Certain (2S)-n-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides for treating bronchiectasis

Abstract

To provide methods for treating bronchiectasis, such as non-cystic fibrosis bronchiectasis.SOLUTION: The methods employ compositions comprising an effective amount of certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds represented by Formula (I), including pharmaceutically acceptable salts thereof, that inhibit dipeptidyl peptidase 1 (DPP1) activity. Methods provided herein are useful for prophylaxis, for increasing the lung function in a patient, and / or for decreasing the rate of pulmonary exacerbation in a patient. In one embodiment, the compound represented by Formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 368,400, filed July 29, 2016, which is incorporated by reference in its entirety for all purposes. [Background technology]

[0002] Bronchiectasis is characterized by localized, irreversible dilation of the bronchi and bronchioles, which can lead to obstructive breathing caused by abnormal mucus production. Symptoms of bronchiectasis typically include a chronic dry or productive cough. Other symptoms include shortness of breath, hemoptysis, and chest pain. Wheezing and clubbing may also occur. People with the disease often suffer from frequent lung infections.

[0003] Bronchiectasis, together with chronic obstructive pulmonary disease (COPD), acute lung injury, acute respiratory distress syndrome and cystic fibrosis (CF), are all conditions of severe pulmonary dysfunction resulting from a massive inflammatory response. The histological hallmark of these inflammatory lung diseases is the accumulation of neutrophils in the pulmonary interstitium and alveoli. Neutrophil activation leads to the release of multiple cytotoxic products, including reactive oxygen species and proteases (serine, cysteine ​​and metalloproteases).

[0004] Patients with bronchiectasis experience an average of 1.5 to 6 pulmonary exacerbations per year (Non-Patent Document 1; Non-Patent Document 2; Non-Patent Document 3). Currently, there is no standard of care (SOC) pharmacological treatment for bronchiectasis. The main goals of treatment are to treat the underlying cause, prevent disease progression, maintain or improve lung function, and improve symptoms and quality of life.

[0005] The present invention addresses the need for effective therapies for the treatment of bronchiectasis, for example in non-cystic fibrosis patients. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Goeminne et al. Respir Med. 2014;108(2):287-96 [Non-Patent Document 2] Kelly et al. Eur J Intern Med 2003; 14(8):488-92 [Non-Patent Document 3] Chalmers et al. Am J Respir Crit Care Med. 2014; 189(5):576-85 Summary of the Invention

[0007] In one embodiment, a method for treating a patient with bronchiectasis is provided. The method includes, in one embodiment, administering to a patient in need of such treatment a compound of formula (I): [ka] [In the formula, R 1 teeth, [ka] and; R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 Alkyl or C 1-3 is alkyl; R 3 are hydrogen, F, Cl, Br, CN, and CF 3 , S.O. 2 C 1-3 Alkyl, CONH 2 or SO 2 NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; R 6 may be substituted by 1, 2 or 3 F and / or OH, OC 1-3 Alkyl, N(C 1-3 Alkyl) 2 , optionally substituted by cyclopropyl or tetrahydropyran; C 1-3 is alkyl; R 7 is hydrogen, F, Cl or CH 3 and; X is O, S or CF 2 and; Y is O or S; Q is CH or N. The present invention relates to a method for treating a patient suffering from a chronic obstructive pulmonary disease (COPD) comprising administering to said patient a pharmaceutical composition comprising an effective amount of a compound of formula (I):

[0008] In one embodiment, the bronchiectasis patient is a cystic fibrosis patient. In another embodiment, the patient treated with one of the methods provided herein does not have cystic fibrosis (referred to herein as "non-CF bronchiectasis").

[0009] In one embodiment of the method for treating bronchiectasis in a patient in need thereof, the pharmaceutical composition comprises (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, [ka] or an effective amount of a pharma- ceutically acceptable salt thereof.

[0010] In one embodiment of the method, the patient receives the composition once a day. In another embodiment, the patient receives the composition twice a day, or every other day, or once a week. In one embodiment, administration is by oral route.

[0011] In one embodiment of the method for treating bronchiectasis, treating includes increasing the length of time to first pulmonary exacerbation compared to untreated bronchiectasis patients.In a further embodiment, the increasing includes increasing by about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks, or by at least about 1 day, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, or by at least about 6 weeks.In another embodiment, the increasing includes increasing by about 20 days to about 100 days, or by about 30 days to about 100 days, or by about 20 days to about 75 days, or by about 20 days to about 50 days, or by about 20 days to about 40 days.

[0012] In another embodiment of the method for treating bronchiectasis, the patient in need of treatment is administered a composition comprising an effective amount of the compound of formula (I) or its pharmacologic acceptable salt. Treating includes reducing the pulmonary exacerbation rate in the patient, compared to the pulmonary exacerbation rate experienced by the patient before treatment, or compared to untreated bronchiectasis patients.In further embodiments, the rate is calculated over about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months or about 24 months. In further embodiments, the rate of pulmonary exacerbations in the patient is reduced by about 15%, about 20%, about 25%, about 30%, about 35%, about 40% or about 50%, about 55%, about 60%, about 65%, about 70%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 70% compared to the rate of pulmonary exacerbations experienced by the patient prior to treatment or compared to an untreated bronchiectasis patient.

[0013] In another embodiment of the method for treating bronchiectasis, a patient in need of treatment is administered a composition comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In this embodiment, treating includes reducing the duration of pulmonary exacerbations in the patient compared to the duration of pulmonary exacerbations experienced by the patient prior to treatment, or compared to an untreated bronchiectasis patient. In a further embodiment, the reduction in duration of pulmonary exacerbations is a reduction in duration of about 12 hours, about 24 hours, about 48 hours, or about 72 hours, at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about 96 hours, at least about 120 hours, at least about 144 hours, or at least about 168 hours. In another embodiment, the reduction in duration of pulmonary exacerbations is a reduction in duration of about 6 hours to about 96 hours, about 12 hours to about 96 hours, about 24 hours to about 96 hours, about 48 hours to about 96 hours, or about 48 hours to about 168 hours. In yet another embodiment, the reduction in pulmonary exacerbation duration is a reduction in duration of about 1 day to about 1 week, about 2 days to about 1 week, about 3 days to about 1 week, about 4 days to about 1 week, about 5 days to about 1 week, or about 6 days to about 1 week. In yet another embodiment, the reduction in pulmonary exacerbation duration is a reduction in duration of about 1 day to about 2 weeks, about 2 days to about 2 weeks, about 4 days to about 2 weeks, about 6 days to about 2 weeks, about 8 days to about 2 weeks, or about 10 days to about 2 weeks.

[0014] In another embodiment of the method for treating bronchiectasis, a patient in need of treatment is administered a composition comprising an effective amount of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof. In this embodiment, treating includes improving the patient's pulmonary function compared to the patient's pulmonary function before treatment or compared to an untreated bronchiectasis patient.

[0015] In one embodiment, the improvement in pulmonary function is greater than or equal to the patient's FEV 1 or compared with untreated bronchiectasis patients. 1In a further embodiment, an increase in FEV 1 The increase in FEV is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%. 1 The increase in FEV is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. 1 In yet another embodiment, the increase in FEV is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%. 1 The increase is from about 25 mL to about 500 mL, or from about 25 mL to about 250 mL.

[0016] In another embodiment, the improvement in pulmonary function in a patient is an increase in forced vital capacity (FVC) when compared to the patient's pulmonary function before treatment or when compared to an untreated bronchiectasis patient. In a further embodiment, the increase in FVC is an increase of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85% or about 90% when compared to the patient's FVC before treatment or when compared to an untreated bronchiectasis patient.

[0017] In another embodiment of the method for treating bronchiectasis, a patient in need of treatment is administered a composition comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. Treating includes improving the patient's quality of life (QOL) compared to the patient's QOL before treatment. QOL is assessed by the Leicester Cough Questionnaire (LCQ), St. George's Respiratory Questionnaire (SGRQ), or Quality of Life-Bronchiectasis (QOL-B) questionnaire.

[0018] In yet another embodiment of the method for treating bronchiectasis, a patient in need of treatment is administered a composition comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.In this embodiment, treating comprises reducing the sputum concentration of active neutrophil elastase (NE) in the patient, compared to the active NE sputum concentration before treatment.In a further embodiment, reducing the active NE sputum concentration comprises reducing by about 1%, about 5%, about 10%, about 20%, about 25%, about 30%, at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%.In another embodiment, a patient treated by one of the methods provided herein has a lower NE sputum concentration, compared to a non-treated patient. In further embodiments, the active NE sputum concentration is about 1%, about 5%, about 10%, about 20%, about 25%, about 30%, at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% lower than the active NE concentration of an untreated patient.

[0019] In yet another embodiment of the method for treating bronchiectasis, a patient in need of treatment is administered a composition comprising an effective amount of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof. In this embodiment, treating comprises lightening the color of the patient's sputum as compared to the color of the patient's sputum before treatment, as measured by the Murray sputum color chart. In a further embodiment, lightening the color of the patient's sputum comprises lightening the color of the patient's sputum one shade. In a further embodiment, lightening is from purulent (dark yellow and / or dark green) to mucopurulent (pale yellow and / or pale green). In another embodiment, lightening is from mucopurulent (pale yellow and / or pale green) to mucoid (clear). In yet another embodiment, lightening is from purulent (dark yellow and / or dark green) to mucoid (clear).

[0020] Detailed Description of the Invention Neutrophils contain four major types of granules: (i) azurophil or primary granules, (ii) specific or secondary granules, (iii) gelatinase or tertiary granules, and (iv) secretory granules. Azurophil granules are thought to form first during neutrophil maturation in the bone marrow and are characterized by the expression of associated neutrophil serine proteases (NSPs): neutrophil elastase (NE), proteinase 3, and cathepsin G. Lysosomal cysteine ​​dipeptidyl peptidase 1 (DPP1) is a proteinase that activates these three NSPs by removing N-terminal dipeptide sequences from their precursors during azurophil granule assembly (Pham et al. (2004). J Immunol. 173(12), pp. 7277-7281). DPP1 is widely expressed in tissues but is highly expressed in cells of the hematopoietic lineage, such as neutrophils.

[0021] These three NSPs, which are abundantly secreted into the extracellular milieu upon activation of neutrophils at inflammatory sites, are thought to act in combination with reactive oxygen species to aid in the degradation of phagocytosed microorganisms inside the phagolysosome. Because a portion of the released proteases remains bound in active form at the outer surface of the plasma membrane, both soluble and membrane-bound NSPs can modulate the activity of various biomolecules, such as chemokines, cytokines, growth factors, and cell surface receptors. Modulation is thought to occur by converting individual biomolecules to their active forms or by degrading biomolecules by proteolytic cleavage. Secreted proteases can stimulate mucus secretion and inhibit mucociliary clearance, but can also activate lymphocytes and cleave apoptotic and adhesion molecules (Bank and Ansorge (2001). J Leukoc Biol. 69, pp. 197-206; Pham (2006). Nat Rev Immunol. 6, pp. 541-550; Meyer-Hoffert (2009). Front Biosci. 14, pp. 3409-3418; Voynow et al. (2004). Am J Physiol Lung Cell Mol Physiol. 287, pp. L1293-302, each of which is incorporated herein by reference in its entirety for all purposes).

[0022] A physiological balance between proteases and antiproteases is necessary for the maintenance of connective tissue in the lungs. For example, an imbalance in favor of proteases can lead to lung injury (Umeki et al. (1988). Am J Med Sci. 296, pp. 103-106; Tetley (1993). Thorax 48, pp. 560-565, each of which is incorporated herein by reference in its entirety for all purposes).

[0023] The methods provided herein use reversible inhibitors of DPP1. Without wishing to be bound by theory, it is believed that the compounds of formula (I) administered by the methods provided herein provide beneficial effects by reducing inflammation and mucus hypersecretion, which in turn leads to fewer pulmonary exacerbations, a lower rate of pulmonary exacerbations, and / or improved cough, sputum production, and / or lung function (e.g., forced expiratory volume in 1 second [FEV 1 Without wishing to be bound by theory, it is believed that the methods provided herein alter bronchiectasis progression by slowing the accelerated rate of lung function decline and / or lung tissue destruction.

[0024] Whenever a group is qualified herein by "as defined above," said group should be understood to include the broadest definition first occurring, as well as each and every other definition of that group.

[0025] As used herein, "C 1-3 " means a carbon group having 1, 2 or 3 carbon atoms.

[0026] The term "alkyl," unless otherwise specified, includes both straight and branched chain alkyl groups, which may be substituted or unsubstituted. "Alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, and pentyl.

[0027] The term "pharmaceutical acceptable" is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being appropriate for use according to sound medical judgment, unless otherwise specified. In general, a pharmaceutical acceptable moiety has one or more benefits that outweigh any adverse effects that the moiety may have. Adverse effects include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0028] As used herein, the compound of formula (I): [ka] [In the formula, R 1 teeth, [ka] and; R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 Alkyl, or C 1-3 is alkyl; R 3 are hydrogen, F, Cl, Br, CN, and CF 3 , S.O. 2 C 1-3 Alkyl, CONH 2 or SO 2 NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; R 6 may be substituted by 1, 2 or 3 F and / or OH, OC 1-3 Alkyl, N(C 1-3 Alkyl) 2 , optionally substituted by cyclopropyl or tetrahydropyran; C 1-3 is alkyl; R 7 is hydrogen, F, Cl or CH 3 and; X is O, S or CF 2 and; Y is O or S; Q is CH or N. The present invention provides a method of treating a patient with bronchiectasis by administration of a pharmaceutical composition comprising an effective amount of a compound of the formula: or a pharma- ceutically acceptable salt thereof.

[0029] Bronchiectasis may be present in patients with cystic fibrosis. In another embodiment, the bronchiectasis is not associated with cystic fibrosis (non-CF bronchiectasis).

[0030] In one embodiment, R 1 teeth, [ka] ;R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 Alkyl, or C 1-3 R is alkyl; 3 are hydrogen, F, Cl, Br, CN, and CF 3 , S.O. 2 C 1-3 Alkyl, CONH 2 or SO 2 NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine ring, a pyrrolidine ring, or a piperidine ring.

[0031] In a further embodiment, R 1 teeth, [ka] ;R 2 is hydrogen, F, Cl or C 1-3 R is alkyl; 3 is hydrogen, F, Cl, CN or SO 2 C 1-3 It is an alkyl.

[0032] In a further embodiment, R 1 teeth, [ka] ;R 2 is hydrogen, F or C 1-3 R is alkyl; 3 is hydrogen, F or CN.

[0033] In another embodiment, R 1 teeth, [ka] and X is O, S or CF 2 Y is O or S; Q is CH or N; R 6 is C 1-3 alkyl, wherein the C 1-3 Alkyl may be substituted by 1, 2 or 3 F and / or OH, OC 1-3 Alkyl, N(C 1-3 Alkyl) 2 , optionally substituted by cyclopropyl or tetrahydropyran; R 7 is hydrogen, F, Cl or CH 3 It is.

[0034] In a further embodiment, R 1 teeth, [ka] and X is O, S or CF 2 Y is O or S; R 6 may be substituted by 1, 2 or 3 F, OH, OC 1-3 Alkyl, N(C 1-3 Alkyl) 2 , optionally substituted by cyclopropyl or tetrahydropyran; C 1-3 R is alkyl; 7 is hydrogen, F, Cl or CH 3 It is.

[0035] In a further embodiment, R 1 teeth, [ka] and X is O, S or CF 2 ;R 6 is C 1-3 alkyl, wherein the C 1-3 Alkyl may be substituted by 1, 2 or 3 F; R7 is hydrogen, F, Cl or CH 3 It is.

[0036] In a further embodiment, R 1 teeth, [ka] X is O; R 6 is C 1-3 alkyl, wherein the C 1-3 Alkyl may be substituted by 1, 2 or 3 F; R 7 is hydrogen.

[0037] In one embodiment, R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 Alkyl or C 1-3 It is an alkyl.

[0038] In a further embodiment, R 2 is hydrogen, F, Cl or C 1-3 It is an alkyl.

[0039] In a further embodiment, R 2 is hydrogen, F or C 1-3 It is an alkyl.

[0040] In one embodiment, R 3 are hydrogen, F, Cl, Br, CN, and CF 3 , S.O. 2 C 1-3 Alkyl, CONH 2 or SO 2 NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine ring, a pyrrolidine ring, or a piperidine ring.

[0041] In a further embodiment, R 3 is hydrogen, F, Cl, CN or SO2 C 1-3 is selected from alkyl.

[0042] In a further embodiment, R 3 is selected from hydrogen, F or CN.

[0043] In one embodiment, R 6 is C 1-3 alkyl, wherein the C 1-3 Alkyl may be substituted by 1, 2 or 3 F, OH, OC 1-3 Alkyl, N(C 1-3 Alkyl) 2 , cyclopropyl or tetrahydropyran.

[0044] In a further embodiment, R 6 is C 1-3 alkyl, wherein the C 1-3 The alkyl may be substituted by 1, 2 or 3 F. In a further embodiment, R 6 is methyl or ethyl. In a further embodiment, R 6 is methyl.

[0045] In one embodiment, R 7 is hydrogen, F, Cl or CH 3 In a further embodiment, R 7 is hydrogen.

[0046] In one embodiment, the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide: [ka] or a pharma- ceutically acceptable salt thereof.

[0047] In one embodiment, the compound of formula (I) is (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, 4'-[(2S)-2-cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate, (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4'-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-(3',4'-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-2-(4'-carbamoyl-3'-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-2-[4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-1-cyano-2-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-2-[4'-(azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide, (2S)-N-[(1S)-1-cyano-2-(4'-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-2-[4-(1,3-benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide, or (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide or a pharma- ceutically acceptable salt of one of the above compounds.

[0048] The method provided herein comprises administering to a patient with bronchiectasis in need of said treatment a composition comprising an effective amount of a compound of formula (I) or a pharmacologic acceptable salt thereof. The compound of formula (I) and its pharmacologic acceptable salts are inhibitors of dipeptidyl peptidase 1 (DPP1) activity. Bronchiectasis can be in a patient with cystic fibrosis or in a patient without cystic fibrosis (often referred to as "non-cystic fibrosis bronchiectasis" or "non-CF bronchiectasis"). The route of administration comprises oral administration. The administration schedule can be determined by the user of the method, e.g., the prescribing physician. In one embodiment, administration is once a day. In another embodiment, administration is twice a day. In another embodiment, administration is every other day, three times a week, or four times a week.

[0049] Non-CF bronchiectasis has been reported to be caused by or associated with multiple etiologies ranging from genetic disease to retained airway foreign bodies, and has been reported to be present in patients with systemic diseases, common respiratory diseases such as chronic obstructive pulmonary disease (COPD), and rare diseases such as sarcoidosis (Chang and Bilton (2008). Thorax 63, pp. 269-276, incorporated by reference in its entirety for all purposes).

[0050] Bronchiectasis is considered the pathological end point resulting from many disease processes and is a persistent or progressive condition characterized by enlarged, thick-walled bronchi. Symptoms vary from intermittent episodes of expectoration and infection localized to affected lung regions to persistent daily expectoration of frequently large amounts of purulent sputum. Bronchiectasis may be associated with other non-specific respiratory symptoms. Without wishing to be bound by theory, the underlying pathological process of bronchiectasis has been reported as damage to the airways resulting from an event or series of events in which inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V. 65(Suppl 1) (incorporated herein in its entirety by reference for all purposes)).

[0051] In one embodiment, the term "treating" includes: (1) preventing or delaying the appearance of clinical symptoms of a developing state, disorder or condition in a patient who is afflicted with or susceptible to the state, disorder or condition, but who has not yet experienced or has not yet manifested the clinical or asymptomatic symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (i.e., preventing, reducing or delaying the onset of the disease, or in the case of maintenance treatment of at least one of its clinical or asymptomatic symptoms, its recurrence); (3) alleviating the condition (i.e., causing the regression of the state, disorder or condition, or at least one of its clinical or asymptomatic symptoms).In one embodiment, the clinical symptoms are pulmonary exacerbations and / or (4) preventing bronchiectasis, such as non-CF bronchiectasis.

[0052] Prevention is expected to be particularly relevant for treating those who have experienced a previous episode of bronchiectasis or are otherwise considered to be at high risk for bronchiectasis.Therefore, in one embodiment of the present invention, a method is provided for providing prevention of bronchiectasis in a patient in need thereof.The patient in need thereof, in one embodiment, has experienced a previous episode of bronchiectasis or is at high risk for being diagnosed with bronchiectasis.The method comprises administering to the patient a composition comprising an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.In a further embodiment, the compound represented by formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide or a pharmaceutically acceptable salt thereof. Without wishing to be bound by theory, it is believed that administration of an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof inhibits neutrophil elastase activity, thereby interrupting the cycle of infection / inflammation / mucociliary clearance failure and tissue destruction observed in patients with bronchiectasis.

[0053] As used herein, a "pulmonary exacerbation" is three or more of the following symptoms exhibited by a patient for at least 48 hours: (1) increased coughing; (2) increased sputum volume or change in sputum consistency; (3) increased purulence of sputum; (4) increased shortness of breath and / or decreased exercise tolerance; (5) fatigue and / or malaise; and (6) hemoptysis. In one embodiment, the three or more symptoms result in a physician's decision to prescribe an antibiotic to a patient exhibiting the symptoms.

[0054] In one embodiment, treating by administering a composition comprising an effective amount of a compound of formula (I) includes increasing the length of time to pulmonary exacerbation compared to the length of time to pulmonary exacerbation in untreated bronchiectasis patients. For example, in some embodiments, the length of time to pulmonary exacerbation is increased by at least about 20 days compared to the length of time to pulmonary exacerbation in untreated bronchiectasis patients. In other embodiments, the length of time to pulmonary exacerbation is increased by about 20 days to about 100 days compared to the length of time to pulmonary exacerbation in untreated bronchiectasis patients. In another embodiment, the length of time to pulmonary exacerbation is increased by about 25 days to about 100 days, about 30 days to about 100 days, about 35 days to about 100 days, or about 40 days to about 100 days compared to the length of time to pulmonary exacerbation in untreated bronchiectasis patients. In other embodiments, the increase is about 25 days to about 75 days, about 30 days to about 75 days, about 35 days to about 75 days, or about 40 days to about 75 days, compared to the length of time to pulmonary exacerbation in untreated bronchiectasis patients. In other embodiments, the increase in time to pulmonary exacerbation is about 30 days to about 60 days, compared to the length of time to pulmonary exacerbation in untreated bronchiectasis patients. In further embodiments, the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, or a pharma- ceutically acceptable salt thereof.

[0055] In one embodiment, increasing the time between pulmonary exacerbations includes increasing by about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks, or by at least about 1 day, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, or at least about 6 weeks. In another embodiment, the increasing includes increasing by about 20 days to about 100 days, or by about 30 days to about 100 days, or by about 20 days to about 75 days, or by about 20 days to about 50 days, or by about 20 days to about 40 days. In a further embodiment, the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, or a pharma- ceutically acceptable salt thereof.

[0056] In yet another embodiment, a method for treating bronchiectasis, such as non-CF bronchiectasis, is provided, comprising administering to a patient in need of said treatment a composition comprising an effective amount of the compound of formula (I) or its pharmacologic acceptable salt.In one embodiment, the compound is orally administered once a day.Treatment includes reducing the pulmonary exacerbation rate compared to the pulmonary exacerbation rate experienced by the patient before treatment, or compared to untreated bronchiectasis patients.Pulmonary exacerbation rate can be calculated by dividing the number of exacerbations by a specific period, such as 1 day, 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months or about 24 months. The reduction in exacerbation rate, in one embodiment, is a reduction of about 15%, about 20%, about 25%, about 30%, about 35%, about 40% or about 50%, about 55%, about 60%, about 65%, about 70%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 50%, at least about 70% when compared to the pulmonary exacerbation rate experienced by the patient prior to treatment or when compared to an untreated bronchiectasis patient.

[0057] In another embodiment, the reduction in exacerbation rate is, in one embodiment, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 50%. In one embodiment, the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, or a pharma- ceutically acceptable salt thereof.

[0058] In yet another embodiment, a method for treating bronchiectasis, such as non-CF bronchiectasis, is provided, comprising administering to a patient in need of said treatment a composition comprising an effective amount of the compound of formula (I) or its pharmacologic acceptable salt.In one embodiment, the compound is orally administered once a day.The method comprises reducing the duration of pulmonary exacerbation compared to the duration of pulmonary exacerbation experienced by the patient before treatment, or compared to untreated bronchiectasis patients.The reduction in the duration of pulmonary exacerbation is a reduction in the duration of about 12 hours, about 24 hours, about 48 hours or about 72 hours, at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about 96 hours, at least about 120 hours, at least about 144 hours or at least about 168 hours. In another embodiment, the reduction in pulmonary exacerbation period is a reduction in a period of about 6 hours to about 96 hours, about 12 hours to about 96 hours, about 24 hours to about 96 hours, about 48 hours to about 96 hours, or about 48 hours to about 168 hours. In yet another embodiment, the reduction in pulmonary exacerbation period is a reduction in a period of about 1 day to about 1 week, about 2 days to about 1 week, about 3 days to about 1 week, about 4 days to about 1 week, about 5 days to about 1 week, or about 6 days to about 1 week. In yet another embodiment, the reduction in pulmonary exacerbation period is a reduction in a period of about 1 day to about 2 weeks, about 2 days to about 2 weeks, about 4 days to about 2 weeks, about 6 days to about 2 weeks, about 8 days to about 2 weeks, or about 10 days to about 2 weeks.

[0059] In another embodiment, the reduction in duration is a reduction of about 6 hours to about 96 hours, about 12 hours to about 96 hours, about 24 hours to about 96 hours, about 48 hours to about 96 hours, or about 48 hours to about 168 hours.

[0060] In one embodiment, the duration reduction is the average reduction in exacerbations experienced during treatment. In a further embodiment, the compound of Formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, or a pharma- ceutically acceptable salt thereof.

[0061] In another embodiment, a method for treating bronchiectasis, such as non-CF bronchiectasis, is provided, comprising administering a compound of formula (I) to a patient in need of such treatment.In one embodiment, the compound is orally administered once a day.In this embodiment, treating comprises reducing the number of pulmonary exacerbation-related hospitalizations of the patient compared to the number of pulmonary exacerbation-related hospitalizations of the patient before treatment or compared to untreated bronchiectasis patients.The number of hospitalizations in one embodiment is measured over a treatment period and compared to the same length of time in untreated bronchiectasis patients before treatment.In a further embodiment, the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0062] In one embodiment of the method provided herein, a method for treating bronchiectasis, such as non-CF bronchiectasis, is provided, comprising administering to a patient in need of the treatment a composition comprising an effective amount of a compound of formula (I) or a pharmacologic acceptable salt thereof, and comprising enhancing the pulmonary function in the patient compared to the pulmonary function in the patient before treatment or compared to an untreated bronchiectasis patient.In one embodiment, the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, or a pharmacologic acceptable salt thereof.

[0063] In one embodiment, the enhancement of lung function is measured by spirometry.

[0064] Increasing pulmonary function refers, in one embodiment, to the increase in forced expiratory volume in 1 second (FEV) after administration of a bronchodilator, compared to the respective values ​​before treatment or compared to untreated bronchiectasis patients.1 In one embodiment, increasing includes increasing the forced vital capacity (FVC), increasing the peak expiratory flow rate (PEFR), or increasing the forced expiratory flow of 25% to 75% of FVC (FEF25-75). In one embodiment, increasing includes increasing by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% of the respective values. In one embodiment, increasing includes increasing by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In yet another embodiment, the increase is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20%. In yet another embodiment, increasing is about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.

[0065] For example, FEV 1 , PEFR or FEF 25-75 Assessment of pulmonary function by measurement, in one embodiment, includes comparing pulmonary function in the patient before treatment, e.g., immediately before treatment, to a time point during treatment, to an average of measurements during treatment, or after treatment is completed.

[0066] As provided herein, treatment according to the invention, in one embodiment, includes improving lung function in a patient, where the lung function is measured by spirometry. Spirometry is a physiological test that measures how much air an individual inhales and exhales. The primary signal measured in spirometry can be volume or flow rate. For the methods described herein, spirometry (e.g., FEV 1 , FVC, PEFR and FEF 25-75Pulmonary function tests (PFTs) are performed according to the American Thoracic Society (ATS) / European Respiratory Society (ERS) standards, e.g., as described by Miller et al. (Miller et al. (2005). Standardization of Spirometry. Eur. Respir. J. 26, pp. 319-38, incorporated herein by reference in its entirety for all purposes).

[0067] In one embodiment, the spirometer is capable of accumulating a volume for 15 seconds or more, e.g., ≧20 seconds, ≧25 seconds, ≧30 seconds, ≧35 seconds. -1 At a flow rate of 14 L s, a volume of ≥ 8 L (BTPS) can be measured with an accuracy of at least ±3% of the reading or ±0.050 L, whichever is greater. -1 The total resistance to airflow in the spirometer is <1.5cmH 2 O / L -1 ·s -1 (0.15kPa?L -1 ·s -1 ). In one embodiment, the total resistance of the spirometer is measured with any included tubing, valves, pre-filters, etc. that may be inserted between the patient and the spirometer. For devices that exhibit changes in resistance due to water vapor condensation, in one embodiment, the spirometer accuracy requirements are met under BTPS (body temperature, ambient pressure, saturated with water vapor) conditions for up to eight consecutive FVC maneuvers performed for 10 minutes without inspiration from the device.

[0068] With respect to the forced expiratory maneuvers described herein, in one embodiment, the range and precision recommendations as set forth in Table 6 of Miller et al. are met (Miller et al. (2005). Standardization of Spirometry. Eur. Respir. J. 26, pp. 319-38, incorporated herein by reference in its entirety for all purposes).

[0069] In one embodiment, the improvement in pulmonary function is an improvement in forced vital capacity (FVC), i.e., the maximum volume of air that can be exhaled with maximal effort from maximal inspiration, as measured in liters at body temperature and ambient pressure saturated with water vapor (BTPS).

[0070] "Forced vital capacity" (FVC) refers to the amount of gas exhaled during forced expiration, starting from a position of full inspiration and ending with a full expiration, and is a measure of treatment effect. In one embodiment of the method provided herein, improving the lung function of a patient includes improving the FVC of a patient compared to the FVC of the patient before treatment or compared to an untreated bronchiectasis patient. In one embodiment, the FVC of a treated patient is about 1% more, about 2% more, about 3% more, about 4% more, about 5% more, about 6% more, about 7% more, about 8% more, about 9% more, about 10% more, about 11% more, about 12% more, about 13% more, about 14% more, or about 15% more than the FVC of a treated patient before treatment or compared to an untreated bronchiectasis patient. , about 15% more, about 16% more, about 17% more, about 18% more, about 19% more, about 20% more, about 25% more, about 30% more, about 35% more, about 40% more, about 45% more, about 50% more, about 55% more, about 60% more, about 65% more, about 70% more, about 75% more, about 80% more, about 85% more, or about 90% more.

[0071] The FVC maneuver can be performed according to procedures known to those skilled in the art. Briefly, the three different stages of the FVC maneuver are (1) maximal inhalation; (2) "blast" exhalation, and (3) continuing to exhale completely until the end of the test (EOT). The maneuver can be performed by closed circuit or open circuit methods. In either case, the subject inhales rapidly and completely, holding for less than one second at total lung capacity (TLC). The subject then exhales maximally while maintaining an upright position until no more air can be exhaled. Exhalation begins with a "blast" exhalation from the lungs, and is then encouraged to exhale fully. The subject's dedicated coaching continues for a minimum of three maneuvers.

[0072] The improvement in pulmonary function, in one embodiment, is an improvement when compared to the pulmonary function immediately prior to treatment or when compared to an untreated bronchiectasis patient. In a further embodiment, improving pulmonary function refers to an improvement in the FEV 1 or in patients with untreated bronchiectasis 1 ) compared with FEV 1 The FEV1 is the volume of gas exhaled within a specific time from the start of the forced vital capacity maneuver (typically 1 second, i.e., FEV 1 ) (Quanjer et al. (1993). Eur. Respir. J. 6, Suppl. 16, pp. 5-40, incorporated herein by reference in its entirety for all purposes).

[0073] FEV 1 In one embodiment, the increase in FEV in the treated patient is at least about 5%, for example, about 5% to about 50%, or about 10% to about 50%, or about 15% to about 50%. 1 is the patient's FEV before treatment 1or compared to untreated bronchiectasis patients, about 1% more, about 2% more, about 3% more, about 4% more, about 5% more, about 6% more, about 7% more, about 8% more, about 9% more, about 10% more, about 11% more, about 12% more, about 13% more, about 14% more, about 15% more, about 16% more, about 17% more, about 18% more, about 19% more, about 20% more, about 25% more, about 30% more, about 35% more, about 40% more, about 45% more, about 50% more, about 55% more, about 60% more, about 65% more, about 70% more, about 75% more, about 80% more, about 85% more, or about 90% more.

[0074] In another embodiment, improving pulmonary function refers to improving the patient's FEV 1 or compared with untreated bronchiectasis patients. 1 by about 25 mL to about 500 mL, or by about 25 mL to about 250 mL, or by about 50 mL to about 200 mL.

[0075] In one embodiment, improving pulmonary function refers to improving the patient's FEF before treatment. 25-75 or compared with untreated bronchiectasis patients, the mean forced expiratory flow (FEF) of 25% to 75% of the patient's FVC. 25-75 ) (also called maximum central expiratory flow). The measurement depends on the validity of the FVC measurement and the level of expiratory effort. FEF 25-75 The index is FEV 1 and FVC.

[0076] In one embodiment, improving lung function includes improving the patient's peak expiratory flow rate (PEFR). The improvement is compared to the PEFR immediately before treatment or compared to an untreated bronchiectasis patient. PEFR measures the fastest air a subject can exhale. In one embodiment, the PEFR of the treated patient is about 1% more, about 2% more, about 3% more, about 4% more, about 5% more, about 6% more, about 7% more, about 8% more, about 9% more, about 10% more, about 11% more, about 12% more, about 13% more, or about 14% more than the PEFR of the patient before treatment or compared to an untreated bronchiectasis patient. or about 15% more, about 16% more, about 17% more, about 18% more, about 19% more, about 20% more, about 25% more, about 30% more, about 35% more, about 40% more, about 45% more, about 50% more, about 55% more, about 60% more, about 65% more, about 70% more, about 75% more, about 80% more, about 85% more, or about 90% more.

[0077] In yet another embodiment of the present invention, there is provided a method for treating bronchiectasis, comprising administering an effective amount of a compound represented by formula (I) to a patient in need of such treatment, wherein treating comprises increasing the quality of life (QOL) of the patient before treatment, e.g., compared to a baseline value. In one embodiment, the compound represented by formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0078] In one embodiment, the patient's QOL is assessed by the Quality of Life-Bronchiectasis (QOL-B) questionnaire, a validated self-administered patient-reported outcome (PRO) that assesses symptoms, function and health-related QOL in subjects with bronchiectasis (Quittner et al. (2014). Chest 146(2), pp. 437-448; Quittner et al. (2015) Thorax 70(1), pp. 12-20, each of which is incorporated herein by reference in its entirety for all purposes). The QOL-B contains 37 items across eight domains: Respiratory Symptoms, Physical Functioning, Role Functioning, Emotional Functioning, Social Functioning, Vitality, Health Perceptions, and Treatment Burden.

[0079] In another embodiment, the patient's quality of life is assessed by the Leicester Cough Questionnaire (LCQ). The improvement in quality of life, in one embodiment, is the change from baseline (pre-treatment) in the patient's LCQ score. The LCQ is a validated questionnaire that assesses cough on quality of life in subjects with bronchiectasis and other conditions in which cough is a common symptom (Murray et al. (2009). Eur Respir J. 34: 125-131, incorporated herein by reference in its entirety for all purposes). The LCQ contains 19 items and takes 5-10 minutes to complete. Each item assesses a symptom or the impact of a symptom over the past two weeks on a seven-point Likert scale. Scores in the three domains (physical, psychological and social) are calculated as the average for each domain (range 1-7). A total score (range 3-21) is also calculated by summing the domain scores. A higher score indicates a better quality of life.

[0080] In another embodiment, the patient's quality of life is assessed by the St. George Respiratory Questionnaire (SGRQ). In one embodiment, the improvement in quality of life is the change in the patient's SGRQ score from baseline (pre-treatment). The St. George Respiratory Questionnaire (SGRQ) is a self-administered questionnaire of 50 questions designed to measure and quantify the health-related health status of subjects with chronic airflow limitation (Jones et al. (1991). Respir Med. 85 Suppl B 25-31; discussion 33-7 (incorporated in its entirety by reference for all purposes)). The SGRQ assesses health-related quality of life by assessing three health domains: (1) symptoms (distress caused by respiratory symptoms), (2) activity (impact of interference with mobility and physical activity), and (3) impact (impact of disease on factors such as employment, personal health care, and need for medication). It has been shown to correlate well with established measures of the three domains in subjects with asthma and COPD. It has also been demonstrated to be used in NCFBE. A composite total score is derived as the sum of the domain scores for symptoms, activities, and impact, with 0 being the highest possible score and 100 being the lowest possible score. A reduction in score of 4 units is generally recognized as a clinically meaningful improvement in quality of life.

[0081] In another embodiment of the method for treating bronchiectasis provided herein, a composition comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient in need of such treatment, and the method comprises reducing the active neutrophil elastase (NE) sputum concentration compared to the patient's NE sputum concentration before treatment. In one embodiment, the compound of formula (I) is administered by oral administration. In a further embodiment, administration is once a day, every other day, twice a week, three times a week, or four times a week. In one embodiment, the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, or a pharma- ceutically acceptable salt thereof.

[0082] Reducing active NE sputum concentration, in one embodiment, includes a reduction of about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%. In another embodiment, reducing active NE sputum concentration includes a reduction of at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% or at least about 80%.

[0083] In yet another embodiment of the method for treating bronchiectasis provided herein, an effective amount of a compound of formula (I) is administered to a patient in need of the treatment, the method comprising lightening the color of the patient's sputum as measured by the Murray 2009 sputum color chart (Murray et al. (2009). Eur Respir J. 2009; 34:361-364, incorporated herein by reference in its entirety for all purposes), compared to the color of the patient's sputum before treatment. In one embodiment, the compound of formula (I) is administered by oral administration. In a further embodiment, administration is once a day, every other day, twice a week, three times a week, or four times a week. In one embodiment, the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, or a pharma- ceutically acceptable salt thereof.

[0084] In one embodiment, the lightening of the color refers to a one-tone lightening. For example, in one embodiment, the lightening is from purulent (dark yellow and / or dark green) to mucopurulent (light yellow and / or light green). In another embodiment, the lightening is from mucopurulent (light yellow and / or light green) to mucous (clear).

[0085] The color change, in another embodiment, is a two-tone lightening, ie, the lightening is from purulent (dark yellow and / or dark green) to mucoid (clear).

[0086] Phlegm induction is performed when the patient is unable to produce phlegm himself. Phlegm induction, in one embodiment, is initiated by the patient's nebulization of a saline solution. The percentage of saline, for example 3% or 7% or 10% or 13%, is determined based on the user's preference for this method. The selected saline is placed in a nebulizer, and the subject is in a sitting or semi-Fowler's position. In one embodiment, the subject wears a nose clip during the entire nebulization. The subject breathes slowly and deeply through the nebulizer mouthpiece to inhale the saline mist. The subject is reminded to breathe slowly and deeply, not quickly, and to pause at the peak to allow the particles to settle. In one embodiment, the nebulization time is 10 minutes.

[0087] At the end of nebulization, the subject is instructed to take several deep breaths, swallow any excess saliva in the mouth, and expectorate a sputum sample. The subject is encouraged to cough forcefully using the deep coughing and / or "huffing" coughing technique. All sputum is deposited in the specimen container. If the amount of sputum collected is insufficient, e.g., less than 1 mL, less than 2 mL, or less than 3 mL, this procedure can be repeated.

[0088] The methods provided herein can be utilized to treat bronchiectasis patients (e.g., non-CF bronchiectasis patients) who have a pulmonary infection. In one embodiment, the pulmonary infection is a mycobacterial infection. The mycobacterial infection can be a Mycobacterium tuberculosis infection or a nontuberculous mycobacterium (NTM) infection. Examples of NTM infections that a patient may present with that can be treated by the methods provided herein include, but are not limited to, Mycobacterium avium, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium, M. avium complex (MAC) (M. avium and Mycobacterium intracellulare, Mycobacterium conspicuum, Mycobacterium kansasii, Mycobacterium peregrinum, Mycobacterium immunogenum, Mycobacterium xenopi, Mycobacterium marinum, Mycobacterium malmoense, Mycobacterium marinum, Mycobacterium mucogenicum, Mycobacterium nonchromogenicum, Mycobacterium scrofulace ... scrofulaceum), Mycobacterium simiae (M. simiae), Mycobacterium smegmatis (M.smegmatis, M. szulgai, M. terrae, M. terrae complex, M. haemophilum, M. genavense, M. asiaticum, M. shimoidei, M. gordonae, M. nonchromogenicum, M. triplex, M. lentiflavum, M. serratium, M. celatum), Mycobacterium fortuitum, M. fortuitum complex (M. fortuitum and M. chelonae), or combinations thereof.

[0089] Other pulmonary infections that patients with bronchiectasis may have include, but are not limited to, Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus, and Moraxella catarrhalis. In further embodiments, the pulmonary bacterial infection is a Pseudomonas aeruginosa infection.

[0090] The compounds of formula (I) or pharma- ceutically acceptable salts thereof may also be administered in combination with other compounds used in the treatment of bronchiectasis by one of the methods described herein.

[0091] The second active ingredient is administered simultaneously, sequentially or in admixture with a compound of formula (I) for the treatment of bronchiectasis, eg non-CF bronchiectasis.

[0092] The second active ingredient, in one embodiment, is a glucocorticoid receptor agonist (steroidal or non-steroidal), such as triamcinolone, triamcinolone acetonide, prednisone, mometasone furoate, loteprednol etabonate, fluticasone propionate, fluticasone furoate, fluocinolone acetonide, dexamethasone cipesilate, desisobutyryl ciclesonide, clobetasol propionate, ciclesonide, butixocort propionate, budesonide, beclomethasone dipropionate, The active ingredients in the formulation are 2,2,2-trifluoro-N-[(1S,2R)-2-[1-(4-fluorophenyl)indazol-5-yl]oxy-2-(3-methoxyphenyl)-1-methyl-ethyl]acetamide, or 3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]benzamide.

[0093] The second active ingredient, in another embodiment, is 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.

[0094] In yet another embodiment, the second active ingredient is a phosphodiesterase (PDE) inhibitor such as methylxanthanine, including theophylline and aminophylline, or tetomilast, roflumilast, oglemilast, ibudilast, GPD-1116 (3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4-one), ronomilast, 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)- and selective PDE isoenzyme inhibitors (including PDE4 inhibitors or inhibitors of the isoform PDE4D) such as 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).

[0095] In yet another embodiment, the second active ingredient is a modulator of chemokine receptor function, such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 or CCR11 (for CC family), such as a CCR1, CCR2B or CCR5 receptor antagonist; CXCR1, CXCR2, CXCR3, CXCR4 or CXCR5 (for CXC family), such as a CXCR2 or CXCR3 receptor antagonist; or a CXCR2 or CXCR3 receptor antagonist. 3 -CX for the C family 3 It's CR1. For example, in one embodiment, the second active ingredient is selected from the group consisting of 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-oxo-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.

[0096] In another embodiment, the second active ingredient is a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase-activating protein (FLAP) antagonist, such as TA270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone), PF-4191834 (2H-pyran-4-carboxamide, tetrahydro-4- [3-[[4-(1-methyl-1H-pyrazol-5-yl)phenyl]thio]phenyl]-), cetileuton, CMI 977 (1-[4-[(2S,5S)-5-[(4-fluorophenoxy)methyl]tetrahydrofuran-2-yl]but-3-ynyl]-1-hydroxy-urea), Fiboflavon (3-[3-tert-butylsulfanyl-1-[[4-(6-ethoxy-3-pyridyl)phenyl]methyl) [(5-methyl-2-pyridyl)methoxy]indol-2-yl]-2,2-dimethyl-propanoic acid), GSK2190915 (1H-indole-2-propanoic acid, 3-[(1,1-dimethylethyl)thio]-1-[[4-(6-methoxy-3-pyridinyl)phenyl]methyl]-α,α-dimethyl-5-[(2-pyridinyl)methoxy]-), Licofelone, Quiflapon (3-[3-tert-butyl]-5-[(5-methyl-2-pyridyl)methoxy]indol-2-yl]-2,2-dimethyl-propanoic acid), tyrsulfanyl-1-[(4-chlorophenyl)methyl]-5-(2-quinolylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid), beliflavon ((2R)-2-cyclopentyl-2-[4-(2-quinolylmethoxy)phenyl]acetic acid), ABT080 (4,4-bis[4-(2-quinolylmethoxy)phenyl]pentanoic acid), zileuton, zafirlukast or montelukast.

[0097] In yet another embodiment, the second active ingredient is a CRTh2 antagonist or a DP2 antagonist, such as ACT129968 (2-[2-[(5-acetyl-2-methoxy-phenyl)methylsulfanyl]-5-fluoro-benzimidazol-1-yl]acetic acid), AMG853 (2-[4-[4-(tert-butylcarbamoyl)-2-[(2-chloro-4-cyclopropyl-phenyl)sulfonylamino]phenoxy]-5-chloro-2-fluoro-phenyl]acetic acid), AM211 (2-[3-[2-[[benzylcarbamoyl(ethyl)amino]methyl]-4 2-[4-(trifluoromethyl)phenyl]-4-methoxy-phenyl]acetic acid), 2-[4-acetamido-3-(4-chlorophenyl)sulfanyl-2-methyl-indol-1-yl]acetic acid, (2S)-2-[4-chloro-2-(2-chloro-4-ethylsulfonyl-phenoxy)phenoxy]propanoic acid, 2-[4-chloro-2-[2-fluoro-4-(4-fluorophenyl)sulfonyl-phenyl]phenoxy]acetic acid, or (2S)-2-[2-[3-chloro-4-(2,2-dimethylpyrrolidine-1-carbonyl)phenyl]-4-fluoro-phenoxy]propanoic acid.

[0098] A myeloperoxidase antagonist, such as resveratrol, piceatannol, or 1-(2-isopropoxyethyl)-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-4-one, is, in another embodiment, the second active ingredient in the combination therapy embodiment.

[0099] In yet another combination therapy embodiment, the second active ingredient is a toll-like receptor agonist (e.g., a TLR7 or TLR9 agonist); an adenosine antagonist; a glucocorticoid receptor agonist (steroidal or non-steroidal); a p38 antagonist; a PDE4 antagonist; a modulator of chemokine receptor function (e.g., a CCR1, CCR2B, CCR5, CXCR2 or CXCR3 receptor antagonist); and / or a CRTh2 antagonist;

[0100] In one combination therapy embodiment, the disclosed compound or its pharmaceutically acceptable salt is administered simultaneously or sequentially with one or more additional active ingredients selected from one or more of those provided above.For example, the compound of formula (I) or its pharmaceutically acceptable salt can be administered simultaneously or sequentially with an additional pharmaceutical composition for use as a medicament for treating bronchiectasis, such as non-CF bronchiectasis.This additional pharmaceutical composition can be a medicament (e.g., an existing standard or care medication) that may already be prescribed to the patient, and can itself be a composition that contains one or more active ingredients selected from those defined above.

[0101] The dosage administered varies depending on the compound used, the mode of administration, the desired treatment and the indicated disorder.For example, in one embodiment, the daily dosage of the compound of formula (I) when inhaled can be within the range of 0.05 μg / kg body weight (μg / kg) to 100 μg / kg body weight (μg / kg).Alternatively, in one embodiment, when the compound is administered orally, the daily dosage of the compound of the present disclosure can be within the range of 0.01 μg / kg body weight (μg / kg) to 100 mg / kg body weight (mg / kg).

[0102] In one embodiment, the compound of formula (I) is administered in a medicinal dosage form. In a further embodiment, the compound of formula (I) is administered as a 10 mg to 50 mg dosage form, for example, a 10 mg dosage form, a 15 mg dosage form, a 20 mg dosage form, a 25 mg dosage form, a 30 mg dosage form or a 50 mg dosage form. In a further embodiment, the dosage form is 10 mg or 25 mg. In a further embodiment, the dosage form is administered once a day. In yet a further embodiment, the compound is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide or a pharma- ceutically acceptable salt thereof.

[0103] The compound of formula (I) or its pharma- ceutically acceptable salt may be used alone, but is generally administered in the form of a pharmaceutical composition in which the compound of formula (I) / salt (active ingredient) is in a composition containing a pharma- ceutically acceptable adjuvant, diluent and / or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in “Pharmaceuticals—The Science of Dosage Form Designs”, ME Aulton, Churchill Livingstone, 2nd Ed. 2002 (incorporated herein in its entirety by reference for all purposes).

[0104] Depending on the mode of administration, the pharmaceutical composition may contain from 0.05 to 99% w (weight %) of active ingredient (all weight % being based on the total composition), for example, from 0.05 to 80% w, or from 0.10 to 70% w, or from 0.10 to 50% w.

[0105] In one oral administration embodiment, the oral dosage form is a film-coated oral tablet. In a further embodiment, the dosage form is an immediate release dosage form having rapid dissolution characteristics under in vitro testing conditions.

[0106] In one embodiment, the oral dosage form is administered once a day.In a further embodiment, the oral dosage form is administered at about the same time every day, for example, before breakfast.In another embodiment, the composition comprising an effective amount of formula (I) is administered twice a day.In yet another embodiment, the composition comprising an effective amount of formula (I) is administered once a week, twice a week, three times a week, four times a week or five times a week.

[0107] For oral administration, the disclosed compounds can be mixed with auxiliary agents, diluents or carriers, such as lactose, saccharose, sorbitol, nanitol; 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 and paraffin, and then compressed into tablets.If coated tablets are required, the cores prepared as above can be coated with a suitable polymer dissolved or dispersed in water or a readily volatile organic solvent.Alternatively, tablets can be coated with concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talicum and titanium dioxide.

[0108] For the preparation of soft gelatin capsules, the disclosed compound can be mixed with, for example, vegetable oil or polyethylene glycol.Hard gelatin capsules can contain the granules of the compound using pharmaceutical excipients such as the excipients mentioned above for tablets.The liquid or semi-solid formulation of the disclosed compound can also be filled into hard gelatin capsules.

[0109] In one embodiment, the composition is an orally disintegrating tablet (ODT). ODTs differ from traditional tablets in that they are designed to dissolve on the tongue rather than being swallowed whole.

[0110] In one embodiment, the composition is an oral thin film or oral disintegrating film (ODF).When such a formulation is placed on the tongue, it hydrates by interacting with saliva and releases active compound from the dosage form.In one embodiment, ODF contains film-forming polymers such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), pullulan, carboxymethylcellulose (CMC), pectin, starch, polyvinyl acetate (PVA) or sodium alginate.

[0111] Oral liquid preparations can be in the form of syrup, solution or suspension.Liquid preparations can contain, for example, the disclosed compound, and the balance is a mixture of sugar, ethanol, water, glycerol and propylene glycol.Optionally, such liquid preparations can contain coloring agents, flavoring agents, saccharin and / or carboxymethylcellulose as a thickening agent.In addition, when preparing preparations for oral use, other excipients known to those skilled in the art can be used.

[0112] Those skilled in the art will recognize that the disclosed compounds can be prepared in a variety of ways using known methods. The routes below are merely illustrative of some of the methods that can be used to synthesize the compounds of formula (I).

[0113] The present disclosure also provides a method for preparing a compound of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof, comprising the step of: [ka] [In the formula, R 1 is the same as defined in formula (I). With a compound represented by formula (III): [ka] [In the formula, PG represents a protecting group (e.g., tert-butoxycarbonyl)] and optionally thereafter reacting a compound represented by the following procedure: converting a compound of formula (I) into another compound of formula (I); removing protecting groups; and / or Formation of pharma- ceutically acceptable salts The present invention provides a method comprising performing one or more of the following:

[0114] The process is conveniently carried out in the presence of a base, such as DiPEA or TEA, and one or more activating agents, such as EDCI, 2-pyridinol-1-oxide or T3P. The reaction is conveniently carried out in an organic solvent, such as DMF or DCM, at a temperature, for example, in the range of 20° C. to 100° C., in particular at room temperature (25° C.).

[0115] The compound represented by formula (II) may be represented by formula (IV): [ka] [In the formula, PG represents a protecting group (e.g., tert-butoxycarbonyl)] With a suitable reagent to remove the protecting group PG. One example of a suitable reagent is formic acid.

[0116] The compound represented by formula (IV) is Pd(dppf)Cl 2 In the presence of a catalyst such as DCM or 1,1-bis(di-tert-butylphosphino)ferrocenepalladium dichloride and a base such as potassium carbonate or sodium carbonate, a compound of formula (V): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl) and Hal represents a halogen (e.g., I or Br). With a compound represented by formula (VI): [ka] [In the formula, R 1 is the same as defined in formula (I). or an ester thereof. The reaction is conveniently carried out in a solvent such as a dioxane / water mixture or an ACN / water mixture at a temperature in the range of, for example, 20° C. to 100° C., in particular at 75° C.

[0117] Compounds of formula (V) can be prepared using standard literature procedures for the dehydration of amides, for example using Burgess reagent or using a reagent such as T3P with or without a base such as DiPEA in a solvent such as DCM or DMF at a temperature in the range of -20°C to 100°C, for example at 0°C, to give compound of formula (VII): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl) and Hal represents a halogen (e.g., I or Br). It can be prepared from a compound represented by the formula:

[0118] Compounds of formula (VII) can be prepared by reaction of amides of formula (VIII): [ka] wherein PG represents a protecting group (e.g., tert-butoxycarbonyl) and Hal represents a halogen (e.g., I or Br). with aqueous ammonia. The reaction is conveniently carried out in an organic solvent such as DMF at a temperature in the range of -20°C to 100°C, for example 0°C.

[0119] Compounds of formula (VIII) are either commercially available, known in the literature (e.g., from Tetrahedron: Asymmetry, 1998, 9, 503, incorporated herein by reference in its entirety for all purposes), or can be prepared using known techniques.

[0120] Also provided is a process for the preparation of a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof, using standard literature procedures for the dehydration of amides, for example by using Burgess reagent or a reagent such as T3P with or without a base such as DiPEA in a solvent such as DCM or DMF at a temperature in the range of -20°C to 100°C, for example at 25°C, to give a compound of formula (IX): [ka] [In the formula, R 1 is as defined above, and PG represents a protecting group (e.g., tert-butoxycarbonyl). and then removing the protecting group PG by reaction with a suitable reagent. One example of a suitable reagent is formic acid.

[0121] The compound of formula (IX) is bis[bis(1,2-diphenylphosphino)ethane]palladium(0) or Pd(dppf)Cl 2 in the presence of a catalyst such as DCM and a base such as potassium carbonate or sodium carbonate, a compound of formula (X): [ka] [In the formula, PG represents a protecting group (e.g., tert-butoxycarbonyl)] The compound represented by formula (XI): [ka] [In the formula, R 1 is the same as defined in formula (I). The reaction is conveniently carried out in a solvent such as a dioxane / water mixture or an ACN / water mixture at a temperature in the range of, for example, 20° C. to 100° C., particularly 80° C.

[0122] The compound of formula (X) can be prepared by reacting Pd(dppf)Cl in a solvent such as DMSO at a temperature in the range of 60° C. to 100° C., for example at 85° C. 2 1,1'-bis(diphenylphosphino)ferrocene or 1,1-bis(di-tert-butylphosphino)ferrocene, in the presence of a suitable catalyst such as DCM, with or without palladium dichloride, using a suitable salt such as potassium acetate, to produce a compound of formula (XII): [ka] [In the formula, PG represents a protecting group (e.g., tert-butoxycarbonyl)] The compound represented by B 2 Pin 2 It can be prepared by reacting

[0123] The compound of formula (XII) can be converted to a compound of formula (XIII): in the presence of a base such as DiPEA or TEA and an activating agent such as EDCI, 2-pyridinol-1-oxide or T3P. [ka] With a compound represented by formula (III): [ka] [In the formula, PG represents a protecting group (e.g., tert-butoxycarbonyl)] The reaction is conveniently carried out in an organic solvent such as DMF or DCM at a temperature in the range of, for example, 20° C. to 100° C., in particular at room temperature (25° C.).

[0124] Compounds of formula (XIII) can be prepared by the synthesis of compounds of formula (XIV): [ka] [In the formula, PG is defined as in formula (VII)] with aqueous ammonia. The reaction is conveniently carried out in an organic solvent such as DMF at a temperature in the range of -20°C to 100°C, for example 0°C.

[0125] The compound of formula (IX) is bis[bis(1,2-diphenylphosphino)ethane]palladium(0) or Pd(dppf)Cl 2 They can be prepared by reacting a compound of formula (XII), in which PG represents a protecting group (e.g. tert-butoxycarbonyl), with a compound of formula (VI) or a boronic ester thereof in the presence of a catalyst such as DCM and a base such as potassium carbonate or sodium carbonate. The reaction is conveniently carried out in a solvent such as a dioxane / water or ACN / water mixture, for example at a temperature in the range of 20° C. to 100° C., in particular at 80° C.

[0126] There is also provided a process for the preparation of a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof, comprising the steps of: 2 In the presence of a catalyst such as DCM or 1,1-bis(di-tert-butylphosphino)ferrocenepalladium dichloride and a base such as potassium carbonate or sodium carbonate, a compound of formula (XV): [ka] [In the formula, PG represents a protecting group (e.g., tert-butoxycarbonyl)] The compound represented by R 1 is as defined in formula (I) with a compound of formula (VI) or an ester thereof. The reaction is conveniently carried out in a solvent such as a dioxane / water mixture or an ACN / water mixture at a temperature in the range of, for example, 20° C. to 100° C., in particular at 75° C., followed by removal of the protecting group PG by reaction with a suitable reagent. An example of a suitable reagent is formic acid.

[0127] Compounds of formula (XV) may be prepared from compounds of formula (XII) using standard literature procedures for dehydration of amides, for example using Burgess reagent, or reagents such as TBTU or T3P, with or without a base such as DiPEA, in a solvent such as DCM or DMF, at temperatures in the range of -20°C to 100°C, for example at 25°C.

[0128] There is also provided a process for the preparation of a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof, which is expediently carried out in the presence of a base, such as DiPEA or TEA, and one or more activating agents, such as EDCI, 2-pyridinol-1-oxide or T3P, followed by reaction in the presence of a dehydrating agent, such as T3P, of a compound of formula (XVI): [ka] [In the formula, R 1 is the same as defined in formula (I). With a compound of formula (III): The reaction is conveniently carried out in an organic solvent such as DMF or DCM at a temperature in the range, for example, 20° C. to 100° C., particularly at room temperature (25° C.).

[0129] The compound represented by formula (XVI) is Pd(dppf)Cl 2 Compounds of formula (VII) can be reacted with R 1 is as defined in formula (I) with a compound of formula (VI) or an ester thereof. The reaction is conveniently carried out in a solvent such as a dioxane / water mixture or an ACN / water mixture at a temperature in the range of, for example, 20° C. to 100° C., in particular at 75° C., followed by deprotection of PG.

[0130] Formula (III): [ka] [In the formula, PG represents a protecting group (e.g., tert-butoxycarbonyl)] Compounds of formula (XVII): [ka] It can be prepared from a compound represented by the formula:

[0131] Compounds of formula (XVII), where PG represents a protecting group, e.g., tert-butoxycarbonyl, can be reacted with a reducing agent, e.g., BH, in a solvent such as THF at a temperature in the range of 0-40° C., e.g., 25° C. 3 - using DMS, formula (XVIII): [ka] It can be prepared from a compound represented by the formula:

[0132] Compounds of formula (XVIII), in which PG represents a protecting group (e.g. tert-butoxycarbonyl), can be converted to lactams of formula (XIX) using a biocatalytic conversion for chemoselective lactam formation, for example using a lipase such as Novozym 435 at a temperature in the range of 0-80° C., e.g. at 55° C., in a solvent such as an ether, e.g. dioxane, followed by conversion to lactams of formula (XIX) under conditions for the introduction of the protecting group PG: [ka] It can be prepared from a compound represented by the formula:

[0133] Compounds of formula (XIX) can be prepared by hydrogenation using conditions for hydrogenation, for example at a temperature in the range of 25-80° C., for example at 40° C., under a pressure of for example 10 bar, in a solvent such as methanol or dioxane. 2 (g), and using a reagent such as palladium dihydroxide on carbon to obtain a compound of formula (XX): [ka] [In the formula, PG 1 and P.G. 2 is a protecting group (e.g., benzyl). It can be prepared from a compound represented by the formula:

[0134] PG 1 and P.G. 2 Compounds of formula (XX), where is a protecting group (e.g., benzyl), can be reacted with methyl propynoate in the presence of a base such as 4-methylmorpholine in a solvent such as toluene at a temperature in the range of 0-100° C., e.g., 25° C., using conditions for the oxa-Michael reaction to give compounds of formula (XXI): [ka] [In the formula, PG 1 and P.G. 2 is a protecting group (e.g., benzyl). It can be prepared from a compound represented by the formula:

[0135] PG 1 and P.G. 2 Compounds of formula (XXI), wherein is a protecting group (e.g., benzyl), may be prepared by reacting a diprotected benzylamine (e.g., dibenzylamine) with (S)-methyl oxirane-2-carboxylate in a solvent such as ethanol at a temperature in the range of 0 to 78°C, e.g., 70°C.

[0136] Alternatively, the compound of formula (III): [ka] [In the formula, PG represents a protecting group (e.g., tert-butoxycarbonyl)] The compound represented by the formula (I) can be prepared by, for example, reacting NaHCO in a solvent such as DCM / water at a temperature in the range of 0 to 100° C., for example at 25° C. 3 and a phase transfer catalyst such as tetrabutylammonium bisulfate, optionally in the presence of a salt such as sodium bromide, using a reagent such as TEMPO and sodium hypochlorite to produce a compound of formula (XXII): [ka] It can be prepared by oxidation of a compound represented by the formula:

[0137] The compound of formula (XXII), in which PG represents a protecting group (e.g., tert-butoxycarbonyl), is reacted with a base, such as sodium hydride, in a solvent, such as THF, at a temperature in the range of 0-60° C., e.g., 25° C., and then the protecting group PG, PG as defined in formulas (XXII) and (XXIII) is reacted with a base, such as sodium hydride, in a solvent, such as THF, at a temperature in the range of 0-60° C., e.g., 25° C., and then the protecting group PG, PG 1 and P.G. 2 by interconversion to obtain a compound of formula (XXIII): [ka] [In the formula, PG 1 and P.G. 2 is a protecting group (e.g., benzyl). It can be prepared from a compound represented by the formula:

[0138] PG 1 and P.G. 2Compounds of formula (XXIII), wherein is a protecting group (e.g. benzyl), may be prepared by reacting a protected 3-aminopropanol (e.g. N-benzyl-3-aminopropanol) with (S)-2-((benzyloxy)methyl)oxirane in a solvent such as ethanol or propanol at a temperature in the range of 0-70° C., for example at 40° C., followed by reacting the crude product with methanesulfonyl chloride in the presence of a base such as DiPEA in a solvent such as DCM at a temperature in the range of −10-25° C., for example at −5° C.

[0139] The compound of formula (VI) or its esters, and the compounds of formulae (VIII), (XI) and (XIV) are either commercially available or known in the literature or may be prepared using known techniques.

[0140] It will be appreciated by those skilled in the art that in the preparation methods of the present disclosure certain functional groups, such as hydroxyl or amino groups in the reagents, may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.

[0141] One of skill in the art will recognize that at any stage in the preparation of a compound of formula (I), a mixture of isomers (e.g., a racemate) of any of the compounds of formulas (II)-(V), (VII)-(X) and (XXII)-(XVI) may be utilized. At any stage in the preparation, a single stereoisomer may be obtained by isolating it from the mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation.

[0142] Protection and deprotection of functional groups is described in 'Protective Groups in Organic Synthesis', 4th Ed, TW Greene and PGM Wuts, Wiley (2006) and 'Protecting Groups', 3rd Ed PJ Kocienski, Georg Thieme Verlag (2005), which are incorporated by reference in their entirety for all purposes.

[0143] As provided throughout, according to the methods provided herein, the compounds of formula (I) may be administered as pharma- ceutically acceptable salts. The pharma- ceutically acceptable salts of the compounds of formula (I) may be administered as pharma- ceutically acceptable salts, which may be stable at different temperatures and humidities, or may be administered in a humidified or humidified state. 2 A salt may be advantageous due to one or more of its chemical or physical properties, such as desirable solubility in water, oil or other solvents. In some cases, a salt may be used to aid in the isolation or purification of the compound of formula (I).

[0144] When the compound of formula (I) is sufficiently acidic, pharma- ceutically acceptable salts include, but are not limited to, alkali metal salts, such as Na or K, alkaline earth metal salts, such as Ca or Mg, or organic amine salts.When the compound of formula (I) is sufficiently basic, pharma-ceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.

[0145] Depending on the number of charged functional groups and the valency of the cations or anions, multiple cations or anions may be present.

[0146] For a review of suitable salts and pharma- ceutically acceptable salts suitable for use herein, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or “Handbook of Pharmaceutical Salts: Properties, selection and use”, PH Stahl, PG Vermuth, IUPAC, Wiley-VCH, 2002, which is incorporated by reference in its entirety for all purposes.

[0147] The compound of formula (I) may form mixtures of its salts and co-crystal forms. It should also be understood that the methods provided herein may employ such salt / co-crystal mixtures of the compound of formula (I).

[0148] The salts and co-crystals can be characterized using well-known techniques, such as X-ray powder diffraction, single crystal X-ray diffraction (e.g., to assess proton positions, bond lengths or bond angles), solid-state NMR (e.g., to assess C, N or P chemical shifts) or spectroscopic techniques (e.g., to measure OH, NH or COOH signals and IR peak shifts caused by hydrogen bonding).

[0149] It is also to be understood that certain compounds of formula (I) may exist in solvated forms, such as hydrates, including solvates of pharma- ceutically acceptable salts of the compounds of formula (I).

[0150] In one embodiment, certain compounds of formula (I) may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. It should be understood that the present disclosure encompasses all such isomers. Certain compounds of formula (I) may also include restrictions caused by the presence of bonds (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) where bond rotation is restricted around that particular bond, such as ring bonds or double bonds. It should be understood that the methods provided herein can therefore employ such isomers. Certain compounds of formula (I) may also contain multiple tautomers. It should be understood that the present disclosure encompasses all such tautomers. Stereoisomers can be separated using conventional techniques, such as chromatography or fractional crystallization, or stereoisomers can be prepared by stereoselective synthesis.

[0151] In further embodiments, compounds of formula (I) include any isotopically labeled (or "radiolabeled") derivatives of compounds of formula (I). Such derivatives are derivatives of compounds of formula (I) in which one or more atoms have been replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that can be incorporated include: 2 H (also written as "D" for deuterium). Thus, in one embodiment, there is provided a compound of formula (I) in which one or more hydrogen atoms are replaced by one or more deuterium atoms; the deuterium compound is used in one of the methods provided herein for treating bronchiectasis. In a further embodiment, the bronchiectasis is non-CF bronchiectasis.

[0152] In a further embodiment, the compounds of formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of formula (I). Examples of pro-drugs include in vivo hydrolysable esters of compounds of formula (I).

[0153] In vivo hydrolysable esters of compounds of formula (I) containing a carboxy or hydroxy group are, for example, pharma- ceutically acceptable esters that hydrolyze in the human or animal body to produce the parent acid or alcohol. For examples of ester prodrug derivatives, see Curr. Drug. Metab. 2003, 4, 461 (incorporated in its entirety by reference for all purposes).

[0154] Various other forms of prodrugs are known in the art and can be used in the methods provided herein. For examples of prodrug derivatives, see Nature Reviews Drug Discovery 2008, 7, 255, the disclosure of which is incorporated herein by reference in its entirety for all purposes. EXAMPLES

[0155] The present invention will be further illustrated with reference to the following examples, however, it should be noted that the examples, like the above embodiments, are illustrative and should not be construed as limiting the scope of the invention in any way.

[0156] Example - Efficacy, safety, and tolerability, and pharmacokinetics 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 administered once daily for 24 weeks in subjects with non-cystic fibrosis bronchiectasis (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, referred to in this example as "INS1007," administered once daily (QD) for 24 weeks in subjects with non-cystic fibrosis (CF) bronchiectasis (NCFBE): [ka] Subjects will be randomized in a 1:1:1 ratio to three treatment arms to receive either (i) INS1007 10 mg; (ii) INS1007 25 mg or (iii) matching placebo.

[0157] After a screening visit (Visit 1) and up to 4-week screening period, subjects are randomized to Visit 2 (Day 1, "Baseline") and then return for study visits at 2 weeks (Visit 3), 4 weeks (Visit 4), 8 weeks (Visit 5), 12 weeks (Visit 6), 16 weeks (Visit 7), 20 weeks (Visit 8), 24 weeks (Visit 9), and 28 weeks (Visit 10). During each visit, assessments and procedures are performed to allow for evaluation of the following criteria: Study treatment is administered during Visits 2-9.

[0158] At Week 28 (Visit 10), blood and sputum samples will be collected for biomarker assessment.

[0159] Time to first pulmonary exacerbation over a 24-week treatment period will be assessed.

[0160] The following additional criteria will be evaluated: 1. Change from baseline in Quality of Life - Bronchiectasis (QOL-B) respiratory symptoms domain score over the 24-week treatment period. 2. Post-bronchodilator FEV over the 24-week treatment period 1 Change from screening. 3. Change in concentration of active neutrophil elastase (NE) in sputum from pre-treatment (defined as the mean of concentrations at screening and day 1) to mid-treatment (defined as the mean of concentrations at weeks 12 and 24). 4. Pulmonary exacerbation rate (number of events per person / hour) over the 24-week treatment period. 5. Change from baseline in QOL-B scores (all domains except respiratory symptoms domain) over the 24-week treatment period. 6. Change from baseline in Leicester Cough Questionnaire (LCQ) scores over the 24-week treatment period. See, e.g., Murray et al. (2003). Thorax 58(4), pp. 339-343, incorporated herein by reference in its entirety. 7. Change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score over the 24-week treatment period. 8. Changes in sputum active NE concentrations from pretreatment to weeks 2, 4, and 28. 9. Changes in the concentration of active NE in reagent-stimulated blood from before treatment to weeks 2, 4, 12, 24, and 28. 10. Change from baseline in sputum color (assessed by sputum color chart) at weeks 2, 4, 12, 24, and 28. 11. Change from baseline in urinary desmosine at weeks 2, 4, 12, 24 and 28. 12. Change from screening in forced vital capacity (FVC) at weeks 12 and 24. 13. Change from screening in peak expiratory flow rate (PEFR) at weeks 12 and 24. 14. Forced expiratory flow rate (FEF) 25%-75% at weeks 12 and 24 25-75 ) change from screening. 15. Total duration of exacerbations (in days) per patient over the 24-week treatment period. 16. Frequency of rescue medication use over the 24-week treatment period. Rescue medications included short-acting beta agonists (SABAs), short-acting muscarinic antagonists (SAMAs), newly prescribed long-acting beta agonists (LABAs), long-acting muscarinic antagonists (LAMAs), and oxygen. 17. Number of subjects hospitalized due to exacerbation of bronchiectasis by the end of the 24-week treatment period.

[0161] Pulmonary Function Tests (PFTs) Spirometry (FEV) 1 , FVC, PEFR, and FEF 25-75 Pulmonary function tests (PFTs) by the American Thoracic Society (ATS / European Respiratory Society [ERS]) will be performed according to American Thoracic Society (ATS / ERS) standards at Visit 1 (screening), Visit 6, and Visit 9. Spirometry standards are described in Miller et al. (2005). Standardization of Spirometry. Eur. Respir. J. 26, pp. 319-38, which is incorporated by reference in its entirety for all purposes. Subjects will be provided with detailed instructions on how to perform the FVC maneuver according to the ATS / ERS spirometry standardization prior to performing the test.

[0162] Subjects are advised to refrain from short-acting inhaled medications (e.g., the beta-agonists albuterol / salbutamol or the anticholinergic ipratropium bromide) for 6 hours prior to the study. Long-acting beta-agonist bronchodilators (e.g., salmeterol or formoterol) or long-acting muscarinic bronchodilators (e.g., tiotropium), or oral therapy with aminophylline or sustained-release beta-agonists should be withheld for 12 to 24 hours, depending on the drug used, prior to the study, with a minimum time for the list of restricted medications.

[0163] Subjects will be advised to refrain from using inhaled corticosteroids for at least 24 hours prior to the study. If a subject takes a restricted medication during the specified period prior to the study, the study will be rescheduled to another visit within the protocol-specified visit window. If rescheduling the visit is not feasible for the subject, the study will proceed as usual with appropriate note in the source documentation.

[0164] Sputum collection If the patient is unable to produce a sputum sample on their own, the following procedure is used: The induction procedure begins with nebulization of a saline solution by the subject. The amount of saline, e.g., 3% or 7%, is determined based on the investigator's preference. Approximately 3-6 mL of the selected saline is placed in the nebulizer, and the subject is in a sitting or semi-Fowler's position. The subject may wear a nose clip throughout the nebulization. The subject breathes slowly and deeply through the nebulizer mouthpiece and inhales the saline mist. The subject is reminded to breathe slowly and deeply, not quickly, and to pause inhaling at the peak to allow the particles to settle. The nebulization time is 10 minutes.

[0165] At the end of nebulization, subjects are instructed to take several deep breaths, swallow any excess saliva in their mouth, and expectorate a sputum sample. Subjects are encouraged to forcefully cough using the deep coughing and / or "huffing" coughing technique. All sputum is deposited into the specimen container. The container is not opened until the sample is ready to be deposited. The container is closed immediately after the sample is deposited.

[0166] The sputum sample should be approximately 3 mL - slightly below the bottom line of the collection container (5 mL). If an adequate sputum sample is not collected and the subject appears to be tolerating the induction procedure well, the subject may pursue an additional 10-minute nebulization period. If a second 10-minute nebulization period is required, it is recommended to increase the sodium chloride concentration (i.e., if 3% was used initially, 7% should be used for the next nebulization; if 7% was used initially, 10% should be used for the next nebulization). Once completed, the sputum sample is refrigerated until sent to the microbiology laboratory for further analysis.

[0167] Bronchiectasis Severity Index (BSI) The BSI score is calculated at baseline as described in Table 1 below. [Table 1] * * * * * * *

[0168] All documents, patents, patent applications, publications, product descriptions and protocols cited throughout this application are hereby incorporated by reference in their entirety for all purposes.

[0169] The embodiments illustrated and described herein are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention. As will be appreciated by those skilled in the art in light of the above teachings, modifications and variations of the above-described embodiments of the invention are possible without departing from the invention. It is therefore understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described. The present invention includes the following embodiments. 1. A method for treating bronchiectasis in a patient in need thereof, comprising administering to the patient a compound of formula (I): [ka] [In the formula, R 1 teeth, [ka] and; R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 Alkyl or C 1-3 is alkyl; R 3 are hydrogen, F, Cl, Br, CN, and CF 3 , S.O. 2 C 1-3 Alkyl, CONH 2 or SO 2 NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; R 6 may be substituted by 1, 2 or 3 F and / or OH, OC 1-3 Alkyl, N(C 1-3 Alkyl) 2 , optionally substituted by cyclopropyl or tetrahydropyran; C 1-3 is alkyl; R 7 is hydrogen, F, Cl or CH 3 and; X is O, S or CF 2 and; Y is O or S; Q is CH or N. or a pharma- ceutically acceptable salt thereof. 2. R 1 but, [ka] The method according to item 1, wherein 3. X is O;R 6 C 1-3 R is alkyl; 7 The method according to item 1 or 2, wherein is hydrogen. 4. The compound of formula (I) (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; 4'-[(2S)-2-cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4'-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(3',4'-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-2-(4'-carbamoyl-3'-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-cyano-2-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4'-(azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-cyano-2-(4'-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(1,3-benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide; or (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; and pharma- ceutically acceptable salts thereof The method according to item 1, wherein the compound is selected from the group consisting of: 5. The compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide: [ka] or a pharma- ceutically acceptable salt thereof. 6. The method according to item 1, wherein the compound represented by formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide. 7. The method of any one of items 1 to 6, wherein the composition comprises a pharma- ceutically acceptable adjuvant, diluent or carrier. 8. The method of any one of items 1 to 8, wherein the administration includes oral administration. 9. The method according to any one of items 1 to 8, wherein administration to a patient is performed once a day. 10. The method according to any one of items 1 to 8, wherein administration to the patient is performed twice a day. 11. The method according to any one of items 1 to 8, wherein administration to the patient is performed every other day. 12. The method according to any one of items 1 to 8, wherein administration to the patient is performed every two days. 13. The method of any one of paragraphs 1 to 12, wherein treating includes increasing the length of time to first pulmonary exacerbation compared to an untreated bronchiectasis patient. 14. The method of paragraph 13, wherein increasing comprises increasing for about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks. 15. The method of item 13, wherein increasing includes increasing for about 20 days to about 100 days, or for about 30 days to about 100 days, or for about 20 days to about 75 days, or for about 20 days to about 50 days, or for about 20 days to about 40 days. 16. The method of any one of paragraphs 1 to 15, wherein treating comprises reducing the rate of pulmonary exacerbations in the patient compared to the rate of pulmonary exacerbations experienced by the patient prior to treatment or compared to an untreated bronchiectasis patient. 17. The method of paragraph 16, wherein the rate is calculated over a period of about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months or about 24 months. 18. The method of paragraph 16 or 17, wherein the rate of pulmonary exacerbations in the patient is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% or about 50% compared to the rate of pulmonary exacerbations experienced by the patient prior to treatment or compared to an untreated bronchiectasis patient. 19. The method of paragraph 16 or 17, wherein the rate of pulmonary exacerbations in the patient is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 50% compared to the rate of pulmonary exacerbations experienced by the patient prior to treatment or compared to an untreated bronchiectasis patient. 20. The method of any one of paragraphs 1 to 19, wherein treating includes reducing the duration of pulmonary exacerbations in the patient compared to the duration of pulmonary exacerbations experienced by the patient prior to treatment or compared to an untreated bronchiectasis patient. 21. The method of paragraph 20, wherein the reduction in duration of a pulmonary exacerbation is a reduction in duration of about 6 hours, about 12 hours, about 24 hours, about 48 hours or about 72 hours, at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about 96 hours, or at least about 168 hours. 22. The method according to item 20 or 21, wherein the reduction in pulmonary exacerbation duration is a reduction in duration of about 6 hours to about 96 hours, about 12 hours to about 96 hours, about 24 hours to about 96 hours, about 48 hours to about 96 hours, or about 48 hours to about 168 hours. 23. The method of any one of paragraphs 13 to 22, wherein the pulmonary exacerbation is characterized by three or more of the following symptoms exhibited by the patient for at least 48 hours: (1) increased coughing; (2) increased sputum volume or change in sputum consistency; (3) increased purulence of sputum; (4) increased shortness of breath and / or decreased exercise tolerance; (5) fatigue and / or malaise; (6) hemoptysis. 24. The method of any one of paragraphs 1 to 23, wherein treating includes improving the patient's lung function compared to the patient's lung function before treatment or compared to an untreated bronchiectasis patient. 25. The method according to item 24, wherein the improvement in pulmonary function is an increase in forced expiratory volume in one second (FEV1). 26. The method of paragraph 25, wherein the increase in FEV1 is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50% increase. 27. The method of paragraph 25, wherein the increase in FEV1 is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50%. 28. The method according to item 25, wherein the increase in FEV1 is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%. 29. The method of paragraph 25, wherein the increase in FEV1 is at least about a 5% increase. 30. The method according to item 25, wherein the increase in FEV1 is about 5% to about 50%, or about 10% to about 50%, or about 15% to about 50%. 31. The method according to any one of items 25 to 30, wherein the increase in FEV1 is an increase of about 25 mL to about 500 mL. 32. The method according to any one of items 25 to 30, wherein the increase in FEV1 is about 25 mL to about 250 mL. 33. The method of paragraph 24, wherein the improvement in pulmonary function in the patient is an increase in forced vital capacity (FVC) when compared to the patient's pulmonary function before treatment or when compared to an untreated bronchiectasis patient. 34. The method of paragraph 33, wherein the increase in FVC is about a 1% increase, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85% or about 90% increase when compared to the patient's FVC before treatment or when compared to an untreated bronchiectasis patient. 35. The method of any one of paragraphs 1 to 34, wherein treating includes improving the patient's quality of life (QOL) compared to the patient's QOL before treatment. 36. The method of paragraph 35, wherein QOL is assessed by the Quality of Life - Bronchiectasis (QOL-B) questionnaire. 37. The method of paragraph 35, wherein the QOL is assessed by the Leicester Cough Questionnaire (LCQ). 38. The method according to paragraph 35, wherein the QOL is assessed by the St. George's Respiratory Questionnaire (SGRQ). 39. The method of any one of paragraphs 1 to 38, wherein treating comprises reducing active neutrophil elastase (NE) sputum concentration in the patient compared to the active NE sputum concentration before treatment. 40. The method of paragraph 39, wherein reducing active NE sputum concentration includes reducing by about 1%, about 5%, about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80%. 41. The method of paragraph 39, wherein reducing active NE sputum concentration includes reducing by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. 42. The method of any one of paragraphs 1 to 41, wherein treating comprises lightening the color of the patient's sputum as measured by the Murray Sputum Color Chart, compared to the color of the patient's sputum before treatment. 43. The method of paragraph 42, wherein lightening the color of the patient's sputum comprises the color of the patient's sputum becoming one shade lighter. 44. The method of paragraph 42 or 43, wherein lightening the color of the patient's sputum comprises lightening from purulent (dark yellow and / or dark green) to mucopurulent (light yellow and / or light green). 45. The method of paragraph 42 or 43, wherein lightening the color of the patient's sputum comprises lightening from mucopurulent (light yellow and / or light green) to mucoid (clear). 46. ​​The method of paragraph 42, wherein lightening the color of the patient's sputum comprises lightening from purulent (dark yellow and / or dark green) to mucoid (clear). 47. The method of any one of paragraphs 1 to 46, wherein the patient has a pulmonary infection. 48. The method of paragraph 47, wherein the pulmonary infection is a mycobacterial infection. 49. The method of paragraph 47, wherein the mycobacterial infection is a Mycobacterium tuberculosis infection. 50. The method of paragraph 47, wherein the mycobacterial infection is a nontuberculous mycobacterial (NTM) infection. 51. NTM infections include Mycobacterium avium, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium, M. avium complex (MAC) (M. avium and M. intracellulare). intracellulare), Mycobacterium conspicuum, Mycobacterium kansasii, Mycobacterium peregrinum, Mycobacterium immunogenum, Mycobacterium xenopi, Mycobacterium marinum, Mycobacterium malmoense, Mycobacterium marinum, Mycobacterium mucogenicum, Mycobacterium nonchromogenicum, Mycobacterium scrofulaceum, Mycobacterium simiae ... simiae, Mycobacterium smegmatis, M. szulgai, M. terrae, M. terrae complex, M. haemophilum, M. genavense, M. asiaticum, M. simiae, M. smegmatis, M. szulgai, M. terrae, M. terrae complex, M. haemophilum, M. genavense, M. asiaticum, M. simiae51. The method of claim 50, wherein the bacterium is selected from the group consisting of Mycobacterium shimoidei, Mycobacterium gordonae, Mycobacterium nonchromogenicum, Mycobacterium triplex, Mycobacterium lentiflavum, Mycobacterium celatum, Mycobacterium fortuitum, Mycobacterium fortuitum complex (Mycobacterium fortuitum and Mycobacterium chelonae), or a combination thereof. 52. The method of paragraph 47, wherein the pulmonary infection is a Mycobacterium avium complex (MAC) (M. avium and M. intracellulare) infection. 53. The method of paragraph 47, wherein the pulmonary infection is a Haemophilus influenzae infection. 54. The method of paragraph 47, wherein the pulmonary infection is a Pseudomonas aeruginosa infection. 55. The method of paragraph 47, wherein the pulmonary infection is a Streptococcus pneumoniae infection. 56. The method of paragraph 47, wherein the pulmonary infection is a Staphylococcus aureus infection. 57. The method of paragraph 47, wherein the pulmonary infection is a Moraxella catarrhalis infection. 58. The method of any one of paragraphs 1 to 57, wherein the patient is a non-cystic fibrosis (CF) bronchiectasis patient. 59. The method of any one of paragraphs 1 to 58, wherein treating includes prevention.

Claims

[Claim 1] The invention described herein.

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