WO2022140516A1

WO2022140516A1 - Certain (25)-iv-[(ls')~ i-c yan0-2-phenylethyl·]- 1,4-oxazepane-2- carboxamides for treating behcet's disease

Info

Publication number: WO2022140516A1
Application number: PCT/US2021/064810
Authority: WO
Inventors: Jimin Zhang
Original assignee: Insmed Incorporated
Priority date: 2020-12-22
Filing date: 2021-12-22
Publication date: 2022-06-30

Abstract

The present disclosure relates to methods for treating Behçet's Disease with compositions comprising an effective amount of certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds of Formula (I), including pharmaceutically acceptable salts thereof that inhibit dipeptidyl peptidase 1 (DPP1) activity. 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 (brensocatib).

Description

CERTAIN (2S)-A-[(15)-l-CYANO-2-PHENYLETHYL]-l,4-OXAZEPANE-2- CARBOXAMIDES FOR TREATING BEHQET’S DISEASE

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. Provisional Application Serial No. 63/129, 133, filed December 22, 2020, the disclosure of which is incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

[0002] Behpet’s Disease (BD) is as a multiorgan inflammatory disease of unknown origin, characterized by a wide clinical spectrum. For example, BD patients have been reported to present with recurrent oral ulcers, genital ulcers, uveitis and skin lesions. Baharav et al. (2006). Drug Discovery Today: Disease Models 3(1), pp. 11-14. Gastrointestinal and central nervous system involvements have also been reported. Sohn et al. (2003). International Immunopharmacology 3, pp. 713-721. Pathologically, patients with BD present with systemic necrotizing vasculitis of small and large vessels, arthritis and a positive pathergy test.. The death rate among BD patients is about 5%, with intestinal perforation, strokes, and a rupture of enlarged, weakened blood vessels (aneuiysms) as common causes of death.

[0003] Therapeutic management of BD typically depends on the clinical presentation and organ involved and consists of treating BD symptoms. For example, for patients presenting mucocutaneous and joint involvement, colchicine, nonsteroidal anti-inflammatory drug (NSAID) and/or topical treatments are often prescribed. Vallet et al. (2015). Journal of Autoimmunity 62, pp. 67-74. For severe symptoms, immunosuppressive agents such as antitumor necrosis factor alpha (TNFa) agents are used (e.g., infliximab or adalimumab).

[0004] Although studies have suggested viral involvement in BD, including herpes simplex vims (HSV) involvement, treatment with the anti-viral acyclovir has not been shown to significantly alleviate the frequency of clinical features of BD. Sohn et al. (2003). International Immunopharmacology 3, pp. 713-721.

[0005] Because current drugs are not totally effective in controlling BD symptoms, let alone effective in treating the cause of BD, and have been associated with significant adverse events, a need exists for new and improved BD treatments. The present invention addresses this and other needs. SUMMARY OF THE INVENTION [0006] In one aspect, a method is provided for treating a Behçet’s Disease (BD) patient in need thereof. The method comprises, in one embodiment, administering to the BD patient in need of treatment, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

R² is hydrogen, F, Cl, Br, OSO₂C_1-3alkyl, or C_1-3alkyl; R³ is hydrogen, F, Cl, Br, CN, CF₃, SO₂C_1-3alkyl, CONH₂ or SO₂NR⁴R⁵, wherein R⁴ and R⁵ together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or R⁶ is C_1-3alkyl, optionally substituted by 1, 2 or 3 F and/or optionally by OH, OC_1-3alkyl, N(C_1-3alkyl)₂, cyclopropyl, or tetrahydropyran; R⁷ is hydrogen, F, Cl or CH₃; X is O, S or CF₂; Y is O or S; and Q is CH or N. [0007] In one embodiment of the method for treating BD in a patient in need thereof, the pharmaceutical composition comprises an effective amount 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, referred to herein by its international nonproprietary name (INN), brensocatib (and formerly known as INS1007 and AZD7986),

or a pharmaceutically acceptable salt thereof. In the present application, brensocatib and INS1007 are used interchangeably and refer to (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. [0008] Administration routes include oral administration. Administration schedules can be determined by the user of the method, e.g., a prescribing physician. In one embodiment, administration is once daily. In another embodiment, administration is twice daily. In another embodiment, administration 1× daily, once every other day, once every third day, once every fourth day, 2× weekly, 3× weekly or 4× weekly. BRIEF DESCRIPTION OF THE FIGURES [0009] Figure 1 is a graph of surface proteinase 3 (PR3) expression (% of untreated cells, mean fluorescence intensity (MFI)) in neutrophils derived from either bone marrow (BM) or umbilical cord (UC) blood stem cells as a function of brensocatib concentration according to Example 1. Brensocatib was added in the cell culture medium during neutrophil differentiation. *P < 0.05 vs. the lowest brensocatib concentration. [0010] Figure 2 is a graph of surface proteinase 3 (PR3) expression (% positive cells) in neutrophils derived from either bone marrow (BM) or umbilical cord (UC) blood stem cells as a function of brensocatib concentration according to Example 1. Brensocatib was added in the cell culture medium during neutrophil differentiation. *P < 0.05 vs. untreated cells. [0011] Figure 3 is a graph of neutrophil elastase (NE) activity (% of untreated control) in neutrophils derived from either bone marrow (BM) or umbilical cord (UC) blood stem cells as a function of brensocatib concentration according to Example 1. Brensocatib was added in the cell culture medium during neutrophil differentiation. *P < 0.05 vs. the lowest brensocatib concentration. [0012] Figure 4 is a graph of proteinase 3 (PR3) activity (% of untreated control) in neutrophils derived from either bone marrow (BM) or umbilical cord (UC) blood stem cells as a function of brensocatib concentration according to Example 1. Brensocatib was added in the cell culture medium during neutrophil differentiation. *P < 0.05 vs. the lowest brensocatib concentration. [0013] Figure 5 is a graph showing the percentage of surviving BD mice during the treatment with the vehicle control (dotted line), 10 mg/kg brensocatib (thick solid line), or 30 mg/kg brensocatib (thin solid line) according to Example 2. DETAILED DESCRIPTION OF THE INVENTION [0014] The methods provided herein employ reversible inhibitors of DPP1 in methods for treating BD. [0015] Neutrophils contain four main types of granules: (i) azurophilic or primary granules, (ii) specific or secondary granules, (iii) gelatinase or tertiary granules, and (iv) secretory granules. Azurophilic granules are believed to be the first to form during neutrophil maturation in the bone marrow and are characterized by the expression of related neutrophil serine proteases (NSPs): neutrophil elastase (NE), proteinase 3, and cathepsin G (CatG). The lysosomal cysteine dipeptidyl peptidase 1 (DPP1) is the proteinase that activates these three NSPs by removal of the N-terminal dipeptide sequences from their precursors during azurophilic granule assembly (Pham et al. (2004). J Immunol.173(12), pp.7277-7281). DPP1 is broadly expressed in tissues but is highly expressed in cells of hematopoietic lineage such as neutrophils. [0016] The three NSPs are abundantly secreted into the extracellular environment upon neutrophil activation at inflammatory sites, which has been reported to occur in Behçet disease pathology (see, e.g., Eksioglu-Demiralp et al. (2001). Clinical and Experimental Rheumatology 19(5), Supp.24), pp. S19-S24, incorporated by reference herein in its entirety), and are thought to act in combination with reactive oxygen species to assist in degradation of engulfed microorganisms inside phagolysosomes. A fraction of the released proteases remains bound in an active form on the external surface of the plasma membrane, so that both soluble and membrane-bound NSPs can regulate the activities of a variety of biomolecules, such as chemokines, cytokines, growth factors, and cell surface receptors. Regulation is thought to occur by either converting the respective biomolecule to an active form or by degrading the biomolecule by proteolytic cleavage. Secreted proteases can stimulate mucus secretion and inhibit mucociliary clearance, but 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; the disclosure of each of which is incorporated by reference in its entirety for all purposes). [0017] The methods provided herein employ reversible inhibitors of DPP1 in methods for treating BD. Without wishing to be bound by theory, it is thought that the compounds of Formula (I), administered via the methods provided herein have beneficial effects via inhibition of activation of the three NSPs via the upstream inhibition of DPP1. Inhibition of DPP1, without wishing to be bound by theory, reduces the amount of activated NSPs available for release during neutrophil degranulation. Moreover, in a small population of Behcet’s Disease patients whose pathogenesis is thought to be driven by PR3-reactive ANCAs, inhibition of PR3 activation by the compounds of Formula (I) in turn leads to reduction of PR3 expression at the neutrophil membrane surface. The decreased membrane-bound PR3 (mbPR3) in turn, might limit the targets to which PR3-specific antineutrophil cytoplasmic autoantibodies (ANCAs) can bind, and in turn, might attenuate neutrophil activation. In addition, in a small population of Behcet’s Disease patients whose pathogenesis is thought to be driven by CatG-reactive ANCAs, similar mechanism of action to the PR3 autoantigen by the compounds of Formula (I) may happen and thus the compounds have potential therapeutic effect for those patients. [0018] As used herein, “C_1-3” means a carbon group having 1, 2 or 3 carbon atoms. [0019] The term “alkyl”, unless otherwise noted, includes both straight and branched chain alkyl groups and may be substituted or non-substituted. “Alkyl” groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl. [0020] The term “pharmaceutically acceptable”, unless otherwise noted, is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications. [0021] Provided herein are methods for treating BD patients via administration of a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

R² is hydrogen, F, Cl, Br, OSO₂C_1-3alkyl, or C_1-3alkyl; R³ is hydrogen, F, Cl, Br, CN, CF₃, SO₂C_1-3alkyl, CONH₂ or SO₂NR⁴R⁵, wherein R⁴ and R⁵ together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or R⁶ is C_1-3alkyl, optionally substituted by 1, 2 or 3 F and/or optionally by OH, OC_1-3alkyl, N(C_1- ₃alkyl)₂, cyclopropyl, or tetrahydropyran; R⁷ is hydrogen, F, Cl or CH₃; X is O, S or CF₂; Y is O or S; and Q is CH or N. [0022] In one embodiment

hydrogen, F, Cl, Br, OSO₂C_1-3alkyl, or C_1-3alkyl; R³ is hydrogen, F, Cl, Br, CN, CF₃, SO₂C_1-3alkyl, CONH₂ or SO₂NR⁴R⁵, wherein R⁴ and R⁵ together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring. [0023] In a further embodiment, h ³

ydrogen, F, Cl or C_1-3alkyl; and R is hydrogen, F, Cl, CN or SO₂C_1-3alkyl. [0024] In still a further embodiment,

hydrogen, F or C_1-3alkyl; and R³ is hydrogen, F or CN.

is O, S or CF₂; Y is O or S; Q is CH or N; R⁶ is C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted by 1, 2 or 3 F and/or optionally substituted by OH, OC_1-3alkyl, N(C_1-3alkyl)₂, cyclopropyl, or tetrahydropyran; and R⁷ is hydrogen, F, Cl or CH₃. In a further embodiment,

CF₂; Y is O or S; R⁶ is C_1-3alkyl, optionally substituted by 1, 2 or 3 F and optionally substituted by OH, OC_1-3alkyl, N(C_1-3alkyl)₂, cyclopropyl, or tetrahydropyran; and R⁷ is hydrogen, F, Cl or CH₃. In a further embodiment,

[0027] In another embodiment,

C_1-3alkyl, ^{wherein the C} _{1-3alkyl is optionally substituted by 1, 2 or 3 F; and R} ⁷ _{is hydrogen, F, Cl or CH3.} [0028] In another embodiment,

C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted by 1, 2 or 3 F; and R⁷ is hydrogen. In a further embodiment, R⁶ is C_1-3alkyl, e.g., methyl, ethyl, or propyl. In still a further embodiment, R⁶ is methyl. [0029] In one embodiment, R² is hydrogen, F, Cl, Br, OSO₂C_1-3alkyl or C_1-3alkyl. [0030] In a further embodiment, R² is hydrogen, F, Cl or C_1-3alkyl. [0031] In still a further embodiment, R² is hydrogen, F or C_1-3alkyl. [0032] In one embodiment, R³ is hydrogen, F, Cl, Br, CN, CF₃, SO₂C_1-3alkyl CONH₂ or SO₂NR⁴R⁵, wherein R⁴ and R⁵ together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring. [0033] In a further embodiment, R³ is selected from hydrogen, F, Cl, CN or SO₂C_1-3alkyl. [0034] In still a further embodiment, R³ is selected from hydrogen, F or CN. [0035] In one embodiment, R⁶ is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC_1-3alkyl, N(C_1-3alkyl)₂, cyclopropyl, or tetrahydropyran. [0036] In a further embodiment, R⁶ is C_1-3alkyl, wherein said C_1-3alkyl is optionally substituted by 1, 2 or 3 F. In still a further embodiment, R⁶ is methyl or ethyl. In still a further embodiment, R⁶ is methyl. [0037] In one embodiment, R⁷ is hydrogen, F, Cl or CH₃. In a further embodiment R⁷ is hydrogen. [0038] In one embodiment of the methods provided herein, the composition administered to the patient comprises an effective amount 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 (brensocatib): or a pharmaceutically acceptable salt thereof. In a further

embodiment, the composition administered to the patient comprises an effective amount of brensocatib. [0039] In one embodiment, the compound of Formula (I) is: [0040] (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, [0041] (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, [0042] (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, [0043] 4’-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate, [0044] (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4- oxazepane-2-carboxamide, [0045] (2S)-N-{(1S)-1-Cyano-2-[4’-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide, [0046] (2S)-N-[(1S)-1-Cyano-2-(3’,4’-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2- carboxamide, [0047] (2S)-N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide, [0048] (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, [0049] (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, [0050] (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, [0051] (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, [0052] (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, [0053] (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, [0054] (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, [0055] (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, [0056] (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, [0057] (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, [0058] (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, [0059] (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, [0060] (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, [0061] (2S)-N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide, [0062] (2S)-N-[(1S)-2-(4’-Carbamoyl-3'-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane- 2-carboxamide, [0063] (2S)-N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}- 1,4-oxazepane-2-carboxamide, [0064] (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, [0065] (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, [0066] (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, [0067] (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, [0068] (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, [0069] (2S)-N-{(1S)-1-Cyano-2-[4’-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide, [0070] (2S)-N-{(1S)-2-[4’-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4- oxazepane-2-carboxamide, [0071] (2S)-N-[(1S)-1-Cyano-2-(4’-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, [0072] (2S)-N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide, or [0073] (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, [0074] or a pharmaceutically acceptable salt of one of the foregoing compounds. [0075] Formula (I), its subgenera, and brensocatib, as well as methods of making the same, are disclosed in U.S. Patent No. 9,522,894, the disclosure of which is incorporated by reference in its entirety for all purposes. [0076] The BD treatment methods provided herein comprise the administration of a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need of BD treatment. The compounds of Formula (I) and their pharmaceutically acceptable salts are inhibitors of dipeptidyl peptidase 1 (DPP1) activity. In one embodiment, the compound is brensocatib, or a pharmaceutically acceptable salt thereof. [0077] Administration routes include oral administration. Administration schedules can be determined by the user of the method, e.g., a prescribing physician. In one embodiment, administration is once daily. In another embodiment, administration is twice daily. In another embodiment, administration 1× daily, once every other day, once every third day, once every fourth day, 2× weekly, 3× weekly or 4× weekly. In one embodiment, the patient is administered a compound of Formula (I) 1× daily at a dosage of 10 mg, 25 mg or 40 mg. [0078] The term “treating” in one embodiment, includes one or more of the following: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in the patient that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); (3) relieving the condition (for example, by causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms); (4) prophylaxis against BD. [0079] The BD treatable by the methods provided herein, in one embodiment, is BD that presents with one or more severe manifestations. The one or more severe manifestations, in one embodiment, is posterior uveitis, retinal vasculitis, vascular manifestation, neurological manifestation or a gastrointestinal (GT) manifestation.

[0080] Successful treatment of the BD will depend on the clinical manifestations of the disease. Typically, attenuation or elimination of a clinical or paraclinical sign of the BD will constitute effective treatment. For example, disappearance or attenuation of muco-cutaneous manifestations, arthralgia/arthritis, a neurological symptom, a GI manifestation or a vascular manifestation, in one embodiment, constitutes effective treatment. In another embodiment, prevention of death or reduction in mortality rate due to BD constitutes effective treatment.

[0081] In a further embodiment, a composition comprising an effective amount of a compound of Formula (I) is administered orally. In a further embodiment, the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof. In yet a further embodiment, administration is lx daily, once every other day, once every third day, once every fourth day, 2* weekly, 3* weekly or 4* weekly. In even a further embodiment, administration of the compound is once daily.

[0082] The dosage administered will vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. In one embodiment, if the compound is administered orally, then the daily dosage of the compound of the disclosure may be in the range from 0.01 micrograms per kilogram body weight (ug/kg) to 100 milligrams per kilogram body weight (mg/kg).

[0083] In one embodiment, the compound of Formula (I) is administered in an oral 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 5 mg dosage form, 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, 35 mg dosage form, a 40 mg dosage form, a 45 mg dosage form or a 50 mg dosage form. In a further embodiment, the dosage form is a 25 mg or 40 mg dosage form. In a further embodiment, the dosage form is administered once daily. In even a further embodiment, the compound is

cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-l,3-benzoxazol-5-yl)phenyl]ethyl}-l,4-oxazepane- 2-carboxamide (i.e., brensocatib), or a pharmaceutically acceptable salt thereof. [0084] Treating, in one embodiment, is carried out over an administration period of about 3 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months or about 24 months. [0085] The compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the Formula (I) compound/salt (active ingredient) is in a composition comprising a pharmaceutically acceptable adjuvant(s), diluents(s) and/or carrier(s). Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals - The Science of Dosage Form _{Designs”, M. E. Aulton, Churchill Livingstone, 2} ^nd _{Ed. 2002, incorporated by reference herein} in its entirety for all purposes. [0086] Depending on the mode of administration, the pharmaceutical composition will comprise from 0.05 to 99 %w (percent by weight), for example, from 0.05 to 80 %w, or from 0.10 to 70 %w, or from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition. [0087] 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 with rapid dissolution characteristics under in vitro test conditions. [0088] In one embodiment, the oral dosage form is administered once daily. In a further embodiment, the oral dosage form is administered at approximately the same time every day, e.g., prior to breakfast. In another embodiment, the composition comprising an effective amount of Formula (I) is administered 2× day. In yet another embodiment, the composition comprising an effective amount of Formula (I) is administered once-a-week, every other day, every third day, 2× per week, 3× per week, 4× per week, or 5× per week. [0089] For oral administration the compound of the disclosure may be admixed with adjuvant(s), diluent(s) or carrier(s), for example, lactose, saccharose, sorbitol, mannitol; starch, for example, potato starch, corn starch or amylopectin; cellulose derivative; binder, for example, gelatine or polyvinylpyrrolidone; disintegrant, for example cellulose derivative, and/or lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a suitable polymer dissolved or dispersed in water or readily volatile organic solvent(s). Alternatively, the tablet may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. [0090] For the preparation of soft gelatine capsules, the compound of the disclosure may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using pharmaceutical excipients like the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the disclosure may be filled into hard gelatine capsules. [0091] In one embodiment, the composition is an oral disintegrating tablet (ODT). ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole [0092] In one embodiment, the composition is an oral thin film or an oral disintegrating film (ODF). Such formulations, when placed on the tongue, hydrate via interaction with saliva, and release the active compound from the dosage form. The ODF, in one embodiment, contains a film-forming polymer such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), pullulan, carboxymethyl cellulose (CMC), pectin, starch, polyvinyl acetate (PVA) or sodium alginate. [0093] Liquid preparations for oral application may be in the form of syrups, solutions or suspensions. Solutions, for example, may contain the compound of the disclosure, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharine and/or carboxymethylcellulose as a thickening agent. Furthermore, other excipients known to those skilled in art may be used when making formulations for oral use. [0094] A compound of Formula (I), or a pharmaceutically acceptable salt thereof, may also be administered in conjunction with a further compound used for the treatment of BD via one of the methods described herein. [0095] The further compound is administered concurrently, sequentially or in admixture with a compound of Formula (I), for the treatment of BD. [0096] In one embodiment, the further compound is an NSAID. [0097] In one embodiment, the further compound is an immunosuppressive agent. [0098] In a further embodiment, the immunosuppresVLYHαDJHQWαLVα71)ĮαLQKLELWRUαα α,QαHYHQαDα IXUWKHUαHPERGLPHQWααWKHα71)ĮαLQKLELWRUαLVαLQIliximab, adalimumab or etanercept. [0099] In one embodiment, the immunosuppressive agent is thalidomide. In another embodiment, the immunosuppressive agent is azathioprine. [0100] In another embodiment, the further compound is colchicine. [0101] In another embodiment, the further compound is interferon alfa-2a. See e.g., Alpsoy et al. (2002). Archives of Dermatology 138, pp. 467-471. [0102] In yet another embodiment, the further compound is colchicine, levamisole hydrochloride, a corticosteroid, chlorambucil, cyclophosphamide, cyclosporine, azathioprine or thalidomide. [0103] In one combination therapy embodiment, the compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered concurrently or sequentially with one or more further active ingredients selected from one or more of those provided above. For example, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered concurrently or sequentially with a further pharmaceutical composition for use as a medicament for the treatment of BD. The further pharmaceutical composition may be a medicament which the patient may already be prescribed (e.g., an existing standard of care medication), and may itself be a composition comprising one or more active ingredients selected from those defined above. [0104] A compound of Formula (I) or a pharmaceutically acceptable salt thereof is synthesized according to the methods set forth in U.S. Patent No. 9,522,894, the disclosure of which is incorporated by reference in its entirety for all purposes. [0105] In various synthesis methods, functional groups can be protected and subsequently deprotected. The protection and deprotection of functional groups is described in ‘Protective _{Groups in Organic Synthesis’, 4} ^th _{Ed, T.W. Greene and P.G.M. Wuts, Wiley (2006) and} _{‘Protecting Groups’, 3} ^rd _{Ed P.J. Kocienski, Georg Thieme Verlag (2005), incorporated by} reference herein in its entirety for all purposes. [0106] As provided throughout, according to the methods provided herein, a compound of Formula (I) can be administered as a pharmaceutically acceptable salt. A pharmaceutically acceptable salt of a compound of Formula (I) may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in H₂O, oil, or other solvent. In some instances, a salt may be used to aid in the isolation or purification of the compound of Formula (I). [0107] Where the compound of Formula (I) is sufficiently acidic, pharmaceutically acceptable salts include, but are not limited to, an alkali metal salt, e.g., Na or K, an alkali earth metal salt, e.g., Ca or Mg, or an organic amine salt. Where the compound of Formula (I) is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts. [0108] There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. [0109] For reviews on suitable salts, and pharmaceutically acceptable salts amenable for use herein, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or “Handbook of Pharmaceutical Salts: Properties, selection and use”, P.H. Stahl, P.G. Vermuth, IUPAC, Wiley-VCH, 2002, incorporated by reference herein in its entirety for all purposes. [0110] The compounds of Formula (I) may form mixtures of its salt and co-crystal forms. It is also to be understood that the methods provided herein can employ such salt/co-crystal mixtures of the compound of Formula (I). [0111] Salts and co-crystals may be characterized using well known techniques, for example X-ray powder diffraction, single crystal X-ray diffraction (for example to evaluate proton position, bond lengths or bond angles), solid state NMR, (to evaluate for example, C, N or P chemical shifts) or spectroscopic techniques (to measure for example, O-H, N-H or COOH signals and IR peak shifts resulting from hydrogen bonding). [0112] It is also to be understood that certain compounds of Formula (I) may exist in solvated form, e.g., hydrates, including solvates of a pharmaceutically acceptable salt of a compound of Formula (I). [0113] In one embodiment, certain compounds of Formula (I) may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. It is to be understood that the present disclosure encompasses all such isomeric forms. Certain compounds of Formula (I) may also contain linkages (e.g., carbon-carbon bonds, carbon- nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g., restriction resulting from the presence of a ring bond or double bond. Accordingly, it is to be understood that the methods provided herein can employ such isomers. Certain compound of Formula (I) may also contain multiple tautomeric forms. It is to be understood that the present disclosure encompasses all such tautomeric forms. Stereoisomers may be separated using conventional techniques, e.g., chromatography or fractional crystallization, or the stereoisomers may be made by stereoselective synthesis. [0114] In a further embodiment, the compounds of Formula (I) encompass any isotopically-labeled (or “radio-labelled”) derivatives of a compound of Formula (I). Such a derivative is a derivative of a compound of Formula (I) wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include ²H (also written as “D” for deuterium). As such, in one embodiment, a compound of Formula (I) is provided where one or more hydrogen atoms are replaced by one or more deuterium atoms; and the deuterated compound is used in one of the methods provided herein for treating BD. [0115] In a further embodiment, the compounds of Formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give rise to a compound of the Formula (I). Examples of prodrugs include in vivo hydrolysable esters of a compound of the Formula (I). [0116] An in vivo hydrolysable (or cleavable) ester of a compound of Formula (I) that contains a carboxy or a hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol. For examples of ester prodrugs derivatives, see: Curr. Drug. Metab. 2003, 4, 461, incorporated by reference herein in its entirety for all purposes. [0117] 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 by reference herein in its entirety for all purposes. EXAMPLES [0118] The present invention is further illustrated by reference to the following Examples. However, it should be noted that these Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the invention in any way. Example 1 – Brensocatib Reduces Neutrophil Serine Protease Activities in Cultured Human Neutrophils [0119] To evaluate the pharmacological effects of brensocatib on surface PR3 expression and NSP activity, stem cells were differentiated to neutrophils in the presence of brensocatib. Primary bone marrow- or umbilical cord blood-derived CD34⁺ neutrophil progenitor cells (AllCells; Alameda, CA) were cultured for 7 days in STEMSPAN SFEM media (Stemcell Technologies; Tukwila, WA) supplemented with recombinant human Stem Cell Factor (Peprotech; Rocky Hill, NJ) and recombinant human IL-3 (Peprotech). The cells were differentiated in culture for another 7 days in STEMSPAN SFEM media (Stemcell Technologies) with recombinant human Granulocyte Colony Stimulating Factor (Peprotech), plus increasing concentrations of brensocatib (0 – ^^α ^0ααα α $Wα WKHα HQGα RIα WKHα differentiation/treatment period, cells were split into two aliquots for analysis. [0120] The first aliquot of differentiated neutrophils was harvested for flow cytometry to quantify PR3 expression on the surface of neutrophils. After harvest, the cells were resuspended in FACS staining buffer and Fc receptors were blocked for 30 min at 4 °C. Cells were stained for 30 min. with a mouse anti-PR3 monoclonal antibody (Abcam; Cambridge, MA) or a mouse monoclonal IgG isotype control (Abcam), followed by a Cy5-conjugated goat anti-mouse IgG secondary antibody (Abcam), and then analyzed using a Guava easyCyte 6HT flow cytometer (Millipore; Billerica, MA). [0121] For the second aliquot, neutrophils were lysed with 10% (v/v) Triton X-100 in PBS and the lysates were added to 96-well plates. Peptide substrates for NE (N-Methoxysuccinyl-Ala- Ala-Pro-Val-7-amido-4-methylcoumarin; Sigma-Aldrich; St. Louis, MO), for PR3 (aminobenzoyl-Val-Ala-Asp-Cys-Ala-Asp-Gln-Lys(2,4-dinitrophenyl); GenScript; Piscataway, NJ), and for CatG (N-Succinyl-Ala-Ala-Pro-Phe p-nitroanilide; Sigma) were added, and either fluorescence or absorbance was quantified using a Synergy microplate reader (BioTek; Winooski, VT). NSP inhibitors were used to test the specificity of enzymatic assays, including elastase inhibitor (Abcam) for NE, sivelestat (Abcam) for PR3, and cathepsin G inhibitor I (Cayman Chemical; Ann Arbor, MI) for CatG. A portion of cell lysate samples were retained for protein quantification using a Pierce™ BCA Protein Assay Kit (Thermo Fisher) according to the manufacturer’s instructions. The NSP activities were normalized to cell lysate protein concentrations and the final data were fit with nonlinear, four-parameter, logistic regression analysis by using GraphPad Prism software (GraphPad Software Inc.; La Jolla, CA). [0122] In a separate experiment, neutrophils were harvested, stained for 30 min with either a mouse anti-PR3 monoclonal antibody (Abcam; Cambridge, MA) or a mouse monoclonal IgG isotype control (Abcam), followed by a Cy5-conjugated goat anti-mouse IgG secondary antibody (Abcam), fixed in 4% formaldehyde, and mounted to glass slides with ProLong™ Diamond Antifade Mountant with DAPI (Thermo Fisher; Waltham, MA). Samples were imaged with an Axio fluorescence microscope (Zeiss; Oberkochen, Germany) using constant settings while imaging samples from different treatment conditions. [0123] The results of the fluorescence microscopy experiments demonstrated that neutrophils derived from either bone marrow or umbilical cord stem cells exhibited robust surface expression of PR3. Differentiation in the presence of 10 μM brensocatib markedly reduced surface PR3 in both cell types. [0124] Flow cytometry was employed to quantify mean fluorescence intensity (MFI) associated with surface PR3 expression in cells differentiated in the presence of brensocatib at various concentrations. Following normalization as percent of untreated cells, brensocatib concentration-dependently reduced surface PR3 expression in neutrophils derived from both bone marrow and umbilical cord blood stem cells, with maximum reductions greater than 60% (Figure 1). In addition, flow cytometry was used to evaluate the percentage of cells without surface PR3 expression. It was found that approximately 30-40% of untreated neutrophils expressed no detectable PR3 on their surface (Figure 2). Brensocatib concentration- dependently increased the percentage of cells with no detectable surface PR3 expression to more than 50% of neutrophils derived from cord blood stem cells and nearly 80% of neutrophils derived from bone marrow stem cells (Figure 2). [0125] In addition to measuring surface PR3, brensocatib effects on neutrophil serine protease (NSP) activities within the differentiated neutrophils was evaluated. Brensocatib concentration-dependently decreased the activities of NE and PR3 > 90%, and > 90%, respectively, at the highest concentration tested (10 μM; Figures 3-4). Example 2 – Therapeutic effects of brensocatib in a HSV model of BD [0126] In this example, a herpes simplex virus (HSV)-induced BD ICR mouse model was used to investigate the therapeutic effects of brensocatib. Specifically, ICR mice were infected with HSV to induce ulceration of mouth, genital, and skin, eye involvement, and other disease symptoms of BD in the mice, followed by treatment with brensocatib at two different doses (i.e., 10 mg brensocatib/kg body weight per mouse or 30 mg brensocatib/kg body weight per mouse) or a vehicle control. BD symptom severity and mortality were compared between the brensocatib-treated groups and the vehicle-treated control group. Materials and methods [0127] ICR mice were infected with HSV as described previously (Shim et al., Cytotherapy 13:835-847 (2011); Sohn et al., Eur J Dermatol.8(1):21-3 (1998); each of which is incorporated by reference herein in its entirety for all purposes). Briefly, earlobes of the mice were scratched with a needle, then inoculated with ^^α^/αof 1.0 x 10⁶ plaque-forming units (pfu)/mL of HSV type l (F strain) solution. Ten days later, a second inoculation was performed using the same method. For virus inoculation, the mice were anesthetized by intraperitoneal injection with 2,2,2-tribromo ethanol (240 mg/kg). After viral inoculation, hydrocortisone (150 μg/mouse) was intraperitoneally injected once a day for 5 days. The mice were kept in a conventional temperature- and light-controlled room (20-22 °C, 12 hr. light cycle starting at 8:00 a.m.). The mice had free access to food and water, and were handled in accordance with a protocol approved by an institutional animal care committee. [0128] Symptoms of BD were confirmed by follow-up for 5 to 16 weeks after the second virus inoculation. Several symptoms, including oral ulcers, genital ulcers, erythema, skin pustules, skin ulcers, arthritis, diarrhea, red-eye, loss of balance, and facial edema, were observed in the mice after HSV inoculation. Oral, genital, skin ulcers, and eye symptoms were classified as major symptoms. Arthritis, intestinal ulceration, and neurological involvement were considered as minor symptoms. Mice with at least one major symptom and at least one minor symptom were classified as having BD. Each symptom was scored as one point. The sum of points was used to determine the severity of BD using 2006 BD Current Activity Form prepared by the International Society for Behçet’s Disease

The disappearance of symptoms or a reduction in skin lesion size of 20% or more indicated improvement of BD. [0129] Brensocatib was dissolved in a tartaric acid solution. When BD symptoms appeared in the mice, the mice were administered the brensocatib solution at 10 mg brensocatib/kg body weight per mouse or 30 mg brensocatib/kg body weight per mouse, or a vehicle solution containing the same concentration of tartaric acid (control group). There were 11, 11, and 15 BD mice in the 10 mg brensocatib, 30 mg brensocatib, and vehicle-treated groups, respectively, at the start of the administration period. Dosing lasted for 4 weeks, with the brensocatib solution or the vehicle solution administered orally twice a day for 2 weeks from the start of the administration, and once a day for the next 2 weeks. Monitoring of BD symptoms was continued throughout the administration period to determine whether any improvement(s) occurred. Mortality rates among the study groups were also determined. After 4 weeks of administration, the mice were sacrificed, and tissue samples, including bone marrows, plasma, and blood cells, were collected from the mice for analysis. Results 1. Brensocatib treatment reduced mortality in HSV-induced BD mice [0130] Figure 5 shows the percentage of surviving BD mice during the treatment with the vehicle control (dotted line), 10 mg/kg brensocatib (thick solid line), or 30 mg/kg brensocatib (thin solid line). Brensocatib treatment at both doses resulted in lower mortality rates (0% in the 10 mg/kg group and 18.2% in the 30 mg/kg group) than the vehicle treatment (33.3% mortality rate) at the end of the treatment period. More notably, mice treated with 10 mg/kg brensocatib displayed 0% mortality rate throughout the treatment period, which was significantly lower as compared to the vehicle control group, with P= 0.0481 using LogRank (Mantel-Cox) test. 2. Brensocatib treatment resulted in higher percentages of HSV-induced BD mice with improvement and/or no change in symptoms [0131] Table 1 shows that, as compared to the vehicle control, brensocatib treatment at both doses resulted in higher percentages of HSV-induced BD mice with improvement in BD symptoms, no change in BD symptoms, and/or a combination of the two, at 2 weeks and 4 weeks of the administration period, based on the disease severity scores. Moreover, brensocatib treatment at the 10 mg/kg dose was more effective than at the 30 mg/kg dose in improving the BD symptoms, consistent with their effects on the reduction in mortality. Table 1. Efficacy of brensocatib on symptoms in HSV-induced BD mice based on disease severity score

Example 3 – Prophylactic effects of brensocatib in a HSV model of BD [0132] In this example, a similar HSV-induced BD C57BL/6 mouse model is used to investigate the prophylactic effects of brensocatib. HSV-induced BD occurrence rate in C57BL/6 mice is estimated to be about 40%, as compared to a 10-15% occurrence rate in ICR mice used in Example 2. [0133] Specifically, C57BL/6 mice in groups of about 30 each are treated with brensocatib at three different doses, i.e., 3 mg/kg, 10 mg/kg, and 30 mg/kg per day, or a vehicle control solution containing tartaric acid (as described in Example 2), via oral administration twice per day, seven days prior to a first inoculation of HSV performed as described in Example 2. Ten days later a second HSV inoculation is performed also as described in Example 2. After the first inoculation of HSV, brensocatib or vehicle treatment is performed 2 times per day for 7 days, and thereafter once a day for the next 16 weeks. Following the second HSV inoculation, BD occurrence rates are determined, BD symptoms are monitored, the disease severity is scored (as described in Example 2), and mortality rates are recorded among the study groups for the next 16 weeks. Thereafter, the mice are sacrificed, and tissue samples, including bone marrows, plasma, and blood cells, are collected from the mice for analysis. * * * * * * * [0134] All, documents, patents, patent applications, publications, product descriptions, and protocols which are cited throughout this application are incorporated herein by reference in their entireties for all purposes. [0135] The embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention. Modifications and variation of the above-described embodiments of the invention are possible without departing from the invention, as appreciated by those skilled in the art in light of the above teachings. It is therefore understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.

Claims

CLAIMS 1. A method for treating Behçet’s Disease (BD) in a patient in need of treatment, comprising, administering to the patient a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

R² is hydrogen, F, Cl, Br, OSO₂C_1-3alkyl, or C_1-3alkyl; R³ is hydrogen, F, Cl, Br, CN, CF₃, SO₂C_1-3alkyl, CONH₂ or SO₂NR⁴R⁵, wherein R⁴ and R⁵ together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or R⁶ is C_1-3alkyl, optionally substituted by 1, 2 or 3 F and/or optionally by OH, OC_1-3alkyl, N(C_1- ₃alkyl)₂, cyclopropyl, or tetrahydropyran; R⁷ is hydrogen, F, Cl or CH₃; X is O, S or CF₂; Y is O or S; and Q is CH or N.

Q ; R⁶ is C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted by 1,

2 or 3 F and optionally by one substituent selected from OH, OC₁-₃alkyl, N(C_1-3alkyl)₂, cyclopropyl, or tetrahydropyran; and R⁷ is hydrogen, F, Cl or CH₃.

3. The method of claim 1 or 2, wherein,

X is O, S or CF₂; Y is O or S; R⁶ is C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; and R⁷ is hydrogen, F, Cl or CH₃.

4. The method of any one of claims 1-3, wherein,

5. The method of any one of claims 1-4, wherein X is O, S or CF₂; R⁶ is C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted by 1, 2 or 3 F; and R⁷ is hydrogen, F, Cl or CH₃.

6. The method of any one of claims 1-4, wherein X is O; R⁶ is C_1-3alkyl, wherein the C_1- ₃alkyl is optionally substituted by 1, 2 or 3 F; and R⁷ is hydrogen.

7. The method of any one of claims 1-4, wherein X is O; R⁶ is C_1-3alkyl; and R⁷ is hydrogen.

8 The method of claim 1, wherein the compound of Formula (I) is selected from the group consisting of (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}- 1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; 4’-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate; (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4’-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(3’,4’-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3- benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol- 5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}- 1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-2-(4’-Carbamoyl-3’-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4- oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3- benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1- cyanoethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-[(1S)-1-Cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5- yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5- yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4’-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-2-[4’-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(4’-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; and pharmaceutically acceptable salts thereof.

9. The method of claim 1, wherein the compound of Formula (I) is brensocatib; or a pharmaceutically acceptable salt thereof.

10. The method of claim 1, wherein the compound of Formula (I) is brensocatib .

11. The method of any one of claims 1-10, wherein the composition comprises a pharmaceutically acceptable adjuvant, diluent or carrier.

12. The method of any one of claims 1-11, wherein the administering comprises oral administration.

13. The method of any one of claims 1-12, wherein the administering to the patient is carried out one time daily.

14. The method of any one of claims 1-12, wherein the administering to the patient is carried out two times daily.

15. The method of any one of claims 1-12, wherein the administering to the patient is carried out once, every other day.

16. The method of any one of claims 1-12, wherein the administering to the patient is carried out once every third day.

17. The method of any one of claims 1-16, wherein the administering is carried out for about 3 months.

18. The method of any one of claims 1-16, wherein the administering is carried out for about 6 months.

19. The method of any one of claims 1-16, wherein the administering is carried out for about 9 months.

20. The method of any one of claims 1-16, wherein the administering is carried out for about 12 months.

21. The method of any one of claims 1-16, wherein the administering is carried out for about 18 months.

22. The method of any one of claims 1-16, wherein the administering is carried out for about 24 months.

23. The method of any one of claims 1-22, further comprising administering one or more additional active agents to the patient in need of treatment.

24. The method of claim 23, wherein the one or more additional active agents comprises colchicine, levamisole hydrochloride, a corticosteroid, chlorambucil, cyclophosphamide, cyclosporine, azathioprine or thalidomide.

25. The method of claim 23, wherein the one or more additional active agents comprises an NSAID.

26. The method of claim 23, wherein the one or more additional active agents comprises an immunosuppressive agent.

27. The method of claim 26, wherein the immunosuppressive agent is a 71)ĮαLQKLELWRUααα 28. The method of claim 27, wherein the 71)ĮαLQKLELWRUαLVαLQIOL[LPDE. 29. The method of claim 27, wherein the 71)ĮαLQKLELWRUαLVαadalimumab. 30. The method of claim 27, wherein the 71)ĮαLQKLELWRUαLVαetanercept. 31. The method of claim 26, wherein the immunosuppressive agent is thalidomide. 32. The method of claim 26, wherein the immunosuppressive agent is azathioprine. 33. The method of any one of claims 23-32, wherein the one or more additional active agents comprises colchicine. 34. The method of any one of claims 23-33, wherein the one or more additional active agents comprises interferon alfa-2a.