl)-1,4-oxazacycloheptane (2.0 g, 3.269 mmol, 1.0 equivalent) in dioxane (10 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DCM (30 mL). TEA (1.65 g, 16.345 mmol, 5.0 equivalent) and di-tert-butyl dicarbonate (1.43 g, 6.538 mmol, 2.0 equivalent) were added in portions to the above mixture at room temperature. The resulting mixture was stirred at room temperature for another 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give tert-butyl (2S)-6-(benzyloxy)-7-fluoro-2-(hydroxymethyl)-1,4-oxazine-heptane-4-carboxylate (400 mg, 34.43% yield) as a colorless oil. LCMS (ES, m / z): [M+H] + : 356.

[0766] Step 6. Synthesis of (2S)-6-(benzyloxy)-4-(tert-butoxycarbonyl)-7-fluoro-1,4-oxazacycloheptane-2-carboxylic acid

[0767]

[0768] At 0 °C, tert-butyl ester (350 mg, 0.985 mmol, 1.0 equivalent) of (2S)-6-(benzyloxy)-7-fluoro-2-(hydroxymethyl)-1,4-oxazacycloheptane-4-carboxylate (350 mg, 0.985 mmol, 1.0 equivalent) and NaBr (20 mg, 0.197 mmol, 0.2 equivalent) in acetone (3 mL) were added to a stirred solution of 2,2,6,6-tetramethylpiperidine-1-ol (15 mg, 0.099 mmol, 0.1 equivalent) and NaHCO3 (165 mg, 1.970 mmol, 2 equivalent) in H2O (1 mL). At 0 °C, trichloro-1,3,5-triazinane-2,4,6-trione (457 mg, 1.970 mmol, 2.0 equivalent) was added to the above mixture. The resulting mixture was stirred at room temperature for another 6 h. The reaction was quenched at 0 °C with saturated NaHCO3 (aqueous solution). The resulting mixture was filtered, and the filter cake was washed with H₂O (1 mL). The filtrate was alkalized to pH 6 with citric acid. The resulting mixture was extracted with CH₂Cl₂ (3 x 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded (2S)-6-(benzyloxy)-4-(tert-butoxycarbonyl)-7-fluoro-1,4-oxazetane-2-carboxylic acid (220 mg, 60.48% yield) as a colorless oil. LCMS (ES, m / z): [M+H] + : 370.

[0769] Step 7. Synthesis of N-[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamate tert-butyl ester

[0770]

[0771] K₂CO₃ (402 mg, 2.914 mmol, 2.0 equivalent) and Pd(dppf)Cl₂ (106 mg, 0.146 mmol, 0.1 equivalent) were added to a stirred solution of N-[(1S)-2-(4-bromophenyl)-1-carbamoylethyl]carbamate (500 mg, 1.457 mmol, 1.0 equivalent) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3-benzoxazol-2-one (480 mg, 1.748 mmol, 1.2 equivalent) in dioxane (5 mL) and H₂O (0.5 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 3 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:2) to give N-[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamate tert-butyl ester (500 mg, 83.42% yield) as a light brown solid. LCMS (ES, m / z): [M+H] + : 412.

[0772] Step 8. Synthesis of (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]acrylamide

[0773]

[0774] TsOH (627 mg, 3.645 mmol, 3.0 equivalent) was added to a stirred solution of N-[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamate (500 mg, 1.215 mmol, 1.0 equivalent) in ACN (8 mL). The resulting mixture was stirred at room temperature for 4 h. The mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]propionamide (300 mg, 79.29% yield) as a pale yellow solid. LCMS (ES, m / z): [M+H] + : 312.

[0775] Step 9. Synthesis of (2S)-6-(benzyloxy)-2-{[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-fluoro-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0776]

[0777] DIEA (83 mg, 0.651 mmol, 3.0 equivalent) and HATU (107 mg, 0.282 mmol, 1.3 equivalent) were added in portions to a stirred solution of (2S)-6-(benzyloxy)-4-(tert-butoxycarbonyl)-7-fluoro-1,4-oxazacycloheptane-2-carboxylic acid (80 mg, 0.217 mmol, 1.0 equivalent) and (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]propionamide (74 mg, 0.239 mmol, 1.1 equivalent) in DCM (2 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to give (2S)-6-(benzyloxy)-2-{[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-fluoro-1,4-oxazetane-4-carboxylic acid tert-butyl ester (90 mg, 62.71% yield) as a pale yellow solid. LCMS (ES, m / z): [M+H + : 663.

[0778] Step 10. Synthesis of (2S)-2-{[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-fluoro-6-hydroxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0779]

[0780] Pd / C (20 mg) was added to a stirred solution of (2S)-6-(benzyloxy)-2-{[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-fluoro-1,4-oxazetane-4-carboxylic acid tert-butyl ester (90 mg, 0.136 mmol, 1.0 equivalent) in methanol (3 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The mixture was filtered, and the filter cake was washed with methanol (3 mL). The filtrate was concentrated under reduced pressure. This yielded a colorless oil, (2S)-2-{[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-fluoro-6-hydroxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (50 mg, 64.30% yield). LCMS (ES, m / z): [M+H + : 573.

[0781] Step 11. Synthesis of (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-fluoro-6-hydroxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0782]

[0783] N-[(triethylammonium)sulfonyl]carbamoyl oxide (41 mg, 0.174 mmol, 2.0 equivalent) was added to a stirred solution of (2S)-2-{[(1S)-1-carbamoyl-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-fluoro-6-hydroxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (50 mg, 0.087 mmol, 1.0 equivalent) in DCM (2 mL). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to give (2S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-fluoro-6-hydroxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (25 mg, 51.62% yield) as a colorless oil. LCMS (ES, m / z): [M+H] + : 555.

[0784] Step 12. Synthesis of (2S,6R,7S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-7-fluoro-6-hydroxy-1,4-oxazetane-2-carboxamide

[0785]

[0786] TSOH (23 mg, 0.135 mmol, 3.0 equivalent) was added to a stirred solution of (2S,6R,7S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-fluoro-6-hydroxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (25 mg, 0.045 mmol, 1.0 equivalent) in ACN (1 mL). The resulting mixture was stirred at room temperature for 3 h. The mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 15 min; detector, UV 254 nm. This yielded (2S,6R,7S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-7-fluoro-6-hydroxy-1,4-oxazetane-2-carboxamide (2.1 mg, 10.25% yield) as a white solid, presumably pure. LCMS (ES, m / z): [M+H] + : 455. 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 1.4 Hz, 1H), 7.46 – 7.34 (m, 4H), 5.62(dd, J = 52.7, 2.7 Hz, 1H), 5.41 (s, 1H), 5.07 (q, J = 8.3 Hz, 1H), 4.61 (d,J = 6.9 Hz, 1H), 3.77 (s, 1H), 3.40 (s, 3H), 3.27 – 3.09 (m, 2H), 2.94 (d, J= 14.4 Hz, 1H), 2.76 – 2.60 (m, 3H).

[0787] Example 32: Synthesis of (2S,6R,7S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-7-methyl-1,4-oxazetane-2-carboxamide (compound 71)

[0788] Step 1. Synthesis of tert-butyl (2S,6S,7R)-6-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)-7-methyl-1,4-oxazetane-4-carboxylate

[0789]

[0790] A solution of (2S,6R,7S)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-1,4-oxazacycloheptan-4-carboxylate tert-butyl ester (450 mg, 0.97 mmol, 1.0 equivalent) in methanol (15 mL) was added to a pressure vessel. Pd / C (90 mg) and palladium hydroxide, Pd 20% on carbon powder, and nominal 50% water (89 mg) were then added. The mixture was hydrogenated at 5 atm hydrogen pressure for 16 hours at room temperature. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. This yielded (2S,6S,7R)-6-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)-7-methyl-1,4-oxazacycloheptan-4-carboxylate tert-butyl ester (300 mg, 82.6%) as a colorless oil. LCMS (ES) [M+1] + m / z: 376.

[0791] Step 2. Synthesis of (2S,6R,7S)-4-(tert-butoxycarbonyl)-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-1,4-oxazacycloheptane-2-carboxylic acid

[0792]

[0793] At 0 °C, tert-butyl ester of (2S,6R,7S)-6-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)-7-methyl-1,4-oxazetane-4-carboxylate (300 mg, 0.80 mmol, 1.0 equivalent) was added in portions to a stirred solution of (2S,6R,7S)-6-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)-7-methyl-1,4-oxazetane-4-carboxylate (9 mL) in acetone and 3 mL of H₂O. NaHCO₃ (134 mg, 1.60 mmol, 2.0 equivalent) and NaBr (16 mg, 0.16 mmol, 0.2 equivalent) and 2,2,6,6-tetramethylpiperidin-1-ol (12 mg, 0.08 mmol, 0.1 equivalent) and trichloro-1,3,5-triazinane-2,4,6-trione (371 mg, 1.60 mmol, 2.0 equivalent) were added in portions. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with saturated NaHCO3 (aqueous solution) (20 mL). The mixture was filtered. The filtrate was acidified to pH 5 with citric acid and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded (2S,6R,7S)-4-(tert-butoxycarbonyl)-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-1,4-oxazacycloheptane-2-carboxylic acid (200 mg, 64.2%), a light brown oil. LCMS (ES) [M+1] + m / z: 390.

[0794] Step 3. Synthesis of (2S,6R,7S)-6-[(tert-butyldimethylsilyl)oxy]-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0795]

[0796] DIEA (159 mg, 1.23 mmol, 3.0 equivalent) and HATU (187 mg, 0.49 mmol, 1.2 equivalent) were added in portions to a stirred solution of (2S,6R,7S)-4-(tert-butoxycarbonyl)-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-1,4-oxazacycloheptane-2-carboxylic acid (160 mg, 0.41 mmol, 1.0 equivalent) and (2S)-2-amino-3-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]propionitrile (132 mg, 0.45 mmol, 1.1 equivalent) in DCM (3 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h. The residue was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / THF (3:1) to give (2S,6R,7S)-6-[(tert-butyldimethylsilyl)oxy]-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester (200 mg, 73%) as a white solid. LCMS (ES) [M+1] + m / z: 665.

[0797] Step 4. Synthesis of (2S,6R,7S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-7-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0798]

[0799] TBAF (0.36 mL, 0.36 mmol, 1.2 equivalent) was added dropwise to a stirred solution of (2S,6R,7S)-6-[(tert-butyldimethylsilyl)oxy]-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-7-methyl-1,4-oxazolidinyl-heptane-4-carboxylic acid tert-butyl ester (200 mg, 0.30 mmol, 1.0 equivalent) in THF (4 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1) to give (2S,6R,7S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-7-methyl-1,4-oxazolidinyl-heptane-4-carboxylic acid tert-butyl ester (130 mg, 78.4%) as a grayish-white solid. LCMS (ES) [M+1] + m / z: 551.

[0800] Step 5. Synthesis of (2S,6R,7S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-7-methyl-1,4-oxazetane-2-carboxamide

[0801]

[0802] TsOH (93 mg, 0.55 mmol, 3.0 equivalent) was added to a stirred solution of (2S,6R,7S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-7-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol, 1.0 equivalent) in ACN (2 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by preparative HPLC under the following conditions: column, XBridge PrepC18 OBD column, 19*150 mm, 5 μm; mobile phase, water (0.1% NH3H2O) and ACN (10% phase B, reaching 80% within 20 min); detector, UV 254 nm. This yielded a presumed (2S,6R,7S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-7-methyl-1,4-oxazetane-2-carboxamide (25 mg, 30.5%) as a white solid. LCMS (ES) [M+1] + m / z: 451.1. 1 H NMR (300 MHz, DMSO-d6) δ8.35 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.57 (s, 1H), 7.45 – 7.35(d, J = 7.8 Hz, 4H), 5.02 (q, J = 8.0 Hz, 1H), 4.03 (dd, J = 9.0, 3.7 Hz,1H), 3.58 – 3.48 (m, 1H), 3.40 (s, 3H), 3.25 – 3.17 (m, 3H), 3.03 (dd, J =13.7, 3.8 Hz, 1H), 2.82 (dd, J = 14.1, 3.5 Hz, 1H), 2.69 (dd, J = 14.1, 5.2Hz, 1H), 2.37 (dd, J = 13.7, 9.0 Hz, 1H), 1.24 (d, J = 6.2 Hz, 3H).

[0803] Example 33: Synthesis of (2S,6S,7S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-7-methyl-1,4-oxazetane-2-carboxamide (compound 72)

[0804] Step 1. Synthesis of (2S,7S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-one

[0805]

[0806] At -78 °C under a nitrogen atmosphere, (2S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-one (2.2 g, 4.39 mmol, 1.0 equivalent) in THF (10 mL) was added dropwise to a stirred solution of KHMDS (1 M in THF) (6.6 mL g, 6.58 mmol, 1.5 equivalent) in THF (30 mL). The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 1 h. Iodomethane (6.22 g, 43.85 mmol, 10.0 equivalent) was added dropwise to the above mixture at -78 °C. The resulting mixture was stirred at -40 °C for 1 h. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (50 mL) at -40 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (20:1) to give a colorless oily substance (2S,7S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-one (1.4 g, 62% yield). LCMS (ES) [M+H] + m / z: 516.

[0807] Step 2. Synthesis of (2S,6S,7S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-ol

[0808]

[0809] Under a nitrogen atmosphere, at 0 °C, lithium aluminum hydride (1.0 M in THF) (1.74 mL, 1.74 mmol, 1.5 equivalent) was added dropwise to a stirred solution of (2S,7S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-one (600 mg, 1.16 mmol, 1.0 equivalent) in 10 mL of THF. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched with Na₂SO₄·10H₂O at 0 °C. The resulting mixture was filtered, and the filter cake was washed with THF (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give (2S,6S,7S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-ol (500 mg, 83% yield) as a colorless oil. LCMS (ES) [M+H + m / z: 518.

[0810] Step 3. Synthesis of (2S,6S,7S)-6-(benzyloxy)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptane

[0811]

[0812] Under a nitrogen atmosphere at 0 °C, NaH (57 mg, 1.45 mmol, 1.5 equivalent, 60% in mineral oil) was added dropwise to a stirred solution of (2S,6S,7S)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptan-6-ol (500 mg, 0.97 mmol, 1.0 equivalent) in DMF (8 mL). The resulting mixture was stirred at 0 °C for 0.5 h. Benzyl bromide (247 mg, 1.45 mmol, 1.5 equivalent) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for another 1 h. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give (2S,6S,7S)-6-(benzyloxy)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptane (500 mg, 85.2% yield) as a colorless oil. LCMS (ES) [M+H] + m / z: 608.

[0813] Step 4. Synthesis of [(2S,6S,7S)-6-(benzyloxy)-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptane-2-yl]methanol

[0814]

[0815] TBAF (215 mg, 0.82 mmol, 1.0 equivalent) was added to a stirred solution of (2S,6S,7S)-6-(benzyloxy)-2-{[(tert-butyldimethylsilyl)oxy]methyl}-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptane (500 mg, 0.82 mmol, 1.0 equivalent) in THF (8 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give a colorless oil, [(2S,6S,7S)-6-(benzyloxy)-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptane-2-yl]methanol (400 mg, 98.5% yield). LCMS (ES) [M+H] + m / z: 494.

[0816] Step 5. Synthesis of tert-butyl (2S,6S,7S)-6-(benzyloxy)-2-(hydroxymethyl)-7-methyl-1,4-oxazetane-4-carboxylate

[0817]

[0818] TsOH (366 mg, 2.13 mmol, 3.0 equivalent) was added to a stirred solution of [(2S,6S,7S)-6-(benzyloxy)-7-methyl-4-(triphenylmethyl)-1,4-oxazacycloheptane-2-yl]methanol (350 mg, 0.71 mmol, 1.0 equivalent) in ACN (5 mL). The resulting mixture was stirred at room temperature for 5 h. H2O (2 mL), K2CO3 (392 mg, 2.84 mmol, 4.0 equivalent), and di-tert-butyl dicarbonate (309 mg, 1.42 mmol, 2.0 equivalent) were added to the mixture. The resulting mixture was stirred at room temperature for another 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (8:1) to give tert-butyl (2S,6S,7S)-6-(benzyloxy)-2-(hydroxymethyl)-7-methyl-1,4-oxazetane-4-carboxylate (220 mg, 88.3% yield) as a colorless oil. LCMS (ES) [M+H] +m / z: 352.

[0819] Step 6. Synthesis of (2S,6S,7S)-6-(benzyloxy)-4-(tert-butoxycarbonyl)-7-methyl-1,4-oxazacycloheptane-2-carboxylic acid

[0820]

[0821] At 0 °C, tert-butyl ester of (2S,6S,7S)-6-(benzyloxy)-2-(hydroxymethyl)-7-methyl-1,4-oxazetane-4-carboxylate (220 mg, 0.63 mmol, 1.0 equivalent) and NaBr (12 mg, 0.13 mmol, 0.2 equivalent) were added in portions to a stirred solution of acetone (3 mL) and H₂O (1 mL). 2,2,6,6-Tetramethylpiperidin-1-ol (9 mg, 0.06 mmol, 0.1 equivalent) and NaHCO₃ (105 mg, 1.25 mmol, 2.0 equivalent) were then added in portions to the mixture. At 0 °C, trichloro-1,3,5-triazinane-2,4,6-trione (290 mg, 1.25 mmol, 2.0 equivalent) was added in portions to the mixture. The resulting mixture was stirred at room temperature for another 5 h. The mixture was alkalized to pH 9 with saturated NaHCO3 (aqueous solution). The resulting mixture was filtered, and the filter cake was washed with H2O (1 mL). The resulting mixture was extracted with hexane (10 mL). The aqueous layer was acidified to pH 5 with citric acid. The resulting mixture was extracted with CH2Cl2 (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded (2S,6S,7S)-6-(benzyloxy)-4-(tert-butoxycarbonyl)-7-methyl-1,4-oxazetane-2-carboxylic acid (180 mg, 78.7% yield) as a colorless oil. LCMS (ES) [M+H] + m / z: 366.

[0822] Step 7. Synthesis of (2S,6S,7S)-4-(tert-butoxycarbonyl)-6-hydroxy-7-methyl-1,4-oxazacycloheptane-2-carboxylic acid

[0823]

[0824] Pd / C (20 mg) and palladium hydroxide, 5% Pd on carbon powder, and nominally 50% water (20 mg) were added to a stirred mixture of (2S,6S,7S)-6-(benzyloxy)-4-(tert-butoxycarbonyl)-7-methyl-1,4-oxazacycloheptane-2-carboxylic acid (180 mg, 0.493 mmol, 1.0 equivalent) in MeOH (5 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 4 h. The mixture was filtered, the filter cake was washed with MeOH (5 mL), and the filtrate was concentrated under reduced pressure. This gave (2S,6S,7S)-4-(tert-butoxycarbonyl)-6-hydroxy-7-methyl-1,4-oxazacycloheptane-2-carboxylic acid (120 mg, 88.49% yield) as a colorless oil. LCMS (ES) [M+H] + m / z: 276.

[0825] Step 8. Synthesis of (2S,6S,7S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-7-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0826]

[0827] At 0 °C, DIEA (118 mg, 0.92 mmol, 3.0 equivalence) and HATU (175 mg, 0.46 mmol, 1.5 equivalence) were added in portions to a stirred solution of (2S,6S,7S)-4-(tert-butoxycarbonyl)-6-hydroxy-7-methyl-1,4-oxazacycloheptane-2-carboxylic acid (101 mg, 0.37 mmol, 1.2 equivalence) in DCM (2 mL). The resulting mixture was stirred at 0 °C for 1 h. The solvent was removed by concentration, and the residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give (2S,6S,7S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-7-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester (120 mg, 71% yield) as a grayish-white solid. LCMS (ES) [M+H + m / z: 551.

[0828] Step 9. Synthesis of (2S,6S,7S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-7-methyl-1,4-oxazheptan-2-carboxamide

[0829]

[0830] TsOH (112 mg, 0.65 mmol, 3.0 equivalent) was added to a stirred solution of (2S,6S,7S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-hydroxy-7-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester (120 mg, 0.22 mmol, 1.0 equivalent) in ACN (3 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel-120 g; mobile phase, MeCN aqueous solution (0.1% NH3·H2O) in a 10% to 50% gradient over 15 min; detector, UV 254 nm. This yielded (2S,6S,7S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-7-methyl-1,4-oxazetane-2-carboxamide (40 mg, 40.7% yield) as a white solid. LCMS (ES) [M+H + m / z: 451.2. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 8.2 Hz,1H), 7.70 – 7.64 (m, 2H), 7.60 – 7.56 (m, 1H), 7.47 – 7.35 (m, 4H), 5.04 (q,J = 7.8 Hz, 1H), 4.54 (d, J = 7.2 Hz, 1H), 4.01 (dd, J = 6.6, 4.9 Hz, 1H), 3.88 (qd, J = 6.5, 1.8 Hz, 1H), 3.53 – 3.46 (m, 1H), 3.41 (s, 3H), 3.26 –3.14 (m, 2H), 3.01 (dd, J = 14.0, 5.0 Hz, 1H), 2.78 (dd, J = 13.8, 3.8 Hz,1H), 2.70 – 2.61 (m, 2H), 2.10 (brs, 1H), 1.20 (d, J = 6.5 Hz, 3H).

[0831] Example 34: Synthesis of (2S,6S,7S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-6-hydroxy-7-methyl-1,4-oxazetane-2-carboxamide (compound 73)

[0832] Step 1. Synthesis of N-(but-3-en-1-yl)-4-nitrobenzenesulfonamide

[0833]

[0834] 2-nitrobenzene-1-sulfonyl chloride (50 g, 223.09 mmol, 1.2 equivalent) was added in portions to a stirred mixture of 3-buten-1-amine hydrochloride (20 g, 185.91 mmol, 1.0 equivalent) and NaHCO3 (46.9 g, 557.72 mmol, 3.0 equivalent) in DCM (300 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. The mixture was filtered, and the filter cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (4:1), to give N-(but-3-en-1-yl)-4-nitrobenzenesulfonamide (45 g, 94.45%) as a pale yellow solid. LCMS (ES) [M+H] + m / z: 257.

[0835] Step 2. Synthesis of N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-N-(but-3-en-1-yl)-4-nitrobenzenesulfonamide

[0836]

[0837] K₂CO₃ (72.8 g, 526.77 mmol, 3.0 equivalent) was added to a stirred solution of (2S)-2-[(benzyloxy)methyl]ethylene oxide (34.6 g, 210.71 mmol, 1.2 equivalents) and N-(but-3-en-1-yl)-4-nitrobenzenesulfonamide (45 g, 175.59 mmol, 1.0 equivalent) in NMP (500 mL). The resulting mixture was stirred at 50 °C for 20 h. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (3:1) to give N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-N-(but-3-en-1-yl)-4-nitrobenzenesulfonamide (40 g, 54%), a pale yellow oil. LCMS (ES) [M+H] + m / z: 421.

[0838] Step 3. Synthesis of (2S)-2-[(benzyloxy)methyl]-7-methyl-4-(4-nitrobenzenesulfonyl)-3,5-dihydro-2H-1,4-oxazapyrrolidone

[0839]

[0840] PdCl₂ (2.11 g, 11.89 mmol, 0.12 equivalents) and Cu(OAc)₂ (4.32 g, 23.78 mmol, 0.25 equivalents) were added to a stirred solution of N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-N-(but-3-en-1-yl)-4-nitrobenzenesulfonamide (40 g, 95.13 mmol, 1.0 equivalent) in DMA (400 mL). The resulting mixture was stirred at 45 °C under an oxygen atmosphere for 40 h. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (4:1) to give a light brown oily substance (2S)-2-[(benzyloxy)methyl]-7-methyl-4-(4-nitrobenzenesulfonyl)-3,5-dihydro-2H-1,4-oxazapyridine (6 g, 15%). LCMS (ES) [MH] - m / z:419.

[0841] Step 4. Synthesis of (2S)-2-[(benzyloxy)methyl]-7-methyl-4-(4-nitrobenzenesulfonyl)-1,4-oxazacycloheptane-6-ol

[0842]

[0843] At 0 °C, 9-{9-boronbicyclo[3.3.1]nonane (2.31 g, 9.56 mmol, 2.0 equivalent) was added dropwise to a stirred solution of (2S)-2-[(benzyloxy)methyl]-7-methyl-4-(4-nitrobenzenesulfonyl)-3,5-dihydro-2H-1,4-oxazapyridine (2.0 g, 4.78 mmol, 1.0 equivalent) in THF (30 mL). The resulting mixture was stirred at room temperature for 12 h. At 0 °C, NaOH (0.96 g, 23.90 mmol, 5.0 equivalent) and H2O2 (2.71 g, 23.90 mmol, 5.0 equivalent, 30%) in H2O (3 mL) were added dropwise. The resulting mixture was stirred at room temperature for another 2 h. The reaction was quenched with Na₂SO₃ (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (2:1), to give (2S)-2-[(benzyloxy)methyl]-7-methyl-4-(4-nitrobenzenesulfonyl)-1,4-oxazetane-6-ol (900 mg, 43%) as a pale yellow oil. LCMS (ES) [M+H] + m / z: 437.

[0844] Step 5. Synthesis of (2S,6R,7S)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-4-(4-nitrobenzenesulfonyl)-1,4-oxazacycloheptane

[0845]

[0846] At room temperature, DMAP (0.03 g, 0.28 mmol, 0.1 equivalent) and TBDMSCl (0.62 g, 4.12 mmol, 1.5 equivalent) were added in portions to a stirred solution of (2S,6R,7S)-2-[(benzyloxy)methyl]-7-methyl-4-(4-nitrobenzenesulfonyl)-1,4-oxazacycloheptane-6-ol (1.2 g, 2.75 mmol, 1.0 equivalent) and imidazole (0.56 g, 8.25 mmol, 3.0 equivalent) in DMF (15 mL). The resulting mixture was stirred at 50 °C for 16 h. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give (2S,6R,7S)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-4-(4-nitrobenzenesulfonyl)-1,4-oxazacycloheptane (1.1 g, 72.6% yield) as a colorless oil. LCMS (ES) [M+H] + m / z: 551.

[0847] Step 6. Synthesis of (2S,6R,7S)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-1,4-oxazacycloheptane

[0848]

[0849] K₂CO₃ (552 mg, 4.00 mmol, 2.00 equivalent) was added to a stirred solution of (2S,6R,7S)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-4-(4-nitrobenzenesulfonyl)-1,4-oxazacycloheptane (1.1 g, 2.00 mmol, 1.0 equivalent) and 4-bromobenzenethiol (755 mg, 4.00 mmol, 2.0 equivalent) in DMF (12 mL). The resulting mixture was stirred at room temperature for 16 h. The crude mixture (2S,6R,7S)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-1,4-oxazacycloheptane (600 mg) was used directly for the next step without further purification. LCMS (ES) [M+H] + m / z: 366.

[0850] Step 7. Synthesis of tert-butyl (2S,6R,7S)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-1,4-oxazetane-4-carboxylate

[0851]

[0852] Di-tert-butyl dicarbonate (537 mg, 2.46 mmol, 1.5 equivalents) was added in portions to a stirred solution of (2S,6R,7S)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-1,4-oxazacycloheptane (600 mg, crude product from the final step) in DMF (10 mL) and H₂O (5 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give (2S,6R,7S)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (600 mg, 78.5% yield) as a colorless oil. LCMS (ES) [M+H] + m / z: 466.

[0853] Step 8. Synthesis of tert-butyl (2S,6R,7S)-2-[(benzyloxy)methyl]-6-hydroxy-7-methyl-1,4-oxazetane-4-carboxylate

[0854]

[0855] TBAF (336 mg, 1.29 mmol, 1.0 equivalent) was added to a stirred solution of (2S,6R,7S)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-7-methyl-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (600 mg, 1.29 mmol, 1.0 equivalent) in THF (10 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (4:1) to give tert-butyl (2S,6R,7S)-2-[(benzyloxy)methyl]-6-hydroxy-7-methyl-1,4-oxazetane-4-carboxylate (340 mg, 75% yield) as a colorless oil. LCMS (ES) [M+H] + m / z: 352.

[0856] Step 9. Synthesis of tert-butyl (2S,6R,7S)-2-[(benzyloxy)methyl]-6-methoxy-7-methyl-1,4-oxazetane-4-carboxylate

[0857]

[0858] Under a nitrogen atmosphere, at 0 °C, tert-butyl NaH (58 mg, 1.45 mmol, 1.5 equivalent, 60% in mineral oil) was added dropwise to a stirred solution of (2S,6R,7S)-2-[(benzyloxy)methyl]-6-hydroxy-7-methyl-1,4-oxazetane-4-carboxylate (340 mg, 0.97 mmol, 1.0 equivalent) in DMF (5 mL). The resulting mixture was stirred at 0 °C for 30 min. Iodomethane (274 mg, 1.93 mmol, 2.0 equivalent) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at room temperature for another 2 h. The reaction was quenched by adding ice water (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give (2S,6R,7S)-2-[(benzyloxy)methyl]-6-methoxy-7-methyl-1,4-oxazetane-4-carboxylic acid tert-butyl ester (300 mg, 84.8% yield) as a colorless oil. LCMS (ES) [M+H] + m / z: 366.

[0859] Step 10. Synthesis of tert-butyl (2S,6R,7S)-2-(hydroxymethyl)-6-methoxy-7-methyl-1,4-oxazacycloheptane-4-carboxylate

[0860]

[0861] At room temperature, tert-butyl (2S,6R,7S)-2-[(benzyloxy)methyl]-6-methoxy-7-methyl-1,4-oxazetane-4-carboxylate (300 mg, 0.82 mmol, 1.0 equivalent) was added to a stirred solution of (2S,6R,7S)-2-[(benzyloxy)methyl]-6-methoxy-7-methyl-1,4-oxazetane-4-carboxylate (300 mg, 0.82 mmol, 1.0 equivalent) in MeOH (10 mL) with Pd / C (50 mg) and palladium hydroxide, Pd 5% on carbon powder, and nominal 50% water (50 mg). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure. This gave tert-butyl (2S,6R,7S)-2-(hydroxymethyl)-6-methoxy-7-methyl-1,4-oxazetane-4-carboxylate (210 mg, 92.9% yield) as a colorless oil. LCMS (ES) [M+H] + m / z: 276.

[0862] Step 11. Synthesis of (2S,6R,7S)-4-(tert-butoxycarbonyl)-6-methoxy-7-methyl-1,4-oxazacycloheptane-2-carboxylic acid

[0863]

[0864] At 0 °C, tert-butyl ester of (2S,6R,7S)-2-(hydroxymethyl)-6-methoxy-7-methyl-1,4-oxazetane-4-carboxylate (240 mg, 0.87 mmol, 1.0 equivalent), NaBr (8.97 mg, 0.09 mmol, 0.1 equivalent), and 2,2,6,6-tetramethylpiperidin-1-ol (13 mg, 0.09 mmol, 0.1 equivalent) in acetone (3 mL) were added in portions to a stirred solution of NaHCO3 (146 mg, 1.74 mmol, 2.0 equivalent) in H2O (1 mL). Trichloro-1,3,5-triazinane-2,4,6-trione (405 mg, 1.74 mmol, 2.0 equivalent) was added in portions to the solution of NaHCO3 (10 mL, aqueous solution). The resulting mixture was stirred at room temperature for 5 h. The resulting mixture was filtered, and the filter cake was washed with H₂O (1 mL). The filtrate was extracted with EtOAc (2 x 15 mL). The aqueous layer was acidified to pH 5 with citric acid. The resulting mixture was extracted with CH₂Cl₂ (4 x 15 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded (2S,6R,7S)-4-(tert-butoxycarbonyl)-6-methoxy-7-methyl-1,4-oxazetane-2-carboxylic acid (170 mg, 67% yield) as a colorless oil, which could be used in the next step without further purification. LCMS (ES) [MH] - m / z: 288.

[0865] Step 12. Synthesis of (2S,6R,7S)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-6-methoxy-7-methyl-1,4-oxazetane-4-carboxy...

Claims

1. A compound of formula (I) (I)， Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein: Ring A is a carbocyclic, aryl, heterocyclic, or heteroaryl ring; R 1 Each can be independently a halogen, oxo, cyano, hydroxyl, -NH2, -COOH, -C1-C6 alkyl, -C1-C6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, -OC1-C6 alkyl, halo-OC1-C6 alkyl, -(C1-C6 alkylene)-carbocyclic or -(C1-C6 alkylene)-heteroaryl; R 2 It is a carbocyclic, aryl, heterocyclic, or heteroaryl ring, wherein each R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace; R 3 It is H, halogen, -OH, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), or -SO2 (C1-C6 alkyl); or R 3 Can be used with R 6 Together, they form a tricyclic ring optionally containing 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the tricyclic ring is optionally connected by 1, 2, 3, or 4 R atoms. 5 replace; Each R 4 It can be halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), or -CN independently; R 5 and R 6 Each of these can be independently a halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkylene)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), -SO2NR 7 R 8 -(C1-C6 alkylene)-carbocyclic, -(C1-C6 alkylene)-heterocyclic, carbocyclic or heterocyclic; Each R 7 and R 8 It is independently H or -C1-C6 alkyl; or R 7 and R 8 Together with the nitrogen atoms they are attached to, they form heterocyclic groups; R 9 It is -OH, -O (C1-C6 alkyl), -O (C1-C6 haloalkyl) or -O (C1-C6 deuterated alkyl); m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3; Where ring A is or And when n is 0, then R 2 no or .

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein ring A is aryl or heteroaryl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein ring A is monocyclic or bicyclic.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It is a single ring, double ring, or triple ring, where R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It is a monocyclic carbocyclic, monocyclic aryl, monocyclic heterocyclic, or monocyclic heteroaryl, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It can be chosen to pass through 1, 2, 3 or 4 Rs. 6 Substituted phenyl groups.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein ring A is phenyl.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the compound has the structure of formula (IA): (I-A), Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein R 3 It's H.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: m is 0 or 1; R 4 It is halogen; and R 6 It is -S (C1-C6 alkyl), -SO (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -SO2N (C1-C6 alkyl), or -SO2NR. 7 R 8 .

10. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: m is 0 or 1; R 4 It is halogen; and R 6 It is a -(C1-C6 alkylene)-heterocyclic ring, wherein the heterocycle is substituted or unsubstituted.

11. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: m is 0 or 1; R 4 It is halogen; and R 6 yes or .

12. The compound according to any one of claims 1 to 4 and 7, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It is a bicyclic carbocyclic ring, a bicyclic aryl ring, a bicyclic heterocyclic ring, or a bicyclic heteroaryl ring, wherein R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace.

13. The compound of claim 12 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It is a fused ring or a spiro ring.

14. The compound according to any one of claims 1 to 4, 7, 12 and 13, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, wherein: R 2 yes , , or ; Each X 1a Independently is -NR 10 -、-O-、-CR 11 R 12 -、-C(O)-、-S-、-S(O)- or -S(O)2-; Each R 10 Independently, it is H, -C1-C6 alkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 or -(C1-C6 alkylene)-heterocyclic; R 11 and R 12 Each is independently selected from H, deuterium, halogen, or -C1-C6 alkyl; and p is 0, 1, 2 or 3.

15. The compound of claim 14 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 yes , , or And p is 0 or 1.

16. The compound according to any one of claims 1 to 4, 7, 12 and 13, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, wherein R 2 yes , , or .

17. The compound according to any one of claims 12 to 15, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the compound has the structure of formula (IB): (I-B); Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form; wherein: R 3 It is H; and R 10 It is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -C1-C6 alkyl-NR 7 R 8 Or -(C1-C6 alkylene)-heterocyclic.

18. The compound according to any one of claims 12 to 17, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein at least one R 4 It is halogen.

19. The compound according to any one of claims 12 to 18, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 10 It is a -C1-C6 alkyl group, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2CH2OCH3, -CH2CH2N(CH3)2 or .

20. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 It is phenyl and R 3 With R 6 One of them, together with ring A, forms a tricycle, wherein the tricycle optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O, and the tricycle optionally passes through 1, 2, 3, or 4 R atoms. 10 replace.

21. The compound according to claim 1 or 20, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the compound has the structure of formula (IC): (I-C); Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein: Ring B is a 5- to 8-membered ring that optionally contains 1, 2, or 3 heteroatoms selected from N, S, or O; p is 0, 1, 2, or 3; and q can be 0, 1, 2 or 3.

22. The compound of claim 21 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: Tricyclic rings containing ring B are , , or ; X 1a Yes -NR 10 -、-O-、-CR 11 R 12 -、-C(O)-、-S-、-S(O)- or -S(O)2-; and R 11 and R 12 Each is independently selected from H, deuterium, halogen, or -C1-C6 alkyl.

23. The compound of claim 22 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein X 1a It is -NH-, -NCH3-, -O-, or -CH2-.

24. The compound according to any one of claims 21 to 23, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the tricyclic ring containing ring B is , , , , , , , or Where m is 0 or 1 and p is 0, 1 or 2.

25. The compound according to any one of claims 21 to 24, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein each R 4 It is independently a halogen, -C1-C3 alkyl, or -CN.

26. The compound according to any one of claims 21 to 25, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein each R 6 Independently, it is a halogen, -OH, -CN, -C1-C3 alkyl, -C1-C3 haloalkyl, -S (C1-C3 alkyl), -SO (C1-C3 alkyl), -SO2 (C1-C3 alkyl), -SO2N (C1-C3 alkyl), -SO2NR 7 R 8 Or 4-6 membered heterocyclic rings.

27. The compound according to any one of claims 21 to 25, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein each R 6 Independently, it is a halogen, -OH, -CN, -SO2CH3, , , or .

28. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the compound has the structure of formula (ID): (I-D); Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein: Ring A is a monocyclic or bicyclic heteroaryl ring; R 3 It is H; and R 10 It is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-O-(C1-C6 alkyl)-OH, -C1-C6 alkyl-NR 7 R 8 Or -(C1-C6 alkylene)-heterocyclic.

29. The compound of claim 28 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein ring A is a 5-membered heteroaryl, a 6-membered heteroaryl, a 5,6-fused heteroaryl, a 6,5-fused heteroaryl, or a 6,6-fused heteroaryl.

30. The compound of claim 28 or 29 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein ring A contains one or two heteroatoms selected from N, S, or O.

31. The compound according to any one of claims 28 to 30, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein ring A is , , or .

32. The compound according to any one of claims 28 to 30, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein ring A is , , or .

33. The compound according to any one of claims 28 to 32, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein each R 4 It is independently a halogen, -C1-C3 alkyl, or -CN.

34. The compound according to any one of claims 28 to 33, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein m is 0 or 1.

35. The compound according to any one of claims 28 to 34, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 10 It is a -C1-C6 alkyl group, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH2CH3, -CH2CH2OCH2CH2OH, -CH2CH2OCH2CH2OCH3, -CH2CH2N(CH3)2 or .

36. The compound according to any one of claims 28 to 35, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 10 It is a -C1-C3 alkyl group.

37. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the compound has the structure of formula (IE): (IE); Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form, wherein: R 2 It is a tricyclic carbocyclic ring, a tricyclic aryl ring, a tricyclic heterocyclic ring, or a tricyclic heteroaryl ring, wherein each R 2 Choose any route via 1, 2, 3, or 4 R's. 6 Replace; and R 3 It's H.

38. The compound of claim 37 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 2 yes or , where R 2 Choose any route via 1, 2, 3, or 4 R's. 6 replace; -DE-is-N(R 10 -C(O)-, -CH2CH2-, -C(O)-O-, or -CH2-O-; W, Y, and Z are each independently CH or N, provided that at most two of W, Y, and Z can be N; X 1a is -NR 13 -, -O-, -CR 11 R 12 -, -C(O)-, -S-, -S(O)- or -S(O)2-; R 10 It is an H or -C1-C6 alkyl group; R 13 It is H, -C1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C 10 Haloalkyl, -C1-C 10 Halogenated alkyl groups -OH, -NR 7 R 8 -C1-C6 alkyl-NR 7 R 8 Heterocyclic or -(C1-C6 alkylene)-heterocyclic; R 11 and R 12 Each is independently selected from H, deuterium, halogen, or -C1-C6 alkyl; s is 1, 2, or 3; and t is 1, 2, or 3; The condition is that the sum of s and t is 2, 3 or 4.

39. The compound of claim 38 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: R 2 yes , , , , , , or , where R 2 Choose either 1 or 2 R 6 replace.

40. The compound of claim 38 or 39 or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, wherein W and Z are both CH or W is CH and Z is N.

41. The compound according to any one of claims 38 to 40, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein X 1a Yes -NR 13 - 42. The compound according to any one of claims 38 to 41, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 13 It is H, -C1-C6 alkyl or 4-6 membered heterocyclic ring.

43. The compound according to any one of claims 38 to 41, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 13 Is it H, methyl or .

44. The compound according to any one of claims 38 to 43, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: a) s is 2 and t is 2; b) s is 1 and t is 3 or s is 3 and t is 1; c) s is 1 and t is 2, or s is 2 and t is 1; or d) s is 1 and t is 1.

45. The compound according to any one of claims 38 to 44, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 2 yes , , , , , , , , , , , , , , or , where R 2 Choose either 1 or 2 R 6 replace.

46. ​​The compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 9 It can be -OH, -OCH3, -OCH2CH3, -OCD3, -OCF3, or -OCHF2.

47. The compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 9 It is -OCH3, -OCH2CH3, -OCD3, -OCF3, or -OCHF2.

48. The compound according to claims 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 9 It is -OH; n is 1; and R 1 It is a halogen or a -C1-C3 alkyl group.

49. The compound according to claims 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein R 9 It is -OH; n is 1; and R 1 It is a halogen or a methyl group.

50. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , or Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form.

51. The compound according to claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , , , , , , or Or its pharmaceutically acceptable salt or deuterated form.

52. The compound according to claim 1 or 17, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is 、 、 , , , , , , , , , , , , , , , , , , , , or Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form.

53. The compound according to claim 1 or 17, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Or its pharmaceutically acceptable salt or deuterated form.

54. The compound according to claim 1 or 21, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , , , , , , , , , , , , , or Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form.

55. The compound according to claim 1 or 21, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , , , , , , , , , , , , , , , , , , , or Or its pharmaceutically acceptable salt or deuterated form.

56. The compound according to claim 1 or 28, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , , , , , , , , , , or Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form.

57. The compound according to claim 1 or 28, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , , , , , , , , , , or Or its pharmaceutically acceptable salt or deuterated form.

58. The compound according to claim 1 or 37, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , , , , , , , , , , , , , , , , , , , or Or its pharmaceutically acceptable salt, stereoisomer, or deuterated form.

59. The compound according to claim 1 or 37, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein said compound is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Or its pharmaceutically acceptable salt or deuterated form.

60. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 58 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier.

61. A method for treating an airway obstructive disease in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 58 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 60.

62. The method of claim 61, wherein the airway obstructive disease 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, allergic pneumonia, pulmonary fibrosis, lung transplant complications, vasculitis and thrombotic conditions of the pulmonary vasculature, pulmonary hypertension; antitussive activity, including treatment of chronic cough associated with airway inflammatory and secretory conditions; 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 caused by respiratory viruses, acute lung injury, or acute respiratory distress syndrome (ARDS).

63. The method of claim 62, wherein the airway obstructive disease is asthma.

64. The method of claim 62, wherein the airway obstructive disease is acute respiratory distress syndrome (ARDS).

65. The method of claim 62, wherein the airway obstructive disease is bronchitis.

66. The method of claim 62, wherein the airway obstructive disease is pulmonary fibrosis.

67. The method of claim 62, wherein the airway obstructive disease is emphysema.

68. The method of claim 62, wherein the airway obstructive disease is cystic fibrosis (CF).

69. The method of claim 62, wherein the airway obstructive disease is bronchiectasis.

70. The method of claim 62, wherein the airway obstructive disease is sarcoidosis.

71. The method of claim 62, wherein the airway obstructive disease is α-1 antitrypsin (A1AT) deficiency.

72. The method of claim 62, wherein the airway obstructive disease is farmer's lung.

73. The method of claim 62, wherein the airway obstructive disease is allergic pneumonia.

74. The method of claim 62, wherein the airway obstructive disease is a lung transplant complication.

75. The method of claim 62, wherein the airway obstructive disease is a vasculitis or thrombotic condition of the pulmonary vasculature.

76. The method of claim 62, wherein the airway obstructive disease is pulmonary hypertension.

77. The method of claim 62, wherein the airway obstructive disease is iatrogenic cough.

78. The method of claim 62, wherein the airway obstructive disease is acute rhinitis.

79. The method of claim 62, wherein the airway obstructive disease is chronic rhinitis.

80. The method of claim 62, wherein the airway obstructive disease is drug-induced rhinitis or vasomotor rhinitis.

81. The method of claim 62, wherein the airway obstructive disease is nasal polyposis.

82. The method of claim 62, wherein the airway obstructive disease is COPD.

83. The method according to claim 63, wherein the asthma is bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, exercise-induced asthma, or drug-induced asthma.

84. The method of claim 83, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

85. The method of claim 65, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, cryptogenic fibrotic alveolitis, idiopathic interstitial pneumonia, or fibrosis resulting from antitumor therapy or chronic infection.

86. The method of claim 69, wherein the bronchiectasis is noncystic fibrotic bronchiectasis (NCFBE).

87. The method of claim 69, wherein the bronchiectasis is associated with cystic fibrosis.

88. The method of claim 76, wherein the pulmonary hypertension is pulmonary arterial hypertension.

89. The method of claim 76, wherein the pulmonary hypertension is pulmonary hypertension caused by left heart disease.

90. The method of claim 76, wherein the pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

91. A method for treating cystic fibrosis in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 60.

92. The method of claim 91, wherein the treatment comprises improving the lung function of the patient compared to the lung function of the patient prior to treatment.

93. The method of claim 92, wherein improving the patient's lung function comprises, compared to corresponding values ​​of the patient before treatment, 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) between 25% and 75% of FVC. (25-75%) ).

94. The method according to claim 92 or 93, wherein the lung function is measured by spirometry.

95. A method for treating bronchiectasis in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 60.

96. The method of claim 95, wherein the bronchiectasis is noncystic fibrotic bronchiectasis (NCFBE).

97. The method of claim 95, wherein the bronchiectasis is associated with cystic fibrosis.

98. The method according to any one of claims 95 to 97, wherein the treatment comprises improving the lung function of the patient compared with the lung function of the patient prior to treatment.

99. The method of claim 98, wherein improving the patient's lung function comprises, compared to corresponding values ​​of the patient before treatment, 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) between 25% and 75% of FVC. (25-75%) ).

100. The method of claim 98 or 99, wherein the lung function is measured by spirometry.

101. The method according to any one of claims 95 to 100, wherein the treatment comprises reducing the rate of lung deterioration compared to the rate of lung deterioration of the patient prior to treatment.

102. The method according to any one of claims 95 to 101, wherein the treatment includes increasing the time before the first lung deterioration compared to an untreated patient.

103. The method according to claim 101 or 102, wherein the lung deterioration is characterized by the patient exhibiting three or more of the following symptoms for at least 48 hours: (1) increased cough; (2) increased sputum volume or altered sputum consistency; (3) increased purulent sputum; (4) worsening dyspnea and / or decreased exercise tolerance; (5) fatigue and / or lethargy; (6) hemoptysis.

104. A method for treating chronic sinusitis (CRS) in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 60.

105. The method of claim 104, wherein the chronic sinusitis is chronic sinusitis without nasal polyps (CRSsNP).

106. The method of claim 104, wherein the chronic sinusitis is chronic sinusitis with nasal polyps (CRSwNP).

107. The method according to any one of claims 104 to 106, wherein the chronic sinusitis is refractory chronic sinusitis.

108. The method according to any one of claims 104 to 107, wherein the treatment comprises alleviating one or more symptoms of CRS, reducing the severity of the one or more symptoms, delaying the onset of the one or more symptoms, or eliminating the one or more symptoms.

109. The method of claim 108, wherein one or more symptoms of CRS are nasal congestion; nasal obstruction; nasal discharge; postnasal drip; facial pressure; facial pain; facial fullness; decreased sense of smell; depression; mucosal edema; mucopurulent discharge; middle nasal meatus obstruction; changes in the mucosa of the ostiomeatal complex and sinuses; or nasal discharge.

110. A method for treating hidradenitis suppurativa (HS) in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 60.

111. The method of claim 110, wherein the suppurative hidradenitis (HS) is Hurley stage I.

112. The method of claim 110, wherein the suppurative hidradenitis (HS) is Hurley stage II.

113. The method of claim 110, wherein the hidradenitis suppurativa (HS) is Hurley stage III.

114. A method for treating cancer in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 60.

115. The method of claim 114, wherein the cancer is a metastatic cancer.

116. The method of claim 115, wherein the metastatic cancer is a breast-to-lung metastatic cancer.

117. The method of claim 115, wherein the metastatic cancer includes breast cancer metastasized to the brain, bone, pancreas, lymph nodes, or liver.

118. The method of claim 115, wherein the metastatic cancer includes bone cancer metastasized to the lungs.

119. The method of claim 115, wherein the metastatic cancer includes colorectal cancer metastasized to the peritoneum, pancreas, stomach, lung, liver, kidney, or spleen.

120. The method of claim 115, wherein the metastatic cancer includes gastric cancer metastasized to the mesentery, spleen, pancreas, lung, liver, adrenal gland, or ovary.

121. The method of claim 115, wherein the metastatic cancer includes liver cancer metastasized to the intestine, spleen, pancreas, stomach, lung, or kidney.

122. The method of claim 115, wherein the metastatic cancer includes lymphoma metastasized to the kidney, ovary, liver, bladder, or spleen.

123. A method for treating lupus nephritis in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 60.

124. A method for treating rheumatoid arthritis in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 60.

125. A method for treating inflammatory bowel disease (IBD) in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 60.

126. The method of claim 125, wherein the inflammatory bowel disease (IBD) is Crohn's disease.

127. The method of claim 125, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

128. A method for treating antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in a patient in need, the method comprising administering to the patient an effective amount of the compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or the composition according to claim 60.

129. The method of claim 128, wherein the ANCA-related disease is granulomatous disease with polyangiitis (GPA).

130. The method of claim 128, wherein the ANCA-related disease is microscopic polyangiitis (MPA).

131. A method for treating a disease in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 60, wherein the disease is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpassuia), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcer, Duchenne muscular dystrophy, obstructive bronchiolitis, atopic dermatitis, pyoderma gangrenosa, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatitis, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or ventilator-induced lung injury.

132. A method for treating heart failure in a patient in need, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition according to claim 60.

133. The method of claim 132, wherein the heart failure is heart failure with reduced ejection fraction.

134. The method of claim 132, wherein the heart failure is heart failure with preserved ejection fraction.

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