(2S)-n-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors

Abstract

To provide compounds that inhibit dipeptidyl peptidase 1 (DPP1) activity.SOLUTION: The present disclosure provides certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds (including pharmaceutically acceptable salts thereof) that inhibit DPP1 activity, their utility in treating and / or preventing clinical conditions including respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), their use in therapy, pharmaceutical compositions containing them, and processes for preparing such compounds.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The technical field relates to certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds (including pharmaceutically acceptable salts thereof) that inhibit dipeptidyl peptidase 1 (DPP1; EC 3.4.14.1) activity, their utility in the treatment and / or prevention of clinical conditions, including respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), their use in therapy, pharmaceutical compositions containing them, and methods for making the compounds. [Background technology]

[0002] Dipeptidyl peptidase 1 (DPP1; EC3.4.14.1), also known as cathepsin C, is a lysosomal cysteine ​​protease with a molecular weight of 200 kDa that belongs to the papain family. DPP1 was first discovered by Gutman and Fruton in 1948 (Non-Patent Document 1); however, the cDNA for the human enzyme was not described until 1995 (Non-Patent Document 2). DPP1 is the only member of the papain family that functions as a tetramer consisting of four identical subunits. Each subunit consists of an N-terminal fragment, a heavy chain, and a light chain (Non-Patent Document 3).

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

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

[0005] Neutrophils play a crucial role in host defense against invading pathogens. They are produced in the bone marrow and are fully mature when released into the circulatory system to serve as the first line of cellular defense. Proinflammatory mediators and chemoattractants activate neutrophils, drawing them to the site of infection, where they act to engulf bacteria by phagocytosis and attack them with an arsenal of antibacterial compounds using both oxidative and nonoxidative attack methods. Neutrophil elastase, a potent serine protease, is one of these antibacterial compounds apparently involved in bacterial destruction. It is released into the phagolysosome that surrounds microorganisms and begins their destruction. Neutrophil elastase can attack the outer membrane protein OmpA of Gram-negative bacteria, helping to directly kill the pathogen by disrupting its membrane, while simultaneously allowing other antibacterial compounds to enter the pathogen. In addition, neutrophil elastase may aid in the processing of other antibacterial compounds, converting them from an inactive propeptide to an active state, as for cathelicidin.

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

[0007] There is strong evidence linking tryptase and chymase to many mast cell-mediated allergic, immunological, and inflammatory diseases. The fact that neutrophil elastase, cathepsin G, and proteinase 3 also appear to play important roles in these diseases indicates that DPPIs are valid therapeutic targets due to their central role in the activation of these proteases (Non-Patent Document 4; Non-Patent Document 5).

[0008] Patent Document 1 relates to certain nitrile derivatives and their use as DPP1 inhibitors.

[0009] WO 02 / 04999 relates to peptidyl nitriles and their use as DPP1 inhibitors.

[0010] WO 02 / 04999 relates to α-aminoamidonitriles and their use as DPP1 inhibitors.

[0011] Patent document 4 relates to peptidyl nitrile compounds and their use as DPP1 inhibitors.

[0012] Patent document 5 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamides and their use as DPP1 inhibitors.

[0013] US Pat. No. 5,629,992 and US Pat. No. 5,629,992 relate to β-aminoamidonitriles having inhibitory activity against cysteine ​​proteases. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] International Publication No. 2004 / 110988 [Patent Document 2] International Publication No. 2009 / 074829 [Patent Document 3] International Publication No. 2010 / 128324 [Patent Document 4] International Publication No. 2012 / 119941 [Patent Document 5] International Publication No. 2013 / 041497 [Patent Document 6] International Publication No. 2001 / 096285 [Patent Document 7] International Publication No. 2003 / 048123 [Non-patent literature]

[0015] [Non-Patent Document 1] J Biol Chem, 174, 851-858 [Non-patent document 2] Paris et al. 1995, FEBS Lett, 369, 326-330 [Non-patent document 3] Dolenc et al. 1995, J Biol Chem, 270, 21626-21631 [Non-patent document 4] Adkison et al. 2002, J Clin Invest, 109, 363-271 [Non-patent document 5] Pham et al. 2004, J Immunol, 173, 7277-7281 Summary of the Invention [Problem to be solved by the invention]

[0016] Amidonitrile compounds having a β-amino acid in the form of the described (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compound have never been disclosed. The present inventors have now found that such compounds have potent DPP1 activity and / or a desirable pharmacological activity profile (e.g., a reduced risk of binding to elastin-rich tissues such as the aorta).

[0017] overview Provided are compounds that are inhibitors of dipeptidyl peptidase 1 (DPP1), their use as pharmaceuticals, pharmaceutical compositions containing the compounds, and synthetic routes for the preparation of the compounds. [Means for solving the problem]

[0018] According to a first embodiment, a compound of formula (I): [ka] [In the formula, R 1 teeth, [ka] and; R 2 are hydrogen, F, Cl, Br, OSOC 1-3 Alkyl or C 1-3 alkyl; R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2 or SO2NR 4 R 5 (where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring); or R 1 teeth, [ka] Selected from; X is selected from O, S, or CF2; Y is selected from O or S; Q is selected from CH or N; R 6 is C 1-3 alkyl (wherein the C 1-3 The alkyl may be substituted by one, two or three F, and may also be substituted by OH, OC 1-3 Alkyl, N(C 1-3 alkyl), optionally substituted by one substituent selected from 2, cyclopropyl, or tetrahydropyran; R 7 is selected from hydrogen, F, Cl or CH3. or a pharmaceutically acceptable salt thereof.

[0019] The described compounds are inhibitors of DPP1. Thus, the described compounds can be used as medicines, particularly for disorders, diseases or conditions that respond to the inhibition of DPP1, more particularly respiratory diseases (e.g., COPD and asthma).

[0020] In another embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (wherein the stereochemistry is not defined, e.g., a racemate or a mixture of diastereomers).

[0021] In another aspect, there is provided a pharmaceutical formulation comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I), and a pharmaceutically acceptable diluent, excipient, and / or inert carrier.

[0022] In a further embodiment, there is provided a pharmaceutical formulation for treating a condition in which inhibition of dipeptidyl peptidase 1 (DPP1) is beneficial, comprising a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I).

[0023] In a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for use in the therapy (particularly for the prevention or treatment) of a respiratory disease in a mammal (particularly a human).

[0024] In a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for use in the therapy (particularly for the prevention or treatment) of asthma in a mammal (particularly a human).

[0025] In a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for use in the therapy (particularly for the prevention or treatment) of COPD in a mammal (particularly a human).

[0026] In a further embodiment, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for the manufacture of a medicament for the treatment and prevention of respiratory diseases.

[0027] In a further embodiment, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for the manufacture of a medicament for the treatment and prevention of asthma.

[0028] In a further embodiment, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for the manufacture of a medicament for the treatment and prevention of COPD.

[0029] In yet a further embodiment, administration of a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) causes a decrease in the level of DPP1 in a mammal (particularly a human).

[0030] In yet further embodiments, administration of a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) causes a decrease in the levels of DPP1, neutrophil elastase, cathepsin G, and proteinase 3 in a mammal (particularly a human).

[0031] In yet a further embodiment, administration of a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) causes a decrease in DPP1 activity in a mammal (particularly a human).

[0032] In yet a further embodiment, administration of a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) causes a decrease in DPP1 activity, neutrophil elastase activity, cathepsin G activity, and proteinase 3 activity in a mammal (particularly a human).

[0033] In accordance with another aspect, there is provided a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I), and intermediates used in said process.

[0034] According to another embodiment, a compound of formula (XXIV): [ka] [In the formula, R 8 is C 1-4 alkyl or aryl, wherein the aryl is selected from R 1 may be substituted by); R 9 and R 10 together with the nitrogen atom to which they are attached represent a 5- to 7-membered saturated or unsaturated ring optionally containing one additional heteroatom which is oxygen, nitrogen or sulfur, wherein the ring is optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; or R 9 and R 10 together with the nitrogen atom to which they are attached, represent a 6- to 10-membered bridged bicyclic ring optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. or a pharmaceutically acceptable salt thereof.

[0035] In a still further embodiment, there is provided a compound of formula (XXIV) or a pharmaceutically acceptable salt of a compound of formula (XXIV) for use in the therapy (particularly for the prevention or treatment) of a respiratory disease in a mammal (particularly a human).

[0036] The compounds of formula (I) exemplified herein exhibit an IC value for DPP1 in an enzyme activity assay (e.g., Test A1 or Test A2 below). 50 is less than 100 nmol / L. Compounds of formula (I) also exhibit a promising pharmacological profile by separating desirable and undesirable effects in vivo. [Brief explanation of the drawings]

[0037] [Figure 1]FIG. 1 shows the powder X-ray diffraction pattern of Example 2: (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, Form A. [Figure 2] FIG. 2 shows the powder X-ray diffraction pattern of Example 2: (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, Form B. [Figure 3] FIG. 3 shows the powder X-ray diffraction pattern of Example 2: (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, Form C. [Figure 4] FIG. 4 shows the powder X-ray diffraction pattern of Example 2: (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide xinafoate, Form A. [Figure 5] FIG. 5 shows the powder X-ray diffraction pattern of Example 2: (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide R-mandelate, Form A. DETAILED DESCRIPTION OF THE INVENTION

[0038] Detailed Description This detailed description is intended to acquaint those skilled in the art with the invention, its spirit and practical application, so that they may readily utilize the invention. While this description and its specific examples illustrate embodiments of the invention, they are given for purposes of illustration only. Accordingly, the invention is not limited to the exemplary embodiments set forth herein. In addition, various features of the invention that are, for clarity, described in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment may also be combined to form subcombinations thereof.

[0039] Set forth below are definitions of various terms used in the specification and claims to describe the invention.

[0040] For the avoidance of doubt, wherever a group is qualified herein by the statement "as defined above," it will be understood that this group encompasses the broadest definition first stated and each and every alternative definition of that group.

[0041] For the avoidance of doubt, it is to be understood that in this specification "C 1-3 " means a carbon group having 1, 2 or 3 carbon atoms.

[0042] In this specification, unless otherwise stated, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but is not limited to, methyl, ethyl, n-propyl, or i-propyl.

[0043] As used herein, unless otherwise specified, the term "pharmaceutically acceptable" is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as appropriate for use in accordance with sound medical judgment. Generally, a pharmaceutically acceptable moiety has one or more benefits that outweigh any adverse effects that the moiety may have. Adverse effects can include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0044] R 1 ~R 7 , X, Y and Q are as defined in formula (I).

[0045] In one embodiment, R 1 teeth, [ka] and; R 2 are hydrogen, F, Cl, Br, OSOC 1-3 Alkyl or C 1-3 alkyl; R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine ring, a pyrrolidine ring, or a piperidine ring.

[0046] In a further embodiment, R 1 teeth, [ka] and; R 2 is hydrogen, F, Cl or C 1-3 alkyl; R 3 is hydrogen, F, Cl, CN or SO2C 1-3 alkyl.

[0047] In still further embodiments, R 1 teeth, [ka] and; R 2 is hydrogen, F or C1-3 alkyl; R 3 is selected from hydrogen, F or CN.

[0048] In still further embodiments, R 1 teeth, [ka] Selected from; X is selected from O, S, or CF2; Y is selected from O or S; Q is selected from CH or N; R 6 is C 1-3 alkyl (wherein the C 1-3 The alkyl may be substituted by one, two or three F, and may also be substituted by OH, OC 1-3 Alkyl, N(C 1-3 alkyl), optionally substituted by one substituent selected from 2, cyclopropyl, or tetrahydropyran; R 7 is selected from hydrogen, F, Cl or CH3.

[0049] In still further embodiments, R 1 teeth, [ka] Selected from; X is selected from O, S, or CF2; Y is selected from O or S; R 6 is C 1-3 alkyl (wherein the C 1-3 The alkyl may be substituted by one, two or three F, and may also be substituted by OH, OC 1-3 Alkyl, N(C 1-3 alkyl), optionally substituted by one substituent selected from 2, cyclopropyl, or tetrahydropyran; R 7is selected from hydrogen, F, Cl or CH3.

[0050] In still further embodiments, R 1 teeth, [ka] Selected from; X is selected from O, S, or CF2; R 6 is C 1-3 alkyl (wherein the C 1-3 The alkyl may be substituted by 1, 2 or 3 F; R 7 is selected from hydrogen, F, Cl or CH3.

[0051] In still further embodiments, R 1 teeth, [ka] Selected from; X is O; R 6 is C 1-3 alkyl (wherein the C 1-3 The alkyl may be substituted by 1, 2 or 3 F; R 7 is hydrogen.

[0052] In one embodiment, R 2 are hydrogen, F, Cl, Br, OSOC 1-3 Alkyl or C 1-3 alkyl.

[0053] In a further embodiment, R 2 is hydrogen, F, Cl or C 1-3 alkyl.

[0054] In still further embodiments, R 2 is hydrogen, F or C 1-3 alkyl.

[0055] In one embodiment, R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine ring, a pyrrolidine ring, or a piperidine ring.

[0056] In a further embodiment, R 3 is hydrogen, F, Cl, CN or SO2C 1-3 alkyl.

[0057] In still further embodiments, R 3 is selected from hydrogen, F or CN.

[0058] In one embodiment, R 6 is C 1-3 alkyl, wherein the C 1-3 The alkyl may be substituted by one, two or three F, and may also be substituted by OH, OC 1-3 Alkyl, N(C 1-3 It may be substituted by one substituent selected from alkyl), cyclopropyl or tetrahydropyran.

[0059] In a further embodiment, R 6 is C 1-3 alkyl, wherein the C 1-3 The alkyl may be substituted by 1, 2 or 3 F.

[0060] In still further embodiments, R 6 is selected from methyl and ethyl.

[0061] In still further embodiments, R 6 is methyl.

[0062] In one embodiment, R 7 is selected from hydrogen, F, Cl or CH3.

[0063] In a further embodiment, R 7 is hydrogen.

[0064] One or more of the above embodiments may be combined to provide more specific embodiments of the present invention.

[0065] In one embodiment, the compound of Formula (I) is selected from: (2S)—N-[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, 4'-[(2S)-2-cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate, (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4'-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-(3′,4′-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,

[0066] (2S)—N-[(1S)-1-cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-2-(4′-carbamoyl-3′-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-2-[4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-2-[4'-(azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-(4′-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-2-[4-(1,3-benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, or (2S)—N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, and pharmaceutically acceptable salts thereof.

[0067] It should be noted that any one of these specific compounds may be disclaimed from the embodiments of the invention described herein.

[0068] Another embodiment is a product obtained by any of the processes or examples described herein.

[0069] Pharmacological properties The compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceutical preparations, in particular as inhibitors of dipeptidyl peptidase 1 activity, and may thus be used in the treatment of obstructive diseases of the airways, including asthma of all severity, both intermittent and persistent, including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced (aspirin-induced and NSAID-induced) asthma and dust-induced asthma, as well as other causes of airway hyperresponsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious bronchitis and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; α1-antitrypsin deficiency; farmer's lung and related diseases; hypersensitivity pneumonitis; idiopathic fibrosing alveolitis, idiopathic interstitial pneumonia, antineoplastic diseases. pulmonary fibrosis, including fibrosis complicating drug therapy and chronic infections (including tuberculosis and aspergillosis) and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the pulmonary vasculature and pulmonary hypertension; antitussive activity, including the treatment of chronic cough associated with inflammatory and secretory states of the airways, and iatrogenic cough; acute and chronic rhinitis, including rhinitis medicamentosa and vasomotor rhinitis; perennial and seasonal allergic rhinitis, including rhinitis neuropathica (hay fever); nasal polyposis; colds and acute viral infections, including infections with respiratory syncytial virus (RSV), influenza, coronaviruses (including SARS) and adenoviruses, acute lung injury, acute respiratory distress syndrome (ARDS), and exacerbations of each of the above inspiratory disease conditions, in particular exacerbations of any type of asthma or COPD.

[0070] Thus, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for use in therapy.

[0071] In a further aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above in the manufacture of a medicament for use in therapy.

[0072] In the context of this specification, the term "treatment" also encompasses "prophylaxis", unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" shall be construed accordingly.

[0073] Prevention is thought to be particularly relevant to the treatment of people who have suffered from a previous episode of the disease or condition in question, or who are otherwise considered to be at high risk of the disease or condition in question. People at risk of developing a particular disease or condition generally include people who have a family history of the disease or condition, or people who have been identified by genetic testing or screening as being particularly susceptible to the disease or condition.

[0074] In particular, the compounds of the present invention (including pharmaceutically acceptable salts) can be used to treat asthma {e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, especially chronic asthma or refractory asthma (e.g., late-onset asthma or airway hyperresponsiveness)}, chronic obstructive pulmonary disease (COPD) or allergic rhinitis.

[0075] There is also provided a method of treating or reducing the risk of an obstructive airways disease or condition (e.g., asthma or COPD), which method comprises administering to a patient in need of such treatment or reduction a therapeutically effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0076] In a further aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above in the manufacture of a medicament for the treatment of COPD.

[0077] In a further aspect there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above in the manufacture of a medicament for the treatment of asthma.

[0078] In a further aspect there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above in the manufacture of a medicament for the treatment of allergic rhinitis.

[0079] In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for use in the treatment of allergic rhinitis.

[0080] In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for use in the treatment of COPD.

[0081] In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for use in the treatment of asthma.

[0082] Combination Therapy The compounds of formula (I) or pharmaceutically acceptable salts thereof may also be administered in combination with other compounds used in the treatment of the above conditions.

[0083] The present invention also relates to combination therapy in which a compound of the present invention, or a pharmaceutically acceptable salt thereof, is administered simultaneously, sequentially, or in admixture with a second active ingredient for the treatment of one or more of the above conditions. Such combinations may be used in conjunction with one or more additional active ingredients.

[0084] The present invention further relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with a glucocorticoid receptor agonist (steroidal or non-steroidal), such as triamcinolone, triamcinolone acetonide, prednisone, mometasone furoate, lotebredonol etabonate, fluticasone propionate, fluticasone furoate, fluocinolone acetonide, dexamethasone cipesilate, desisobutyryl ciclesonide, clobetasol propionate, ciclesonide, butixocort propionate, budesonide, benzyl dipropionate, benzodiazepine, benzophenone, benzophenone dipropionate ... in combination with clomethasone, alclometasone dipropionate, 2,2,2-trifluoro-N-[(1S,2R)-2-[1-(4-fluorophenyl)indazol-5-yl]oxy-2-(3-methoxyphenyl)-1-methyl-ethyl]acetamide, or 3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]benzamide.

[0085] The present invention further relates to a combination of the compound of the present invention or a pharmaceutically acceptable salt thereof with a p38 antagonist, for example, PH797804 (3-[3-bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-yl]-4,N-dimethyl-benzamide), losmapimod, PF03715455 (1-[5-tert-butyl-2-(3-chloro-4-hydroxyphenyl)pyrazole-3 -yl]-3-[[2-[[3-[2-(2-hydroxyethylsulfanyl)phenyl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl]phenyl]methyl]urea) or N-cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-pyrazin-1-yl]benzamide.

[0086] The present invention further relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with a phosphodiesterase (PDE) inhibitor, such as methylxanthanine (including theophylline and aminophylline), or a selective PDE isoenzyme inhibitor (including PDE4 inhibitors, or inhibitors of the isoform PDE4D), such as tetomilast, roflumilast, oglemilast, ibudilast, GPD-1116 (3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4-one), lonomimilast, NVP ABE 171 (4-[8-(2,1,3-benzoxadiazol-5-yl)-1,7-naphthyridin-6-yl]benzoic acid), RPL554 (2-[(2E)-9,10-dimethoxy-4-oxo-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[6,1-a]isoquinolin-3-yl]ethyl urea), CHF5480 ([(Z)-2-(3,5-dichloro-4-pyridyl)-1-(3,4-dimethoxyphenyl)vinyl](2S)-2-(4-isobutylphenyl)propanoate), or GSK256066 (6-[3-(dimethylcarbamoyl)phenyl]sulfonyl-4-(3-methoxyanilino)-8-methyl-quinoline-3-carboxamide).

[0087] The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function, such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 or CCR11 (for the CC family), e.g., a CCR1, CCR2B or CCR5 receptor antagonist; CXCR1, CXCR2, CXCR3, CXCR4 or CXCR5 (for the CXC family), e.g., a CXCR2 or CXCR3 receptor antagonist; or CX3CR1 for the C-X3-C family. For example, the present invention relates to a method for treating a pulmonary arthritis with a compound of the present invention, such as PS-031291 (pyrrolidine-1,2-dicarboxylic acid 2-[(4-chloro-benzyl)-methyl-amide] 1-[(4-trifluoromethyl-phenyl)-amide]), CCX-354 (1-[4-(4-chloro-3-methoxy-phenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone), vicriviroc, maraviroc, cenicriviroc, navarixin (2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1-(5-methyl-2-furyl)propyl]amino]-3,4-dioxo-cyclobuten-1-yl]amino]benzamide), SB656933 (1-(2-chloro-3-fluoro-phenyl)-3-( 4-chloro-2-hydroxy-3-piperazin-1-ylsulfonyl-phenyl)urea), N-[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[(1R,2S)-2,3-dihydroxy-1-methyl-propoxy]pyrimidin-4-yl]azetidine-1-sulfonamide, N-[6-[(1R,2S)-2,3-dihydroxy-1-methyl-propoxy]-2-[(4-fluorophenyl)methylsulfanyl]pyrimidin-4-yl]-3-methyl-azetidine-1-sulfonamide or N-[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(1R,2R)-2,3-dihydroxy-1-methyl-propyl]amino]pyrimidin-4-yl]azetidine-1-sulfonamide.

[0088] The present invention further relates to a method for treating leukotriene biosynthesis by the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor, or a 5-lipoxygenase-activating protein (FLAP) antagonist, such as TA270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone), PF-4191834 (2H-pyran-4-carbohydrate), or a leukotriene biosynthesis inhibitor, such as TA270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone), or a leukotriene biosynthesis inhibitor, such as PF-4191834 (2H-pyran-4-carbohydrate ... oxamide, tetrahydro-4-[3-[[4-(1-methyl-1H-pyrazol-5-yl)phenyl]thio]phenyl]-), cetileuton, CMI977 (1-[4-[(2S,5S)-5-[(4-fluorophenoxy)methyl]tetrahydrofuran-2-yl]but-3-ynyl]-1-hydroxy-urea), fiboflavon (3-[3-tert-butylsulfanyl-1-[[4-(6-ethoxy -3-pyridyl)phenyl]methyl]-5-[(5-methyl-2-pyridyl)methoxy]indol-2-yl]-2,2-dimethyl-propanoic acid), GSK2190915 (1H-indole-2-propanoic acid, 3-[(1,1-dimethylethyl)thio]-1-[[4-(6-methoxy-3-pyridinyl)phenyl]methyl]-α,α-dimethyl-5-[(2-pyridinyl)methoxy]-), licofelone, quiflapon (3-[3-t ert-butylsulfanyl-1-[(4-chlorophenyl)methyl]-5-(2-quinolylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid), veriflavone ((2R)-2-cyclopentyl-2-[4-(2-quinolylmethoxy)phenyl]acetic acid), ABT080 (4,4-bis[4-(2-quinolylmethoxy)phenyl]pentanoic acid), zileuton, zafirlukast or montelukast.

[0089] The present invention further relates to a method for treating rheumatoid arthritis (rheumatoid arthritis) by the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a CRTh2 antagonist or a DP2 antagonist, such as ACT129968 (2-[2-[(5-acetyl-2-methoxy-phenyl)methylsulfanyl]-5-fluoro-benzimidazol-1-yl]acetic acid), AMG853 (2-[4-[4-(tert-butylcarbamoyl)-2-[(2-chloro-4-cyclopropyl-phenyl)sulfonylamino]phenoxy]-5-chloro-2-fluoro-phenyl]acetic acid), AM211 (2-[3-[2-[[benzylcarbamoyl(ethyl)amino]methyl] 2-[4-(trifluoromethyl)phenyl]-4-methoxy-phenyl]acetic acid), 2-[4-acetamido-3-(4-chlorophenyl)sulfanyl-2-methyl-indol-1-yl]acetic acid, (2S)-2-[4-chloro-2-(2-chloro-4-ethylsulfonyl-phenoxy)phenoxy]propanoic acid, 2-[4-chloro-2-[2-fluoro-4-(4-fluorophenyl)sulfonyl-phenyl]phenoxy]acetic acid, or (2S)-2-[2-[3-chloro-4-(2,2-dimethylpyrrolidine-1-carbonyl)phenyl]-4-fluoro-phenoxy]propanoic acid.

[0090] The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a myeloperoxidase antagonist, such as resveratrol, piceatannol, or 1-(2-isopropoxyethyl)-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-4-one.

[0091] In a further aspect of the invention, a compound of the invention or a pharmaceutically acceptable salt thereof is combined with a) Toll-like receptor agonists (e.g., TLR7 agonists or TLR9 agonists); b) adenosine antagonists; c) glucocorticoid receptor agonists (steroidal or nonsteroidal); d) p38 antagonists; e) PDE4 antagonists; f) a chemokine receptor function modulator (e.g., a CCR1 receptor antagonist, a CCR2B receptor antagonist, a CCR5 receptor antagonist, a CXCR2 receptor antagonist, or a CXCR3 receptor antagonist); or g) CRTh2 antagonist There is provided a pharmaceutical composition (e.g., for use as a medicament for the treatment of one of the diseases or conditions described herein, such as COPD, asthma, or allergic rhinitis) comprising at least one active ingredient selected from:

[0092] In one embodiment, the compound of the present invention or its pharmaceutically acceptable salt is administered simultaneously or successively with one or more additional active ingredients selected from those defined above.For example, the compound of the present invention or its pharmaceutically acceptable salt can be administered simultaneously or successively with an additional pharmaceutical composition for use as a medicament for treating one of the above-mentioned diseases or conditions, such as respiratory conditions (e.g., COPD, asthma, or allergic rhinitis).This additional pharmaceutical composition can be a medicament (e.g., an existing standard care medication) that the patient may already be prescribed, and can itself be a composition containing one or more additional active ingredients selected from those defined above.

[0093] Pharmaceutical Composition For the above therapeutic uses, the dosage will vary depending on the compound used, the mode of administration, the desired treatment, and the indicated disease. For example, the daily dose of the compounds of the present invention, when inhaled, can range from 0.05 μg per kg body weight (μg / kg) to 100 μg per kg body weight (μg / kg). Alternatively, when the compound is administered orally, the daily dose of the compounds of the present invention can range from 0.01 μg per kg body weight (μg / kg) to 100 mg per kg body weight (mg / kg).

[0094] The compound of formula (I) or its pharmaceutically acceptable salt may be used alone, but is generally administered in the form of a pharmaceutical composition in which the compound of formula (I) / salt (active ingredient) is associated with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 2nd Ed. 2002.

[0095] Depending on the mode of administration, the pharmaceutical composition preferably contains 0.05 to 99% w (wt %) of the active ingredient, more preferably 0.05 to 80% w, even more preferably 0.10 to 70% w, and even more preferably 0.10 to 50% w (all wt % based on the total composition).

[0096] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0097] The present invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0098] The pharmaceutical compositions may be administered topically (e.g., to the skin, or to the lungs and / or airways), for example, in the form of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powders (e.g., formulations in inhalers known as Turbuhaler®); or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders or granules; or parenterally in the form of sterile solutions, suspensions or emulsions for injection (including intravenously, subcutaneously, intramuscularly, intravascularly or infusion); or rectally in the form of suppositories.

[0099] For oral administration, the compound of the present invention can be mixed with adjuvants, diluents or carriers, such as lactose, saccharose, sorbitol, mannitol; starches, such as potato starch, corn starch or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; disintegrants, such as cellulose derivatives, and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets.If coated tablets are required, the cores prepared as described above can be coated with a suitable polymer dissolved or dispersed in water or a readily volatile organic solvent.Alternatively, tablets can be coated with a concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talc and titanium dioxide.

[0100] For the preparation of soft gelatin capsules, the compound of the present invention can be mixed with, for example, vegetable oil or polyethylene glycol.Hard gelatin capsules can contain granules of the compound using pharmaceutical excipients such as those described above for tablets.Liquid or semi-solid formulations of the compound of the present invention can also be filled into hard gelatin capsules.

[0101] Oral liquid preparations may be in the form of syrups, solutions, or suspensions. Liquid preparations may contain, for example, the compound of the present invention, the balance of sugar, and a mixture of ethanol, water, glycerol, and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, saccharin, and / or carboxymethylcellulose as thickeners. In addition, other additives known to those skilled in the art may be used when preparing oral preparations.

[0102] Compound production The present invention further provides a process for preparing compounds of formula (I) as defined above.

[0103] General manufacturing method Those skilled in the art will recognize that the compounds of the present invention can be prepared in a variety of ways in a known manner. The following routes are merely illustrative of some of the methods that can be used to synthesize compounds of formula (I).

[0104] The present invention further provides a method for preparing a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (II): [ka] [In the formula, R 1 is as defined in formula (I). with a compound represented by formula (III): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl). and optionally thereafter reacting a compound of formula (I) with a compound of formula (II) - converting a compound of formula (I) into another compound of formula (I); - removing the protecting group; - Formation of pharmaceutically acceptable salts The method may include performing one or more of the following:

[0105] The process is conveniently carried out in the presence of a base such as DiPEA or TEA and one or more activating agents such as EDCI, 2-pyridinol-1-oxide or T3P. The reaction is conveniently carried out in the presence of an organic solvent such as DMF or DCM at a temperature in the range, for example, 20° C. to 100° C., especially at ambient temperature (25° C.).

[0106] The compound of formula (II) may be a compound of formula (IV): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl). can be prepared by reacting a compound of the formula: with a suitable reagent to remove the protecting group PG. An example of a suitable reagent is formic acid.

[0107] Compounds of formula (IV) can be prepared by reacting compounds of formula (V): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl), and Hal represents a halogen (e.g., I or Br). with a compound represented by formula (VI): [ka] [In the formula, R 1 is as defined in formula (I). or an ester thereof. The reaction is conveniently carried out at a temperature in the range of, for example, 20° C. to 100° C., especially 75° C., in a solvent such as a dioxane / water mixture or an ACN / water mixture.

[0108] The compound of formula (V) may be represented by formula (VII): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl), and Hal represents a halogen (e.g., I or Br). can be prepared from a compound of the formula:

[0109] Compounds of formula (VII) can be prepared by the conversion of compounds of formula (VIII): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl), and Hal represents a halogen (e.g., I or Br). with aqueous ammonia. The reaction is conveniently carried out in an organic solvent such as DMF at a temperature in the range of -20°C to 100°C, for example 0°C.

[0110] Compounds of formula (VIII) are commercially available, known in the literature (eg Tetrahedron: Asymmetry, 1998, 9, 503), or can be prepared using known techniques.

[0111] Further, there is also provided a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, using standard literature procedures for the dehydration of amides, for example at a temperature in the range of -20°C to 100°C, for example at 25°C, in a solvent such as DCM or DMF, with or without a base such as DiPEA, to give a compound of formula (IX): [ka] [In the formula, R 1 is as defined above, and PG represents a protecting group (e.g., tert-butoxycarbonyl). with a reagent such as Burgess's reagent or T3P, followed by reaction with a reagent suitable for removing the protecting group PG. An example of a suitable reagent is formic acid.

[0112] Compounds of formula (IX) can be prepared by reaction of compounds of formula (X): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl). with a compound of formula (XI): [ka] [In the formula, R 1 is as defined in formula (I). The reaction is conveniently carried out at a temperature in the range of, for example, 20° C. to 100° C., especially at 80° C., in a solvent such as a dioxane / water mixture or an ACN / water mixture.

[0113] Compounds of formula (X) can be prepared by reacting 1,1'-bis(diphenylphosphino)ferrocene or 1,1-bis(di-tert-butylphosphino)ferrocene with a suitable salt such as potassium acetate in a solvent such as DMSO at a temperature in the range of 60°C to 100°C, for example at 85°C, with or without palladium dichloride in the presence of a suitable catalyst such as Pd(dppf)Cl.DCM to give compounds of formula (XII): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl). can be prepared by reacting a compound of the formula: with B2Pin2.

[0114] The compound of formula (XII) can be converted to a compound of formula (XIII): [ka] with a compound represented by formula (III): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl). The reaction is conveniently carried out in an organic solvent such as DMF or DCM at a temperature in the range, for example, 20° C. to 100° C., particularly ambient temperature (25° C.).

[0115] Compounds of formula (XIII) can be prepared by the conversion of compounds of formula (XIV): [ka] wherein PG is as defined in formula (VII). with aqueous ammonia. The reaction is conveniently carried out in an organic solvent such as DMF at a temperature in the range of -20°C to 100°C, for example 0°C.

[0116] Compounds of formula (IX) can be prepared by reacting compounds of formula (XII) (wherein PG represents a protecting group, such as tert-butoxycarbonyl) with compounds of formula (VI) or a boronic ester thereof in the presence of a catalyst such as bis[bis(1,2-diphenylphosphino)ethane]palladium(0) or Pd(dppf)Cl·DCM and a base such as potassium carbonate or sodium carbonate. The reaction is conveniently carried out at a temperature in the range of 20°C to 100°C, particularly at 80°C, in a solvent such as dioxane / water or ACN / water mixtures.

[0117] Furthermore, there is provided a method for preparing a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula (XV) in the presence of a catalyst such as Pd(dppf)Cl·DCM or 1,1-bis(di-tert-butylphosphino)ferrocenepalladium dichloride and a base such as potassium carbonate or sodium carbonate: [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl). a compound represented by formula (VI) [wherein R 1 is as defined above] or an ester thereof. The reaction is conveniently carried out at a temperature in the range of 20°C to 100°C, in particular at 75°C, in a solvent such as a dioxane / water mixture or an ACN / water mixture, followed by reaction with a suitable reagent to remove the protecting group PG. An example of a suitable reagent is formic acid.

[0118] Compounds of formula (XV) may be prepared from compounds of formula (XII) using standard literature procedures for the dehydration of amides, for example using reagents such as Burgess' reagent or TBTU or T3P, with or without a base such as DiPEA, in a solvent such as DCM or DMF, at temperatures in the range of -20°C to 100°C, for example at 25°C.

[0119] Furthermore, there is provided a process for preparing a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, conveniently carried out in the presence of a base such as DiPEA or TEA and one or more activating agents such as EDCI, 2-pyridinol-1-oxide or T3P, followed by a dehydrating agent such as T3P, by reaction of a compound of formula (XVI): [ka] [In the formula, R 1 is as defined in formula (I). With a compound of formula (III): The reaction is conveniently carried out in an organic solvent such as DMF or DCM at a temperature in the range, for example, 20°C to 100°C, particularly ambient temperature (25°C).

[0120] Compounds of formula (XVI) can be prepared by converting compounds of formula (VII) to compounds of formula (VI) [wherein R 1 is as defined in formula (I) or an ester thereof. The reaction is conveniently carried out in a solvent such as a dioxane / water mixture or an ACN / water mixture at a temperature in the range of, for example, 20° C. to 100° C., in particular at 75° C., followed by deprotection of the PG.

[0121] Formula (III): [ka] Compounds of formula (XVII): wherein PG represents a protecting group (e.g., tert-butoxycarbonyl) are commercially available or can be prepared by reaction of the formula (XVII): [ka] can be prepared from the compound of formula (I) using literature procedures for mild ester hydrolysis (e.g., Tetr. Lett., 2007, 48, 2497), for example, using LiBr and a base such as TEA in a solvent such as an ACN / water mixture at, for example, 25°C.

[0122] The compound of formula (XVII) [wherein PG represents a protecting group (e.g., tert-butoxycarbonyl)] can be prepared by the reaction of formula (XVIII): [ka] using a reducing agent such as BH3-DMS in a solvent such as THF at a temperature in the range of 0-40°C, for example at 25°C.

[0123] The compound of formula (XVIII) [wherein PG represents a protecting group (e.g., tert-butoxycarbonyl)] can be prepared by the reaction of formula (XIX): [ka] can be prepared from a compound of the formula:

[0124] The compound represented by formula (XIX) can be prepared by the reaction of a compound represented by formula (XX): [ka] [In the formula, PG 1 and P.G. 2 represents a protecting group (e.g., benzyl)] can be prepared from a compound of the formula:

[0125] Formula (XX) [wherein, PG 1 and P.G. 2 represents a protecting group (e.g., benzyl) can be prepared by the compound of formula (XXI): [ka] [In the formula, PG 1 and P.G. 2 represents a protecting group (e.g., benzyl)] by reacting with methyl propionate in the presence of a base such as 4-methylmorpholine in a solvent such as toluene at a temperature in the range of 0 to 100°C, for example at 25°C, using conditions for the Oxa-Michael reaction.

[0126] Formula (XXI) [wherein, PG 1 and P.G. 2 represents a protecting group (e.g., benzyl)] can be prepared by reacting a diprotected benzylamine (e.g., dibenzylamine) with methyl (S)-oxirane-2-carboxylate in a solvent such as ethanol at a temperature in the range of 0 to 78°C, e.g., 70°C.

[0127] Alternatively, the compound of formula (III): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl). can be obtained by reacting a compound of formula (XXII): with a reagent such as TEMPO and sodium hypochlorite in a solvent such as DCM / water, optionally in the presence of a salt such as sodium bromide, in the presence of a buffer such as NaHCO3 and a phase transfer catalyst such as tetrabutylammonium bisulfate, at a temperature in the range of 0 to 100°C, e.g., 25°C. [ka] It can be prepared by oxidation of a compound of the formula:

[0128] The compound of formula (XXII) [wherein PG represents a protecting group (e.g., tert-butoxycarbonyl)] can be prepared by the reaction of formula (XXIII): [ka] [In the formula, PG 1 and P.G. 2 represents a protecting group (e.g., benzyl)] with a base such as sodium hydride in a solvent such as THF at a temperature in the range of 0-60°C, for example at 25°C, followed by the addition of a protecting group PG, PG as defined in formula (XXII) and (XXIII). 1 and P.G. 2 can be prepared by the interconversion of

[0129] Formula (XXIII) [wherein, PG 1 and P.G. 2 represents a protecting group (e.g., benzyl)] can be prepared by reacting a protected 3-aminopropanol (e.g., N-benzyl-3-aminopropanol) with (S)-2-((benzyloxy)methyl)oxirane in a solvent such as ethanol or propanol at a temperature in the range of 0 to 70°C, for example, at 40°C, followed by reacting the crude product with methanesulfonyl chloride in the presence of a base such as DiPEA in a solvent such as DCM at a temperature in the range of -10 to 25°C, for example, at -5°C.

[0130] The compound of formula (VI) or its ester, and the compounds of formulae (VIII), (XI) and (XIV) are either commercially available, known in the literature, or can be prepared using known techniques.

[0131] It will be appreciated by those skilled in the art that in the preparation processes of the present invention, certain functional groups, such as hydroxyl or amino groups in the reagents, may require protection by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.

[0132] Those skilled in the art will appreciate that at any stage in the preparation of a compound of formula (I), an isomeric mixture (e.g., a racemate) of a compound corresponding to any of formulas (II)-(V), (VII)-(X), and (XXII)-(XVI) is available. At any stage in the preparation, a single stereoisomer can be obtained by isolation from the isomeric mixture (e.g., a racemate) using, for example, chiral chromatographic separation.

[0133] Protection and deprotection of functional groups is described in 'Protective Groups in Organic Synthesis', 4th Ed, TW Greene and PGM Wuts, Wiley (2006) and 'Protecting Groups', 3rd Ed, PJ Kocienski, Georg Thieme Verlag (2005).

[0134] A further embodiment includes pharmaceutically acceptable salts of compounds of formula (I).

[0135] The salt of the compound of formula (I) may be advantageous due to one or more of its chemical or physical properties, for example, stability at different temperatures and humidities, or desirable solubility in H2O, oil or other solvents.In some cases, salt can be used to aid in the isolation or purification of the compound.In some embodiments (especially when the salt is intended to be administered to animals (e.g., humans), or when the salt is a reagent used to prepare compounds or salts intended to be administered to animals), the salt is pharmaceutically acceptable.

[0136] When the compound of formula (I) is sufficiently acidic, pharmaceutically acceptable salts include, but are not limited to, alkali metal salts such as Na or K, alkaline earth metal salts such as Ca or Mg, or organic amine salts.When the compound of formula (I) is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic acid addition salts or organic acid addition salts.

[0137] There may be more than one cation or anion depending on the number of charged functional groups and the valence of the cation or anion.

[0138] For a review of suitable salts, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or "Handbook of Pharmaceutical Salts: Properties, selection and use", PH Stahl, PG Vermuth, IUPAC, Wiley-VCH, 2002.

[0139] In salts, proton transfer occurs between the compound of formula (I) and the counterion of the salt. However, in some cases, proton transfer may not be complete, and therefore the solid is not a true salt. In such cases, the compound of formula (I) and the "co-former" molecule in the solid interact primarily through non-ionic forces, such as hydrogen bonding. It is accepted that proton transfer is in fact a continuum and can vary with temperature, and therefore the point at which a salt is more desirably described as a cocrystal is somewhat subjective.

[0140] If the acid or base coformer is a solid at room temperature and there is no or only partial proton transfer between the compound of formula (I) and such an acid or base coformer, a co-crystal of the coformer with the compound of formula (I) may form, rather than a salt. All such co-crystals of the compound of formula (I) are encompassed by the present invention.

[0141] Compounds of formula (I) may form co-crystal mixtures with their salts, and the present invention should be understood to encompass salt / co-crystal mixtures of compounds of formula (I).

[0142] The salts and co-crystals can be characterized using well-known techniques, such as powder X-ray diffraction, single crystal X-ray diffraction (e.g., to assess proton positions, bond lengths or bond angles), solid state NMR (e.g., to assess C, N or P chemical shifts) or spectroscopic techniques (e.g., to measure OH, NH or COOH signals and IR peak shifts resulting from hydrogen bonding).

[0143] Certain compounds of formula (I) may exist in solvated form, for example hydrates and this should be understood to include solvates of pharmaceutically acceptable salts of compounds of formula (I).

[0144] In further embodiments, certain compounds of Formula (I) may exist as racemates and racemic mixtures, single enantiomers, and individual diastereomers and diastereomeric mixtures. The present invention should be understood to encompass all such isomers. Certain compounds of Formula (I) may also contain linking groups (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) where bond rotation is restricted for that particular linking group, for example, due to the presence of a ring bond or a double bond. Thus, the present invention should be understood to encompass all such isomers. Certain compounds of Formula (I) may also contain multiple tautomers. The present invention should be understood to encompass all such tautomers. Stereoisomers can be separated using conventional techniques, such as chromatography or fractional crystallization, or the stereoisomers can be prepared by stereoselective synthesis.

[0145] In further embodiments, compounds of Formula (I) include any isotopically labeled (or "radiolabeled") derivatives of compounds of Formula (I). Such derivatives are derivatives of compounds of Formula (I) in which one or more atoms have been replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that can be incorporated include:2 H (also written as "D" for deuterium).

[0146] In a further embodiment, the compounds of formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of formula (I). Examples of prodrugs include in vivo hydrolysable esters of compounds of formula (I).

[0147] In vivo hydrolyzable (cleavable) esters of compounds of formula (I) containing a carboxy or hydroxy group are, for example, pharmaceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent acid or alcohol. For examples of ester prodrug derivatives, see Curr. Drug. Metab. 2003, 4, 461.

[0148] Various other forms of prodrugs are known in the art. For examples of prodrug derivatives, see Nature Reviews Drug Discovery 2008, 7, 255 and references cited therein. [Example]

[0149] The invention will now be further described by reference to the following non-limiting examples.

[0150] (i) Unless otherwise specified: 1 H NMR spectra were recorded on a Bruker Avance III spectrometer operating at field strengths of 400, 500, or 600 MHz. H 7.27 ppm), dimethyl sulfoxide-d6 (d3-DMSO; δ H 2.50 ppm) or methanol-d4 (CD3OD; δ H The central peak of either the chromatogram or the chromatogram (3.31 ppm) was used as a reference.

[0151] (ii) MS spectra were recorded on either a Micromass ZQ single quadrupole LC-MS or a Quattro Micro LC-MS-MS following analytical HPLC using a Phenomenex Luna 5μ C18 (2), 100 × 4.6 mm (plus guard cartridge) column and a gradient of 0.1% formic acid in ACN in 0.1% formic acid or a Waters Xterra MS 5μ C18, 100 × 4.6 mm (plus guard cartridge) column and a gradient of ACN in 10 mM ammonium bicarbonate. Ionization was routinely electrospray ionization (ESI), with the option to obtain both ESI and APCI data in a single run. Alternatively, LC-MS experiments were performed using a Waters Acquity UPLC system coupled to a Waters Xevo Q-ToF Mass Spectrometer in ESI mode. The UPLC system was equipped with both a BEH C18 column (1.7 μm, 2.1 × 50 mm) coupled with 46 mM ammonium carbonate / NH3 buffer (pH 10) and an HSS C18 column (1.8 μm, 2.1 × 50 mm) coupled with 10 mM formic acid, 1 mM ammonium formate buffer (pH 3). When m / z values ​​are available, generally only ions indicating the parent mass are listed; the quoted mass ions are either positive or negative mass ions: [M] + , [M+H] + , [MH] - or [M+2H-BOC] + .

[0152] (iii) The title and subtitle compounds of the Examples and Preparations have been named using the IUPAC naming program ACD / Name2012 from Acdlabs.

[0153] (iv) Unless otherwise stated, starting materials were commercially available and all solvents and commercially available reagents were experimental and used as received. Unless otherwise stated, operations were carried out at ambient temperature, i.e., in the range of 17-28°C, and, where necessary, under an atmosphere of an inert gas such as nitrogen.

[0154] (iv) X-ray diffraction analysis was carried out according to standard methods which can be found, for example, in Kitaigorodsky, AI (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, CW (1948), Chemical Crystallography, Clarendon Press, London; or Klug, HP & Alexander, LE (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York.

[0155] Samples were mounted on single-crystal silicon (SSC) wafer mounts, and powder X-ray diffraction was recorded using a PANalytical X'Pert PRO (reflection position, X-ray wavelength 1.5418 Å, nickel-filtered Cu irradiation, voltage 45 kV, filament emission 40 mA). Automatic variable divergence and anti-scatter slits were used, and the sample was rotated during the measurement. Using a PIXCEL detector (effective length 3.35° 2θ), the sample was scanned from 2 to 50° 2θ with a step width of 0.013° and a count time of 116 or 233 seconds.

[0156] It is known in the art that powder X-ray diffraction patterns may have one or more measurement errors depending on the measurement conditions (e.g., the equipment, sample preparation, or machine used). In particular, it is generally known that the intensities of powder X-ray diffraction patterns may vary depending on the measurement conditions and sample preparation. For example, those skilled in the art of powder X-ray diffraction fully understand that the relative intensities of peaks may vary depending on the orientation of the sample under test and the type and settings of the tool used. Those skilled in the art also fully understand that the position of reflections may be affected by the exact height at which the sample rests within the diffractometer and the zero calibration of the diffractometer. The planarity of the surface of the sample may also have a small effect. Therefore, those skilled in the art will fully understand that the diffraction pattern data presented herein should not be interpreted as absolute, and that crystals that give powder diffraction patterns substantially identical to those described herein are within the scope of the present invention (for further information, see Jenkins, R & Snyder, RL 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons, 1996).

[0157] Generally, the measurement error of diffraction angles in powder X-ray diffractograms can be approximately ±0.1° 2θ, and this degree of measurement error should be taken into account when examining powder X-ray diffraction data. Furthermore, it should be understood that intensities will vary depending on the experimental conditions and therapeutic preparation (e.g., desired orientation). The following definitions for relative intensity (%) were used: 81-100%, vs (very strong); 41-80%, str (strong); 21-40%, med (moderate); 10-20%, w (weak); and 1-9%, vw (very weak).

[0158] The following abbreviations are used: [Table 1]

[0159] Preparation of Boronic Ester Intermediates

[0160] Boronic ester 1 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3,7-dimethyl-1,3-benzoxazol-2(3H)-one i) 5-chloro-7-methyl-1,3-benzoxazol-2(3H)-one To a solution of 2-amino-4-chloro-6-methylphenol (2.5 g, 15.9 mmol) in THF (65 mL) was added CDI (3.09 g, 19.0 mmol). The reaction was heated at reflux for 2.5 hours and then cooled to room temperature. The reaction mixture was transferred to a separatory funnel and diluted with EtOAc (100 mL). The mixture was washed successively with 2 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated sodium chloride. The organic extract was dried (sodium sulfate), filtered, and concentrated under reduced pressure to give the subtitle compound as a light brown solid (2.89 g, 98%). 1 H NMR (400 MHz, DMSO-d6): 11.84 (s, 1H), 7.10 (d, 1H), 7.06 (d, 1H), 2.37 (s, 3H).

[0161] ii) 5-chloro-3,7-dimethyl-1,3-benzoxazol-2(3H)-one To a solution of 5-chloro-7-methyl-1,3-benzoxazol-2(3H)-one (1.50 g, 8.12 mmol) in DMF (100 mL) was added cesium carbonate (2.65 g, 8.12 mmol). After 20 min, methyl iodide (0.61 mL, 9.84 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 h before being poured into ice water (100 mL). The resulting brown precipitate was collected by filtration and dried in a vacuum oven to give the subtitle compound as a brown solid (1.6 g, 100%). 1 H NMR (400 MHz, DMSO-d6): 7.27 (s, 1H), 7.07 (s, 1H), 2.31 (s, 3H) (one CH3 under a weak peak).

[0162] iii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3,7-dimethyl-1,3-benzoxazol-2(3H)-one To a solution of 5-chloro-3,7-dimethyl-1,3-benzoxazol-2(3H)-one (200 mg, 1.01 mmol) in 1,4-dioxane (5 mL) was added bis(neopentylglycolato)diboron (342 mg, 1.52 mmol) and potassium acetate (198 mg, 2.02 mmol). After degassing the reaction mixture under nitrogen for 15 minutes, XPhos (19 mg, 0.040 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos-Pd-G2, 16 mg, 0.020 mmol) were added. The reaction mixture was heated at 80 °C for 3 hours. The reaction mixture was then concentrated under reduced pressure and purified by silica gel column chromatography eluting with 0-20% EtOAc in isohexane to give the title compound as a pale brown oil (184 mg, 66%). 1 H NMR (400 MHz, CDCl3): δ 7.44 (s, 1H), 7.23 (s, 1H), 3.80 (s, 4H), 3.40 (s, 3H), 2.39 (s, 3H), 1.04 (s, 6H).

[0163] Boronic ester 2 7-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methylquinoxalin-2(1H)-one To a solution of 7-bromo-1-methylquinoxalin-2(1H)-one (1.0 g, 4.2 mmol) in 1,4-dioxane (15 mL) was added bis(neopentylglycolato)diboron (1.42 mg, 6.30 mmol) and potassium acetate (823 mg, 8.40 mmol). The reaction mixture was degassed under nitrogen for 30 minutes, and then Pd(dppf)Cl·DCM (171 mg, 0.21 mmol) was added. The reaction mixture was heated at 80° C. for 3 hours. The reaction mixture was then concentrated under reduced pressure and purified by silica gel column chromatography eluting with 30% EtOAc in isohexane to give an orange solid. Trituration with diethyl ether afforded the title compound as an off-white solid (340 mg, 30%). 1 H NMR (400 MHz, CDCl3): δ 8.37-8.30 (m, 1H), 7.79 (m, 3H), 3.82 (s, 4H), 3.75 (s, 3H), 1.06 (s, 6H).

[0164] Boronic ester 3 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-1,3-benzoxazol-2(3H)-one i) 5-Bromo-3-ethyl-1,3-benzoxazol-2(3H)-one To a solution of 5-bromo-1,3-benzoxazol-2(3H)-one (1.07 g, 5.0 mmol) in DMF (10 mL) was added cesium carbonate (1.79 g, 5.5 mmol). Ethyl iodide (0.44 mL, 5.5 mmol) was added dropwise, and the reaction was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, and the resulting oil was dissolved in EtOAc. The organic extract was washed successively with water and saturated sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography eluting with 1:2 DCM:isohexane to give the subtitle compound as a white solid (1.06 g, 88%). 1H NMR (400 MHz, CDCl3): δ 7.25 (dd, 1H), 7.13 (d, 1H), 7.08 (d, 1H), 3.87 (dd, 2H), 1.39 (t, 3H).

[0165] ii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-1,3-benzoxazol-2(3H)-one To a solution of 5-bromo-3-ethyl-1,3-benzoxazol-2(3H)-one (600 mg, 2.48 mmol) in 1,4-dioxane (10 mL) was added bis(neopentylglycolato)diboron (616 mg, 2.73 mmol) and potassium acetate (487 mg, 4.96 mmol). The reaction mixture was degassed under nitrogen for 30 minutes, and then Pd(dppf)Cl·DCM (101 mg, 0.12 mmol) was added. The reaction mixture was heated at 80° C. for 4 hours. The reaction mixture was then concentrated under reduced pressure and purified by silica gel column chromatography eluting with 0-20% EtOAc in isohexane to give the title compound (338 mg, 57%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 7.60 (d, 1H), 7.41 (s, 1H), 7.19 (d, 1H), 3.90 (dd, 2H), 3.79 (s, 4H), 1.43-1.35 (m, 3H), 1.04 (s, 6H).

[0166] Boronic ester 4 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-7-methyl-1,3-benzoxazol-2(3H)-one i) 5-chloro-3-ethyl-7-methyl-1,3-benzoxazol-2(3H)-one Prepared according to the procedure of boronic ester 3, step i) using 5-chloro-7-methyl-1,3-benzoxazol-2(3H)-one (boronic ester 1, step i) to afford the subtitle compound as a brown solid (258 mg, 82%). 1H NMR (400 MHz, CDCl3): δ 6.93 (s, 1H), 6.82 (d, 1H), 3.85 (q, 2H), 2.35 (s, 3H), 1.37 (t, 3H).

[0167] ii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-ethyl-7-methyl-1,3-benzoxazol-2(3H)-one Prepared according to the procedure in step iii) of boronic ester 1 using 5-chloro-3-ethyl-7-methyl-1,3-benzoxazol-2(3H)-one to afford the title compound as an orange solid (285 mg, 81%). 1 H NMR (400 MHz, CDCl3): δ 7.42 (s, 1H), 7.24 (s, 1H), 3.93-3.83 (m, 2H), 3.78 (s, 4H), 2.37 (s, 3H), 1.41-1.32 (m, 3H), 1.04 (s, 6H).

[0168] Boronic ester 5 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2(3H)-one i) 5-Bromo-3-(2-oxopropyl)-1,3-benzoxazol-2(3H)-one Prepared according to the procedure in step i) of boronic ester 3 using 5-bromo-1,3-benzoxazol-2(3H)-one and chloroacetone to afford the sub-title compound as a yellow solid (1.31 g, 94%). 1 H NMR (400 MHz, CDCl3): δ 7.28-7.24 (m, 1H), 7.11 (d, 1H), 6.93 (d, 1H), 4.59 (s, 2H), 2.31 (s, 3H).

[0169] ii) 5-bromo-3-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2(3H)-one To a solution of 5-bromo-3-(2-oxopropyl)-1,3-benzoxazol-2(3H)-one (1.31 g, 4.87 mmol) in THF (20 mL) was added methylmagnesium chloride (1.62 mL, 4.87 mmol, 3 M solution in THF) with stirring at 0° C. After 1 hour, additional methylmagnesium chloride (0.81 mL, 2.43 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 1 hour before being quenched with ammonium chloride (saturated aqueous solution). The reaction mixture was diluted with EtOAc and the layers separated. The organic extract was washed successively with water and saturated sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EtOAc and isohexane to give the subtitle compound as a brown solid (428 mg, 31%). 1 H NMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 7.28-7.23 (m, 1H), 7.16-7.03 (m, 1H), 7.00-6.89 (m, 1H), 3.86 (s, 2H), 1.61 (s, 6H).

[0170] iii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2(3H)-one Prepared according to the procedure in step ii) of boronic ester 3 using 5-bromo-3-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2(3H)-one to afford the title compound as an orange solid (269 mg, 56%). 1 H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 7.62 (dd, 1H), 7.42 (d, 1H), 7.06 (d, 1H), 3.96 (s, 2H), 3.76 (s, 4H), 1.62 (s, 6H), 1.11-0.96 (m, 6H).

[0171] Boronic ester 6 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one i) 5-Bromo-7-fluoro-1,3-benzoxazol-2(3H)-one To a solution of 2-amino-4-bromo-6-fluorophenol (2.5 g, 12.25 mmol) in THF (65 mL) was added CDI (2.38 g, 14.70 mmol). The reaction was heated at reflux for 2.5 hours and then cooled to room temperature. The reaction mixture was transferred to a separatory funnel and diluted with EtOAc (100 mL). The mixture was washed successively with 2 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated sodium chloride. The organic extract was dried (sodium sulfate), filtered, and concentrated under reduced pressure. The resulting dark brown solid was triturated with diethyl ether and isohexane to give the subtitle compound as a light brown solid (2.01 g, 71%). 1 H NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1H), 7.38 (dd, 1H), 7.16-7.15 (m, 1H).

[0172] ii) 5-bromo-7-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one A solution of 5-bromo-7-fluoro-1,3-benzoxazol-2(3H)-one (2.01 g, 8.74 mmol) in 30 mL of DMF was added dropwise to a suspension of sodium hydride (419 mg, 10.49 mmol, 60% dispersion in mineral oil) in 50 mL of DMF while stirring at 0° C. The reaction was allowed to warm to room temperature for 30 minutes and then re-cooled to 0° C. Methyl iodide (653 μL) was added dropwise and the reaction was allowed to warm to room temperature. After 18 hours, the reaction was carefully quenched with water and transferred to a separatory funnel. The mixture was extracted with diethyl ether (×3). The organic extract was washed successively with saturated sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The resulting material was triturated with diethyl ether and isohexane to give the subtitle compound as a pale brown solid (1.38g, 64%). 1H NMR (400 MHz, DMSO-d6): δ 7.49 (d, 1H), 7.44 (dd, 1H), 3.35 (s, 3H).

[0173] iii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one To a solution of 5-bromo-7-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one (1.38 g, 5.60 mmol) in 1,4-dioxane (20 mL) was added bis(neopentylglycolato)diboron (1.39 g, 6.17 mmol) and potassium acetate (1.10 g, 11.20 mmol). The reaction mixture was degassed with nitrogen for 15 minutes, and then Pd(dppf)Cl·DCM (229 mg, 0.28 mmol) was added. The reaction mixture was heated at 80° C. for 3 hours. The reaction mixture was then concentrated under reduced pressure and purified by silica gel column chromatography eluting with 20% EtOAc in isohexane to give the title compound as a light brown solid (1.16 g, 75%). 1 H NMR (400 MHz, CDCl3): δ 7.36 (d, 1H), 7.19 (m, 1H), 3.78 (s, 4H), 3.42 (s, 3H), 1.03 (s, 6H).

[0174] Boronic ester 7 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2,2-difluoroethyl)-1,3-benzoxazol-2(3H)-one i) 5-bromo-3-(2,2-difluoroethyl)-7-fluoro-1,3-benzoxazol-2(3H)-one Prepared according to the procedure of boronic ester 3, step i) using 5-bromo-7-fluoro-1,3-benzoxazol-2(3H)-one (boronic ester 6, step i) and 2,2-difluoroethyl trifluoromethanesulfonate to give the subtitle compound as a brown solid (2.49 g, 89%). 1H NMR (400 MHz, CDCl3): δ 7.16 (dd, 1H), 7.05 (s, 1H), 6.08 (tt, 1H), 4.16 (td, 2H).

[0175] ii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2,2-difluoroethyl-2-methylpropyl)-1,3-benzoxazol-2(3H)-one Prepared according to the procedure in step ii) of boronic ester 3 using 5-bromo-3-(2,2-difluoroethyl)-7-fluoro-1,3-benzoxazol-2(3H)-one to afford the title compound as an off-white solid (1.15 g, 41%). 1 H NMR (400 MHz, CDCl3): δ 7.40 (d, 1H), 7.30-7.24 (m, 1H), 6.10 (tt, 1H), 4.23-4.12 (m, 2H), 3.78 (s, 4H), 1.03 (s, 6H).

[0176] Boronic ester 8 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-(dimethylamino)ethyl)-1,3-benzoxazol-2(3H)-one i) 5-Bromo-3-(2-(dimethylamino)ethyl)-1,3-benzoxazol-2(3H)-one To 5-bromo-1,3-benzoxazol-2(3H)-one (1.80 g, 8.41 mmol) and potassium carbonate (3.87 g, 28.0 mmol) in DMF (10 mL) was added 2-dimethylaminoethyl chloride hydrochloride (1.21 g, 8.41 mmol). The reaction was heated at 125° C. for 3.5 h, then cooled to room temperature and poured into ice water. The aqueous layer was extracted with EtOAc (100 mL×4). The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The resulting oil was dissolved in diethyl ether, washed with water, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give the subtitle compound as a light brown oil (1.63 g, 68%). 1H NMR (400 MHz, CDCl3): δ 7.23 (dd, 1H), 7.15 (d, 1H), 7.10-7.02 (m, 1H), 3.93-3.85 (m, 2H), 2.69-2.61 (m, 2H), 2.30 (s, 6H).

[0177] ii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-(dimethylamino)ethyl)-1,3-benzoxazol-2(3H)-one The preparation was carried out according to the procedure in step ii) of boronic ester 3 using 5-bromo-3-(2-(dimethylamino)ethyl)-1,3-benzoxazol-2(3H)-one to give the title compound as an off-white solid (1.15 g, 41%), which was used in the next step without further purification.

[0178] Boronic ester 9 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-one i) 6-Bromo-3,3-difluoro-1,3-dihydro-2H-indol-2-one To a suspension of 6-bromoisatin (2.0 g, 8.75 mmol) in DCM (90 mL) stirred at room temperature was added bis(2-methoxyethyl)aminosulfur trifluoride (deoxo-fluor, 44.25 mL, 22.12 mmol, 50% solution in THF) dropwise over 30 minutes. After 24 hours, the reaction was carefully quenched with saturated sodium bicarbonate solution (40 mL) at 0° C. The aqueous layer was separated and the organic extract was dried (hydrophobic frit / phase separator) and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 20% EtOAc in isohexane to give the subtitle compound as an orange solid (1.63 g, 74%). 1 H NMR (400 MHz, CH3OH-d4): δ 7.50-7.46 (m, 1H), 7.36 (dd, 1H), 7.18 (d, 1H), (no exchanger observed).

[0179] ii) 6-bromo-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-one The procedure for step i) of boronic ester 3 was followed using 6-bromo-3,3-difluoro-1,3-dihydro-2H-indol-2-one and methyl iodide to give the subtitle compound as an orange solid (1.39 g, 82%), which was used in the next step without further purification.

[0180] iii) 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-one Prepared according to the procedure in step ii) of boronic ester 3 using 6-bromo-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-one to afford the title compound as an off-white solid (120 mg, 8%). 1 H NMR (400 MHz, CDCl3): δ 7.62 (t, 1H), 7.55-7.47 (m, 1H), 7.31-7.28 (m, 1H), 3.80 (s, 4H), 3.22 (s, 3H), 1.04 (s, 6H).

[0181] Boronic ester 10 3-(Cyclopropylmethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-one i) 5-Bromo-3-(cyclopropylmethyl)-1,3-benzoxazol-2(3H)-one To a solution of 5-bromo-1,3-benzoxazol-2(3H)-one (1.07 g, 5.0 mmol) in DMF (10 mL) was added cesium carbonate (1.79 g, 5.5 mmol). (Bromomethyl)cyclopropane (743 mg, 5.5 mmol) was added dropwise, and the reaction was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, and the resulting oil was dissolved in EtOAc. The organic extract was washed with water and saturated sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography eluting with 1:2 DCM:isohexane to give the subtitle compound as a white solid (918 mg, 68%). 1 H NMR (400 MHz, CDCl3): δ 7.24 (dd, 1H), 7.17 (d, 1H), 7.13-7.04 (m, 1H), 3.68 (d, 2H), 1.29-1.17 (m, 1H), 0.69-0.54 (m, 2H), 0.51-0.41 (m, 2H).

[0182] ii) 3-(cyclopropylmethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-one The preparation was carried out according to the procedure in step ii) of boronic ester 3 using 5-bromo-3-(cyclopropylmethyl)-1,3-benzoxazol-2(3H)-one to give the title compound as a brown solid (520 mg, 62%), which was used in the next step without further purification.

[0183] Boronic ester 11 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-one i) 5-chloro-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-one Prepared according to the procedure in step ii) of boronic ester 1 using 5-chloro-1,3-benzothiazol-2(3H)-one and 1-bromo-2-methoxyethane to afford the subtitle compound as a yellow solid (3.5 g, 89%). 1 H NMR (400 MHz, CDCl3): δ 7.32 (d, 1H), 7.22 (d, 1H), 7.13 (dd, 1H), 4.12-4.06 (m, 2H), 3.71-3.65 (m, 2H), 3.34 (s, 3H).

[0184] ii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-one Prepared according to the procedure in step iii) of boronic ester 1 using 5-chloro-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-one to give the title compound as a pale brown solid (1.02 g, 64%), which was used in the next step without further purification.

[0185] Boronic ester 12 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-isopropyl-1,3-benzoxazol-2(3H)-one i) 5-Bromo-3-isopropyl-1,3-benzoxazol-2(3H)-one The procedure for step i) of boronic ester 3 was followed using 5-bromo-1,3-benzoxazol-2(3H)-one and 2-iodopropane to give the subtitle compound as a white solid (510 mg, 66%), which was used in the next step without further purification.

[0186] ii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-isopropyl-1,3-benzoxazol-2(3H)-one Prepared according to the procedure in step ii) of boronic ester 3 using 5-bromo-3-isopropyl-1,3-benzoxazol-2(3H)-one to give the subtitle compound as a brown solid (132 mg, 19%), which was used in the next step without further purification.

[0187] Boronic ester 13 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-methyl-2H-1,4-benzoxazin-3(4H)-one The preparation was carried out according to the procedure in step ii) of boronate ester 3 using commercially available 6-bromo-4-methyl-2H-1,4-benzoxazin-3(4H)-one to give the title compound as a brown solid (520 mg, 62%), which was used directly without further purification.

[0188] Boronic ester 14 7-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methylquinolin-2(1H)-one i) 7-Bromoquinolin-2(1H)-one A stirred mixture of 7-bromo-2-chloroquinoline (5.0 g, 20.6 mmol) in 5 M aqueous hydrochloric acid (133 mL) and 1,4-dioxane (14 mL) was heated at reflux for 2 h. The reaction was cooled and the resulting precipitate was collected by filtration and washed with water to give the subtitle compound as a colorless solid (4.3 g, 93%). 1 H NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 7.91 (d, 1H), 7.63 (d, 1H), 7.48 (d, 1H), 7.34 (dd, 1H), 6.53 (d, 1H).

[0189] ii) 7-bromo-1-methylquinolin-2(1H)-one To a solution of 7-bromoquinolin-2(1H)-one (1.5 g, 6.64 mmol) in anhydrous THF was added sodium hydride (320 mg, 7.98 mmol, 60% dispersion in mineral oil) while stirring at room temperature under a nitrogen atmosphere. After 1 hour, the reaction mixture was cooled to 0° C., methyl iodide (1.88 g, 0.81 ml, 13.28 mmol) was added, and the reaction was allowed to warm slowly to room temperature. After 18 hours, the reaction was carefully quenched with water (1 mL) and concentrated under reduced pressure. The resulting residue was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was added isohexane and recrystallized from DCM to give the subtitle compound as a colorless solid (650 mg, 40%). 1 H NMR (400 MHz, CDCl3): δ 7.62 (d, 1H), 7.53 (d, 1H), 7.40 (s, 1H), 7.35 (dd, 1H), 6.75-6.66 (m, 1H), 3.69 (s, 3H).

[0190] ii) 7-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methylquinolin-2(1H)-one Prepared according to the procedure for boronic ester 2 starting from 7-bromo-1-methylquinolin-2(1H)-one to afford the title compound as a pale pink solid (650 mg, 88%). 1 H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.69-7.60 (m, 2H), 7.53 (d, 1H), 6.73 (d, 1H), 3.82 (s, 4H), 3.78 (s, 3H), 1.05 (s, 6H).

[0191] Boronic ester 15 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-benzoxazol-2(3H)-one i) 5-Bromo-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-benzoxazol-2(3H)-one To 5-bromo-2-benzoxazolinone (795 mg, 3.7 mmol) and cesium carbonate (500 mg, 7.4 mmol) in DMF (10 mL) was added 4-(chloromethyl)tetrahydro-2H-pyran (500 mg, 3.7 mmol). The reaction was heated at 110 ° C for 48 hours, then cooled to room temperature and poured into ice water. The resulting precipitate was collected by filtration and dried in vacuo to give the subtitle compound as a light brown oil (840 mg, 73%). 1 H NMR (400 MHz, DMSO-d6): δ 7.70 (s, 1H), 7.34-7.27 (m, 2H), 3.88-3.78 (m, 2H), 3.71 (d, 2H), 3.25 (td, 2H), 2.11-1.99 (m, 1H), 1.53 (d, 2H), 1.35-1.22 (m, 2H).

[0192] ii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-benzoxazol-2(3H)-one Prepared according to the procedure for boronic ester 2 starting from 5-bromo-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-benzoxazol-2(3H)-one to afford the title compound as an orange solid (440 mg, 47%). 1 H NMR (400 MHz, CDCl3): δ 7.61 (dd, 1H), 7.37 (s, 1H), 3.98 (dd, 2H), 3.79 (s, 3H), 3.75-3.69 (m, 2H), 3.40-3.32 (m, 2H), 2.25-2.11 (m, 1H), 1.66-1.53 ​​(m, 3H), 1.53-1.39 (m, 2H), 1.04 (s, 6H) (one H below the CHCl3 peak).

[0193] Boronic ester 16 7-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-one i) 4-Bromo-2-chloro-6-nitrophenol To a solution of 4-bromo-2-chlorophenol (20.0 g, 96.4 mmol) in acetic acid (100 mL) at room temperature was slowly added 70% aqueous nitric acid (11.5 mL, 190 mol). The resulting precipitate was collected by filtration to give the subtitle compound as a yellow solid (24.0 g). This was used in the next step without further purification.

[0194] ii) 2-amino-4-bromo-6-chlorophenol To a solution of 4-bromo-2-chloro-6-nitrophenol (10.0 g) in ethanol (400 mL) and water (100 mL) was added calcium chloride (443 mg, 4 mmol) and iron (11.16 g, 0.2 mol). The suspension was heated at 80° C. for 2 hours. The reaction was cooled, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with saturated sodium chloride solution (500 mL) and extracted with EtOAc (500 mL×2). The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give the subtitle compound as a black solid (4 g, 45%). 1 H NMR (400 MHz, CDCl3): δ 6.85 (d, 1H), 6.75 (d, 1H), 5.38 (s, 1H), 3.92 (bs, 2H).

[0195] iii) 5-bromo-7-chloro-1,3-benzoxazol-2(3H)-one To a stirred solution of 2-amino-4-bromo-6-chlorophenol (2.0 g, 9.0 mmol) in anhydrous THF (50 mL) was added CDI (4.0 g, 24.6 mmol). The mixture was heated at reflux under a nitrogen atmosphere for 2.5 hours. The reaction was cooled and the solvent was removed under reduced pressure. The resulting residue was washed with 2N aqueous hydrochloric acid and then triturated with methanol to give the subtitle compound (0.8 g, 36%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 12.18 (s, 1H), 7.46 (d, 1H), 7.27 (d, 1H).

[0196] iv) 5-bromo-7-chloro-3-methyl-1,3-benzoxazol-2(3H)-one Prepared according to the procedure of step ii) of boronic ester 1 starting from 5-bromo-7-chloro-1,3-benzoxazol-2(3H)-one using potassium carbonate instead of cesium carbonate to give the subtitle compound as a brown solid (700 mg, 83%). 1 H NMR (400 MHz, CDCl3): δ 7.26 (s, 1H), 7.02 (d, 1H), 3.40 (s, 3H).

[0197] v) 7-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-one Prepared according to the procedure for boronic ester 2 starting from 5-bromo-7-chloro-3-methyl-1,3-benzoxazol-2(3H)-one to afford the title compound as an off-white solid (170 mg, 22%). 1 H NMR (400 MHz, CDCl3): δ 7.59 (s, 1H), 7.28 (s, 1H), 3.78 (s, 4H), 3.41 (s, 3H), 1.03 (s, 6H).

[0198] Boronic ester 17 3-(2,2-Difluoroethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-one i) 5-chloro-3-(2,2-difluoroethyl)-1,3-benzoxazol-2(3H)-one To a solution of 5-chloro-1,3-benzoxazol-2(3H)-one (1 g, 5.89 mmol) in DMF (20 mL) was added cesium carbonate (3.83 g, 11.8 mmol), followed by dropwise addition of 2,2-difluoroethyl trifluoromethanesulfonate (1.38 g, 6.5 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. Water (60 mL) was then added, and the resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give the subtitle compound as a white solid (1.25 g, 91%). 1 H NMR (400 MHz, CDCl3): δ 7.24-7.18 (m, 1H), 7.08 (m, 1H), 7.01 (s, 1H), 6.17-5.85 (m, 1H), 4.14-4.04 (m, 2H).

[0199] ii) 3-(2,2-difluoroethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-one Prepared according to the procedure in step iii) of boronic ester 1 using 5-chloro-3-(2,2-difluoroethyl)-1,3-benzoxazol-2(3H)-one to afford the title compound as an off-white solid (670 mg, 40%). 1 H NMR (400 MHz, CDCl3): δ 7.67-7.61 (m, 1H), 7.48 (s, 1H), 7.21 (d, 1H), 6.26-5.93 (m, 1H), 4.22-4.10 (m, 2H), 3.78 (s, 4H), 1.03 (s, 6H).

[0200] Boronic ester 18 3-(2,2,2-trifluoroethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-one i) 5-chloro-3-(2,2,2-trifluoroethyl)-1,3-benzoxazol-2(3H)-one To a solution of 5-chloro-1,3-benzoxazol-2(3H)-one (1 g, 5.89 mmol) in DMF (20 mL) was added cesium carbonate (3.83 g, 11.8 mmol), followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.5 g, 6.5 mmol). The resulting mixture was stirred at room temperature for 30 minutes. Water (60 mL) was added, and the resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give the subtitle compound as a white solid (1.31 g, 89%). 1 H NMR (400 MHz, CDCl3): δ 7.19-7.15 (m, 2H), 7.08 (s, 1H), 4.40 (q, 2H).

[0201] ii) 3-(2,2,2-trifluoroethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzoxazol-2(3H)-one Prepared according to the procedure in step iii) of boronic ester 1 using 5-chloro-3-(2,2,2-trifluoroethyl)-1,3-benzoxazol-2(3H)-one to afford the title compound as an off-white solid (670 mg, 40%). 1 H NMR (400 MHz, CDCl3): δ 7.67 (dd, 1H), 7.47 (s, 1H), 7.22 (d, 1H), 4.41 (dd, 2H), 3.78 (s, 4H), 1.03 (s, 6H).

[0202] Boronic ester 19 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzothiazol-2(3H)-one i) 5-chloro-3-methyl-1,3-benzothiazol-2(3H)-one To a solution of 5-chloro-1,3-benzothiazol-2(3H)-one (5.0 g, 26.9 mmol) in DMF (70 mL) was added cesium carbonate (17.5 g, 53.8 mmol). After 20 min, methyl iodide (2.51 mL, 40.4 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h and then poured into ice water (300 mL). The resulting brown precipitate was collected by filtration and dried in a vacuum oven to give the subtitle compound as a colorless solid (4.42 g, 82%). 1 H NMR (400 MHz, CDCl3): δ 7.35 (d, 1H), 7.17 (dd, 1H), 7.06 (d, 1H), 3.45 (s, 3H).

[0203] ii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzothiazol-2(3H)-one Prepared according to the procedure in step iii) of boronic ester 1 using 5-chloro-3-methyl-1,3-benzothiazol-2(3H)-one to afford the title compound as an off-white solid (620 mg, 15%). 1 H NMR (400 MHz, CDCl3): δ 7.61 (dd, 1H), 7.50-7.36 (m, 2H), 3.80 (s, 4H), 3.48 (s, 3H), 1.04 (s, 6H).

[0204] Boronic ester 20 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one i) 2-((4-bromo-2-nitrophenyl)thio)acetic acid To a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.02 g, 15 mmol) in DMF (20 mL) was added potassium carbonate (4.55 g, 33 mmol) and thioacetic acid (1.15 mL, 16.5 mmol) successively with stirring at room temperature. After 18 hours, the reaction was diluted with EtOAc and water. The layers were separated. The aqueous layer was acidified and extracted with EtOAc. The organic extract was dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give the subtitle compound as a yellow solid (2.60 g, 59%). 1 H NMR (400 MHz, DMSO-d6): δ 13.04 (s, 1H), 8.37 (d, 1H), 7.96-7.91 (m, 1H), 7.54 (d, 1H), 4.05 (s, 2H).

[0205] ii) 6-bromo-2H-1,4-benzothiazin-3(4H)-one To a solution of ammonium hydroxide (26 mL) and 2-((4-bromo-2-nitrophenyl)thio)acetic acid (2.6 g, 8.93 mmol) at room temperature was slowly added iron(II) sulfate heptahydrate (18.12 g, 65.17 mmol) in water (25 mL). After 3 h, the reaction mixture was filtered through Celite and washed with ammonium hydroxide and water. The filtrate was acidified with concentrated hydrochloric acid, and the resulting precipitate was collected by filtration. The solid was dissolved in EtOAc, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give the subtitle compound as a yellow solid (1.9 g, 93%). 1 H NMR (400 MHz, DMSO-d6): δ 10.64 (br, 1H), 7.36-7.26 (m, 1H), 7.15 (dd, 2H), 3.49 (s, 2H).

[0206] iii) 6-bromo-4-methyl-2H-1,4-benzothiazin-3(4H)-one Prepared according to the procedure of boronic ester 1 step ii) starting from 6-bromo-2H-1,4-benzothiazin-3(4H)-one to give the sub-title compound as a yellow solid (1.16 g, 86%). 1H NMR (400 MHz, CDCl3): δ 7.25 (d, 1H), 7.21 (d, 1H), 7.15 (dd, 1H), 3.42 (s, 3H), 3.40 (s, 2H).

[0207] iv) 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one Prepared according to the procedure in step ii) of boronic ester 3 using 6-bromo-4-methyl-2H-1,4-benzothiazin-3(4H)-one to afford the title compound as a white solid (655 mg, 45%). 1 H NMR (400 MHz, CDCl3): δ 7.58-7.44 (m, 1H), 7.45 (dd, 1H), 7.38-7.30 (m, 1H), 3.77 (s, 4H), 3.48 (s, 3H), 3.47-3.35 (m, 2H), 1.03 (s, 6H).

[0208] Boronic ester 21 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-methoxyethyl)-1,3-benzoxazol-2(3H)-one i) 5-Bromo-3-(2-methoxyethyl)-1,3-benzoxazol-2(3H)-one Prepared according to the procedure in step i) of boronic ester 3 using 5-bromo-1,3-benzoxazol-2(3H)-one to afford the sub-title compound as a yellow solid (1.15 g, 85%). 1 H NMR (400 MHz, CDCl3): δ 7.27-7.20 (m, 2H), 7.06 (d, 1H), 3.97 (t, 2H), 3.72-3.66 (m, 2H), 3.35 (s, 3H).

[0209] ii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(2-methoxyethyl)-1,3-benzoxazol-2(3H)-one The preparation was carried out according to the procedure in step ii) of boronic ester 3 using 5-bromo-3-(2-methoxyethyl)-1,3-benzoxazol-2(3H)-one to give the title compound as a yellow oil (1.15 g, 85%), which was used in the next step without further purification.

[0210] Boronic ester 22 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-one [ka]

[0211] i) 5-chloro-3-methyl-1,3-benzoxazol-2(3H)-one [ka] To a solution of 5-chloro-1,3-benzoxazol-2(3H)-one (10 g, 58.96 mmol) in DMF (100 mL) was added cesium carbonate (19.21 g, 58.96 mmol). After 30 min, methyl iodide (4.40 mL, 70.75 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 18 h and then poured into ice water (500 mL). The resulting white precipitate was collected by filtration and dried over P2O5 in a vacuum oven to give the subtitle compound as a white solid (9.92 g, 92%). 1 H NMR (400 MHz, DMSO-d6): δ 7.46 (d, 1H), 7.36 (d, 1H), 7.17 (dd, 1H), 3.34 (s, 3H).

[0212] ii) 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-one To a solution of 5-chloro-3-methyl-1,3-benzoxazol-2(3H)-one (3.0 g, 16.3 mmol) in 1,4-dioxane (80 mL) was added bis(neopentylglycolato)diboron (5.54 g, 24.5 mmol) and potassium acetate (3.21 g, 32.7 mmol). The reaction mixture was degassed under nitrogen for 40 minutes, followed by the addition of XPhos (311 mg, 0.65 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos-Pd-G2, 257 mg, 0.33 mmol). The reaction mixture was heated at 80 °C for 2 hours. The reaction mixture was then concentrated under reduced pressure and purified by silica gel column chromatography eluting with 0-10% EtOAc in isohexane to give the title compound as a yellow solid (4.8 mg, >100%). 1 H NMR (400 MHz, CDCl3): δ 7.61 (dd, 1H), 7.40 (s, 1H), 7.21-7.13 (m, 1H), 3.79 (s, 4H), 3.41 (s, 3H), 1.04 (s, 6H).

[0213] Preparation of intermediate building blocks

[0214] Intermediate 1 4'-[(2S)-2-amino-2-cyanoethyl]biphenyl-4-carbonitrile i) tert-butyl [(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]carbamate To a suspension of tert-butyl N-[(1S)-1-cyano-2-(4-iodophenyl)ethyl]carbamate (prepared according to the procedure on page 47 of WO 2009 / 74829) (5.99 g, 16 mmol) and (4-cyanophenyl)boronic acid (2.64 g, 18 mmol) in 1,4-dioxane (60 mL) and water (8 mL) was added potassium carbonate (4.5 g, 36 mmol). The suspension was stirred under a stream of nitrogen for 15 minutes, after which Pd(dppf)Cl·DCM (1.3 g) was added. The reaction was heated at 75° C. for 45 minutes and then concentrated under reduced pressure. The resulting oil was diluted with EtOAc (200 mL) and washed with water (100 mL) and saturated sodium chloride solution (50 mL). The organic extract was dried (magnesium sulfate), filtered, and evaporated under reduced pressure to give a brown oil. The oil was purified by silica gel column chromatography eluting with 20-30% EtOAc in isohexane to give the sub-title compound as a colourless solid (5.9g, 90%). 1 H NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 7.96-7.81 (m, 4H), 7.73 (d, 2H), 7.45 (d, 2H), 4.71 (q, 1H), 3.18-3.05 (m, 2H), 1.36 (s, 9H).

[0215] ii) 4'-[(2S)-2-amino-2-cyanoethyl]biphenyl-4-carbonitrile Tert-butyl [(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]carbamate (5.4 g, 15.5 mmol) was dissolved in formic acid (50 mL) and heated to 50 ° C. on a preheated hotplate stirrer for 15 minutes. The solution was evaporated under reduced pressure and diluted with EtOAc (150 mL). Saturated aqueous sodium bicarbonate solution was added to basify the mixture (pH 8). The EtOAc was separated, washed with saturated sodium chloride, dried (magnesium sulfate), filtered, and evaporated under reduced pressure to obtain a yellow oil. The oil was purified by silica gel column chromatography, eluting with EtOAc, to obtain the title compound as a colorless solid (2.88 g, 74%). 1H NMR (400 MHz, CDCl): δ 7.62 (m, 4H), 7.52 (m, 2H), 7.35 (d, 2H), 3.92 (t, 1H), 3.10-2.96 (m, 2H) (two exchangeable protons not observed).

[0216] Intermediate 2 (2S)-2-Amino-3-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]propanenitrile i) tert-butyl {(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamate [ka] 5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-one (boronic ester 22, 3.34 g, 12.81 mmol) and (S)-tert-butyl(1-cyano-2-(4-iodophenyl)ethyl)carbamate (prepared according to the procedure on page 47 of WO 2009 / 074829) (12.81 mmol) were dissolved in 1,4-dioxane (340 mL) and water (12 mL). The reaction mixture was degassed under nitrogen for 30 minutes, after which potassium carbonate (2.66 g, 19.21 mmol) and Pd(dppf)Cl·DCM (1.05 g, 1.28 mmol) were added. The reaction mixture was heated at 80° C. for 1.5 hours. The reaction was then concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL) and water (50 mL). The mixture was filtered through Celite and the layers were separated. The organic extract was washed with saturated sodium chloride solution, dried (magnesium sulfate), filtered and evaporated. The resulting oil was purified by silica gel column chromatography eluting with a gradient of 0-40% EtOAc in isohexane to give the subtitle compound as a white solid (3.87 mg, 77%). 1H NMR (400 MHz, CDCl3): δ 7.51-7.46 (m, 2H), 7.31 (d, 2H), 7.21-7.17 (m, 3H), 7.12-7.06 (m, 1H), 4.78 (s, 1H), 3.39 (s, 3H), 3.14-2.98 (m, 2H), 1.39 (s, 9H).

[0217] ii) (2S)-2-amino-3-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]propanenitrile [ka] To tert-butyl {(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamate (3.87 g, 9.84 mmol) was added formic acid (32 mL). The mixture was heated on a preheated hotplate stirrer at 50° C. for 15 minutes. The solvent was then removed under reduced pressure. The residue was dissolved in DCM, washed with saturated bicarbonate solution, dried (phase separator cartridge), and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 80-100% EtOAc in isohexane to give the title compound as a white solid (1.76 g, 59%). 1 H NMR (400 MHz, CDCl3): δ 7.60-7.50 (m, 2H), 7.39 (d, 2H), 7.34-7.30 (m, 1H), 7.25 (t, 1H), 7.14 (d, 1H), 4.02-3.96 (m, 1H), 3.45 (s, 3H), 3.18-3.01 (m, 2H), 1.67 (s, 2H).

[0218] Intermediate 3 (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid [ka]

[0219] i) 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol [ka] A solution of N-benzylpropanolamine (3.3 g) and benzyl (S)-(+)-glycidyl ether (3.6 g) in ethanol (40 mL) was heated at 40° C. for 18 h. The solvent was evaporated under reduced pressure to give the subtitle compound as a colourless oil (6.8 g, 100%), which was used without further purification. 1 H NMR (400 MHz, DMSO-d6): δ 7.29 (m, 10H), 4.54 (m, 1H), 4.45 (s, 2H), 4.36 (t, 2H), 3.76 (m, 1H), 3.44 (m, 5H), 2.47 (m, 4H), 1.57 (m, 2H).

[0220] ii) (2S)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane [ka] To a stirred solution of 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol (50.0 g, 0.153 mol) in THF (2.5 L) at 0° C. was added sodium hydride (15.2 g, 0.38 mol, 60% dispersion in oil) dropwise. The reaction was stirred at 0° C. for 30 minutes, after which p-toluenesulfonylimidazole (37.8 g, 0.17 mol) was added dropwise. The reaction was warmed to room temperature and stirred for 4 hours before being cooled to 0° C. The reaction was quenched by careful addition of saturated sodium bicarbonate solution (70 mL). The solvent was removed under reduced pressure, and the crude residue was partitioned between water (400 mL) and EtOAc (400 mL). The layers were separated, and the aqueous portion was extracted with EtOAc (400 mL x 2). The combined organic extracts were dried (magnesium sulfate), filtered and evaporated under reduced pressure to give an oil which was purified by silica gel column chromatography eluting with a 0-50% EtOAc in isohexane gradient to give the sub-title compound as a colourless oil (12.2 g, 26%). 1 H NMR (400 MHz, DMSO-d6): δ 7.36-7.20 (m, 10H), 4.45-4.35 (m, 2H), 3.81-3.65 (m, 2H), 3.60-3.39 (m, 2H), 3.42-3.31 (m, 2H), 3.25 (dd, 1H), 2.86 (d, 1H), 2.78-2.70 (m, 1H), 2.54-2.46 (m, 1H) 2.37 (dd, 1H), 1.89-1.77 (m, 1H), 1.78-1.66 (m, 1H).

[0221] iii) (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate tert-butyl [ka] To a solution of (2S)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane (12.2 g, 39.2 mmol) in ethanol (250 mL) under nitrogen, di-tert-butyl dicarbonate (10.22 g, 47.1 mmol) and 20% palladium on carbon (16.5 g) were added. The reaction mixture was shaken under a hydrogen atmosphere at 50 psi for 18 hours. The reaction mixture was then filtered through Celite and washed with methanol. The solvent was evaporated under reduced pressure to give the subtitle compound as a colorless oil (11.16 g). 1 H NMR (400 MHz, DMSO-d6): δ 4.72-4.66 (m, 1H), 4.00-3.89 (m, 1H), 3.80-3.61 (m, 1H), 3.60-3.47 (m, 2H), 3.49-3.21 (m, 4H), 3.07-2.88 (m, 1H), 1.79-1.69 (m, 2H), 1.40 (s, 9H).

[0222] iv) (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid Sodium bromide (1.46 g) and TEMPO (218 mg) were added to a solution of tert-butyl (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (13.2 g, 46.6 mmol) in acetone (730 mL) and saturated sodium bicarbonate (218 mL) at 0° C. 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (23.9 g, 102.5 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature over 18 hours. Isopropanol (30 mL) was added to quench the reaction and stirred for 30 minutes. The reaction mixture was filtered through Celite and washed with EtOAc. The filtrate was evaporated under reduced pressure, dissolved in 1 M sodium carbonate solution (100 mL), and extracted with EtOAc (200 mL×2). The aqueous solution was acidified with 2 M HCl (150 mL) and extracted with EtOAc (400 mL x 3). The combined organic extracts were dried (magnesium sulfate), filtered, and evaporated under reduced pressure to give the title compound as a colorless solid (7.86 g, 68%). 1H NMR (400 MHz, DMSO-d6): δ 12.71 (s, 1H), 4.22-4.15 (m, 1H), 3.98-3.80 (m, 2H), 3.70-3.50 (m, 2H), 3.45-3.11 (m, 1H), 3.21-3.06 (m, 1H), 1.71 (s, 2H), 1.40 (d, 9H).

[0223] Intermediate 3 (first alternative synthesis method) (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid i) (2S)-3-(dibenzylamino)-2-hydroxypropanoic acid methyl ester [ka] Under a nitrogen atmosphere, (S)-methyl oxirane-2-carboxylate (117 g, 1134 mmol) and dibenzylamine (226 g, 1123 mmol) were heated at 70° C. overnight. Further (S)-methyl oxirane-2-carboxylate (1.15 g, 11.2 mmol) was added and stirred at 80° C. for 5 hours. The mixture was then left overnight at 50° C. under reduced pressure (0-10 mbar). This gave the desired product as a light brown viscous oil (342.7 g, 1145 mmol). 1 Assay by H NMR = 89% w / w, effective yield 91%. 1 H NMR (400 MHz, CDCl3): δ 2.77 - 2.92 (m, 2H), 3.13 - 3.4 (s, broad, 1H), 3.49 (d, J=13.5, 2H), 3.63 (s, 3H), 3.74 (d, J=13.5, 2H), 4.21 (dd, J=4.3, 6.7, 1H), 7.18 - 7.34 (m, 10H).

[0224] ii) 3-{[(2S)-3-(dibenzylamino)-1-methoxy-1-oxopropan-2-yl]oxy}prop-2-enoic acid methyl ester [ka] Methyl (2S)-3-(dibenzylamino)-2-hydroxypropanoate (342.7 g, 1018.8 mmol) was dissolved in toluene (200 mL). 4-Methylmorpholine (22.4 mL, 203.8 mmol) was added, followed by the slow addition of methyl propiolate (108.8 g, 1273.6 mmol) over a 60-minute period. The reaction temperature was maintained between 20 and 25°C throughout the addition by cooling in a water / ice bath. After stirring for 3 hours, the mixture was concentrated to give the desired product as a brown, viscous oil (447.6 g, 1167 mmol, Z / E isomer mixture). 1 H NMR assay = 87% w / w (contains both Z and E isomers). 1 H NMR (400 MHz, CDCl3): δ 2.9 - 3.02 (m, 2H), 3.53 (d, 2H), 3.64 (s, 3H), 3.66 (s, 2H), 3.70 (d, 2H), 4.41 (td, 1H), 4.86 (d, 0.08H), 5.20 (d, 0.92H), 6.33 (d, 0.08H), 7.16 - 7.34 (m, 11H), 7.43 (d, 0.92H). 13 C NMR (101 MHz, CDCl3): δ 51.13 (s), 52.30 (s), 54.64 (s), 58.92 (d, J = 5.6 Hz), 79.19 (s), 82.16 (s), 97.20 (s), 98.20 (s), 127.14 (s), 128.18 (d, J = 8.0 Hz), 128.88 (s), 138.54 (s), 138.88 (s), 156.76 (s), 161.01 (s), 167.59 (s), 169.04 (s).

[0225] iii) (2S)-3-amino-2-(3-methoxy-3-oxopropoxy)propanoic acid methyl ester [ka] Pd(OH)2 (20% charcoal, 50% water) (11.17 g, 79.50 mmol) was dried overnight under a stream of nitrogen. It was then suspended in 1,4-dioxane (200 mL) and then added to a solution of methyl 3-{[(2S)-3-(dibenzylamino)-1-methoxy-1-oxopropan-2-yl]oxy}prop-2-enoate (438 g, 994 mmol) dissolved in 1,4-dioxane (3800 mL). The mixture was hydrogenated overnight at 30°C under 10 bar hydrogen pressure. The temperature was raised to 40°C, and the mixture was stirred for an additional 2 days. The mixture was filtered and rinsed with dioxane (200 mL). The dioxane solution (4527 g) was then used directly in the next step. Assay = 4.6% w / w, effective yield 103%. 1 H NMR (400 MHz, CDCl3): δ 1.4 (s, 2H), 2.55 - 2.73 (m, 2H), 2.90 - 2.97 (dd, J=6.7, 13.5, 1H), 3.00 - 3.08 (dd, J=3.8, 13.5, 1H), 3.69 (s, 3H), 3.72 - 3.74 (m, 1H), 3.75 (s, 3H), 3.87 - 3.98 (ddd, 3.7, 6.3, 13.5, 2H).

[0226] iv) (2S)-5-oxo-1,4-oxazepane-2-carboxylic acid methyl ester [ka] To a crude solution of methyl (2S)-3-amino-2-(3-methoxy-3-oxopropoxy)propanoate (204 g, 994 mmol) in dioxane (4.2 L) was added Novozyme 435 (immobilized, 75 g). The mixture was stirred at 45° C. for 2 days. Additional Novozyme 435 (immobilized, 25 g) was added and the mixture was stirred for an additional 2 hours. The temperature was increased to 55° C. and the mixture was stirred for 24 hours. The mixture was filtered through a Celite filter, rinsed with MeOH, and then concentrated to give a soap-like solid (254 g). This was further purified by preparative HPLC to give 85.2 g (492 mmol) of the desired product as a colorless solid (>90% w / w, 1 by H NMR). 1 H NMR (400 MHz, CDCl3): δ 6.98, (1H, s), 4.19 (2H, m), 3.77 (3H,s), 3.69 (1H,m), 3.59 (2H,m), 2.83 (1H, ddd) and 2.63 (1H, dd).

[0227] v) (2S)-5-oxo-1,4-oxazepane-2,4-dicarboxylic acid 4-tert-butyl, 2-methyl [ka] To a mixture of methyl (2S)-5-oxo-1,4-oxazepane-2-carboxylate (152.5 g, 863.0 mmol), N,N-dimethylpyridin-4-amine (2.11 g, 17.3 mmol), and THF (1200 mL) was added di-tert-butyl dicarbonate (192 g, 863.0 mmol). The resulting yellow suspension was then stirred at 30 °C for 20 h. Further di-tert-butyl dicarbonate (11.30 g, 51.8 mmol) was added, and the mixture was stirred at 30 °C for another 20 h. The mixture was concentrated to near dryness in a 37 °C water bath. MTBE (400 mL) was added, followed by concentration to near dryness. This procedure was repeated once more to remove t-BuOH formed in the reaction. Finally, THF (300 mL) was added, followed by concentration to give a yellow oil, which was used directly in the next step. Completion was considered quantitative.1 H NMR (400 MHz, CDCl3): δ 1.48 (s, 9H); 2.77 (ddd, 1H, J = 16.1, 7.0, 1.9 Hz); 2.94 (ddd, 1H, J = 16.1, 9.3, 2.5 Hz); 3.75 (s, 3H); 3.80 (ddd, 1H, J = 12.9, 9.1, 2.0 Hz); 3.91 (dd, 1H, J = 16.0, 7.2 Hz); 4.12-4.30 (m, 2H); 4.38 (dd, 1H, J = 16.0, 1.4 Hz). 13 C NMR (126 MHz, CDCl3): δ 27.9, 42.3, 48.8, 52.6, 63.4, 77.5, 83.8, 152.1, 169.0, 172.6.

[0228] vi) (2S)-1,4-oxazepane-2,4-dicarboxylic acid 4-tert-butyl, 2-methyl [ka] To the crude mixture of 2-methyl 4-tert-butyl (2S)-5-oxo-1,4-oxazepane-2,4-dicarboxylate (212.4 g, 777.2 mmol) from the previous step in THF (2 L) was added BH3-DMS solution (118 g, 1554 mmol) over a 30 min period. The reaction temperature was maintained between 20 and 23 °C throughout the addition. The mixture was then stirred at 23 °C for 17 h. The mixture was slowly transferred to MeOH solution (1.5 L). This mixture was then combined with the crude material obtained in a small-scale experiment (starting with 23.6 g of 4-tert-butyl, 2-methyl (2S)-5-oxo-1,4-oxazepane-2,4-dicarboxylate, using the procedure described above). The clear homogeneous solution was then stirred at 20° C. for 1 hour and then concentrated to near dryness. MeOH (500 mL) was added, then concentrated to near dryness, and repeated once more. ACN (500 mL) was then added, then concentrated to near dryness, and repeated once more. The crude product (24% w / w, 1Determined by H NMR, internal standard: benzyl benzoate) stored as a solution in ACN (500 mL). Effective yield = 71%. 1 H NMR (400 MHz, MeOD, approximately 50:50 rotamer mixture): δ 1.51 (s, 9H); 1.84-1.93 (m, 2H); 3.20-3.34 (m, 1H); 3.42-3.56 (m, 1H); 3.70-3.81 (m, 5H); 4.02-4.12 (m, 2H); 4.36-4.41 (m, 1H). 13 C NMR (100.6 MHz, MeOD, approximately 50:50 rotamer mixture) δ 28.6, 31.0, 31.5, 47.8, 48.2, 51.0, 51.2, 52.6, 68.6, 68.7, 77.6, 77.8, 81.4, 81.6, 156.7, 156.9, 172.8, 172.9.

[0229] vii) (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid To a mixture of ACN (700 mL), water (30 mL), TEA (187 g, 1851 mmol), and water (30 mL) was added LiBr (375 g, 4319 mmol). Next, 4-tert-butyl, 2-methyl (2S)-1,4-oxazepane-2,4-dicarboxylate (160 g, 617 mmol) dissolved in ACN (200 mL) was added at a reaction temperature of 30° C. The mixture was vigorously stirred at 20° C. overnight. Most of the ACN was removed by concentration. MTBE (500 mL) was added to the residue. The yellow aqueous layer was washed with MTBE (200 mL). MTBE (400 mL) was then added to the aqueous layer, which was then acidified to about pH 2 using 2M KHSO4. The aqueous layer was extracted with MTBE (300 mL x 2), and the pooled organic layers were washed with water (100 mL), then concentrated to give a colorless solid (170 g, 80% w / w). The solid was suspended in 30% MTBE in heptane (600 mL), and the mixture was then stirred overnight. The mixture was filtered and the solid was washed with 25% MTBE in heptane (100 mL) and then dried under reduced pressure at 40° C. This gave 140.1 g (571 mmol) of the desired product ( 1 93% w / w by H NMR and 99.7% ee by HPLC). 1 H NMR (400 MHz, MeOD, mixture of two rotamers): δ 1.46 (s, 9H); 1.77-1.90 (m, 2H); 3.15-3.77 (m, 4H); 3.91-4.17 (m, 2H); 4.22-4.32 (m, 1H). 13 C NMR (100.6 MHz, MeOD, mixture of two rotamers) δ 28.5, 28.6, 31.0, 31.3, 47.8, 47.9, 51.4, 68.6, 69.0, 77.7, 78.0, 81.4, 81.7, 156.8, 157.0, 174.0, 174.2.

[0230] Intermediate 3 (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (Second alternative synthesis method) i) 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol [ka] The reactants, 1219 g (7.16 mol) of 3-(benzylamino)propan-1-ol and 1200 g (7.16 mol) of (S)-2-((benzyloxy)methyl)oxirane, were separately dissolved in 3 L of 2-propanol each, charged separately to inerted reactors, and heated at 50° C. for 24 hours. The reaction mixture was evaporated at 60° C. and 110 mbar to give 2.48 kg of oil. The oil was dissolved in 1 L of toluene and evaporated to dryness. Yield: 2.45 kg, Assay: approx. 95%, Effective yield: approx. 98%. 1H NMR (400 MHz, CDCl3): δ 1.59 - 1.78 (m, 2H), 2.47 (dd, J=13.3, 1H), 2.53 - 2.65 (m, 2H), 2.71-2.78 (ddd, 5.6, 7.7, 13.2, 1H), 3.31 - 3.45 (m, 3H), 3.50 (d, 1H), 3.67 - 3.74 (m, J=13.3, 3H), 3.93-3.99 (ddt, J=4.1,4.1,6.2, 8.3, 1H), 4.48 (s, 2H), 7.18 - 7.36 (m, 10H).

[0231] ii) 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propyl methanesulfonate [ka] 147 g (446 mmol) of the diol product from the previous experiment was dissolved in 400 mL of DCM and cooled to -1°C. 72.3 mL (446 mmol) of DIPEA was added to the reactor at -1°C. The solution was cooled to -6°C. 51.1 g (446 mmol) of methanesulfonyl chloride in 200 mL of DCM was then added dropwise to the diol solution over a period of 1 hour at approximately -6°C to -2°C. After the addition, the mixture was stirred for 30 minutes and then poured onto 400 mL of ice. The phases were separated and washed twice with cold water, then twice with brine, and then evaporated to give an oil. The oil was diluted with DCM, extracted with aqueous sodium sulfate, filtered, and evaporated to give 176 g (97%) of an oil (assay 85%). 1 H NMR (600 MHz, CDCl3): δ 1.82-1.87 (m, 2H), 2.47 - 2.56 (m, 3H), 2.59 - 2.67 (m, 1H), 2.86 (s, 3H), 3.02 (s, 1H), 3.38 - 3.45 (m, 2H), 3.49 (d,1H), 3.69 (d, 1H), 3.83 - 3.87 (m, 1H), 4.14-4.20 (m, 2H), 4.49 (s, 2H), 7.20 - 7.32 (m, 10H).

[0232] iii) (2S)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane [ka] 169 g of the crude product from the previous experiment (assay approximately 85%, 143.65 g, 0.35 mol) was dissolved in 300 mL of dry THF and slowly (5 h) added to NaH (1.4 eq, 18.46 g, 0.423 mol) in 200 mL of dry THF (addition started after washing the sodium hydride paste with heptane) in a dry reactor at 25 °C under nitrogen. The reaction mixture was stirred overnight at 25 °C. The next day, 400 mL of saturated aqueous bicarbonate solution was added to the reaction mixture at room temperature. Initially, gas was evolved. The phases were separated and the aqueous phase was discarded. The organic phase was evaporated to give an oil. The oil was dissolved in 400 mL of isopropyl acetate. The isopropyl acetate solution was washed with 100 mL of 2 M NaOH (aq), then twice with water (100 mL), and then with brine. Evaporation gave 136 g of product (assay 65% ​​w / w). Estimated yield: 88 g (81%) 0.28 mol. Chromatography: EtOAc / heptane 254 nm. Isolated yield: 81.6 g (0.26 mol, 74%) 1 H NMR (400 MHz, DMSO-d6): δ 1.66 - 1.76 (m, 1H), 1.77 - 1.87 (m, 1H), 2.37 (dd, 1H), 2.46 - 2.5 (m, 1H), 2.68 - 2.77 (m, 1H), 2.81 - 2.89 (m, 1H), 3.24 (dd, 1H), 3.37 (dd, 1H), 3.64 (d, 2H), 3.64 - 3.74 (m, 1H), 3.76 (ddd, 2H), 4.35 - 4.43 (m, 2H), 7.18 - 7.37 (m, 10H).

[0233] iv) (2S)-1,4-Oxazepan-2-ylmethanol [ka] 81.6 g (0.26 mol) of the product from the previous experiment was dissolved in 1 L of methanol and charged to a hydrogenation vessel under nitrogen. The catalyst, PdOH (20%) (50% humidity)-charcoal 10 g (3 mol%), was slurried in ethanol and charged to a reaction vessel under nitrogen. The mixture was hydrogenated at ambient temperature and 4.5 bar for 72 hours. About 50% conversion was achieved, 10 g of fresh catalyst was added, the pressure was increased to 8 bar, and the temperature was increased from ambient to 45°C. Hydrogenation was carried out overnight. About 96% conversion was achieved. 3 g of catalyst was added to the reaction mixture, and hydrogenation was continued for 6 hours. Complete conversion was achieved, and the reaction mixture was filtered and the sample evaporated to give an oil. 1 H NMR (500 MHz, MeOD): δ 1.60-1.79 (m, 2H), 2.42 - 2.53 (dd,J=8.8, 14, 1H), 2.62-2.81 (dddd, J=4.2,7.3,13.5,49,2H), 2.81-2.89 (dd, 1H), 2.94 (dd, 1H), 3.17 (s, 1H), 3.24 - 3.37 (qd, J=5.6, 11.4, 11.4, 11.4, 2H), 3.41-3.48 (m, 1H), 3.53 (td, J=3.9, 7.9, 7.8, 1H), 3.74-3.84 (dt, J=5.5, 5.5, 12.2, 1H).

[0234] v) tert-butyl (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate [ka] A solution of the product from the previous experiment (approximately 0.26 mol) in methanol (approximately 1.2 L), after filtering off the catalyst, was treated with 54.3 g (0.25 mol) of Boc anhydride under CO (g) at room temperature to initiate direct formation. The reaction was left stirring under nitrogen overnight. The reaction mixture was evaporated to dryness to give 59 g (98%) of a light yellow liquid. 1 H NMR (500 MHz, MeOD): δ 1.47 (s, 9H), 1.81-1.93 (qt, J=3.51, 3.51, 6.3, 6.3, 6.3, 2H), 3.03-3.16 (ddd, J=9.5, 14.4, 21.8, 1H), 3.29-3.32 (dt, J=1.6, 1.6, 3.3, 1H), 3.32 - 3.41 (m, 1H), 3.43 - 3.56 (m, 3H), 3.56 - 3.71 (m, 2H), 3.78 (dd, 1H), 4.07 (tq, 1H).

[0235] vi) (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid Dissolve 52.5 g (40.7 g, assay 85%) of tert-butyl (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate in 300 mL of DCM. Dissolve 0.5 g of TEMPO in 100 mL of DCM. Dissolve 3.88 g of tetrabutylammonium hydrogen sulfate in 100 mL of DCM. These three DCM solutions were charged to a reaction vessel and 100 mL of water was added. A 350 mL solution of 10-15% sodium hypochlorite was adjusted to approximately pH 8-9 with approximately 100 mL of sodium bicarbonate (liquid + solid). 58 mL of a 0.5 M solution of sodium bromide was added to the buffered solution. The resulting aqueous solution was added dropwise to a two-phase system consisting of a DCM mixture and water at 0°C with stirring. The reaction was exothermic. Following the addition, a color change occurred (from yellow to pale yellow). This color change indicated when the oxidant was consumed. After 10 minutes, the jacket was set to -5°C to maintain an internal temperature of approximately 10°C. The addition was complete in 45 minutes, and the reaction mixture was allowed to stand overnight. Workup: At room temperature, the off-white reaction mixture was adjusted to approximately pH 2-3 with approximately 40 g of potassium hydrogen sulfate. The phases were separated, and the aqueous phase was washed with DCM (100 mL x 3). The resulting DCM (800 ml) solution was evaporated to give approximately 100 g of oil. The oil was dissolved in 400 ml of bicarbonate solution and extracted with DCM (75 ml x 2). The remaining aqueous phase was acidified to pH 2-3 with approximately 35-40 g of potassium hydrogen sulfate and extracted with DCM (75 ml x 5). Evaporation of the DCM gave 40.7 g of white crystals; yield: 40.7 g, 85% yield based on assay of starting material. The product contained 10% water. Purification: The product was slurried with 200 mL of toluene and heated to 60° C. to form a solution. Approximately 100 mL of toluene was removed by evaporation, and the acidic product began to crystallize at 60° C. The mixture was cooled to room temperature. The product was filtered and washed with toluene. The product was dried under reduced pressure. 1 H NMR (600 MHz, CDCl3): δ 1.46 (s, 9H), 1.93 (s, 2H), 3.23 (ddt, 1H), 3.33 - 3.78 (m, 3H), 3.95 - 4.38 (m, 3H), 9.91(s,1H).

[0236] Intermediate 4 tert-Butyl (2S)-2-{[(2S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate To T3P (25 g, 39.3 mmol, 50% solution in DMF) in DMF (200 mL) was added (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (Intermediate 3, 7.9 g, 32.2 mmol) and (S)-2-amino-3-(4-iodophenyl)propanamide (9.0 g, 32.2 mmol, prepared according to the procedure in WO 2009 / 074829, p. 45). TEA (25 mL, 180.3 mmol) was added, and the reaction was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure. The resulting oil was dissolved in EtOAc and washed successively with 2 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and sodium chloride solution. The organic extract was dried (magnesium sulfate), filtered and concentrated in vacuo to give the title compound as a yellow foamy oil (13.1 g, 79%) which was used in the next step without further purification.

[0237] Intermediate 5 tert-Butyl (2S)-2-{[(1S)-1-cyano-2-(4-iodophenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate To a solution of tert-butyl (2S)-2-{[(2S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate (Intermediate 4, 8.86 g, 17.13 mmol) in DCM (740 mL) was added Burgess reagent (8.16 g, 34.27 mmol). After stirring the reaction mixture at room temperature for 24 hours, the reaction mixture was transferred to a separatory funnel and washed with water. The organic extract was dried (phase separator cartridge) and concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography eluting with 25% EtOAc in isohexane to give a yellow oil. Trituration with diethyl ether gave the title compound as an off-white solid (6.05 g, 71%). 1H NMR (400 MHz, CDCl3): δ 7.66 (d, 2H), 6.98 (m, 3H), 5.06 (s, 1H), 4.22-3.92 (m, 3H), 3.70 (m, 0.5H), 3.54-3.20 (m, 2.5H), 3.09-2.89 (m, 3H), 1.88 (s, 2H), 1.42 (s, 9H).

[0238] Intermediate 6 tert-Butyl (2S)-2-[[(1S)-2-amino-2-oxo-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]ethyl]carbamoyl]-1,4-oxazepane-4-carboxylate To a stirred solution of tert-butyl (2S)-2-{[(2S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate (Intermediate 4, 0.5 g, 0.97 mmol) in dry DMSO (2.5 mL) under nitrogen, Pin2B2 (0.32 g, 1.26 mmol), potassium acetate (0.28 g, 2.9 mmol), and Pd(dppf)Cl·DCM (0.039 g, 5 mol%) were added. The reaction was heated at 85 °C for 5 h and allowed to stand at room temperature overnight. Water (15 mL) was added, and the mixture was extracted with EtOAc (50 mL × 2). The combined extracts were washed with saturated sodium chloride (20 mL), dried (magnesium sulfate), and evaporated under reduced pressure. The resulting oil was purified by silica gel column chromatography eluting with EtOAc to give the title compound as a colorless oil (0.3 g, 60%). 1H NMR (400 MHz, CDCl): δ 7.75 (d, 2H), 7.28-7.21 (m, 2H), 5.30 (s, 1H), 4.60 (m, 1H), 4.18-3.98 (m, 2H), 3.51-3.42 (m, 1H), 3.12 (t, 2H), 2.80 (s, 1H), 2.05 (s, 2H), 1.88 (s, 1H), 1.60 (s, 4H), 1.54-1.33 (m, 6H), 1.40-1.16 (m, 12H) (three exchangeable protons not observed).

[0239] Example

[0240] Example 1 (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide [ka] i) tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate To a solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (Intermediate 3, 0.294 g, 1.2 mmol) in DCM (15 mL) was added 2-pyridinol-1-oxide (0.155 g, 1.4 mmol), TEA (0.36 g, 3.6 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.268 g, 1.4 mmol). After 20 min, 4'-[(2S)-2-amino-2-cyanoethyl]biphenyl-4-carbonitrile (Intermediate 1, 0.296 g, 1.2 mmol) was added, and the mixture was stirred for 3 h and then left at room temperature for 18 h. The mixture was heated at 40 °C for 4 h, after which water (15 mL) was added. After 10 min, the DCM was dried (phase separator cartridge) and evaporated under reduced pressure. The resulting yellow oil was purified by silica gel column chromatography to give the sub-title compound (0.29 g, 52%), which was used in the next step without further purification.

[0241] ii) (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide Prepared according to the procedure in step ii) of Method A using tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate to afford the title compound as a white solid (60 mg, 28%). 1 H NMR (400 MHz, CDCl): δ 7.77-7.65 (m, 4H), 7.62-7.57 (m, 2H), 7.40 (d, 2H), 7.11 (d, 1H), 5.18-5.11 (m, 1H), 4.19-4.14 (m, 1H), 4.06-3.96 (m, 2H), 3.75-3.69 (m, 1H), 3.56-3.48 (m, 2H), 3.18-3.05 (m, 3H), 2.95-2.90 (m, 1H), 2.70 (ddd, 1H) (one exchangeable proton not observed). LCMS (10cm_ESCI_Formic_MeCN) t R 2.57 (min) m / z 375 (MH + ).

[0242] Example 2 (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide [ka]

[0243] i) tert-butyl (2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate [ka] To a solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (Intermediate 3, 490 mg, 2.0 mmol) in DCM (15 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (468 mg, 2.44 mmol) and 2-pyridinol 1-oxide (271 mg, 2.44 mmol). The reaction was stirred at room temperature for 30 minutes, after which (2S)-2-amino-3-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]propanenitrile (Intermediate 2, 586 mg, 2.0 mmol) and DiPEA (1.79 mL, 10 mmol) were added. The reaction was stirred at room temperature for 18 hours and then transferred to a separatory funnel. The mixture was washed with 2M hydrochloric acid, saturated sodium bicarbonate solution, and brine. The organic extract was passed through a hydrophobic frit / phase separator and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 0-60% EtOAc in isohexane to give the subtitle compound as an oil (457 mg, 44%). 1 H NMR (400 MHz, CDCl3): δ 7.63-7.52 (m, 2H), 7.38 (d, 2H), 7.36-7.24 (m, 2H), 7.35-6.98 (m, 2H), 5.18 (t, 1H), 4.22-3.97 (m, 2H), 3.76-3.67 (m, 0.5H), 4.10-2.94 (m, 4.5H), 3.35-3.26 (m, 1H), 3.24-3.04 (m, 3H), 2.06-1.82 (m, 2H), 1.47 (s, 10H).

[0244] ii) (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide tert-Butyl (2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (457 mg, 0.85 mmol) was dissolved in formic acid (3 mL) and heated on a preheated hotplate stirrer at 50° C. for 10 minutes. The reaction was then concentrated under reduced pressure, dissolved in DCM, and washed with saturated sodium bicarbonate solution. The organic extract was passed through a hydrophobic frit / phase separator and concentrated under reduced pressure. The resulting foam was purified by silica gel column chromatography eluting with 0-5% methanolic ammonia (7N) in DCM to give the title compound as a solid (230 mg, 64%). 1 H NMR (400 MHz, CDCl): δ 7.59-7.51 (m, 2H), 7.39 (dd, 2H), 7.33-7.23 (m, 3H), 7.14 (d, 1H), 5.23-5.12 (m, 1H), 4.12-4.06 (m, 1H), 4.05-3.95 (m, 1H), 3.81-3.71 (m, 1H), 3.46 (s, 3H), 3.34-3.26 (m, 1H), 3.19-3.00 (m, 3H), 2.99-2.82 (m, 2H), 1.92-1.77 (m, 2H) (one exchangeable proton not observed). LCMS (10cm_ESCI_Formic_MeCN) t R 2.48 (min) m / z 375 (MH + ).

[0245] Example 2 (Alternative synthesis method) (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide i) 5-chloro-1,3-benzoxazol-2(3H)-one [ka] CDI (497 g, 3.07 mol) was added to a solution of 2-amino-4-chlorophenol (400 g, 2.79 mol) in 2-MeTHF (6 L) under N2 (exotherm 11.0 °C to 22.0 °C). The reaction mixture was heated at reflux for 1 h. The mixture was cooled to room temperature and washed with 2 M HCl (aq) (6 L), 8% NaHCO3 (aq) (6 L), and brine (3 L). The organic layer was dried over MgSO4, filtered, and evaporated. This gave the product as a light brown solid (456.1 g, 97% yield, LC purity >99%). 1 H NMR (270 MHz, DMSO-d6): δ 12.0-11.5 (brs, 1H), 7.31 (d, 1H), 7.12 (m, 2H). LCMS (5cm_ESCI, aq. formic acid_metanol) t R 3.87 (min) m / z 169.8 (MH + ).

[0246] ii) 5-chloro-3-methyl-1,3-benzoxazol-2(3H)-one [ka] To a solution of 5-chloro-1,3-benzoxazol-2(3H)-one (step i) (1111.8 g, 6.56 mol) in DMF (4.12 L) was added CsCO (2136.4 g, 6.56 mol), while maintaining the temperature at 0-5 °C. Next, MeI (450 mL, 7.21 mol) was added slowly, while maintaining the temperature at 0-5 °C. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was cooled to 0-5 °C, and HO (4.12 L) was added slowly. Next, the reaction mixture was warmed to room temperature and stirred for 15 min. The solid was filtered and washed with water (980 mL × 4). The filter cake was dried under vacuum at 55 °C overnight (1149.9 g, 96% yield, LC purity >99%, HO: (Karl Fischer) 0.1%). 1H NMR (270 MHz, DMSO-d6): δ 7.45 (d, 1H), 7.35 (d, 1H), 7.15 (dd, 1H), 3.35 (s, 3H). LCMS (5cm_ ESCI_aq. formic acid_methanol) t R 4.13 (min) m / z 183.8 (M + ).

[0247] iii) 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one [ka] A solution of 5-chloro-3-methyl-1,3-benzoxazol-2(3H)-one (step ii)) (350 g, 1.91 mol), B2pin2 (581.0 g, 2.29 mol), and KOAc (561.3 g, 5.72 mol) was degassed under vacuum and purged with N2 (×3). Pd(OAc)2 (12.9 g, 57.2 mmol) and XPhos (54.6 g, 114 mmol) were added, and the mixture was degassed under vacuum and purged with N2 (×3). The mixture was heated to 75°C. A large exotherm was observed at approximately 70°C, causing the mixture to warm to reflux (100°C). The reaction mixture was stirred without heating for 1 hour. HPLC analysis indicated that 2.5% starting material remained, so the mixture was heated at 85°C for 1 hour. No further change was observed at this stage. Further B2pin2 (14.6 g, 57.2 mmol), KOAc (5.7 g, 57.2 mmol), Pd(OAc)2 (12.9 g, 57.2 mmol), and XPhos (27.3 g, 57.2 mmol) were added, and the mixture was stirred at 75° C. for 1 hour. HPLC analysis showed that no starting material remained. The mixture was cooled to room temperature, filtered through a pad of Celite (501 g), and the cake was washed with EtOAc (2240 ​​ml). The filtrate was combined with two other batches (350 g × 2) prepared in the same way and evaporated. This gave 1865.1 g of product as a gray solid (97% yield, 90.0% purity by LC). 1 Purity 82±2% by H NMR (DMSO-d6) assay vs. TCNB. 1H NMR (270MHz, DMSO-d6): δ 7.40-7.50 (m, 2H), 7.30 (d, 1H), 3.40 (s, 3H), 1.30 (s, 12H). LCMS (5cm_ ESCI_aq. formic acid_methanol_) t R 4.91 (min) m / z 276.1 (MH + ).

[0248] iv) Nα-(tert-butoxycarbonyl)-4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide [ka] To a suspension of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one (step iii)) (859 g, 700 g active, 2.544 mol) and (S)-1-carbamoyl-2-(4-iodophenyl)ethyl tert-butyl carbamate (prepared according to the procedure on page 47 of WO 2009 / 074829) (903 g, 2.313 mol) in dioxane (4.1 L) was added 2 M K2CO3 (2.3 L). The suspension was degassed under vacuum and purged with N2 (x3). Pd(dppf)Cl2·DCM (28.33 g, 0.0347 mol) was added and the reaction mixture was heated at 75 °C for 3 h. The mixture was cooled to room temperature and diluted with water (6.4 L). The suspension was stirred at room temperature overnight; the solid was filtered and washed with water (1 L x 3). The product was dried at 45°C for 3 days (1269.1 g, 1 133% yield by H NMR - contains pinacol related impurities and dioxane, LC purity 94.3%, HO:(Karl Fischer) 3.35%). 1 H NMR (270 MHz, DMSO-d6): δ 7.62-7.34 (m, 7H), 7.04 (brs, 2H), 6.86 (d, 1H) 4.12 (m, 1H), 3.40 (s, 3H), 3.00 (dd, 1H), 2.78 (dd, 1H), 1.30 (s, 9H). LCMS (5cm_ESI_Water_MeCN) R 4.51 (min) m / z 312 (MH + ).

[0249] v) 4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide [ka] To a very thick suspension of Nα-(tert-butoxycarbonyl)-4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide (step iv) (1269 g, estimated activity 952 g, 2.3138 mol) in DCM (2.1 L) under N2, 4.1 M HCl in dioxane (2.7 L, 11.06 mol) was added dropwise over 1 h, maintaining the temperature at about 15 °C (the suspension became more mobile after the addition of about 0.5 L of 4.1 M HCl in dioxane). After 2 h, the mixture was diluted with water (5.6 L) and stirred at room temperature for 30 min. The mixture was then filtered through a pad of Celite (500 g) to remove undissolved material - a very slow filtration; the Celite was checked for product by LC. The pad was washed with water (400 ml). The layers were separated into DCM / dioxane-water. The aqueous layer was cooled to about 5°C and 35% NH3(aq) (700 ml) was added slowly to reach pH=9-10. The suspension was stirred overnight, then the product was filtered and washed with water (400 ml x 3). The product was dried under vacuum at 45°C (off-white solid, 489.4 g, 68% yield over two steps, 99.4% purity by LC, >99% EP, 1 Purity 98 ± 2% by H NMR assay vs. TCNB in ​​DMSO, HO: (Karl Fischer) 0.92%). 1 H NMR (270 MHz, DMSO-d6): δ 7.59-7.30 (m, 7H), 6.98 (brs, 1H), 3.36 (m, 4H), 2.95 (dd, 1H), 2.67 (dd, 1H) 1.86 (brs, 2H). LCMS (5cm_ESI_Water_MeCN) R 2.76 (min) m / z 312 (MH + ).

[0250] vi) tert-butyl (2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate [ka] To a solution of 4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide (step v)) (756 g, active 733 g, 2.354 mol) and (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (577 g, 2.354) (Intermediate 3) in DMF (3 L) was added DiPEA (1230 ml, 7.062 mol) under N2. T3P in DMF (50% w / w, 1924 ml, 3.296 mol) was added dropwise over 1.5 hours, maintaining the temperature below 25°C. After 30 minutes, an LC completion check indicated the coupling reaction was complete. DiPEA (1230 ml, 7.062 mol) was then added, and the reaction mixture was heated to 50°C. T3P in DMF (50% w / w, 3986 ml, 6.827 mol) was added dropwise over 1 hour (no exotherm was observed). The reaction mixture was stirred at 50°C for 4 hours and then at room temperature overnight. The mixture was cooled to 10°C and diluted with 2-MeTHF (4 L) and water (5.6 L, exotherm). The layers were separated and the aqueous layer was extracted with 2-MeTHF (4 L x 2). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. This gave the product as a light brown solid in 98% yield (1242 g (active 1205 g), corrected yield 98%, LC purity 98.4%, 1 H NMR assay vs. TCNB 97±2%, 1 Major impurities by H NMR: 2-MeTHF 1.9%, DMF 0.6%).

[0251] vii) (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide A solution of tert-butyl (2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (step vi)) (1776 g, activity 1671 g, 3.210 mol) in formic acid / water (4.2 L / 440 ml) was stirred on a buchi under reduced pressure (300-500 mbar) at 35-37° C. After 3 h, an LCMS completion check showed 93.95% product and 0.5% starting material. The mixture was concentrated (4 h) to give an oily residue. The residue was dissolved in water (4.4 L) and washed with TBME (2.2 L). The aqueous layer was vigorously stirred and treated with NH3(aq) (1.8 L) at <25°C to reach pH = 9-10. The mixture was stirred at room temperature for 3 hours. The solid was filtered and washed with water (1 L x 3). The filter cake was dried at 45°C overnight. This gave the product as a light brown solid (1498 g, activity 1333 g, LC 91.5%, 1 H NMR assay vs. TCNB 89±2%, HO:(Karl Fischer) 4.63%).

[0252] The crude product was recrystallized from EtOH / H2O in two batches (747 g x 2). Batch A: The crude product (747 g) was dissolved in EtOH (8 L) under reflux under N2. Water (1.6 L) was slowly added. The mixture was hot filtered (65 ° C) to remove black particles (filtrate temperature 50 ° C), and then stirred at 40 ° C overnight. The suspension was cooled to 10 ° C over 4 hours and maintained at this temperature for 3 hours. The product was filtered and washed with EtOH / H2O (8:2, 500 ml × 3), then with water (500 ml × 3). The filter cake was dried overnight at 45 ° C (473 g, purity by LC 97.7%, Pd level 71.4 ppm). Batch B yielded 436 g of product (95.8% purity by LC, Pd level 65.8 ppm). The liquid from both batches was combined and concentrated to approximately 8 L. The liquid was left at room temperature overnight. The solid was filtered and washed with EtOH / HO (8:2, 400 ml x 3), then with water (400 ml x 3). The product was dried at 45 °C overnight. This gave an additional 88 g of product (LC purity 95.0%).

[0253] The products (LC purity of the blend 95.69%) were recrystallized from EtOH / H2O in two batches (Batch C: 520 g, Batch D: 520 g). Batch C: The crude product (520 g) was dissolved in EtOH (6.24 L) under reflux under N2. Water (1248 ml) was added slowly. The mixture was cooled to 40°C (3 h), seeded with 0.5 g of the title compound, and stirred at 40°C for 10 h. The mixture was then cooled to 26°C over 7 h. The resulting suspension was cooled to 10°C and stirred at that temperature for 6 h. The product was filtered and washed with EtOH / water (8:2, 500 ml x 3) and water (500 ml x 3). The filter cake was dried at 45°C for 2 days. The product was obtained as a grey solid (418 g, yield approx. 56%, LCMS purity 97.5%, chiral LC 100%, 1 H NMR (DMSO-d6) assay vs. TCNB 100±2%). Batch D: 418g, yield approximately 56%, LCMS purity 97.5%, chiral LC 100% 1 H NMR (DMSO-d6) assay vs. TCNB 100±2%

[0254] These products were blended with material from an intermediate scale reaction carried out in the same manner and reanalyzed (968 g, LC purity 98.04%, chiral LC 100%, 1 H NMR assay vs. TCNB 99±2%, 1 0.35% EtOH, HO: (Karl Fischer) 4.58% by H NMR, Pd 57.6 ppm, XRPD (X-ray powder diffraction) Form A.

[0255] [Table 2] [Table 3]

[0256] Example 2. Preparation of Crystalline Form B (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, Form A (5 g), prepared by the method described above, was charged to a reaction vessel. Acetone (35 ml) was added, and the mixture was heated in a heating block at 60-65°C. The heating block was turned off, and the resulting solution was allowed to cool to room temperature. The resulting suspension was filtered, and the filtrate was dried in a vacuum oven at 40°C and ≦600 mbar overnight. XRPD (X-ray powder diffraction), Form B.

[0257] [Table 4] [Table 5]

[0258] Example 2. Preparation of Crystalline Form C (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, Form A (50 mg) prepared by the method described above was loaded into a 1.5 mL scintillation vial. Propan-2-ol (1 ml) was added, and the mixture was placed in an orbital shaker equipped with a heating block at 40° C. for 1 day. The resulting suspension was filtered, and the filtrate was dried. XRPD (X-ray powder diffraction), Form C.

[0259] [Table 6] [Table 7]

[0260] Example 2. Preparation of Xinafoate Salt, Crystalline Form A (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, Form A (100 mg) prepared by the method described above was loaded into a 1.5 mL scintillation vial. Approximately 48 mg of 1-hydroxy-2-naphthoic acid was added. Subsequently, 1.5 mL of ACN and 0.03 mL of water were added, and the mixture was stirred at room temperature using a magnetic stir bar for approximately 6 hours. The vial was closed during this stirring period. The resulting suspension was centrifuged at 7500 rpm for 5 minutes, and the supernatant was removed using a Pasteur pipette. The moist solid residue was dried in a vacuum oven at 30°C and 30 mbar for approximately 60 hours. XRPD (X-ray powder diffraction), Form A xinafoate salt.

[0261] [Table 8] [Table 9]

[0262] Example 2. Preparation of R-Mandelate Salt, Crystalline Form A (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, Form A (120 mg) prepared by the method described above was loaded into a 1.5 mL scintillation vial. Approximately 45 mg of R-(-)-mandelic acid was added. Subsequently, 1.5 mL of ACN and 0.04 mL of water were added, and the mixture was stirred at room temperature using a magnetic stir bar for approximately 6 hours. The vial was closed during this stirring period. The resulting suspension was centrifuged at 7500 rpm for 5 minutes, and the supernatant was removed using a Pasteur pipette. The moist solid residue was dried in a vacuum oven at 30°C and 30 mbar for approximately 60 hours. XRPD (X-ray powder diffraction), R-mandelate salt, Form A.

[0263] [Table 10] [Table 11]

[0264] Example 3 (Method A) (2S)-N-{(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide [ka] i) tert-butyl (2S)-2-({(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3,7-dimethyl-1,3-benzoxazol-2(3H)-one (boronic ester 1, 154 mg, 0.56 mmol) and tert-butyl (2S)-2-{[(1S)-1-cyano-2-(4-iodophenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (Intermediate 5, 266 mg, 0.53 mmol) were dissolved in ACN (13 mL) and water (0.5 mL). Potassium carbonate (110 mg, 0.80 mmol) was added, and the reaction mixture was degassed for 20 minutes. Pd(dppf)Cl·DCM (43 mg, 0.053 mmol) was then added. The reaction mixture was heated at 80° C. for 90 minutes. The reaction was then concentrated in vacuo and purified by silica gel column chromatography eluting with a gradient of 0-80% EtOAc in isohexane to give the subtitle compound as a pale brown solid (242 mg, 85%). 1 H NMR (400 MHz, CDCl3): δ 7.55 (d, 2H), 7.36 (d, 2H), 7.16-7.02 (m, 3H), 6.96 (s, 1H), 5.16 (s, 1H), 4.17-4.00 (m, 3H), 3.56-3.48 (m, 1H), 3.53-3.36 (m, 3H), 3.21-3.12 (m, 2H), 2.44 (s, 3H), 1.95 (d, 2H), 1.47 (s, 9H), 0.94-0.87 (m, 2H).

[0265] ii) (2S)-N-{(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide tert-Butyl (2S)-2-({(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (240 mg, 0.45 mmol) was dissolved in formic acid (3 mL) and heated on a preheated hotplate stirrer at 50° C. for 10 minutes. The reaction was then concentrated under reduced pressure, dissolved in DCM, and washed with saturated sodium bicarbonate solution. The organic extract was dried (phase separator cartridge) and concentrated under reduced pressure. The solid was purified by silica gel column chromatography eluting with 0-2% methanolic ammonia (7N) in DCM to give the title compound as a white solid (54 mg, 27%). 1 H NMR (400 MHz, DMSO-d): δ 8.62 (d, 1H), 7.65 (d, 2H), 7.38 (d, 3H), 7.28 (s, 1H), 5.03 (q, 1H), 4.00 (dd, 1H), 3.90-3.82 (m, 1H), 3.73 (ddd, 1H), 3.39 (s, 3H), 3.32 (s, 3H), 3.24-3.13 (m, 2H), 3.04 (dd, 1H), 2.82-2.74 (m, 1H), 2.38 (s, 2H), 1.80-1.68 (m, 2H) (one exchangeable proton not observed). LCMS (10cm_ESCI_Formic_MeCN) t R 2.58 (min) m / z 435 (MH + ).

[0266] Example 4 (Method B) 4'-[(2S)-2-cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate [ka] i) tert-butyl (2S)-2-{[(2S)-1-amino-3-{3'-[(methylsulfonyl)oxy]biphenyl-4-yl}-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate (2S)-2-[[(1S)-2-amino-2-oxo-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]ethyl]carbamoyl]-1,4-oxazepane-4-carboxylate tert-butyl 2-({(2S)-1-amino-1-oxo-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 A suspension of tert-butyl (3-iodophenyl)propan-2-yl}carbamoyl)-1,4-oxazepane-4-carboxylate (Intermediate 6, 0.21 g, 0.4 mmol), (3-iodophenyl)methanesulfonate (0.13 g, 0.44 mmol), and potassium carbonate (0.16 g, 1.2 mmol) in ACN (30 mL) and water (1.2 mL) was degassed under nitrogen for 10 min. Pd(dppf)Cl·DCM complex (0.032 g, 10 mol%) was added, and the reaction mixture was heated at 80 °C for 120 min. The solvent was removed under reduced pressure, and the residue was treated with water (20 mL) and DCM (25 mL). The DCM was dried (phase separation cartridge) and evaporated under reduced pressure to give the subtitle compound as a dark brown glass (0.24 g, >100%). 1 H NMR (400 MHz, CDCl): δ 7.54-7.43 (m, 5H), 7.35-7.19 (m, 3H), 5.58 (m, 1H), 4.71 (s, 1H), 4.21-3.94 (m, 3H), 3.81-3.76 (m, 1H), 3.52-3.44 (m, 3H), 3.23-3.14 (m, 4H), 2.80 (s, 1H), 2.20-1.54 (m, 1H), 1.45 (s, 9H) (three exchangeable protons not observed).

[0267] ii) tert-butyl (2S)-2-{[(1S)-1-cyano-2-{3'-[(methylsulfonyl)oxy]biphenyl-4-yl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate To a stirred solution of tert-butyl (2S)-2-{[(2S)-1-amino-3-{3'-[(methylsulfonyl)oxy]biphenyl-4-yl}-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate (0.24 g) in DCM (20 mL) was added Burgess reagent (0.11 g, 0.046 mmol). After 3 days, additional reagent (0.11 g, 0.046 mmol) was added and stirring continued for 6 h. The reaction was left overnight and then washed with water (20 mL). The organic extract was dried (phase separation cartridge) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in isohexane to give the subtitle compound as a colorless glass (0.18 g, 83% over two steps). 1 H NMR (400 MHz, CDCl): δ 7.61-7.45 (m, 5H), 7.38 (m, 3H), 7.06 (s, 1H), 5.17 (s, 1H), 4.20-3.99 (m, 2H), 3.75-3.63 (m, 1H), 3.57-3.37 (m, 3H), 3.49-2.85 (m, 3H), 1.94 (s, 2H), 1.57 (s, 1H), 1.51-1.35 (m, 9H), 1.33 (s, 1H) (one exchangeable proton not observed).

[0268] iii) 4'-[(2S)-2-cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate A solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-{3'-[(methylsulfonyl)oxy]biphenyl-4-yl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (0.18 g, 0.33 mmol) in formic acid (3 mL) was heated at 50° C. for 15 minutes. The mixture was evaporated under reduced pressure. The residue was dissolved in DCM (20 mL) and stirred with saturated sodium bicarbonate (30 mL). The layers were separated, and the organic extract was dried (phase separation cartridge) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 2% 7N methanolic ammonia in DCM. The resulting solid was recrystallized from 1:1 diisopropyl ether: EtOAc to give the title compound as a colorless solid (50 mg, 34%). 1 H NMR (400 MHz, CDCl): δ 7.61-7.46 (m, 5H), 7.40 (dd, 2H), 7.38-7.18 (m, 1H), 7.18 (d, 1H), 5.23-5.12 (m, 1H), 4.12-4.06 (m, 1H), 4.05-3.95 (m, 1H), 3.81-3.71 (m, 1H), 3.35-3.26 (m, 1H), 3.22-3.09 (m, 4H), 3.07-2.81 (m, 3H), 1.91-1.77 (m, 2H) (two exchangeable protons not observed). LCMS (10cm_ESCI_Bicarb_MeCN) t R 2.75 (min) m / z 444 (MH + ).

[0269] Examples 5 to 33 Using the methods and intermediates described above, the following compounds were prepared: [ka] [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8] [Table 12-9] [Table 12-10] [Table 12-11] [Table 12-12] [Table 12-13] [Table 12-14] [Table 12-15]

[0270] Example 34 Diastereomeric mixture of (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide and (2R)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide [ka] i) tert-butyl 2-{[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate To T3P (700 mg, 50% solution in DMF) in DMF (2 mL) was added rac-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (248 mg, 1.01 mmol) and 4'-[(2S)-2-amino-2-cyanoethyl]biphenyl-4-carbonitrile (Intermediate 1, 1200 mg, 0.81 mmol). TEA (640 μL, 4.54 mmol) was added, and the reaction was stirred at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure. The resulting oil was dissolved in EtOAc and washed successively with 2 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and sodium chloride solutions. The organic extract was dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give the subtitle compound as a yellow oil, which was used in the next step without further purification.

[0271] ii) Diastereomeric mixture of (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide and (2R)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide The preparation was carried out according to the procedure in step ii) of Method A using tert-butyl 2-{[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate to give the title compound as a white solid (150 mg, 50% over two steps). The isolated compound was a mixture of two diastereomers that were not separated. 1H NMR (400 MHz, CDCl): δ 7.75-7.64 (m, 4H), 7.59 (dd, 2H), 7.43 (dd, 2H), 7.30-7.22 (m, 1H), 5.25-5.11 (m, 1H), 4.12-4.06 (m, 1H), 4.05-3.95 (m, 1H), 3.81-3.70 (m, 1H), 3.33 (ddd, 1H), 3.25-3.09 (m, 2H), 3.08-3.00 (m, 1H), 2.98-2.81 (m, 2H), 1.92-1.75 (m, 2H) (one exchangeable proton not observed). LCMS (10cm_ESCI_Formic_MeCN) tR 2.58 (min) m / z 375 (MH + ).

[0272] Example 35 (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide [ka] i) tert-butyl (2S)-2-({(2S)-1-amino-3-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]-1-oxopropan-2-yl}carbamoyl)-1,4-oxazepane-4-carboxylate 7-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-1-methylquinoxalin-2(1H)-one (boronic ester 2, 100 mg, 0.37 mmol) and tert-butyl (2S)-2-{[(2S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylate (Intermediate 4, 182 mg, 0.35 mmol) were dissolved in ACN (9 mL) and water (0.4 mL). The reaction mixture was degassed under nitrogen for 30 minutes, after which potassium carbonate (73 mg, 0.53 mmol) and Pd(dppf)Cl·DCM (29 mg, 0.035 mmol) were added. The reaction mixture was heated at 80° C. for 1 hour. The reaction was then concentrated under reduced pressure. Purification by silica gel column chromatography eluting with 8% methanol in EtOAc gave the subtitle compound as a brown oil (192 mg, 100%) which was used in the next step without further purification.

[0273] ii) tert-butyl (2S)-2-({(1S)-1-cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate To a solution of tert-butyl (2S)-2-({(2S)-1-amino-3-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]-1-oxopropan-2-yl}carbamoyl)-1,4-oxazepane-4-carboxylate (192 mg, 0.35 mmol) in DCM (15 mL) was added Burgess's reagent (167 mg, 0.70 mmol). The reaction mixture was stirred at room temperature for 24 hours. After which time the reaction was transferred to a separatory funnel and washed with water. The organic extract was dried (phase separator cartridge) and concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography eluting with 65% EtOAc in isohexane to give a yellow oil. Trituration with diethyl ether gave the subtitle compound as an oil (101 mg, 54%). 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 7.95 (d, 1H), 7.67 (d, 2H), 7.58 (dd, 1H), 7.49 (d, 1H), 7.43 (d, 2H), 7.10-7.03 (m, 1H), 5.25-5.12 (m, 1H), 4.23-4.10 (m, 3H), 3.77 (s, 3H), 3.54-3.49 (m, 3H), 3.28-3.19 (m, 3H), 2.05-1.89 (m, 2H), 1.47 (s, 9H).

[0274] iii) (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide tert-Butyl (2S)-2-({(1S)-1-cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (101 mg, 0.19 mmol) was dissolved in formic acid (2 mL) and heated on a preheated hotplate stirrer at 50° C. for 10 minutes. The reaction was then concentrated under reduced pressure, dissolved in DCM, and washed with saturated sodium bicarbonate solution. The organic extract was passed through a hydrophobic frit / phase separator and concentrated under reduced pressure. The solid was purified by silica gel column chromatography eluting with 0-2% methanolic ammonia (7N) in DCM to give the title compound as a yellow solid (65 mg, 80%). 1H NMR (400 MHz, CDCl): δ 8.32 (s, 1H), 7.95 (d, 1H), 7.65 (d, 2H), 7.57 (dd, 1H), 7.47 (m, 3H), 7.21 (d, 1H), 5.22 (dt, 1H), 4.11 (dd, 1H), 4.00 (dt, 1H), 3.75 (m, 5H), 3.32 (dd, 1H), 3.17 (m, 2H), 3.06 (dd, 1H), 2.99-2.87 (m, 2H), 1.89-1.81 (m, 2H) (two exchangeable protons not observed). LCMS (10cm_ESCI_Formic_MeCN) tR 2.38 (min) m / z 432 (MH + ).

[0275] Example 36 (2S)-2-[(3S,4E)-6-(2,3-dihydro-1H-indol-1-yl)-6-oxohex-4-en-3-yl]-1,4-oxazepane-2-carboxamide trifluoroacetic acid [ka] i) tert-butyl (2S)-2-{[(3S,4E)-6-(2,3-dihydro-1H-indol-1-yl)-6-oxohex-4-en-3-yl]carbamoyl}-1,4-oxazepane-4-carboxylate [ka] HATU (2.33 g, 6.12 mmol) was added to (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (Intermediate 3, 1.25 g, 5.10 mmol), [(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-ethyl-4-oxo-buten-1-yl]amine trifluoroacetate (Intermediate 6 from WO 2012 / 109415, 1.76 g, 5.10 mmol), and DiPEA (4.45 mL, 25.5 mmol) in DCM (25 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (100 mL) and washed successively with 0.1 M aqueous HCl (100 mL), saturated aqueous NaHCO (100 mL), and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give the subtitle product (1.50 g, 64%). LC-MS m / z 358 (M-Boc+H + ). A sample of the crude product (190 mg, 0.42 mmol) was purified by preparative chiral HPLC on a CHIRALPAK IC-3 column, eluting isocratically with 50% EtOH in hexanes as eluent. Fractions containing the desired compound were evaporated to dryness to give the subtitle product as a colorless oil (180 mg, 95%). LC-MS m / z 358 (M-Boc+H + ). To tert-butyl (2S)-2-{[(3S,4E)-6-(2,3-dihydro-1H-indol-1-yl)-6-oxohex-4-en-3-yl]carbamoyl}-1,4-oxazepane-4-carboxylate (180 mg, 0.39 mmol) in DCM (10 mL) at room temperature was added TFA (2 mL, 26.0 mmol). The resulting solution was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative flash chromatography (C18 column) using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired product were lyophilized to dryness to give the title product (100 mg, 54%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.80-9.10 (m, 2H), 8.30 (d,1H), 8.15 (d, 1H), 7.10-7.30 (m, 2H), 6.95-7.10 (m, 1H), 6.70-6.85 (m, 1H), 6.45 (d, 1H), 4.10-4.70 (m, 4H), 3.90-4.10 (m, 1H), 3.75-3.85 (m, 1H), 3.55-3.70 (m, 1H), 3.05-3.40 (m, 5H), 1.90-2.10 (m, 2H), 1.50-1.75 (m, 2H), 0.85 (t, 3H). LCMS m / z 358 (MH + ).

[0276] Example 37 (2S)-2-[(2E,4S)-1-(2,3-Dihydro-1H-indol-1-yl)-6-methyl-1-oxohept-2-en-4-yl]-1,4-oxazepane-2-carboxamide trifluoroacetate [ka] i) tert-butyl (2S)-2-{[(2E,4S)-1-(2,3-dihydro-1H-indol-1-yl)-6-methyl-1-oxohept-2-en-4-yl]carbamoyl}-1,4-oxazepane-4-carboxylate [ka] To (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (Intermediate 3, 150 mg, 0.61 mmol), [(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-(2-methylpropyl)-4-oxo-2-buten-1-yl]amine trifluoroacetate (Intermediate 13 from WO 2012 / 109415, 174 mg, 0.47 mmol), and DiPEA (0.427 mL, 2.45 mmol) in DMF (5.0 mL) at 0 °C, HATU (465 mg, 1.22 mmol) was added. The resulting solution was stirred at room temperature for 2.5 h. The reaction mixture was evaporated to dryness, redissolved in EtOAc (25 mL), and washed successively with saturated aqueous NH4Cl (20 mL x 4), saturated brine (20 mL x 3), and water (20 mL x 3). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude subtitle product as a yellow oil (200 mg, 67%). LC-MS m / z 486 (MH + The crude product was used in the next step without further purification. TFA (0.635 mL, 8.24 mmol) was added to tert-butyl (2S)-2-{[(2E,4S)-1-(2,3-dihydro-1H-indol-1-yl)-6-methyl-1-oxohept-2-en-4-yl]carbamoyl}-1,4-oxazepane-4-carboxylate (200 mg, 0.41 mmol) in DCM (5.0 mL) at 0 °C. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μ silica, 19 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.5% TFA) and MeCN as eluents. Fractions containing the desired product were evaporated to dryness to give the title product as a yellow gum (130 mg, 63%). LC-MS m / z 386 (MH + ). 1H-NMR (300 MHz, CD3OD): δ 8.15 (1H, d), 7.10-7.30 (2H, m), 7.05 (1H, t), 6.75-6.90 (1H, m), 6.50 (1H, d), 4.60-4.80 (1H, m), 4.40-4.55 (1H, m), 4.10-4.30 (3H, m), 3.70-3.95 (2H, m), 3.15-3.50 (5H, m), 2.05-2.25 (2H, m), 1.40-1.70 (3H, m), 0.95 (6H, t), 1.35 (1H, d) (two exchangeable protons not observed).

[0277] Pharmacological activity Test A1: Fluorescence assay of recombinant human (RH) DPP1 DPP1 activity was determined by measuring the enzymatic release of aminomethylcoumarin (AMC) from the peptide substrate (H-Gly-Arg-AMC), which resulted in an increase in fluorescence intensity at λex = 350 nm and λem = 450 nm. The assay was performed in a black 384-well plate in a final volume of 50 μl at 22 °C. Assay conditions included: 25 mM piperazine buffer pH 5.0; 50 mM NaCl; 5 mM DTT; 0.01% (v / v) Triton X-100; 100 μM H-Gly-Arg-AMC and rhDPP1 (approximately 50 pM). Potential inhibitors were prepared in DMSO and diluted in the assay so that the final concentration did not exceed 1% (v / v) DMSO. Serial 10-point half-log dilutions of inhibitors (typically a highest concentration of 10 μM) were tested, and pIC was determined using a four-parameter logistic equation with nonlinear curve fitting. 50was calculated. A standard DPP1 inhibitor, 4-amino-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide (Example 3 of WO 2010 / 128324), was used as a positive control in the assay. Routinely, the inhibitor was preincubated with rhDPP1 for 30-60 minutes, after which the peptide substrate was added and the reaction was initiated for an additional 60 minutes at 22°C. The plate was then immediately read using a fluorescent plate reader at the above emission and excitation wavelengths (Kam, CM, Gotz, MG, Koot, G, McGuire, MJ, Thiele, DL, Hudig, D & Powers, JC (2004). Arch Biochem Biophys, 427, 123-134 & McGuire, MJ, Lipsky, PE & Thiele, DL (1992). Arch Biochem Biophys, 295, 280-288). The results obtained are shown in Table 11 below (Examples 1-35).

[0278] Test A2: Fluorescence assay of recombinant human (RH) DPP1 DPP1 activity was determined by measuring the enzymatic release of aminomethylcoumarin (AMC) from the peptide substrate (H-Gly-Arg-AMC), which resulted in an increase in fluorescence intensity at λex = 350 nm and λem = 450 nm. The assay was performed in a black 384-well plate in a final volume of 10 μl at room temperature. Assay conditions included: 25 mM piperazine buffer pH 5.0; 50 mM NaCl, 5 mM DTT; 0.005% (v / v) Triton X-100; 50 μM H-Gly-Arg-AMC and 96.4 pM rhDPP1. Potential inhibitors were diluted in DMSO to obtain 100 times the final assay concentration. Compounds were tested at 10 concentrations using half-log dilution steps (typically a maximum concentration of 1 μM) with a final DMSO concentration of 1% (v / v). Routinely, inhibitors were pre-incubated with rhDPP1 for 30 minutes, followed by addition of the peptide substrate and initiating the reaction for an additional 30 minutes. After incubation, plates were read on a fluorescent plate reader using the emission and excitation wavelengths listed above. pIC was calculated using a four-parameter logistic equation with nonlinear curve fitting. 50 was determined (Smartfit, Genedata Screener®). A standard DPP1 inhibitor, 4-amino-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide (Example 3 of WO 2010 / 128324), was used as a positive control. [Modified from Kam, CM, Gotz, MG, Koot, G, McGuire, MJ, Thiele, DL, Hudig, D & Powers, JC (2004). Arch Biochem Biophys, 427, 123-134 & McGuire, MJ, Lipsky, PE & Thiele, DL (1992). Arch Biochem Biophys, 295, 280-288]. The results are shown in Table 11 below (Examples 36-37).

[0279] [Table 13-1] [Table 13-2]

[0280] Aortic connection Numerous compounds have been described in the literature as selectively retained in the aorta in quantitative whole-body autoradiography (QWBA) studies, which induce concomitant ultrastructural changes when examined by electron microscopy (see, for example, muzolimine (Schmidt et al. 1984, Biochem. Pharmacol., 33, 1915-1921)). Additionally, the α-aminoamidonitrile 4-amino-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide (Example 3 of WO 2010 / 128324), which has been described as a DPP1 inhibitor, showed high levels of aortic retention in rat QWBA studies. To aid in the design of DPP1 inhibitors with reduced risk of binding to elastin-rich tissues (e.g., the aorta), the following in vitro competitive aortic binding assay (Test B) was developed to facilitate the selection process. Reference compounds and selected compounds described herein were tested by Method B and the results obtained are shown in Table 12.

[0281] Test B: In vitro competitive aortic binding assay Aortic homogenates were prepared from the thoracic aorta of Han Wistar rats. Freshly isolated thoracic aortas were frozen, thawed, and stripped of inelastic material. The stripped aortas were then weighed, cut into small pieces, and homogenized first with a rotor-stator homogenizer; then, in Puck's saline (137 mM NaCl, 5.37 mM KCl, 4.17 mM NaHCO3, and 5.55 mM D-glucose), using a Dounce homogenizer with a loose fit and then a tight fit. The homogenate concentration was adjusted to 30 mg / mL in Puck's saline, and aliquots were stored at -80°C until use. Positive and negative control compounds and test compounds were prepared at 100 mM in DMSO and added to 1 mL aliquots of the aortic homogenate in Puck's saline to a final concentration of 100 μM. Homogenate samples were pre-incubated with test compounds overnight at 37°C with rotation. 14[C]4-amino-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide was added to a final concentration of 100 μM, and the samples were incubated at 37°C for an additional 2 hours with rotation. Protein was precipitated from each sample by adding 10 mL of acetone and pre-cooling it to -20°C. The samples were left overnight at -20°C to complete the precipitation. The precipitate was pelleted by centrifugation at 4,500 × g for 20 minutes at 4°C, and an aliquot of the supernatant was removed for analysis, with the remaining supernatant discarded. The precipitate was washed by resuspending it in 10 mL of 80% methanol in distilled water and repelleted by centrifugation at 4,500 × g for 20 minutes at 4°C. The wash was repeated four times with 80% methanol and two more times with 100% methanol, removing an aliquot of the supernatant for analysis each time. After the final wash, the pellet was air-dried and dissolved overnight in 1 mL of NCSII Tissue Solubiliser. A 1 mL aliquot of the supernatant was added to 5 mL of Ultima Gold scintillation fluid (Perkin Elmer, MA, USA), and 1 mL of the solubilized pellet was added to 5 mL of Hionic-Fluor scintillation fluid (Perkin Elmer, MA, USA). The radioactivity of the samples was measured using a Beckman LS6500 multipurpose scintillation counter (Beckman Coulter, IN, USA). In each experiment, 4-amino-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide was used as a positive control, and N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4-(methylsulfonyl)phenyl]acetamide (Compound 1, WO 2006 / 001751) and DMSO vehicle were used as negative controls. Two samples of each compound were tested per experiment, and at least two experiments were performed for each test compound.The mean radioactivity of each sample preincubated with the DMSO vehicle control was taken as 100% bound, and the results of samples preincubated with different compounds were expressed as % difference from the vehicle control. One-way ANOVA and Bonferroni multiple comparison test were performed to calculate the significance of differences from the vehicle control.

[0282] The results obtained are shown below in Table 12. The results were quantified and divided into four categories: strong binder, medium binder, binder, and no binder.

[0283] [Table 14-1] [Table 14-2]

[0284] [ 14 C]4-amino-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide [ka] i) 4-Bromobenzo-[14C]-nitrile 1-Methylpyrrolidin-2-one (4 mL) was treated with 1-bromo-4-iodobenzene (473 mg, 1.67 mmol) and [ 14 [C] Copper(I) cyanide (1850 MBq, 77 mg, 0.84 mmol) was dissolved and heated to 150 ° C. for 3 hours with ultrasound. The reaction was diluted with EtOAc (150 ml) and washed with 2% aqueous ferric chloride solution (100 ml), 2% w / v aqueous sodium thiosulfate solution (100 ml), and saturated brine (25 mL × 3). The organic material was passed through a phase separator and the solvent was removed to give the crude product. The crude material was purified by silica gel column chromatography, eluting with 2% EtOAc in isoheptane to give the title compound as a white solid (442 MBq, 37 mg, 24%).

[0285] ii) (S)-4-(1-amino-3-(4'-[14C]-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate tert-butyl (S)-tert-butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (243 mg, 0.47 mmol), Pd-118 (30.6 mg, 0.05 mmol), and potassium carbonate (195 mg, 1.41 mmol) were added to a flask under a nitrogen atmosphere. 4-Bromobenzo-[ 14 C]-nitrile (973 MBq, 86 mg, 0.47 mmol) was added, followed by water (3 mL). The mixture was heated under nitrogen at 73° C. for 4 hours and left at room temperature overnight. The reaction was diluted with water (50 mL) and the product was extracted into DCM (25 mL×4). The combined organics were washed with saturated brine (50 mL), and the organic portion was passed through a phase separator containing magnesium sulfate. The organics were concentrated in vacuo to give a dark brown oil. The crude material was purified by silica gel column chromatography eluting with 0-100% EtOAc in heptane to give a gum, which was triturated with ether / heptane to give the title compound as an off-white solid (802 MBq, 189 mg, 82%). m / z (ES+) 395 [M+2H-BOC] + .

[0286] iii) (S)-4-(1-cyano-2-(4'-[14C]-cyanobiphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate tert-butyl (S)-tert-Butyl 4-(1-amino-3-(4'-[14C]-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (802 MBq, 189 mg, 0.38 mmol) was dissolved in DCM (4 mL) and stirred at room temperature under nitrogen. Burgess reagent (137 mg, 0.57 mmol) was added and the reaction was stirred for 6.5 hours. The crude mixture was purified by silica gel column chromatography eluting with 25-100% EtOAc in heptane to give the title compound as a white solid (714 MBq, 164 mg, 90%). 1 H NMR (500 MHz, DMSO-d6): δ 1.38 (s, 9H), 1.55 - 1.77 (m, 2H), 1.84 - 2.02 (m, 1H), 3.07 - 3.25 (m, 3H), 3.43 - 3.53 (m, 1H), 3.54 - 3.62 (m, 1H), 5.04 - 5.13 (m, 1H), 7.04 (s, 1H), 7.43 (d, 2H), 7.71 (d, 2H), 7.87 (d, 2H), 7.93 (d, 2H), 8.46 (s, 1H). m / z (ES-) 475 [MH] - .

[0287] iv) (S)-4-amino-N-(1-cyano-2-(4'-[14C]-cyanobiphenyl-4-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide To the preheated formic acid solution (500 μl, 13.04 mmol, 50° C.) was added tert-butyl (S)-4-(1-cyano-2-(4′-[14C]-cyanobiphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (133 MBq, 29 mg, 0.06 mmol), and the reaction was heated with stirring at 50° C. for 15 minutes. The reaction was quenched and added to a cooled mixture of saturated sodium bicarbonate (5 ml) and DCM (5 ml). The aqueous portion was further washed with two aliquots of DCM (5 ml), and the combined organics were washed with water (10 ml) and dried over sodium sulfate. The organics were stripped to give a colorless oil, which was triturated with ether to give a white solid. The crude mixture was purified by silica gel column chromatography eluting with 0-2% methanol in DCM to give the title compound (93 MBq, 68%), which was stored as a solution in MeCN. 1 H NMR (500 MHz, DMSO-d6): δ 1.12 (d, 1H), 1.20 (d, 1H), 1.73 (ddd, 1H), 1.89 (ddd, 1H), 3.18 - 3.25 (m, 2H), 3.45 (dt, 1H), 3.53 - 3.66 (m, 3H), 5.02 (t, 1H), 7.43 (d, 2H), 7.71 (d, 2H), 7.89 (dd, 4H). m / z (ES+) 377 [M+H] + .

[0288] The present application also includes the following aspects. [Aspect 1] Formula (I): [ka] [In the formula, R 1 teeth, [ka] and; R 2 are hydrogen, F, Cl, Br, OSOC 1-3 Alkyl or C1-3 alkyl; R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2 or SO2NR 4 R 5 (where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring); or R 1 teeth, [ka] Selected from; X is selected from O, S, or CF2; Y is selected from O or S; Q is selected from CH or N; R 6 is C 1-3 alkyl (wherein the C 1-3 The alkyl may be substituted by one, two or three F, and may also be substituted by OH, OC 1-3 Alkyl, N(C 1-3 alkyl), optionally substituted by one substituent selected from 2, cyclopropyl, or tetrahydropyran; R 7 is selected from hydrogen, F, Cl or CH3. or a pharmaceutically acceptable salt thereof. [Aspect 2] R 1 but [ka] That is, 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof. [Aspect 3] X is O; R 6 C 1-3 is alkyl; R 7 is hydrogen, 3. A compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof. [Aspect 4] (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; 4'-[(2S)-2-cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4'-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(3',4'-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-2-(4'-carbamoyl-3'-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4'-(azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(4'-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(1,3-benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; or (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide 2. A compound of formula (I) according to embodiment 1, selected from: or a pharmaceutically acceptable salt thereof. [Aspect 5] [ka] or a pharmaceutically acceptable salt thereof. [Aspect 6] [ka] 2. The compound according to embodiment 1, wherein the compound is (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, [Aspect 7] A pharmaceutical composition comprising a compound of formula (I) according to any one of aspects 1 to 6, and a pharmaceutically acceptable adjuvant, diluent or carrier. [Aspect 8] A compound of formula (I) according to any one of aspects 1 to 6 for use in therapy. [Aspect 9] A compound of formula (I) according to any one of aspects 1 to 6 for use in the treatment of asthma or chronic obstructive pulmonary disease. [Aspect 10] Use of a compound of formula (I) according to any one of aspects 1 to 6 in the manufacture of a medicament for the treatment of asthma or chronic obstructive pulmonary disease. [Aspect 11] A method for treating asthma or chronic obstructive pulmonary disease in a patient suffering from said disease, the method comprising administering a therapeutically effective amount of a compound of formula (I) according to any one of aspects 1 to 6. [Aspect 12] a compound of formula (I) according to any one of aspects 1 to 6; and · Nonsteroidal glucocorticoid receptor agonists; · Selective beta2 adrenoceptor agonist; Phosphodiesterase inhibitors; · Protease inhibitors; Glucocorticoids; · Anticholinergics; Modulators of chemokine receptor function; and Inhibitors of kinase function A combination of one or more drugs independently selected from:

Claims

1. Formula (I): 【Chemical 1】 [In the formula, R 1 teeth, 【Chemistry 2】 and R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 Alkyl or C 1-3 is alkyl; R 3 is hydrogen, F, Cl, Br, CN, CF 3 , S.O. 2 C 1-3 Alkyl, CONH 2 or SO 2 NR 4 R 5 (where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or R 1 teeth, 【Chemistry 3】 and X is O, S or CF 2 and Y is O or S; Q is CH; R 6 is C 1-3 alkyl (wherein the C 1-3 Alkyl may be substituted by 1, 2 or 3 F and may also be substituted by OH, OC 1-3 Alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, and tetrahydropyran; R 7 is hydrogen, F, Cl or CH 3 is] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier, wherein the pharmaceutically acceptable adjuvant, diluent or carrier comprises a cellulose derivative.

2. R 1 but, 【Chemistry 4】 and X is O, S or CF 2 and Y is O or S; Q is CH; R 6 But C 1-3 alkyl (wherein the C 1-3 Alkyl may be substituted by 1, 2 or 3 F and may also be substituted by OH, OC 1-3 Alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, and tetrahydropyran; R 7 is hydrogen, F, Cl or CH 3 That is, The pharmaceutical composition of claim 1.

3. R 1 but, 【Chemistry 5】 and X is O, S or CF 2 and Y is O or S; R 6 But C 1-3 alkyl (wherein the C 1-3 Alkyl may be substituted by 1, 2 or 3 F and may also be substituted by OH, OC 1-3 Alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, and tetrahydropyran; R 7 is hydrogen, F, Cl or CH 3 That is, The pharmaceutical composition according to claim 1 or 2.

4. R 1 but 【Chemistry 6】 That is, The pharmaceutical composition according to any one of claims 1 to 3.

5. X is O; R 6 is C 1-3 is alkyl; R 7 is hydrogen, The pharmaceutical composition according to claim 4.

6. R 1 but, 【Chemistry 7】 and X is O; R 6 But C 1-3 alkyl (wherein the C 1-3 The alkyl may be substituted by 1, 2 or 3 F; R 7 is hydrogen, The pharmaceutical composition of claim 1.

7. The pharmaceutical composition comprises a compound of formula (I), R 1 but, 【Chemistry 8】 and X is O; R 6 But C 1-3 is alkyl; R 7 is hydrogen, The pharmaceutical composition of claim 1.

8. The compound of formula (I) (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; 4'-[(2S)-2-cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4'-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(3',4'-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)—N-{(1S)-1-cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)—N-{(1S)-1-cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-2-(4'-carbamoyl-3'-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)—N-[(1S)-1-cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4'-(azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(4'-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(1,3-benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide; and (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

9. The compound of formula (I) 【Chemistry 9】 2. The pharmaceutical composition according to claim 1, wherein the compound is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide represented by the formula:

10. The compound of formula (I) 【Chemistry 10】 2. The pharmaceutical composition according to claim 1, wherein the compound is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide represented by the formula:

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the airway obstructive disease is bronchiectasis.

12. The pharmaceutical composition according to any one of claims 1 to 10, wherein the obstructive airway disease is cystic fibrosis.

13. The pharmaceutical composition according to any one of claims 1 to 10, wherein the airway obstructive disease is asthma.

14. The pharmaceutical composition according to any one of claims 1 to 10, wherein the obstructive airway disease is chronic obstructive pulmonary disease (COPD).

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition is administered orally to the patient.

16. 16. The pharmaceutical composition of claim 15, wherein the daily dose of the compound of formula (I) administered orally to the patient is from 0.01 μg per kg of body weight (μg / kg) to 100 mg per kg of body weight (mg / kg).

17. The pharmaceutical composition according to any one of claims 1 to 16, which is in the dosage form of a tablet, capsule, syrup, liquid, suspension, powder or granule.

18. 18. The pharmaceutical composition of claim 17, in the form of a tablet.

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