(2S)-N-[(1S)-1-Cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide as a dipeptidyl peptidase 1 inhibitor

Abstract

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

Description

Technical Field

[0001] The present technical field relates to certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds (including their pharmaceutically acceptable salts) that inhibit dipeptidyl peptidase 1 (DPP1; EC 3.4.14.1) activity, their usefulness 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 producing the compounds.

Background Art

[0002] Dipeptidyl peptidase 1 (DPP1; EC 3.4.14.1), also known as cathepsin C, is a lysosomal cysteine protease belonging to the papain family with a molecular weight of 200 kDa. DPP1 was first discovered in 1948 by Gutman and Fruton (Non-Patent Document 1); however, the cDNA of the human enzyme was first described in 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 and is at the highest levels in the lung, kidney, liver, and spleen. DPP1 catalyzes the removal of dipeptides from the N-terminus of polypeptide substrates with broad specificity. Recent data suggest that in addition to being an important enzyme in lysosomal proteolysis, DPP1 also functions as a key enzyme for the activation of granule serine proteases in cytotoxic T lymphocytes and natural killer cells (granzyme 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, with the majority being present along the inner epithelial layer of the body such as the skin, respiratory tract, and gastrointestinal tract. In humans, two types of mast cells have been identified. A T type that expresses only tryptase, and an MC type that expresses both tryptase and chymase. In humans, T-type mast cells are mainly in alveolar tissue and intestinal mucosa, while TC-type cells are mainly in the skin and conjunctiva. Tryptase and chymase are thought to be important mediators of allergic diseases involved in the processes of inflammation, bronchoconstriction, and mucus secretion.

[0005] Neutrophils play a decisive role in host defense against pathogen invasion. Neutrophils are produced in the bone marrow and are released into the circulatory system fully mature to serve as the front line of cellular defense. Inflammatory mediators and chemotactic attractants activate neutrophils, attract the neutrophils to the site of infection, where the neutrophils act to phagocytose bacteria by phagocytosis and attack the bacteria with weapons of antibacterial compounds using both oxidative and non-oxidative attack methods. Neutrophil elastase, a powerful serine protease, is one of these antibacterial compounds clearly involved in bacterial destruction. Neutrophil elastase is released into the phagolysome surrounding the microorganism and begins to destroy the microorganism. Neutrophil elastase can attack the outer membrane protein OmpA of Gram-negative bacteria, helping to directly kill the pathogen by disrupting the membrane of the pathogen and at the same time allowing other antibacterial compounds to penetrate the pathogen. In addition, neutrophil elastase helps in the processing of other antibacterial compounds and can convert the antibacterial compounds from inactive propeptides to the active state, such 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, having the ability to degrade extracellular matrix proteins (including collagen, proteoglycan, 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 control the activity of neutrophil elastase under physiological conditions. However, neutrophil elastase can evade control at the site of inflammation, and once uncontrolled, it can induce the release of pro-inflammatory 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 tissue destruction and inflammation that characterize many diseases, including hereditary emphysema, chronic obstructive pulmonary disease, cystic fibrosis, adult respiratory distress syndrome, ischemic reperfusion injury, and rheumatoid arthritis.

[0007] There is strong evidence associating tryptase and chymase with 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 this type of disease indicates that DPPI is a valid therapeutic target due to its 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] Patent Document 2 relates to peptidyl nitriles and their use as DPP1 inhibitors.

[0010] Patent Document 3 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-carboxamide and their use as DPP1 inhibitors.

[0013] Patent Documents 6 and 7 relate to β-aminoamidonitriles having inhibitory activity against cysteine proteases.

Prior Art Documents

Patent Documents

[0014]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Non-Patent Documents

[0015]

Non-Patent Document 1

Non-Patent Document 2

[0016] There is no disclosure at all of an amidonitrile compound having a β-amino acid in the form of the described (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compound. Now, the present inventors have found that such a compound has potent DPP1 activity and / or has a desirable pharmacological activity profile (e.g., a reduced risk of binding to elastin-rich tissues such as the aorta).

[0017] [Summary] Compounds that are inhibitors of dipeptidyl peptidase 1 (DPP1), the use of such compounds as medicaments, pharmaceutical compositions containing such compounds, and synthetic routes for the production of such compounds are provided. [Means for Solving the Problems]

[0018] According to a first aspect, formula (I): [Chemical formula] [wherein, R 1 is [Chemical formula] and; R 2 is selected from hydrogen, F, Cl, Br, OSO2C 1-3 alkyl or C 1-3 alkyl; R 3 is selected from hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 alkyl, CONH2 or SO2NR 4 R 5 (wherein 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); or R 1 is

Chemical formula

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

[0020] In another aspect, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound represented by formula (I), wherein the stereochemistry is not defined and is, for example, 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 represented by formula (I) or a pharmaceutically acceptable salt of the compound represented by formula (I), and a pharmaceutically acceptable diluent, excipient and / or inert carrier.

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

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

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

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

[0026] In a further embodiment, there is provided the use of a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound represented by 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 an even 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 an even 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 levels of DPP1, neutrophil elastase, cathepsin G, and proteinase 3 in a mammal (particularly a human).

[0031] In an even 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 activity of DPP1 in a mammal (particularly a human).

[0032] In an even 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 activities of DPP1, neutrophil elastase, cathepsin G, and proteinase 3 in a mammal (particularly a human).

[0033] According to 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 an intermediate used in the process.

[0034] According to another aspect, formula (XXIV):

Chemical formula

[0035] In yet a further embodiment, there is provided a compound represented by formula (XXIV) or a pharmaceutically acceptable salt of a compound represented by formula (XXIV) for the treatment (particularly for prophylaxis or treatment) of respiratory diseases in mammals (particularly humans).

[0036] The compounds represented by formula (I) exemplified herein have an IC 50 against DPP1 of less than 100 nmol / L in an enzyme activity assay (e.g., Test A1 or Test A2 below). The compounds represented by formula (I) also exhibit a promising pharmacological profile by differentiating between desirable and undesirable effects in vivo.

Brief Description of the Drawings

[0037]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Mode for Carrying Out the Invention

[0038] Detailed Description This detailed description is intended to inform those skilled in the art of the invention, its gist, and its practical application so that they can easily utilize the invention. This description and its specific examples show embodiments of the invention, but are for illustrative purposes only. Therefore, the invention is not limited to the exemplary embodiments described herein. In addition, various features of the invention described in connection with separate embodiments for clarity can also be combined to form one embodiment. Conversely, for the sake of brevity, various features of the invention described in one embodiment can also be combined to form its sub-combinations.

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

[0040] To avoid misunderstanding, when a group is conditioned in this specification by the statement "as defined above", this group of course encompasses all of the broadest definition first described and any other definition for that group.

[0041] To avoid misunderstanding, of course, in this specification, "C 1-3 " means a carbon group having one, two, or three carbon atoms.

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

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

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

[0045] In one embodiment, R 1 is

Chemical formula

[0046] In a further embodiment, R 1 is

Chemical formula

[0047] In yet a further embodiment, R 1 is

Chemical formula

[0048] In yet a further embodiment, R 1 is

Chemical formula

[0049] In yet a further embodiment, R 1 is

Chemical formula

[0050] In a further embodiment, R 1 is

Chemical formula

[0051] In a further embodiment, R 1 is

Chemical formula

[0052] In one embodiment, R 2 is selected from hydrogen, F, Cl, Br, OSO2C 1-3 alkyl or C 1-3 alkyl.

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

[0054] In a further further embodiment, R 2 is selected from hydrogen, F or C 1-3 alkyl.

[0055] In one embodiment, R 3 is selected from hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 alkyl, CONH2 or SO2NR 4 R 5 wherein 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 selected from hydrogen, F, Cl, CN or SO2C 1-3 alkyl.

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

[0058] In one embodiment, R 6 is selected from C 1-3 alkyl, wherein the C 1-3 alkyl may be substituted by 1, 2 or 3 Fs and may also be substituted by one substituent selected from OH, OC 1-3 alkyl, N(C 1-3 alkyl)2, cyclopropyl or tetrahydropyran.

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

[0060] In a further further embodiment, R 6 is selected from methyl and ethyl.

[0061] In yet a further embodiment, 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] Combining one or more of the above embodiments provides yet more specific embodiments of the present invention.

[0065] In one embodiment, the compound represented by formula (I) is selected from the following: (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-oxazepane-2-ylcarbonyl]amino}ethyl]biphenyl-3-ylmethanesulfonate, (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 production methods or examples described herein.

[0069] Pharmacological properties The compounds represented by formula (I) and their pharmaceutically acceptable salts are active as pharmaceutical formulations, particularly as inhibitors of dipeptidyl peptidase 1 activity, and can thus be used in the treatment of obstructive airway diseases including the following: bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced (aspirin-induced and NSAID-induced) asthma and dust-induced asthma, and asthma including other causes of airway hyperreactivity, in all severities of both intermittent and persistent types; 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 fibrotic alveolitis, idiopathic interstitial pneumonia, fibrosis associated with antineoplastic chemotherapy and chronic infections (including tuberculosis and aspergillosis) and other fungal infections, including pulmonary fibrosis; 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 conditions of the airway, and iatrogenic cough; acute and chronic rhinitis including drug-induced rhinitis and vasomotor rhinitis; perennial allergic rhinitis and seasonal allergic rhinitis including allergic rhinitis (hay fever); nasal polyposis; colds, and acute viral infections including infections caused by RS (respiratory syncytial) virus, influenza, coronavirus (including SARS) and adenovirus, acute lung injury, acute respiratory distress syndrome (ARDS), and exacerbations of each of the above inhalation disease states, particularly exacerbations of any type of asthma or COPD.

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

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

[0072] In the context of this specification, the term "treatment" includes "prevention" as well, unless there are specific contrary instructions. The terms "therapeutic" and "therapeutically" shall be construed accordingly.

[0073] Prevention is considered to be particularly relevant to the treatment of those who have suffered from past episodes of the disease or condition in question or who are otherwise considered to be at high risk of the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those with a family history of the disease or condition or those identified as particularly susceptible to the disease or condition by genetic testing or screening.

[0074] In particular, the compounds of the present invention (including pharmaceutically acceptable salts) can be used for the treatment of 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 an obstructive airway disease or condition (e.g., asthma or COPD) or reducing the risk thereof, which 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) as defined above or a pharmaceutically acceptable salt thereof 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) as defined above or a pharmaceutically acceptable salt thereof 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) as defined above or a pharmaceutically acceptable salt thereof 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) as defined above or a pharmaceutically acceptable salt thereof for use in the treatment of allergic rhinitis.

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

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

[0082] Combination therapy The compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with another compound used in the treatment of the above conditions.

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

[0084] The present invention also 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, loteprednol etabonate, fluticasone propionate, fluticasone furoate, fluocinonide acetonide, dexamethasone cypionate, desisobutyryl ciclesonide, clobetasol propionate, ciclesonide, butixocort propionate, budesonide, beclomethasone dipropionate, 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-difluoropropanoyl amino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]benzamide.

[0085] The present invention also further relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with a p38 antagonist, such as 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-hydroxy-phenyl)pyrazol-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 also 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 isozyme inhibitor (including a PDE4 inhibitor, or an inhibitor of isoform PDE4D), such as tetomilast, roflumilast, oglemilast, ibudilast, GPD-1116 (3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4-one), lonmilast, 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]ethylurea), 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 also further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a modulator of chemokine receptor function, for example, an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 or CCR11 (for the C-C family), for example, a CCR1, CCR2B or CCR5 receptor antagonist; CXCR1, CXCR2, CXCR3, CXCR4 or CXCR5 (for the C-X-C family), for example, a CXCR2 or CXCR3 receptor antagonist; or a combination with CX3CR1 for the C-X3-C family. For example, the present invention relates to a combination of a compound of the invention with 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 also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof 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-sinapinoyl amino-2(1H)-quinolinone), PF-4191834 (2H-pyran-4-carboxamide, tetrahydro-4-[3-[[4-(1-methyl-1H-pyrazol-5-yl)phenyl]thio]phenyl]-), setileuton, CMI977 (1-[4-[(2S,5S)-5-[(4-fluorophenoxy)methyl]tetrahydrofuran-2-yl]but-3-ynyl]-1-hydroxy-urea), fiboflapon (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, kifflapon (3-[3-tert-butylsulfanyl-1-[(4-chlorophenyl)methyl]-5-(2-quinolylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid), verlafapon ((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 also relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a CRTh2 antagonist or a DP2 antagonist, for example, ACT129968 (2-[2-[(5-acetyl-2-methoxyphenyl)methylsulfanyl]-5-fluoro-benzoimidazol-1-yl]acetic acid), AMG853 (2-[4-[4-(tert-butylcarbamoyl)-2-[(2-chloro-4-cyclopropylphenyl)sulfonylamino]phenoxy]-5-chloro-2-fluorophenyl]acetic acid), AM211 (2-[3-[2-[[benzylcarbamoyl(ethyl)amino]methyl]-4-(trifluoromethyl)phenyl]-4-methoxyphenyl]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-fluorophenoxy]propanoic acid.

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

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

[0092] In one embodiment, the compound of the invention or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with one or more additional active ingredients selected from those defined above. For example, the compound of the invention or a pharmaceutically acceptable salt thereof can be administered simultaneously or sequentially with a further pharmaceutical composition for use as a medicament for the treatment of one of the above diseases or conditions such as a respiratory condition (e.g., COPD, asthma or allergic rhinitis). This further pharmaceutical composition can be a medicament that the patient may already be prescribed (e.g., an existing standard of care medication) and can itself be a composition comprising 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 disease indicated. For example, the daily dosage of the compound of the invention, when inhaled, can range from 0.05 μg (μg / kg) per kg of body weight to 100 μg (μg / kg) per kg of body weight. Alternatively, when the compound is administered orally, the daily dosage of the compound of the invention can be from 0.01 μg (μg / kg) per kg of body weight to 100 mg (mg / kg) per kg of body weight.

[0094] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be used alone, but generally, the compound / salt of formula (I) (active ingredient) is administered in the form of a pharmaceutical composition accompanied by 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”, M. E. Aulton, Churchill Livingstone, 2nd Ed. 2002.

[0095] Depending on the mode of administration, the pharmaceutical composition preferably contains the active ingredient in an amount of 0.05 - 99% w (weight %), more preferably 0.05 - 80% w, still more preferably 0.10 - 70% w, and even more preferably 0.10 - 50% w (all based on the weight of the whole composition).

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

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

[0098] The pharmaceutical composition can be administered locally (e.g., to the skin, or to the lung and / or airway), for example, in the dosage forms of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosol agents and dry powders (e.g., the formulations in inhalers known as Turbuhaler®); or systemically by oral administration, for example, in the dosage forms of tablets, capsules, syrups, powders or granules; or parenterally in the dosage forms of sterile solutions, suspensions or emulsions for injection (including intravenous, subcutaneous, intramuscular, intra-arterial or infusion); or rectally in the dosage form of suppositories.

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

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

[0101] Liquid formulations for oral administration can be in the form of syrups, solutions or suspensions. Solutions can contain, for example, the compounds of the present invention, balance being sugar, and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid formulations can contain colorants, flavoring agents, saccharin and / or carboxymethylcellulose as thickening agents. Furthermore, other additives known to those skilled in the art can be used when preparing formulations for oral use.

[0102] Production of the Compounds The present invention further provides a process for producing the compounds represented by formula (I) as defined above.

[0103] General Production Methods Those skilled in the art will recognize that the compounds of the present invention can be prepared in various ways in a known manner. The following routes merely illustrate some of the methods that can be used for the synthesis of the compounds represented by formula (I).

[0104] The present invention further provides a process for preparing a compound represented by formula (I) as defined above or a pharmaceutically acceptable salt thereof, comprising reacting a compound represented by formula (II):

Chemical formula

Chemical formula

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

[0106] The compound represented by formula (II) is a compound represented by formula (IV):

Chemical formula

[0107] The compound represented by formula (IV) is in the presence of a catalyst such as Pd(dppf)Cl2·DCM or 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and a base such as potassium carbonate or sodium carbonate, formula (V): [Chemical formula] [In the formula, PG represents a protecting group (for example, tert-butoxycarbonyl), and Hal represents a halogen (for example, I or Br)] The compound represented by the formula is reacted with a compound represented by formula (VI): [Chemical formula] [In the formula, R 1 is as defined in formula (I)] It can be produced by reacting with a compound represented by the formula or its ester. The reaction is preferably 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, particularly at 75°C.

[0108] The compound represented by formula (V) is formula (VII): [Chemical formula] [In the formula, PG represents a protecting group (for example, tert-butoxycarbonyl), and Hal represents a halogen (for example, I or Br)] The compound represented by can be produced from the compound shown by using the standard procedures described in the literature for the dehydration of amides, for example, at a temperature in the range of -20 °C to 100 °C, for example, at 0 °C, in a solvent such as DCM or DMF, with or without using a base such as DiPEA, using a reagent such as the Burgess reagent or T3P.

[0109] The compound represented by formula (VII) can be produced by reacting the compound represented by formula (VIII): [Chemical formula] [wherein, PG represents a protecting group (for example, tert-butoxycarbonyl), and Hal represents a halogen (for example, I or Br)] with an aqueous ammonia solution. The reaction is preferably carried out at a temperature in the range of -20 °C to 100 °C, for example, at 0 °C, in an organic solvent such as DMF.

[0110] The compound represented by formula (VIII) is either a commercially available product or a compound known from the literature (for example, Tetrahedron: Asymmetry, 1998, 9, 503) or can be produced using known techniques.

[0111] Furthermore, a method for producing the compound represented by formula (I) as defined above or a pharmaceutically acceptable salt thereof, using the standard procedures described in the literature 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 using a base such as DiPEA, formula (IX): [Chemical formula] [wherein, R 1is as defined above, and PG represents a protecting group (e.g., tert-butoxycarbonyl). There is provided a method comprising reacting a compound represented by with a reagent such as a Burgess reagent or T3P, and then reacting with a reagent suitable for removing the protecting group PG. An example of a suitable reagent is formic acid.

[0112] The compound represented by formula (IX) is, in the presence of a catalyst such as bis[bis(1,2-diphenylphosphino)ethane]palladium(0) or Pd(dppf)Cl2·DCM and a base such as potassium carbonate or sodium carbonate, of formula (X):

Chemical formula

Chemical formula

[0113] The compound represented by formula (X) is, at a temperature in the range of 60 °C to 100 °C, for example, 85 °C, in a solvent such as DMSO, with a suitable salt such as potassium acetate, with or without using 1,1'-bis(diphenylphosphino)ferrocene or palladium dichloride 1,1-bis(di-tert-butylphosphino)ferrocene, in the presence of a suitable catalyst such as Pd(dppf)Cl2·DCM, of formula (XII):

Chemical formula

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

[0115] The compound represented by formula (XIII) is obtained by using a standard procedure described in the literature for amide formation, for example, in the presence of a base such as N-ethyl-morpholine or DiPEA and an activator such as a "uronium" reagent (e.g., TBTU) or T3P, and reacting a compound represented by formula (XIV): [Chemical formula] [In the formula, PG is as defined in formula (VII)] It can be produced by reacting the compound represented by the formula with an aqueous ammonia solution. The reaction is preferably carried out in an organic solvent such as DMF at a temperature in the range of -20°C to 100°C, for example, at 0°C.

[0116] The compound represented by formula (IX) can be produced by reacting a compound represented by formula (XII) [wherein PG represents a protecting group (for example, tert-butoxycarbonyl)] with a compound represented by formula (VI) or its boronic acid ester in the presence of a catalyst such as bis[bis(1,2-diphenylphosphino)ethane]palladium(0) or Pd(dppf)Cl2·DCM and a base such as potassium carbonate or sodium carbonate. The reaction is preferably carried out at a temperature in the range of 20°C to 100°C, particularly at 80°C, in a solvent such as a dioxane / water or ACN / water mixture.

[0117] Furthermore, a method for producing the compound represented by formula (I) as defined above or a pharmaceutically acceptable salt thereof, which comprises reacting a compound represented by formula (XV):

Chemical formula

[0118] The compound represented by formula (XV) can be produced from the compound represented by formula (XII) using a standard procedure described in the literature for the dehydration of amides, for example, at a temperature in the range of -20°C to 100°C, such as 25°C, in a solvent such as DCM or DMF, with or without using a base such as DiPEA, using a reagent such as the Burgess reagent or TBTU or T3P.

[0119] Furthermore, a method for producing a compound represented by formula (I) as defined above or a pharmaceutically acceptable salt thereof, preferably in the presence of a base such as DiPEA or TEA and one or more activators such as EDCI, 2-pyridinol-1-oxide or T3P, and then in the presence of a dehydrating reagent such as T3P, of formula (XVI):

Chemical formula

[0120] The compound represented by formula (XVI) can be produced by reacting a compound represented by formula (VII) with a compound represented by formula (VI) [wherein, R 1 is as defined in formula (I)] or an ester thereof in the presence of a catalyst such as Pd(dppf)Cl2·DCM or 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and a base such as potassium carbonate or sodium carbonate. The reaction is preferably 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, particularly at 75 °C, and then the deprotection of PG is carried out.

[0121] Formula (III):

Chemical formula

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

[0123] The compound represented by formula (XVIII) [wherein PG represents a protecting group (e.g., tert-butoxycarbonyl)] is of formula (XIX): [Chemistry] It can be produced from the compounds represented by, using biocatalytic conversion for chemoselective lactam formation, for example, at a temperature within the range of 0 to 80 °C, for example, at 55 °C, in a solvent such as ether (e.g., dioxane), using a lipase such as Novozym 435, and then using the conditions for the introduction of the protecting group PG.

[0124] The compound represented by formula (XIX) is of formula (XX): [Chemistry] [wherein PG 1 and PG 2represents a protecting group (e.g., benzyl) can be produced from the compound represented by using conditions for hydrogenation, for example, at a temperature within the range of 25 to 80 °C, such as 40 °C, in a solvent such as methanol or dioxane under a pressure of, for example, 10 bar, using H2(g) and a reagent such as palladium hydroxide-carbon.

[0125] Formula (XX) [wherein PG 1 and PG 2 represent a protecting group (e.g., benzyl)] The compound represented by is Formula (XXI):

Chemical formula

[0126] Formula (XXI) [wherein PG 1 and PG 2 represent a protecting group (e.g., benzyl)] The compound represented by can be produced by reacting bis-protected benzylamine (e.g., dibenzylamine) with methyl (S)-oxirane-2-carboxylate in a solvent such as ethanol at a temperature within the range of 0 to 78 °C, such as 70 °C.

[0127] Alternatively, Formula (III):

Chemical formula

[0128] The compound represented by formula (XXII) [wherein PG represents a protecting group (for example, tert-butoxycarbonyl)] is obtained from the compound represented by formula (XXIII): [Chemical formula] [wherein PG 1 and PG 2 represent protecting groups (for example, benzyl)] by reacting with a base such as sodium hydride at a temperature within the range of 0 to 60 °C, such as 25 °C, in a solvent such as THF, and then by interconversion of the protecting groups PG, PG 1 and PG 2 defined in formulas (XXII) and (XXIII).

[0129] The compound represented by formula (XXIII) [wherein PG 1 and PG 2 represent protecting groups (for example, benzyl)] can be produced by reacting protected 3-aminopropanol (for example, N-benzyl-3-aminopropanol) with (S)-2-((benzyloxy)methyl)oxirane at a temperature within the range of 0 to 70 °C, such as 40 °C, in a solvent such as ethanol or propanol, and then reacting the crude product with methanesulfonyl chloride at a temperature within the range of -10 to 25 °C, such as -5 °C, in a solvent such as DCM in the presence of a base such as DiPEA.

[0130] The compounds represented by formula (VI) or their esters, and the compounds represented by formula (VIII), (XI) and (XIV) are commercially available, known from the literature, or can be produced using known techniques.

[0131] Those skilled in the art will fully understand that in the production method of the present invention, certain functional groups such as hydroxyl or amino groups in the reagent may require protection by a protecting group. Thus, the production of the compound represented by formula (I) involves removing one or more protecting groups at an appropriate stage.

[0132] Those skilled in the art will understand that at any stage of the production of the compound represented by formula (I), a mixture of isomers (e.g., a racemate) of a compound corresponding to any of formulas (II) to (V), (VII) to (X), and (XXII) to (XVI) can be used. At any stage of the production, one type of stereoisomer can be obtained by isolating it from the mixture of isomers (e.g., a racemate) using, for example, chiral chromatography separation.

[0133] The protection and deprotection of functional groups are described in 'Protective Groups in Organic Synthesis', 4th Ed, T.W. Greene and P.G.M. Wuts, Wiley (2006) and 'Protecting Groups', 3rd Ed P.J. Kocienski, Georg Thieme Verlag (2005).

[0134] A further embodiment includes pharmaceutically acceptable salts of the compound represented by formula (I).

[0135] Salts of the compounds represented by formula (I) can be advantageous for one or more of their chemical or physical properties, for example, stability at different temperatures and humidities, or desirable solubility in H2O, oil or other solvents. In some cases, salts can be used to assist in the isolation or purification of the compound. In some embodiments (particularly when the salt is intended for administration to an animal (e.g., a human), or when the salt is a reagent used in the manufacture of a compound or salt intended for administration to an animal), the salt is pharmaceutically acceptable.

[0136] When the compound represented by 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 represented by 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 can be two or more cations or anions depending on the number of charged functional groups and the valence of the cation or anion.

[0138] For consideration of suitable salts, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or “Handbook of Pharmaceutical Salts: Properties, selection and use”, P.H. Stahl, P.G. Vermuth, IUPAC, Wiley-VCH, 2002.

[0139] In a salt, proton transfer occurs between the compound represented by formula (I) and the counterion of the salt. However, in some cases, the proton transfer may not be complete and thus the solid may not be a true salt. In such cases, the compound represented by formula (I) and the "co-former" molecules in the solid interact mainly via non-ionic forces such as hydrogen bonds. Proton transfer is, in fact, a continuum and may vary with temperature, and thus it is recognized that the point at which a salt is more desirably described as a co-crystal is somewhat subjective.

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

[0141] The compound represented by formula (I) may form a mixture of its salt and co-crystal. The present invention should be understood to include salt / co-crystal mixtures of the compound represented by formula (I).

[0142] 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 evaluate the position of protons, bond lengths or bond angles), solid state NMR (e.g., to evaluate the chemical shifts of C, N or P) or spectroscopic techniques (e.g., to measure O-H, N-H or COOH signals, and IR peak shifts obtained by hydrogen bonding).

[0143] Certain compounds represented by formula (I) may exist in a solvated form, such as a hydrate, and it should be understood to include solvates of pharmaceutically acceptable salts of the compound represented by formula (I).

[0144] In further embodiments, certain compounds of formula (I) can exist as racemates and racemic mixtures, single enantiomers, as well as individual diastereomers and diastereomeric mixtures. The present invention should be understood to encompass all such isomers. Certain compounds of formula (I) can 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, e.g., due to the presence of a ring bond or double bond. Accordingly, the present invention should be understood to encompass all such isomers. Certain compounds of formula (I) can also contain multiple tautomers. The present invention should be understood to encompass all such tautomers. Stereoisomers can be separated using conventional techniques, e.g., chromatography or fractional crystallization, or the stereoisomers can be prepared by stereoselective synthesis.

[0145] In further embodiments, compounds of formula (I) include isotopically labeled (or "radioactively labeled") derivatives of any of the compounds of formula (I). Such derivatives are derivatives of the 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 denoted as "D" for deuterium).

[0146] In further embodiments, compounds of formula (I) can be administered in the form of prodrugs that are broken down in the human or animal body to give the compounds of formula (I). Examples of prodrugs include in vivo hydrolysable esters of the compounds of formula (I).

[0147] In vivo hydrolysable (cleavable) esters of the compounds represented by formula (I) containing a carboxy group or a hydroxy group are pharmaceutically acceptable esters that hydrolyze in the body of a human or animal, for example, to produce the parent acid or parent 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 the references cited therein.

Examples

[0149] Here, the present invention will be further described by referring to the following non-limiting examples.

[0150] (i) Unless otherwise specified, 1 1H NMR spectra were recorded on a Bruker Avance III spectrometer operating at a field strength of 400, 500 or 600 MHz. Chloroform-d (CDCl3; δ H 7.27 ppm), dimethyl sulfoxide-d6 (d6-DMSO; δ H 2.50 ppm) or methanol-d4 (CD3OD; δ H 3.31 ppm) of any of the central peaks were used as references.

[0151] (ii) The 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 in an aqueous solution of 0.1% formic acid containing 0.1% ACN, or a Waters Xterra MS 5μ C18, 100×4.6 mm (plus guard cartridge) column and a gradient in an aqueous solution of 10 mM ammonium bicarbonate in ACN. Ionization was ESI as per the specification, and the option was such that data for both ESI and APCI could be obtained in a single operation. Alternatively, the LC-MS experiments were performed using a Waters Acquity UPLC system combined with 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) combined with a 46 mM ammonium carbonate / NH3 buffer (pH 10), and an HSS C18 column (1.8 μm, 2.1×50 mm) combined with a 10 mM formic acid, 1 mM ammonium formate buffer (pH 3). When m / z values are given, generally only the ions indicating the parent mass are described, and the cited mass ions are either positive or negative mass ions: [M] + , [M+H] + , [M-H] - or [M+2H-BOC] + .

[0152] (iii) The compounds in the titles and subtitles of the Examples and Preparation Examples were named using the IUPAC naming program ACD / Name2012 from Acdlabs.

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

[0154] (iv) X-ray diffraction analysis was performed according to standard methods that can be found, for example, in Kitaigorodsky, A.I. (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, L.E. (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York.

[0155] The sample was mounted on a single crystal silicon (SSC) wafer mount, and powder X-ray diffraction was recorded using 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 measurement. A PIXCEL detector (effective length 3.35° 2θ) was used to scan the sample at 2 - 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 having one or more measurement errors can be obtained depending on the measurement conditions (e.g., the apparatus, sample preparation, or machine used). In particular, it is generally known that the intensity of a powder X-ray diffraction pattern can 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 intensity of peaks can vary according to the orientation of the sample under test and the type and settings of the tools used. Those skilled in the art also fully understand that the position of the reflection can be affected by the exact height on which it is placed within the diffractometer and the zero calibration of the diffractometer. The flatness of the surface of the sample can also have a small effect. Thus, those skilled in the art will fully understand that the diffraction pattern data presented herein should not be interpreted as absolute, and that crystals giving powder diffraction patterns substantially identical to the powder diffraction patterns described herein are within the scope of the present invention (for further information, see Jenkins, R & Snyder, R.L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons, 1996).

[0157] Generally, the measurement error of the diffraction angle in a powder X-ray diffractogram can be about ±0.1° 2θ, and such an extent of measurement error should be considered when examining powder X-ray diffraction data. Furthermore, the intensity should be understood to vary depending on the experimental conditions and treatment preparation (e.g., desired orientation). The following definitions were used for relative intensity (%): 81 - 100%, vs (very strong); 41 - 80%, str (strong); 21 - 40%, med (medium); 10 - 20%, w (weak); 1 - 9%, vw (very weak).

[0158] The following abbreviations are used:

Table 1

[0159] Production of boronic ester intermediates

[0160] Boronic acid 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 for 2.5 hours while refluxing 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 hydrogen carbonate, and saturated sodium chloride solution. The organic extract was dried (sodium sulfate), filtered, and concentrated under reduced pressure to give the title 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 minutes, methyl iodide (0.61 mL, 9.84 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours and then poured into ice water (100 mL). The resulting brown precipitate was collected by filtration and dried in a vacuum oven to give the title 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) were added bis(neopentyl glycolato)diboron (342 mg, 1.52 mmol) and potassium acetate (198 mg, 2.02 mmol). The reaction mixture was degassed under nitrogen for 15 minutes, and then 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. Then, the reaction mixture was 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) were added bis(neopentyl glycolato)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)Cl2·DCM (171 mg, 0.21 mmol) was added. The reaction mixture was heated at 80 °C for 3 hours. Then, the reaction mixture was 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 acid 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 DCM:isohexane in a ratio of 1:2 to give the subtitle compound as a white solid (1.06 g, 88%). 11H 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) were added bis(neopentyl glycolato)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)Cl2·DCM (101 mg, 0.12 mmol) was added. The reaction mixture was heated at 80 °C for 4 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with 0 - 20% EtOAc in isohexane to obtain the title compound as an off-white solid (338 mg, 57%). 1 1H 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 5-Chloro-7-methyl-1,3-benzoxazol-2(3H)-one (Step i of Boronic ester 1) was used and prepared according to the procedure of Step i of Boronic ester 3 to obtain the subtitle compound as a brown solid (258 mg, 82%). 11H 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 Using 5-chloro-3-ethyl-7-methyl-1,3-benzoxazol-2(3H)-one, the title compound was prepared according to the procedure of step iii) of boronic ester 1 and obtained as an orange solid (285 mg, 81%). 1 1H 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 Using 5-bromo-1,3-benzoxazol-2(3H)-one and chloroacetone, the title compound was prepared according to the procedure of step i) of boronic ester 3 and obtained as a yellow solid (1.31 g, 94%). 1 1H 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 While stirring at 0 °C, methylmagnesium chloride (1.62 mL, 4.87 mmol, 3 M solution in THF) was added 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). After 1 hour, additional methylmagnesium chloride (0.81 mL, 2.43 mmol) was added. The reaction was warmed to room temperature, stirred for 1 hour, and then quenched with ammonium chloride (saturated aqueous solution). The reaction mixture was diluted with EtOAc and the layers were 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 title 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 Using 5-bromo-3-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2(3H)-one, the preparation was carried out according to the procedure of step ii) of boronic ester 3, to give 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 for 2.5 h while refluxing 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 solution. 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 title 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 DMF (30 mL) was added dropwise to a suspension of sodium hydride (419 mg, 10.49 mmol, 60% dispersion in mineral oil) in DMF (50 mL) while stirring at 0 °C. The reaction was warmed to room temperature for 30 min and then recooled to 0 °C. Methyl iodide (653 μL) was added dropwise and the reaction was warmed to room temperature. After 18 h, 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 title compound as a light brown solid (1.38 g, 64%). 11H 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) were added bis(neopentyl glycolato)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)Cl2·DCM (229 mg, 0.28 mmol) was added. The reaction mixture was heated at 80 °C for 3 hours. Thereafter, the reaction mixture was 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 1H 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 acid 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 5-Bromo-7-fluoro-1,3-benzoxazol-2(3H)-one (from Step i of Boronic acid ester 6) and 2,2-difluoroethyl trifluoromethanesulfonate were used to carry out the production according to the procedure of Step i of Boronic acid ester 3 to obtain the subtitle compound as a brown solid (2.49 g, 89%). 11H 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 Using 5-bromo-3-(2,2-difluoroethyl)-7-fluoro-1,3-benzoxazol-2(3H)-one, the title compound was prepared according to the procedure of step ii) of boronic acid ester 3 and obtained as an off-white solid (1.15 g, 41%). 1 1H 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 acid 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%). 11H 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 Using 5-bromo-3-(2-(dimethylamino)ethyl)-1,3-benzoxazol-2(3H)-one, the title compound was prepared according to the procedure of step ii) of boronic ester 3 and obtained as an off-white solid (1.15 g, 41%). It 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 While stirring at room temperature, bis(2-methoxyethyl)aminosulfur trifluoride (deoxo-fluor, 44.25 mL, 22.12 mmol, 50% solution in THF) was added dropwise to a suspension of 6-bromo isatin (2.0 g, 8.75 mmol) in DCM (90 mL) over 30 minutes. After 24 hours, the reaction was carefully quenched with saturated sodium hydrogen carbonate solution (40 mL) at 0 °C. The aqueous layer was separated, 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 1H NMR (400 MHz, CH3OH-d4): δ 7.50 - 7.46 (m, 1H), 7.36 (dd, 1H), 7.18 (d, 1H), (no exchangeable one was observed).

[0179] ii) 6-Bromo-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-one Using 6-bromo-3,3-difluoro-1,3-dihydro-2H-indol-2-one and methyl iodide, the compound was prepared according to the procedure of step i) of boronic ester 3, and the titled compound was obtained as an orange solid (1.39 g, 82%). It 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 Using 6-bromo-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-one, the compound was prepared according to the procedure of step ii) of boronic ester 3, and the titled compound was obtained 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 A solution of 5-bromo-1,3-benzoxazol-2(3H)-one (1.07 g, 5.0 mmol) in DMF (10 mL) was added with 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 h. 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 DCM:isohexane in a ratio of 1:2 to give the title 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 Using 5-bromo-3-(cyclopropylmethyl)-1,3-benzoxazol-2(3H)-one, the title compound was prepared according to the procedure of step ii) of boronic ester 3 and obtained as a brown solid (520 mg, 62%). It 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 Using 5-chloro-1,3-benzothiazol-2(3H)-one and 1-bromo-2-methoxyethane, the title compound was prepared according to the procedure of step ii) of boronic ester 1 and obtained 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 Using 5-chloro-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-one, the title compound was prepared according to the procedure of step iii) of boronic ester 1 and obtained as a pale brown solid (1.02 g, 64%). It 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 Using 5-bromo-1,3-benzoxazol-2(3H)-one and 2-iodopropane, the title compound was prepared according to the procedure of step i) of boronic ester 3 and obtained as a white solid (510 mg, 66%). It 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 Using 5-bromo-3-isopropyl-1,3-benzoxazol-2(3H)-one, the compound of the subtitle was prepared according to the procedure of step ii) of boronic ester 3 and obtained as a brown solid (132 mg, 19%). It 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 Using commercially available 6-bromo-4-methyl-2H-1,4-benzoxazin-3(4H)-one, the title compound was prepared according to the procedure of step ii) of boronic ester 3 and obtained as a brown solid (520 mg, 62%). It 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 under reflux for 2 h. The reaction was cooled and the resulting precipitate was collected by filtration and washed with water to give the compound of the subtitle 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 A solution of 7-bromoquinolin-2(1H)-one (1.5 g, 6.64 mmol) in anhydrous THF was stirred at room temperature under a nitrogen atmosphere, and sodium hydride (320 mg, 7.98 mmol, 60% dispersion in mineral oil) was added. 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 slowly warmed 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. Each layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Isohexane was added to the residue, and recrystallization from DCM gave the title 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-dioxaborolan-2-yl)-1-methylquinolin-2(1H)-one Starting from 7-bromo-1-methylquinolin-2(1H)-one, it was prepared according to the procedure of boronic ester 2, and the title compound was obtained 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-dioxaborolan-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 h, then cooled to room temperature and poured into ice water. The resulting precipitate was collected by filtration and dried in vacuo to give the title 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 Starting from 5-bromo-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-benzoxazol-2(3H)-one, it was prepared according to the procedure of boronic ester 2 to give 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) (1 H under 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 solution (11.5 mL, 190 mol). The resulting precipitate was collected by filtration to obtain the title compound as a yellow solid (24.0 g). It 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) were 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 obtain the title 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 for 2.5 hours while refluxing under a nitrogen atmosphere. The reaction was cooled and the solvent was removed under reduced pressure. The resulting residue was washed with 2N aqueous hydrochloric acid solution and then triturated with methanol to obtain the title compound as a brown solid (0.8 g, 36%). 11H 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 Starting from 5-bromo-7-chloro-1,3-benzoxazol-2(3H)-one and using potassium carbonate instead of cesium carbonate, the compound was prepared according to the procedure of step ii) of boronic ester 1, and the title compound was obtained as a brown solid (700 mg, 83%). 1 1H 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 Starting from 5-bromo-7-chloro-3-methyl-1,3-benzoxazol-2(3H)-one and following the procedure of boronic ester 2, the title compound was obtained as an off-white solid (170 mg, 22%). 1 1H 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 A solution of 5-chloro-1,3-benzoxazol-2(3H)-one (1 g, 5.89 mmol) in DMF (20 mL) was added with cesium carbonate (3.83 g, 11.8 mmol), and then 2,2-difluoroethyl trifluoromethanesulfonate (1.38 g, 6.5 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. Then, water (60 mL) was added, and the resulting precipitate was collected by filtration, washed with water, and dried in vacuo to obtain the title 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 Using 5-chloro-3-(2,2-difluoroethyl)-1,3-benzoxazol-2(3H)-one, the preparation was carried out according to the procedure of step iii) of boronic ester 1, and the title compound was obtained 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 A solution of 5-chloro-1,3-benzoxazol-2(3H)-one (1 g, 5.89 mmol) in DMF (20 mL) was added with cesium carbonate (3.83 g, 11.8 mmol), and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.5 g, 6.5 mmol) was added. 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 obtain the title 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 Using 5-chloro-3-(2,2,2-trifluoroethyl)-1,3-benzoxazol-2(3H)-one, production was carried out according to the procedure of step iii) of boronic ester 1, and the title compound was obtained 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 A solution of 5-chloro-1,3-benzothiazol-2(3H)-one (5.0 g, 26.9 mmol) in DMF (70 mL) was added with cesium carbonate (17.5 g, 53.8 mmol). After 20 minutes, methyl iodide (2.51 mL, 40.4 mmol) was added dropwise. After the addition was completed, the reaction mixture was stirred at room temperature for 2 hours and then poured into ice water (300 mL). The resulting brown precipitate was collected by filtration and dried in a vacuum oven to obtain the title 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 Using 5-chloro-3-methyl-1,3-benzothiazol-2(3H)-one, the preparation was carried out according to the procedure of step iii) of boronic ester 1 to obtain 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 A solution of 4-bromo-1-fluoro-2-nitrobenzene (3.02 g, 15 mmol) in DMF (20 mL) was successively added with potassium carbonate (4.55 g, 33 mmol) and thioacetic acid (1.15 mL, 16.5 mmol) while stirring at room temperature. After 18 h, the reaction was diluted with EtOAc and water. Each layer was 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 title 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 Iron(II) sulfate heptahydrate (18.12 g, 65.17 mmol) in water (25 mL) was slowly added 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. 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 title 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 Starting from 6-bromo-2H-1,4-benzothiazin-3(4H)-one, the title compound was prepared according to the procedure of step ii) of boronic ester 1 and obtained as a yellow solid (1.16 g, 86%). 11H 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 Using 6-bromo-4-methyl-2H-1,4-benzothiazin-3(4H)-one, the title compound was prepared according to the procedure of step ii) of boronic acid ester 3 and obtained as a white solid (655 mg, 45%). 1 1H 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 acid 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 Using 5-bromo-1,3-benzoxazol-2(3H)-one, the subtitle compound was prepared according to the procedure of step i) of boronic acid ester 3 and obtained as a yellow solid (1.15 g, 85%). 1 1H 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 Using 5-bromo-3-(2-methoxyethyl)-1,3-benzoxazol-2(3H)-one, the title compound was prepared according to the procedure of step ii) of boronic ester 3 and obtained as a yellow oil (1.15 g, 85%). It 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

Chemical formula

[0211] i) 5-Chloro-3-methyl-1,3-benzoxazol-2(3H)-one

Chemical formula

[0212] ii) 5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-one 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 with bis(neopentyl glycolato)diboron (5.54 g, 24.5 mmol) and potassium acetate (3.21 g, 32.7 mmol). After the reaction mixture was degassed under nitrogen for 40 minutes, 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) were added. The reaction mixture was heated at 80 °C for 2 hours. Then, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with 0 - 10% EtOAc in isohexane to obtain 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] Production of Intermediate Components

[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 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) were suspended in 1,4-dioxane (60 mL) and water (8 mL), and potassium carbonate (4.5 g, 36 mmol) was added. The suspension was stirred for 15 minutes under a nitrogen stream, and then Pd(dppf)Cl2·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 title compound as a colorless solid (5.9 g, 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 [(1S)-1-Cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]carbamic acid tert-butyl ester (5.4 g, 15.5 mmol) was dissolved in formic acid (50 mL) and heated to 50 °C for 15 minutes on a pre-heated hot plate stirrer. The solution was evaporated under reduced pressure and diluted with EtOAc (150 mL). Saturated aqueous sodium bicarbonate 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 give a yellow oil. The oil was purified by silica gel column chromatography, eluting with EtOAc, to give the title compound as a colorless solid (2.88 g, 74%). 11H NMR (400 MHz, CDCl3): δ 7.62 (m, 4H), 7.52 (m, 2H), 7.35 (d, 2H), 3.92 (t, 1H), 3.10 - 2.96 (m, 2H) (no exchangeable protons were 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 [Chemical Structure] 5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-methyl-1,3-benzoxazol-2(3H)-one (boronic acid ester 22, 3.34 g, 12.81 mmol) and tert-butyl (S)-(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, and then potassium carbonate (2.66 g, 19.21 mmol) and Pd(dppf)Cl2·DCM (1.05 g, 1.28 mmol) were added. The reaction mixture was heated at 80 °C for 1.5 hours. Then, the reaction was 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 title compound as a white solid (3.87 mg, 77%). 11H 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

Chem.

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

Chem.

[0219] i) 3-{Benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol

Chem.

[0220] ii) (2S)-4-Benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane

Chem.

[0221] iii) (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylic acid tert-butyl

Chemical Structure

[0222] iv) (2S)-4-(tert-Butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid 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 were added sodium bromide (1.46 g) and TEMPO (218 mg). 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 warmed to room temperature over 18 h. Isopropanol (30 mL) was added to quench the reaction and the mixture was stirred for 30 min. 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 × 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%). 11H 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) Methyl (2S)-3-(dibenzylamino)-2-hydroxypropanoate

Chemical Structure

[0224] ii) Methyl 3-{[(2S)-3-(dibenzylamino)-1-methoxy-1-oxopropan-2-yl]oxy}prop-2-enoate

Chemical Structure

[0225] iii) Methyl (2S)-3-amino-2-(3-methoxy-3-oxopropoxy)propanoate

Chemical formula

[0226] iv) Methyl (2S)-5-oxo-1,4-oxazepane-2-carboxylate

Chemical Structure

[0227] v) 4-tert-Butyl 2-methyl (2S)-5-oxo-1,4-oxazepane-2,4-dicarboxylate [Chemical formula] 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 a further 20 h. The mixture was almost concentrated to dryness on a 37 °C water bath. MTBE (400 mL) was added and then it was almost concentrated to dryness. This procedure was repeated once more to remove the t-BuOH formed in the reaction. Finally, THF (300 mL) was added and then concentrated to give a yellow oil which was used directly in the next step. Completion is thought to be quantitative.1 1H 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 13C 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)-4-tert-Butyl 2-methyl 1,4-oxazepane-2,4-dicarboxylate

Chemical Structure

[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, at a reaction temperature of 30 °C, (2S)-1,4-oxazepane-2,4-dicarboxylic acid 4-tert-butyl, 2-methyl (160 g, 617 mmol) dissolved in ACN (200 mL) was added. The mixture was stirred vigorously 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). Next, MTBE (400 mL) was added to the aqueous layer, which was then acidified to ca. pH 2 using 2 M KHSO\(_4\). The aqueous layer was extracted with MTBE (300 mL × 2), and the pooled organic layers were washed with water (100 mL) and 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 (100 mL) in heptane and then dried at 40 °C under reduced pressure. Thereby, 140.1 g (571 mmol) of the desired product was obtained ( 1 93% w / w by 1H NMR and 99.7% ee by HPLC). 1 1H 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 13C 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

Chemical Structure

[0231] ii) 3-{Benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propyl methanesulfonate

Chem.

[0232] iii) (2S)-4-Benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane

Chem.

[0233] iv) (2S)-1,4-Oxazepan-2-ylmethanol

Chemistry

[0234] v) (2S)-2-(Hydroxymethyl)-1,4-oxazepane-4-carboxylic acid tert-butyl

Chemistry

[0235] vi) (2S)-4-(tert-Butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid 52.5 g (assay 85%, 40.7 g) of tert-butyl (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate was dissolved in 300 mL of DCM. 0.5 g of TEMPO was dissolved in 100 mL of DCM. 3.88 g of tetrabutylammonium hydrogensulfate was dissolved in 100 mL of DCM. These three DCM solutions were charged into a reaction vessel, and 100 mL of water was added. A 10 - 15% sodium hypochlorite solution (350 mL) was adjusted to pH about 8 - 9 with sodium hydrogen carbonate (liquid + solid) (about 100 ml). A 0.5 M solution of sodium bromide (58 mL) was added to the above buffered solution. The resulting aqueous solution was added dropwise to a two-phase system consisting of a DCM mixed solution and water with stirring at 0 °C. The reaction was exothermic. Following the addition, the color changed (from yellow to pale yellow). This color change indicates the time when the oxidant was consumed. After 10 minutes, the jacket was set to -5 °C and the internal temperature was maintained at about 10 °C. The addition was completed in 45 minutes, and the reaction mixture was left overnight. Work-up: At room temperature, the off-white reaction mixture was adjusted to pH about 2 - 3 with about 40 g of potassium hydrogen sulfate, the phases were separated, and the aqueous phase was washed with DCM (100 ml × 3). The obtained DCM (800 ml) solution was evaporated to obtain about 100 g of an oil. The oil was dissolved in 400 ml of bicarbonate solution and extracted with DCM (75 ml × 2). The remaining aqueous phase was acidified to pH 2 - 3 with about 35 - 40 g of potassium bisulfate and extracted with DCM (75 ml × 5). The DCM was evaporated to obtain 40.7 g of white crystals; Yield: 40.7 g, 85% yield based on the assay of the starting material. The product contained 10% water. Purification: The product was slurried in 200 mL of toluene, heated to 60 °C to become a solution state. About 100 mL of toluene was evaporated off, 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 (2S)-2-{[(2S)-1-Amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl (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 on page 45 of WO 2009 / 074829) were added to T3P (25 g, 39.3 mmol, 50% solution in DMF) in DMF (200 mL). TEA (25 mL, 180.3 mmol) was added and the reaction was stirred at room temperature for 4 h. 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 hydrogen carbonate and sodium chloride solution. The organic extract was dried (magnesium sulfate), filtered and concentrated under reduced pressure 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 (2S)-2-{[(1S)-1-Cyano-2-(4-iodophenyl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl To a solution of (2S)-2-{[(2S)-1-Amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl (Intermediate 4, 8.86 g, 17.13 mmol) in DCM (740 mL) was added Burgess reagent (8.16 g, 34.27 mmol). The reaction mixture was stirred at room temperature for 24 h after which 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 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%). 11H 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 (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-carboxylic acid tert-butyl Under nitrogen, to a stirred solution of (2S)-2-{[(2S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl (Intermediate 4, 0.5 g, 0.97 mmol) in dry DMSO (2.5 mL) were added Pin2B2 (0.32 g, 1.26 mmol), potassium acetate (0.28 g, 2.9 mmol) and Pd(dppf)Cl2·DCM (0.039 g, 5 mol%). The reaction was heated at 85 °C for 5 h and left 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%). 11H NMR (400 MHz, CDCl3): 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) (No exchangeable protons were observed).

[0239] Example

[0240] Example 1 (2S)-N-[(1S)-1-Cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide [Chemical formula] i) (2S)-2-{[(1S)-1-Cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl 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) were 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 minutes, 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 hours and left at room temperature for 18 hours. The mixture was heated at 40 °C for 4 hours and then water (15 mL) was added. After 10 minutes, 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 title compound (0.29 g, 52%). It 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 (2S)-2-{[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl was used to carry out the production according to the procedure of step ii) of Method A, and the title compound was obtained as a white solid (60 mg, 28%). 1 H NMR (400 MHz, CDCl3): 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 was not observed). LCMS (10cm_ESCI_Formic_MeCN) t R 2.57 (mim) 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

Chemical Structure

[0243] i) (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-carboxylic acid tert-butyl [Chemical formula] 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) were added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (468 mg, 2.44 mmol) and 2-pyridinol 1-oxide (271 mg, 2.44 mmol). After stirring the reaction at room temperature for 30 minutes, (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. After stirring the reaction at room temperature for 18 hours, it was transferred to a separatory funnel. The mixture was washed with 2 M 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 title 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 (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-carboxylic acid tert-butyl (457 mg, 0.85 mmol) was dissolved in formic acid (3 mL) and heated at 50 °C for 10 minutes on a pre-heated hot plate stirrer. The reaction was then concentrated under reduced pressure, dissolved in DCM, and washed with saturated sodium hydrogen carbonate 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, CDCl3): 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 was 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

Chemical Structure

[0246] ii) 5-Chloro-3-methyl-1,3-benzoxazol-2(3H)-one

Chemical Structure

[0247] iii) 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one [Chemical Structure] A solution of 5-chloro-3-methyl-1,3-benzoxazol-2(3H)-one (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 about 70 °C, which warmed the mixture to reflux (100 °C). The reaction mixture was stirred for 1 h without heating. HPLC analysis showed that 2.5% of the starting material remained, so the mixture was heated at 85 °C for 1 h. No further change was seen 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 h. HPLC analysis showed that no starting material remained. The mixture was cooled to room temperature and 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 manner and evaporated. Thereby, 1865.1 g of the product was obtained as a gray solid (yield 97%, purity 90.0% by LC, 1 purity by 1H NMR (DMSO-d6) assay against TCNB 82 ± 2%). 1H NMR (270 MHz, DMSO-d6): δ 7.40 - 7.50 (m, 2H), 7.30 (d, 1H), 3.40 (s, 3H), 1.30 (s, 12H). LCMS (5 cm_ ESCI_aq. formic acid_methanol_) t R 4.91 (mim) m / z 276.1 (MH + ).

[0248] iv) Nα-(tert-Butoxycarbonyl)-4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalanine amide [Chemical formula] 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 tert-butyl (S)-1-carbamoyl-2-(4-iodophenyl)ethylcarbamate (prepared according to the procedure on page 47 of WO 2009 / 074829) (903 g, 2.313 mol) in dioxane (4.1 L) were added 2M K2CO3 (2.3 L). The suspension was degassed under vacuum and purged with N2 (×3). Pd(dppf)Cl2·DCM (28.33 g, 0.0347 mol) was added and the reaction mixture was heated at 75 °C for 3 hours. 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 × 3). The product was dried at 45 °C for 3 days (1269.1 g, 1 Yield by 1H NMR 133% - containing pinacol-related impurities and dioxane, LC purity 94.3%, H2O: (Karl Fischer) 3.35%). 1 1H 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) t R 4.51 (mim) m / z 312 (MH + )

[0249] v) 4-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalanine amide [Chemical] Nα-(tert-Butoxycarbonyl)-4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalanine amide (step iv)) (1269 g, estimated active 952 g, 2.3138 mol with 100% conversion in step iv)) in a very thick suspension in DCM (2.1 L) was added dropwise with 4.1 M HCl in dioxane (2.7 L, 11.06 mol) over 1 hour while maintaining the temperature at about 15 °C (the suspension became more fluid after the addition of about 0.5 L of 4.1 M HCl in dioxane). After 2 hours, the mixture was diluted with water (5.6 L) and stirred at room temperature for 30 minutes. Next, the mixture was filtered through a pad of Celite (500 g) to remove undissolved substances - a very slow filtration; the Celite was checked by LC for the product. The pad was washed with water (400 ml). It separated into the DCM / dioxane - water layers. 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 and then the product was filtered and washed with water (400 ml × 3). The product was dried under vacuum at 45 °C (off - white solid, 489.4 g, yield 68% over two steps, purity 99.4% by LC, >99% EP, 1 Purity by H NMR assay against TCNB in DMSO 98 ± 2%, H2O: (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 ) t R 2.76 (mim) m / z 312 (MH + ).

[0250] vi) (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-carboxylic acid tert-butyl

Chem.

[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 (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-carboxylic acid tert-butyl (step vi)) (1776 g, active 1671 g, 3.210 mol) in a solution of formic acid / water (4.2 L / 440 ml) was stirred at 35 - 37 °C under reduced pressure (300 - 500 mbar) on a Buchi. After 3 hours, LCMS completion check showed 93.95% of the product and 0.5% of the starting material. The mixture was concentrated (4 hours) 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 strongly 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 × 3). The filter cake was dried at 45 °C overnight. Thereby, the product was obtained as a light brown solid (1498 g, active 1333 g, LC 91.5%, 1 H NMR assay vs TCNB 89 ± 2%, H2O: (Karl Fischer) 4.63%).

[0252] The crude product was recrystallized from EtOH / H2O in two batches (747 g × 2). Batch A: The crude product (747 g) was dissolved in EtOH (8 L) while refluxing 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 held at this temperature for 3 hours. The product was filtered, washed with EtOH / H2O (8:2, 500 ml × 3), and then with water (500 ml × 3). The filter cake was dried at 45 °C overnight (473 g, purity by LC 97.7%, Pd level 71.4 ppm). From batch B, 436 g of the product was obtained (purity by LC 95.8%, Pd level 65.8 ppm). The liquids obtained from both batches were combined and concentrated to approximately 8 L. The liquid was left standing overnight at room temperature. The solid was filtered, washed with EtOH / H2O (8:2, 400 ml × 3), and then washed with water (400 ml × 3). The product was dried at 45 °C overnight. As a result, an additional 88 g of the product was obtained (LC purity 95.0%).

[0253] These 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) while refluxing under N2. Water (1248 ml) was slowly added. The mixture was cooled to 40 °C (3 hours), seeded with 0.5 g of the title compound, and stirred at 40 °C for 10 hours. Next, the mixture was cooled to 26 °C over 7 hours. The resulting suspension was cooled to 10 °C and stirred at that temperature for 6 hours. The product was filtered, washed with EtOH / water (8:2, 500 ml × 3) and water (500 ml × 3). The filter cake was dried at 45 °C for 2 days. The product was obtained as a gray solid (418 g, yield approximately 56%, LCMS purity 97.5%, chiral LC 100%, 1 H NMR (DMSO-d6) assay vs TCNB 100 ± 2%). Batch D: 418 g, 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 the material obtained from the intermediate-scale reaction carried out in the same manner and re-analyzed (968 g, LC purity 98.04%, chiral LC 100%, 1 H NMR assay vs TCNB 99 ± 2%, 1 0.35% EtOH by H NMR, H2O: (Karl Fischer) 4.58%, Pd 57.6 ppm, XRPD (powder X-ray diffraction) form A.

[0255]

Table 2

Table 3

[0256] Example 2, Preparation of Crystal 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 above method was charged into a reaction vessel. Acetone (35 ml) was added and the mixture was heated at 60 - 65 °C in a heating block. The power of the heating block was turned off and the resulting solution was left 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 (Powder X-ray Diffraction), Form B.

[0257]

Table 4

Table 5

[0258] Example 2, Preparation of Crystal 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 above method was charged into a 1.5 mL scintillation vial. 2-Propanol (1 ml) was added and the mixture was placed at 40 °C for 1 day in an orbital shaker equipped with a heating block. The resulting suspension was filtered and the filtrate was dried. XRPD (Powder X-ray Diffraction), Form C.

[0259]

Table 6

Table 7

[0260] Preparation of Example 2, cinacalcet hydrochloride, 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 above method was charged 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 for about 6 hours using a magnetic stir bar. During this stirring, the vial was closed. The resulting suspension was centrifuged at 7500 rpm for 5 minutes, and the supernatant was removed with a Pasteur pipette. The wet solid residue was dried in a vacuum oven at 30 °C and 30 mbar for about 60 hours. XRPD (powder X-ray diffraction), cinacalcet hydrochloride, form A.

[0261]

Table 8

Table 9

[0262] Preparation of Example 2, R-mandelate, 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) was charged 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 for about 6 hours using a magnetic stir bar. During this stirring, the vial was closed. The resulting suspension was centrifuged at 7500 rpm for 5 minutes and the supernatant was removed with a Pasteur pipette. The wet solid residue was dried in a vacuum oven at 30 °C and 30 mbar for about 60 hours. XRPD (powder X-ray diffraction), R-mandelate salt of 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

Chem.

[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 (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-carboxylic acid tert-butyl (240 mg, 0.45 mmol) was dissolved in formic acid (3 mL) and heated at 50 °C for 10 minutes on a pre-heated hot plate stirrer. Then, the reaction was concentrated under reduced pressure, dissolved in DCM, and washed with saturated sodium hydrogen carbonate solution. The organic extract was dried (phase separator cartridge) and concentrated under reduced pressure. The solid was purified by silica gel column chromatography and eluted with 0 - 2% methanol ammonia (7N) in DCM to obtain the title compound as a white solid (54 mg, 27%). 1 H NMR (400 MHz, DMSO-d6): 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 was not observed). LCMS (10cm_ESCI_Formic_MeCN) t R 2.58 (mim) m / z 435 (MH + )。

[0266] Example 4 (Method B) 4'-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepane-2-ylcarbonyl]amino}ethyl]biphenyl-3-ylmethanesulfonate

Chemical Structure

[0267] ii) (2S)-2-{[(1S)-1-cyano-2-{3'-[(methylsulfonyl)oxy]biphenyl-4-yl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl (2S)-2-{[(2S)-1-amino-3-{3'-[(methylsulfonyl)oxy]biphenyl-4-yl}-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl (0.24 g) was added to a stirred solution in DCM (20 mL) with Dess-Martin periodinane (0.11 g, 0.046 mmol). After 3 days, additional reagent (0.11 g, 0.046 mmol) was added and stirring was continued for 6 h. After leaving the reaction overnight, it was 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 title compound as a colorless glass (0.18 g, 83% over two steps). 1 H NMR (400 MHz, CDCl3): 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 was not observed).

[0268] iii) 4'-[(2S)-2-cyano-2-{[(2S)-1,4-oxazepane-2-carbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate (0.18 g, 0.33 mmol) of tert-butyl (2S)-2-{[(1S)-1-cyano-2-{3'-[(methylsulfonyl)oxy]biphenyl-4-yl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate 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, CDCl3): 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 were not observed). LCMS (10cm_ESCI_Bicarb_MeCN) t R 2.75 (min) m / z 444 (MH + )。

[0269] Examples 5 to 33 Using the above methods and intermediates, the following compounds were prepared:

Chemical formula

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

[0270] Example 34 A 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 [Chemical formula] 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) were 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 h. 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 hydrogen carbonate and sodium chloride solution. The organic extract was dried (magnesium sulfate), filtered and concentrated under reduced pressure to give the title compound as a yellow oil, which was used in the next step without further purification.

[0271] ii) A 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 Using 2-{[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl, the preparation was carried out according to the procedure of step ii) of Method A, and the title compound was obtained as a white solid (150 mg, 50% over two steps). The isolated compound was a mixture of two diastereomers and was not separated. 1 H NMR (400 MHz, CDCl3): 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 was 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 [Chemical formula] i) (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-carboxylic acid tert-butyl 7-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-1-methylquinoxalin-2(1H)-one (boronic acid ester 2, 100 mg, 0.37 mmol) and (2S)-2-{[(2S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-yl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl (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, then potassium carbonate (73 mg, 0.53 mmol) and Pd(dppf)Cl2·DCM (29 mg, 0.035 mmol) were added. The reaction mixture was heated at 80 °C for 1 hour. Then, the reaction was concentrated under reduced pressure. Purification by silica gel column chromatography, eluting with 8% methanol in EtOAc, gave the title compound as a brown oil (192 mg, 100%). It was used in the next step without further purification.

[0273] ii) (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-carboxylic acid tert-butyl 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 with Dess-Martin periodinane (167 mg, 0.70 mmol). The reaction mixture was stirred at room temperature for 24 h. Then, 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 title compound as an oil (101 mg, 54%). 1 H 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 (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-carboxylic acid tert-butyl (101 mg, 0.19 mmol) was dissolved in formic acid (2 mL) and heated at 50 °C for 10 minutes on a pre-heated hot plate stirrer. Then, the reaction was concentrated under reduced pressure, dissolved in DCM, and washed with saturated sodium hydrogen carbonate 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% methanol ammonia (7N) in DCM to give the title compound as a yellow solid (65 mg, 80%). 1 H NMR (400 MHz, CDCl3): 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 were 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 trifluoroacetate

Chemical Structure

[0276] Example 37 (2S)-2-[(2E,4S)-1-(2,3-Dihydro-1H-indol-1-yl)-6-methyl-1-oxohepta-2-en-4-yl]-1,4-oxazepane-2-carboxamide trifluoroacetate

Chemical formula

[0277] Pharmacological activity Test A1: Fluorescent assay of recombinant human (RH) DPP1 The activity of DPP1 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 with a final volume of 50 μl at 22 °C. The 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 (approx. 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 the inhibitor (typically up to a maximum concentration of 10 μM) were tested, and a 4-parameter logistic equation was used with non-linear curve fitting to determine pIC 50It was calculated. The standard DPP1 inhibitor, 4-amino-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide (Example 3 of International Publication No. 2010 / 128324) was used as a positive control in the assay. As per the regulations, the inhibitor was pre-incubated with rhDPP1 for 30 - 60 minutes, then the peptide substrate was added to initiate the reaction at 22°C for an additional 60 minutes. Immediately thereafter, the plate was read using a fluorescence plate reader with the above emission and excitation wavelengths [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 obtained are shown in Table 11 below (Examples 1 - 35).

[0278] Test A2: Fluorescence Assay of Recombinant Human (RH) DPP1 The activity of DPP1 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 with a final volume of 10 μl at room temperature. The 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-fold the final assay concentration. Compounds were tested at 10 concentrations with a final DMSO concentration of 1% (v / v) using a half-log dilution series (typically up to a maximum concentration of 1 μM). As per the protocol, inhibitors were pre-incubated with rhDPP1 for 30 minutes, followed by the addition of the peptide substrate to initiate the reaction for an additional 30 minutes. After incubation, the plate was read on a fluorescence plate reader using the above emission and excitation wavelengths. The 4-parameter logistic equation was used with non-linear curve fitting to determine pIC 50 (Smartfit, Genedata Screener®). The standard DPP1 inhibitor, 4-amino-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide (Example 3 of International Publication No. 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 obtained are shown in Table 11 below (Examples 36 - 37).

[0279]

Table 13-1

Table 13-2

[0280] Aortic binding A number of compounds have been described in the literature as being selectively retained in the aorta in quantitative whole body autoradiography (QWBA) studies that cause associated ultrastructural changes when examined by electron microscopy (see, for example, muzolimine (Schmidt et al. 1984, Biochem. Pharmacol., 33, 1915-1921)). Also, the α-aminoamidonitrile 4-amino-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide (Example 3 of International Publication No. 2010 / 128324), described as a DPP1 inhibitor, has been shown to have a high aortic retention level in rat QWBA studies. To assist in the design of DPP1 inhibitors that reduce the risk of binding to elastin-rich tissues (such as the aorta), the following in vitro competitive aortic binding assay (Test B) was developed to facilitate the selection process. Reference compounds and the 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 and later thawed, and non-elastic materials were removed. Next, the removed aortas were weighed, cut into small pieces, and first homogenized 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), homogenized with a loose fit and then a tight fit using a Dounce homogenizer. The homogenate concentration was adjusted to 30 mg / mL with Puck's saline, and aliquots were stored at -80 °C until use. Positive control compounds, negative control compounds, and test compounds were prepared at 100 mM in DMSO and added to 1 mL aliquots of aortic homogenate in Puck's saline to a final concentration of 100 μM. The homogenate samples were pre-incubated with the test compounds at 37 °C overnight with rotation. Next, 14C] 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. 10 mL of acetone was added to precipitate the protein from each sample, which was pre-cooled to -20 °C. The samples were left at -20 °C overnight to complete the precipitation. The samples were centrifuged at 4,500 × g for 20 minutes at 4 °C to pellet the precipitate, an aliquot of the supernatant was taken for analysis, and the remaining supernatant was discarded. The precipitate was washed by resuspending it in 10 mL of 80% methanol in distilled water and centrifuged at 4,500 × g for 20 minutes at 4 °C to re-pellet. The washing was repeated 4 times with 80% methanol and an additional 2 times with 100% methanol, and an aliquot of the supernatant was taken for analysis each time. After the last wash, the precipitate was air-dried and dissolved in 1 mL of NCSII Tissue Solubiliser overnight. 1 mL of the aliquot of the supernatant was added to 5 mL of Ultima Gold scintillation fluid (Perkin Elmer, MA, U.S.A.), and 1 mL of the solubilized pellet was added to 5 mL of Hionic-Fluor scintillation fluid (Perkin Elmer, MA, U.S.A.). The radioactivity of the samples was measured using a Beckman LS6500 multipurpose scintillation counter (Beckman Coulter, IN, U.S.A.). Each time, 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, International Publication No. WO 2006 / 001751) and DMSO vehicle were used as negative controls. Two samples were tested for each compound for each experiment, and at least two experiments were performed for each test compound.The average radioactivity of each sample pre-incubated with DMSO vehicle control was taken as 100% binding, and the results of samples pre-incubated with another compound were expressed as the percentage difference from the vehicle control. One-way ANOVA and Bonferroni multiple comparison tests were performed to calculate the significance of the difference from the vehicle control.

[0282] The results obtained are shown in Table 12 below. The results were quantified and divided into four categories: strong binders, moderate binders, binders, and non-binders.

[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

Chemical formula

[0285] ii) (S)-4-(1-Amino-3-(4'-[14C]-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamic acid tert-butyl (S)-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-ylcarbamic acid tert-butyl (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-Bromo- 14 C]-nitrile (973 MBq, 86 mg, 0.47 mmol) in degassed ACN (6 mL) was added to the reaction flask, and then water (3 mL) was added. The mixture was heated at 73 °C for 4 hours under nitrogen and left overnight at room temperature. The reaction was diluted with water (50 ml) and the product was extracted with DCM (25 mL × 4). The combined organic materials were washed with saturated brine (50 ml) and the organic material portion was passed through a phase separator containing magnesium sulfate. The organic material was 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 labeled 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-ylcarbamic acid tert-butyl (S)-4-(1-Amino-3-(4'-[14C]-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamic acid tert-butyl (802 MBq, 189 mg, 0.38 mmol) was dissolved in DCM (4 mL) and stirred at room temperature under nitrogen. The Burgess reagent (137 mg, 0.57 mmol) was added and the reaction was stirred for 6.5 h. 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 [M-H] - 。

[0287] iv) (S)-4-Amino-N-(1-cyano-2-(4'-[14C]-cyanobiphenyl-4-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide To a 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 at 50 °C for 15 minutes with stirring. 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 5 ml aliquots of DCM, and the combined organic materials were washed with water (10 ml) and dried over sodium sulfate. The organic material was removed 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 MeCN solution. 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] This application also encompasses the following aspects. [Aspect 1] Formula (I): [Chemical formula] [Wherein, R 1 is [Chemical formula] ; R 2 is hydrogen, F, Cl, Br, OSO2C 1-3 alkyl or C1-3 selected from alkyl; R 3 is hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 alkyl, CONH2 or SO2NR 4 R 5 selected from (wherein 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); or R 1 is

Chemical formula

Chemical formula

Claims

**Claim 1** Crystals B of (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, comprising powder X-ray diffraction peaks at 12.3 ± 0.1, 14.3 ± 0.1, 15.6 ± 0.1, 16.3 ± 0.1 and 17.2 ± 0.1 (°2θ), and Crystals C of (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, comprising powder X-ray diffraction peaks at 9.0 ± 0.1, 14.0 ± 0.1, 16.0 ± 0.1, 16.4 ± 0.1 and 21.0 ± 0.1 (°2θ), selected from the group consisting of 【Chemical 1】 Crystals of (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 **Claim 2** The crystals of (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 according to claim 1, which are crystals B of (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, comprising powder X-ray diffraction peaks at 12.3 ± 0.1, 14.3 ± 0.1, 15.6 ± 0.1, 16.3 ± 0.1 and 17.2 ± 0.1 (°2θ). **Claim 3** The crystal B of the aforesaid (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 further includes powder X-ray diffraction peaks at 18.3±0.1, 18.5±0.1, 19.7±0.1, 21.2±0.1 and 23.6±0.1 (°2θ). The crystal of (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 according to claim 1 or 2.

4. The crystal C of (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 includes powder X-ray diffraction peaks at 9.0±0.1, 14.0±0.1, 16.0±0.1, 16.4±0.1 and 21.0±0.1 (°2θ). The crystal of (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 according to claim 1.

5. The crystal C of the aforesaid (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 further includes powder X-ray diffraction peaks at 7.8±0.1, 14.4±0.1, 17.9±0.1, 18.9±0.1 and 19.6±0.1 (°2θ). The crystal of (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 according to claim 1 or 4.

6. A pharmaceutical composition for treating an obstructive airway disease in a patient in need of treatment for an obstructive airway disease, comprising crystals of (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 according to any one of claims 1 to 5.

7. The pharmaceutical composition according to claim 6, wherein the obstructive airway disease is bronchiectasis.

8. The pharmaceutical composition according to claim 6, wherein the obstructive airway disease is cystic fibrosis.

9. The pharmaceutical composition according to claim 6, wherein the obstructive airway disease is asthma.

10. The pharmaceutical composition according to claim 6, wherein the obstructive airway disease is chronic obstructive pulmonary disease (COPD).

11. The pharmaceutical composition according to any one of claims 6 to 10, which is orally administered to the patient.

12. The pharmaceutical composition according to any one of claims 6 to 11, wherein the daily dose of (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 orally administered to the patient ranges from 0.01 μg (μg / kg) per kg of body weight to 100 mg (mg / kg) per kg of body weight.

13. The pharmaceutical composition according to any one of claims 6 to 12, which is in the form of tablets, capsules, syrups, solutions, suspensions, powders or granules.

14. The pharmaceutical composition according to any one of claims 6 to 13, which is in the form of tablets.

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