Certain N-(1-cyano-2-phenylethyl)-1,4-oxazepane-2-carboxamides for the treatment of hidradenitis suppurativa

Abstract

The present disclosure relates to a method for treating hidradenitis suppurativa with a composition comprising an effective amount of a N-(1-cyano-2-phenylethyl)-1,4-oxazepane-2-carboxamide DPP1 inhibitor compound of formula (I), or a pharma- ceutically acceptable salt thereof. 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). [Formula 1] TIFF2025508359000067.tif78170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 310,751, filed February 16, 2022, the disclosure of which is incorporated by reference in its entirety herein. [Background technology]

[0002] Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory disorder. Symptoms include skin lesions, often with associated hair follicles, which may be painful, inflamed, and / or swollen. In some cases, once the skin lesions have healed, they may recur, resulting in subcutaneous tunnels and progressive scarring. Because HS is a chronic condition, it may persist for years and worsen over time, severely impacting quality of life, physiological and emotional well-being. In fact, HS patients have increased rates of anxiety and depression, and are 2.5 times more likely to commit suicide than the general population.

[0003] Patients with HS are classified according to the severity of the disease, called the Hurley stage, as mild (Stage I), moderate (Stage II), or severe (Stage III). Although more than 200,000 cases of HS are diagnosed in the United States annually, the disease can be difficult to diagnose and requires special care. HS may be mistaken for an infection, ingrown hair, or other conditions. Furthermore, current treatment options are limited and lack effectiveness.

[0004] Thus, there is an unmet need to develop more effective therapies for patients with HS, particularly those that target the underlying inflammation that leads to symptomatic skin lesions. Summary of the Invention

[0005] The invention in one aspect provides a method of treating hidradenitis suppurativa (HS) in a subject in need thereof, the method comprising administering to the subject, for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharma- ceutical acceptable salt thereof; [ka] During the ceremony, 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 and R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, or piperidine ring, X is O, S, or CF 2 and Y is O or S; Q is CH or N; R 6 is C 1-3 is an alkyl group, 1-3 Alkyl is optionally substituted by one, two or three F and is substituted with OH, OC 1 - 3 Alkyl, N(C 1-3 Alkyl) 2, cyclopropyl, and tetrahydropyran; R 7 is hydrogen, F, Cl, or CH 3 It is.

[0006] In one embodiment of the methods provided herein, the compound of formula (I) is an S,S diastereomer, i.e., the compound of formula (I) has the following stereochemistry: [ka]

[0007] Other diastereomeric forms of the compound of formula (I) are also contemplated by the present invention. For example, in one embodiment, the compound of formula (I) is the R,R diastereomer. In another embodiment, the compound of formula (I) is the R,S diastereomer. In yet another embodiment, the compound of formula (I) is the S,R diastereomer.

[0008] In some embodiments, R 1 teeth, [ka] and X is O, S, or CF 2 and Y is O or S; Q is CH or N; R 6 is C 1-3 is an alkyl group, 1-3 Alkyl is optionally substituted by one, two or three F and is substituted with OH, OC 1 - 3 Alkyl, N(C 1-3 Alkyl) 2 , cyclopropyl, and tetrahydropyran; R 7 is hydrogen, F, Cl, or CH 3 It is.

[0009] In some embodiments, R 1 teeth, [ka] and X is O, S, or CF 2 and Y is O or S; R 6 is C 1-3 is an alkyl group, 1-3 Alkyl is optionally substituted by one, two or three F and is substituted with OH, OC 1 - 3 Alkyl, N(C 1-3 Alkyl) 2 , cyclopropyl, and tetrahydropyran; R 7 is hydrogen, F, Cl, or CH 3 It is.

[0010] In some embodiments, R 1 teeth, [ka] It is.

[0011] In some embodiments, X is O and R 6 is C 1-3 is alkyl, R 7 is hydrogen.

[0012] In some embodiments, R 1 teeth, [ka] X is O and R 6 is C 1-3 is an alkyl group, 1-3The alkyl is optionally substituted by one, two, or three F; R 7 is hydrogen.

[0013] In some embodiments, R 1 teeth, [ka] X is O and R 6 is C 1-3 is alkyl, R 7 is hydrogen.

[0014] In some 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, referred to herein as its International Nonproprietary Name (INN), brensocatib (formerly known as INS1007 and AZD7986): [ka] , or a pharma- ceutically acceptable salt thereof.

[0015] In one embodiment, the HS is Hurley stage I HS, Hurley stage II HS, or Hurley stage III HS.

[0016] In one embodiment, the method of treating HS disclosed herein comprises reducing the severity of one or more symptoms of HS in a subject during or after an administration period, compared to the one or more symptoms prior to the administration period, or eliminating one or more symptoms of HS in a subject. The one or more symptoms, in one embodiment, are (a) one or more skin lesions, (b) one or more skin abscesses, (c) one or more fistulas, (d) one or more fistulas, (e) skin scarring, (f) anxiety, (g) depression, (h) suicidal ideation, or (i) any combination thereof. In a further embodiment, the one or more fistulas include one or more draining fistulas.

[0017] In one embodiment, the subject has not been previously treated with an anti-TNFα agent (eg, an anti-TNFα antibody).

[0018] In one embodiment, the subject is unresponsive to a previous, different HS treatment, for example, administration of a systemic antibiotic.

[0019] In one embodiment, the subject achieves a Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) during or after the administration period, where HiSCR50 is at least a 50% reduction in total AN count, no increase in skin abscess count, and no increase in draining fistula count, compared to the subject's total AN count, skin abscess count, and draining fistula count before the administration period, respectively.

[0020] In one embodiment, the subject achieves a hidradenitis suppurativa clinical response 75 (HiSCR75) during or after the administration period, where HiSCR75 is at least a 75% reduction in total AN count, no increase in skin abscess count, and no increase in draining fistula count, compared to the subject's total AN count, skin abscess count, and draining fistula count before the administration period, respectively.

[0021] In one embodiment, the methods of treating HS disclosed herein comprise reducing the subject's Hidradenitis Suppurativa-Investigator Global Assessment (HS-IGA) score during or after the administration period, compared to the subject's HS-IGA score before the administration period. In a further embodiment, the subject's HS-IGA score is reduced by ≧2 points during or after the administration period.

[0022] In one embodiment, the methods of treating HS disclosed herein include reducing the subject's skin abscess and inflammatory skin nodule count (AN count) during or after the administration period compared to the subject's AN count before the administration period.

[0023] In one embodiment, the methods of treating HS disclosed herein comprise reducing or maintaining a fistula count in a subject during or after an administration period, as compared to the fistula count in the subject before the administration period. In a further embodiment, the fistula count is a draining fistula count.

[0024] In one embodiment, the methods of treating HS disclosed herein include reducing the occurrence of HS flares in a subject during or after the administration period compared to the occurrence of HS flares in a subject prior to the administration period.

[0025] In one embodiment, the methods of treating HS disclosed herein include reducing the subject's International Hidradenitis Suppurativa Severity Scale (IHS4) score during or after the administration period, compared to the subject's IHS4 score before the administration period. In a further embodiment, the subject's IHS4 score is ≧4 before the administration period, e.g., ≧11 before the administration period.

[0026] In one embodiment, the methods of treating HS disclosed herein include reducing a subject's Dermatological Life Quality Index (DLQI) score during or after the administration period compared to the subject's DLQI score before the administration period.

[0027] In one embodiment, the methods of treating HS disclosed herein comprise reducing the subject's Patient Global Assessment of Cutaneous Pain (PGA-SP) score during or after the administration period, compared to the subject's PGA-SP score before the administration period.

[0028] In one embodiment, the methods of treating HS disclosed herein comprise reducing the subject's Hidradenitis Suppurativa Quality of Life (HiSQOL) score during or after the administration period compared to the subject's HiSQOL score before the administration period.

[0029] In one embodiment, the pharmaceutical composition is administered once daily during the administration period.

[0030] In one embodiment, the pharmaceutical composition is administered orally during the administration period.

[0031] In one embodiment, the compound of formula (I) is present in the pharmaceutical composition in an amount of about 1 mg to about 100 mg, such as about 10 mg, about 25 mg, or about 40 mg.In a further embodiment, the compound of formula (I) is brensocatib.

[0032] In one embodiment, the administration period is the overall survival of the subject after initial diagnosis of HS, hi another embodiment, the administration period is from about 1 year to about 50 years, from about 1 year to about 30 years, or from about 1 year to about 10 years.

[0033] In one embodiment, the method of treating HS disclosed herein includes administering a secondary therapy to the subject. The secondary therapy can be administered (a) before the administration period, (b) during or after the administration period, or (c) simultaneously with administration of the pharmaceutical composition. In some embodiments, the secondary therapy includes one or more of the following: antibiotics, steroids, biologics, hormones, retinoids, anti-inflammatory drugs, surgical intervention, or any combination thereof. [Brief description of the drawings]

[0034] [Figure 1]FIG. 1 is a schematic diagram of the study design described in Example 1. IHS4 = International Hidradenitis Suppurativa Severity Score 4, PD = pharmacodynamics, Q2W = every 2 weeks, Q4W = every 4 weeks, QD = once daily, TNF = tumor necrosis factor. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that mainly affects gland-rich areas of the body and presents with skin nodules, skin abscesses, fistulas, and skin scarring. Neutrophils are the main leukocyte infiltration in HS-related skin lesions. Lysosomal cysteine ​​proteinase dipeptidyl peptidase 1 (DPP1, also known as cathepsin C) activates neutrophil serine proteases (NSPs), which are pro-inflammatory and generally destructive to surrounding tissues when released from neutrophils. Without being bound by theory, it is believed that inhibition of DPP1 activity (e.g., by administering the compounds disclosed herein) in patients with HS can lead to a reduction in the formation of active NSPs, thereby preventing the propagation of inflammatory responses.

[0036] Aspects of the present invention provide reversible inhibitors of dipeptidyl peptidase 1 (DPP1) or cathepsin C and methods of use thereof to treat HS. DPP1 catalyzes the removal of dipeptides from the N-terminus of protein and peptide substrates. Through this enzymatic function, DPP1 activates many serine proteases in immune / inflammatory cells, such as neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), and neutrophil serine protease 4 (NSP4). Neutrophil serine proteases can mediate neutrophilic inflammation, which is often seen in patients with hidradenitis suppurativa. Thus, in some embodiments, the method of use is a method of treating hidradenitis suppurativa.

[0037] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this application, representative methods and materials are described herein.

[0039] In accordance with the rules of long-term patent law, the terms "a," "an," and "the" when used in this application, including the claims, refer to "one or more." Thus, for example, reference to a "carrier" includes one or more carriers, mixtures of two or more carriers, etc., and reference to a "process" includes references to equivalent steps and / or methods known to those skilled in the art.

[0040] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and the like used in the present specification and claims should be understood to be modified in all cases by the term "about". Thus, unless otherwise indicated, the numerical parameters described in the present specification and the appended claims are approximate and may vary depending on the desired properties sought to be obtained by the present application. In general, as used herein, the term "about" refers to measurable values ​​such as weight, time, dosage, and the like, and is meant to encompass values ​​within the degree of variation acceptable in the art. In some embodiments, the degree of variation is based on FDA guidelines.

[0041] Also, as used herein, "and / or" refers to any and all possible combinations of one or more of the associated listed items, and includes the absence of a combination when interpreted in the alternative ("or").

[0042] As used herein, "C 1-3 " means a carbon group having 1, 2, or 3 carbon atoms.

[0043] The term "alkyl", unless otherwise specified, includes both straight and branched chain alkyl groups, and may be substituted or unsubstituted. "Alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, and pentyl.

[0044] The term "pharmaceutical acceptable" is used, unless otherwise specified, to characterize a moiety (e.g., a salt, dosage form, or excipient) as appropriate for use according to sound medical judgment. Generally, a pharmaceutical acceptable moiety has one or more benefits that outweigh any adverse effects that the moiety may have. Adverse effects may include, for example, excessive toxicity, irritation, allergic responses, and other problems and complications.

[0045] As used herein, "treatment" or "treat" and "ameliorate" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results, including but not limited to therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to any therapeutically relevant improvement or effect on one or more diseases, conditions, or symptoms being treated. In one embodiment, the term "treating" includes: (1) preventing or delaying the appearance of clinical symptoms of a condition, disorder, or condition that develops in a patient who may be afflicted or affected by the condition, disorder, or condition, but who has not yet experienced or exhibited a clinical or subclinical symptom of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition (e.g., halting, reducing, or delaying the onset of the disease with respect to at least one clinical or subclinical symptom thereof, or, in the case of maintenance treatment, halting, reducing, or delaying its recurrence); and (3) alleviating the condition (e.g., by causing regression or a reduction in severity of the condition, disorder, or condition, or at least one of its clinical or subclinical symptoms).

[0046] The term "effective amount" as used herein refers to an amount of an agent (e.g., a compound of formula (I)) that is sufficient to produce a result, e.g., a beneficial or desired result. The effective amount may vary depending on one or more of the subject being treated and the severity of the disease, the weight and age of the subject, the method of administration, etc. The effective amount may refer to the amount of agent administered to the subject in a single administration session or in multiple administration sessions.

[0047] As used herein, the terms "subject," "individual," and "patient" are used interchangeably to refer to vertebrates, such as mammals. A mammal may be, for example, a mouse, rat, rabbit, cat, dog, pig, sheep, horse, non-human primate (e.g., cynomolgus monkey, chimpanzee), or human. Also included are subject tissues, cells, or derivatives thereof obtained in vivo or cultured in vitro. A human subject may be an adult, teenager, child (2-14 years), infant (1-24 months), or newborn (up to 1 month). In some embodiments, an adult subject is about 65 years of age or older, or about 60 years of age or older. In some embodiments, the subject is a pregnant woman or a woman who is contemplating pregnancy.

[0048] As used herein, a "skin lesion" is a portion of the skin that has an abnormal growth, appearance, or combination thereof compared to the surrounding skin.

[0049] As used herein, a "skin abscess" is an area of ​​pus associated with skin tissue. In some embodiments, a skin abscess appears as a swelling on or below the surface of the skin. In some embodiments, a skin abscess has a diameter of at least about 10 mm. In some embodiments, the pus contains bacteria, white blood cells, and / or dead skin.

[0050] As used herein, a "fistula" is an abnormal channel between two cavities or surfaces. A fistula may be a draining fistula or a non-draining fistula. In some embodiments, a fistula (e.g., a draining fistula) may exude fluid. Further details regarding fistulas may be found in Kimball et al. Journal of the European Academy of Dermatology and Venereology 2016,30,989-994, the contents of which are incorporated herein by reference in their entirety. In this application, a "fistula" is also referred to as a "tunnel." These two terms are used interchangeably.

[0051] As used herein, a "fistula" (or sinus) is a small, featureless channel in the body. In some embodiments, the sinus has one open draining end and the channel terminates in a blind end. For example, in some embodiments, the fistula extends from a wound under the skin to the soft tissue. In some embodiments, the fistula creates a dead space that can lead to the formation of a skin abscess.

[0052] As used herein, a "skin nodule" is a raised lesion on or in the skin. In some embodiments, the skin nodule is a solid and / or palpable mass. In some embodiments, the skin nodule is an inflammatory skin nodule. In some embodiments, the skin nodule is raised, three-dimensional, round, and / or infiltrated. In some embodiments, the skin nodule is at least about 10 mm in diameter.

[0053] In one aspect, a method of inhibiting dipeptidyl peptidase (DPP1) in a subject in need thereof is provided, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, during an administration period. In some embodiments, DPP1 is expressed by neutrophils. The subject has HS or is at risk of developing HS. In some embodiments, the administration results in the treatment of HS or delay of the onset of HS in the subject.

[0054] In one aspect, a method of treating HS in a subject in need thereof is provided. The method, in one embodiment, comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, during the administration period. In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0055] The methods provided herein are not limited to the administration of compounds of formula (I). Other DPP1 inhibitors, such as those described in Banerjee, et al., Bioorganic & Medicinal Chemistry Letters Volume 47, 1 September 2021, 128202, Chinese Patent Application Publication No. 112920124A, Chen et al. Journal of Medicinal Chemistry 64.16(2021):11857-11885, and International Patent Publication No. 2022 / 020245, may be used in the methods disclosed herein, and the contents of each of these references are incorporated herein by reference in their entirety for all purposes.

[0056] In the methods of treating HS described herein, the HS is Hurley stage I HS, Hurley stage II HS, or Hurley stage III HS. In some embodiments, the HS is Hurley stage I HS. In some embodiments, the HS is Hurley stage II HS. In some embodiments, the HS is Hurley stage III HS.

[0057] In one aspect, a method of treating hidradenitis suppurativa in a subject in need thereof is provided, the method comprising administering to the subject, for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharma- ceutical acceptable salt thereof; [ka] During the ceremony, R 1teeth, [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 and R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, or piperidine ring; or R 6 is C 1-3 alkyl, optionally substituted by 1, 2 or 3 F, and / or OH, OC 1-3 Alkyl, N(C 1-3 Alkyl) 2 , cyclopropyl, or tetrahydropyran; 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.

[0058] In one embodiment, the subject has not been previously treated with an anti-tumor necrosis factor alpha (TNFα) agent (e.g., an anti-TNFα antibody). In another embodiment of the treatment methods described herein, the HS is refractory HS, e.g., the subject has not responded to a previous, different HS treatment. In a further embodiment, the previous, different HS treatment comprises a systemic antibiotic.

[0059] In one embodiment of the methods provided herein, the compound of formula (I) is an S,S diastereomer. In other words, the compound of formula (I) has the following stereochemistry: [ka]

[0060] Other diastereomeric forms of the compound of formula (I), and mixtures thereof, are also contemplated by the present invention. For example, in one embodiment, the compound of formula (I) is the R,R diastereomer. [ka]

[0061] In another embodiment, the compound of formula (I) is the R,S diastereomer. [ka]

[0062] In yet another embodiment, the compound of formula (I) is the S,R diastereomer. [ka]

[0063] In one embodiment of the methods provided herein, R 1 teeth, [ka] and X is O, S, or CF 2 where Y is O or S, Q is CH or N, and R 6 is C 1-3 is an alkyl group, 1-3 Alkyl is optionally substituted by one, two or three F and is substituted with OH, OC 1 - 3 Alkyl, N(C 1-3 Alkyl) 2, cyclopropyl, and tetrahydropyran; R 7 is hydrogen, F, Cl, or CH 3 It is.

[0064] In one embodiment, 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 and R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, or piperidine ring.

[0065] In a further embodiment, R 1 teeth, [ka] and R 2 is hydrogen, F, Cl, or C 1-3 is alkyl, R 3 is hydrogen, F, Cl, CN, or SO 2 C 1-3 It is an alkyl.

[0066] In yet a further embodiment, R 1 teeth, [ka] and R 2 is hydrogen, F, or C 1-3is alkyl, R 3 is hydrogen, F, or CN.

[0067] In another embodiment, R 1 teeth, [ka] and X is O, S, or CF 2 and Y is O or S; R 6 is C 1-3 Alkyl, C 1-3 Alkyl is optionally substituted by one, two or three F and is substituted with OH, OC 1-3 Alkyl, N(C 1-3 Alkyl) 2 , cyclopropyl, or tetrahydropyran; R 7 is hydrogen, F, Cl, or CH 3 It is.

[0068] In one embodiment, R 1 teeth, [ka] It is.

[0069] In another embodiment, R 1 teeth [ka] where X is O and R 6 is C 1-3 is alkyl, R 7 is hydrogen. In a further embodiment, R 6 is methyl.

[0070] In one embodiment, R 1 teeth, [ka] and X is O, S, or CF 2 and Y is O or S; R 6 is C optionally substituted with one, two or three F 1-3 is alkyl, R 7 is hydrogen, F, Cl, or CH 3 It is.

[0071] In another embodiment, R 1 teeth, [ka] and X is O, S, or CF 2 and R 6 is C 1-3 Alkyl, C 1-3 Alkyl is optionally substituted with 1, 2, or 3 F; R 7 is hydrogen, F, Cl, or CH 3 It is.

[0072] In one embodiment, R 1 teeth, [ka] In one embodiment, X is O and R 6 is C 1-3 is alkyl, R 7 is hydrogen.

[0073] In one embodiment, R 1 teeth, [ka] X is O and R 6 is C 1-3 is alkyl, R 7 is hydrogen.

[0074] In another embodiment, R 1 teeth, [ka] X is O and R 6 is C 1-3 Alkyl, C 1-3 The alkyl is optionally substituted by one, two, or three F; R 7 is hydrogen.

[0075] In one embodiment, R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 Alkyl or C 1-3 It is an alkyl.

[0076] In a further embodiment, R 2 is hydrogen, F, Cl, or C 1-3 It is an alkyl.

[0077] In yet a further embodiment, R 2 is hydrogen, F, or C 1-3 It is an alkyl.

[0078] In one embodiment, R 3 are hydrogen, F, Cl, Br, CN, CF3, and SO 2 C 1-3 Alkyl, CONH 2 , or SO 2 NR 4 R 5 and R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, or piperidine ring.

[0079] In a further embodiment, R 3 is hydrogen, F, Cl, CN, or SO 2 C 1-3 It is an alkyl.

[0080] In yet a further embodiment, R 3 is hydrogen, F, or CN.

[0081] In one embodiment, R 6is C 1-3 is an alkyl group, 1-3 Alkyl is optionally substituted by 1, 2 or 3 F and OH, OC 1-3 Alkyl, N(C 1-3 Alkyl) 2 , cyclopropyl, and tetrahydropyran;

[0082] In a further embodiment, R 6 is C 1-3 is an alkyl group, 1-3 The alkyl is optionally substituted with one, two, or three F. In yet a further embodiment, R 6 is methyl or ethyl. In yet a further embodiment, R 6 is methyl.

[0083] In one embodiment, R 7 is hydrogen, F, Cl, or CH 3 In a further embodiment, R 7 is hydrogen.

[0084] 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 (referred to herein by its International Nonproprietary Name (INN) brensocatib), [ka] , or a pharma- ceutically acceptable salt thereof.

[0085] 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 foregoing compounds.

[0086] It will also be understood that certain compounds of formula (I) may exist in solvated forms such as hydrates, including solvates of pharma- ceutically acceptable salts of compounds of formula (I).

[0087] In one embodiment, the compound of Formula (I) provided in the methods described herein is a hydrate. In a further embodiment, the compound is a hydrate of brensocatib.

[0088] In one embodiment, the compound of formula (I) is a racemate, a racemic mixture, a single enantiomer, an individual diastereomer, or a diastereomeric mixture. It should be understood that the present disclosure encompasses all such isomeric forms, such as the S,S diastereomer, the S,R diastereomer, the R,S diastereomer, and the R,R diastereomer disclosed herein, as well as mixtures of any two or more of the foregoing diastereomers.

[0089] Thus, 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 (i.e., brensocatib, S,S isomer), as shown below: [ka] , or a pharma- ceutically acceptable salt thereof. In one embodiment, brensocatib is in the form of a hydrate.

[0090] In one embodiment, the compound of formula (I) is (2R)-N-{(1R)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (i.e., the R,R isomer), [ka] , or a pharma- ceutically acceptable salt thereof.

[0091] In one embodiment, the compound of formula (I) is (2S)-N-{(1R)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (i.e., the S,R isomer), [ka] , or a pharma- ceutically acceptable salt thereof.

[0092] In one embodiment, the compound of formula (I) is (2R)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (i.e., the R,S isomer), [ka] , or a pharma- ceutically acceptable salt thereof.

[0093] In one embodiment, the composition comprises a mixture of one or more of the foregoing stereoisomers. In one embodiment, the mixture comprises a mixture of the S,S isomer (brensocatib) and the S,R isomer of brensocatib. In another embodiment, the composition comprises a mixture of the S,S isomer (brensocatib) and the R,S isomer. In yet another embodiment, the composition comprises a mixture of the S,S isomer (brensocatib) and the R,R isomer.

[0094] Certain compounds of formula (I) may also contain linkages (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) and bond rotation is restricted for that particular linkage (e.g., restrictions resulting from the presence of ring bonds or double bonds). It is therefore to be understood that the present disclosure encompasses all such isomers. Certain compounds 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, such as chromatography or fractional crystallization, or stereoisomers may be made by stereoselective synthesis.

[0095] In a further embodiment, the compounds of formula (I) include any isotopically labeled (or radiolabeled) derivatives of the compounds of formula (I). Such derivatives are derivatives of the compounds of formula (I) in which one or more atoms are replaced by atoms 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: 2 H (also represented 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, and the deuterated compound is used in one of the methods provided herein.

[0096] In a further embodiment, the compound of formula (I) is administered in the form of a pro-drug, which is broken down in the human or animal body to ultimately provide a compound of formula (I). Examples of pro-drugs include in vivo hydrolysable esters of a compound of formula (I).

[0097] In vivo hydrolyzable (or cleavable) esters of compounds of formula (I) containing a carboxy or hydroxy group are, for example, pharma- ceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent acid or alcohol. For examples of ester prodrug derivatives, see, for example, Curr. Drug. Metab. 2003, 4, 461 (incorporated herein by reference in its entirety for all purposes).

[0098] 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 (incorporated herein by reference in its entirety for all purposes).

[0099] The methods provided herein include administering to a patient in need of treatment for hidradenitis suppurativa a composition comprising an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. The compounds of formula (I) and their pharma- ceutically acceptable salts are inhibitors of dipeptidyl peptidase 1 (DPP1) activity. In one embodiment, the compound is brensocatib, or a pharma- ceutically acceptable salt thereof. In a further embodiment, the compound is brensocatib.

[0100] In some embodiments, the subject exhibits one or more symptoms of hidradenitis suppurativa (HS). In some embodiments, administration of a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein treats one or more symptoms of HS, for example, by reducing the severity of the one or more symptoms. In some embodiments, administration of the pharmaceutical composition alleviates, reduces the severity, delays the onset, or eliminates one or more symptoms of HS. In some embodiments, the one or more HS symptoms are one or more of the following: (a) one or more skin lesions, (b) one or more skin abscesses, (c) one or more fistulas, (d) one or more fistulas, (e) skin scarring, (f) anxiety, (g) depression, (h) suicidal thoughts, or (i) any combination thereof. In one embodiment, the one or more symptoms of HS are one or more skin lesions. In one embodiment, the one or more symptoms of HS are one or more skin abscesses. In one embodiment, the one or more symptoms of HS are one or more fistulas. In further embodiments, the one or more fistulas are one or more draining fistulas. In one embodiment, the one or more symptoms of HS are one or more fistulas. In one embodiment, the one or more HS symptoms include skin scarring. In one embodiment, the one or more HS symptoms include anxiety. In one embodiment, the one or more HS symptoms include depression. In one embodiment, the one or more HS symptoms include suicidal ideation. In some embodiments, the one or more skin lesions, one or more skin abscesses, one or more fistulas, one or more fistulas, or combinations thereof, are painful, inflamed, swollen, or any combination thereof, prior to the administration period. In some embodiments, during or after the administration period, the one or more skin lesions, one or more skin abscesses, one or more fistulas, and / or one or more fistulas are reduced in size and / or inflammation, swelling, and / or pain associated with the one or more skin lesions, one or more skin abscesses, one or more fistulas, and / or one or more fistulas are reduced.

[0101] As used herein, "prior to the administration period" refers to the period from about 28 days prior to the first administration of a pharmaceutical composition or compound of Formula (I) provided herein to just prior to the first administration of a pharmaceutical composition or compound of Formula (I). In one embodiment, "just prior to the administration period" is from about 24 hours prior to about 1 minute prior to the first administration of a pharmaceutical composition or compound of Formula (I) provided herein.

[0102] In one embodiment, the administration period is from about 28 days to about 28 days before the administration period. In another embodiment, the administration period is from about 21 days to about 21 days before the administration period. In another embodiment, the administration period is from about 14 days to about 14 days before the administration period. In yet another embodiment, the administration period is from about 10 days to about 10 days before the administration period. In yet another embodiment, the administration period is from about 7 days to about 7 days before the administration period. In yet another embodiment, the administration period is from about 4 days to about 4 days before the administration period.

[0103] In one embodiment, the "before the administration period" is from about 28 days to about 1 day before the administration period. In another embodiment, the before the administration period is from about 21 days to about 1 day before the administration period. In another embodiment, the before the administration period is from about 14 days to about 1 day before the administration period. In yet another embodiment, the before the administration period is from about 10 days to about 1 day before the administration period. In yet another embodiment, the before the administration period is from about 7 days to about 1 day before the administration period. In yet another embodiment, the before the administration period is from about 4 days to about 1 day before the administration period.

[0104] The one or more skin lesions, one or more skin abscesses, one or more fistulas, one or more fistulas, or combinations thereof may be found in any part of the subject's body, for example, in a part of the body where skin tissue rubs against other skin tissue. In some embodiments, the one or more skin lesions, one or more skin abscesses, one or more fistulas, one or more fistulas, or combinations thereof are present in one or both of the subject's axillae, groin, buttocks, or combinations thereof. In some embodiments, the one or more skin lesions, one or more skin abscesses, one or more fistulas, one or more fistulas, or combinations thereof are associated with hair follicles. In some embodiments, the one or more skin lesions are one or more skin nodules. In some embodiments, the one or more skin nodules are one or more inflammatory skin nodules. In some embodiments, the one or more skin lesions are interconnected by one or more fistulas. In some embodiments, the one or more skin lesions are one or more fistulas. In further embodiments, the one or more fistulas are one or more draining fistulas.

[0105] In some embodiments, the method of treating HS comprises reducing the subject's skin abscess and inflammatory skin nodule count (AN count) during or after the administration period, compared to the subject's AN count before the administration period. As used herein, the subject's "AN count" includes the total number of skin abscesses and inflammatory skin nodules counted by the subject. Further details regarding AN count are provided in Kimball et al. Journal of the European Academy of Dermatology and Venereology 2016,30,989-994, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the subject's AN count before the administration period is 3 or more. For example, in one embodiment, the subject's AN count before the administration period is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more than 15.

[0106] In some embodiments, the AN count of the subject during or after the administration period is lower than the AN count of the subject before the administration period. In some embodiments, the AN count of the subject during or after the administration period is at least about 2% lower than the AN count of the subject before the administration period (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% (including all values ​​and subranges therebetween)). In some embodiments, the AN count of the subject during or after the administration period is at least 10% lower than the AN count of the subject before the administration period. In some embodiments, the AN count of the subject during or after the administration period is at least 50% lower than the AN count of the subject before the administration period.

[0107] In one embodiment, reducing the AN count comprises reducing the AN count by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10. In another embodiment, reducing the AN count comprises reducing the AN count by at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, or at least about 10.

[0108] In one embodiment, the methods of the invention include reducing the occurrence of an HS flare in a subject during or after the administration period compared to the occurrence of an HS flare in a subject prior to the administration period. As used herein, "HS flare" refers to at least a 25% increase in an AN count with an absolute increase in AN count of >= 2 compared to a baseline AN count.

[0109] In some embodiments, the method includes reducing or maintaining the fistula count (e.g., draining fistula count) of the subject during or after the administration period compared to the fistula count (e.g., draining fistula count) of the subject before the administration period. As used herein, the fistula count of the subject is a count of the total number of fistulas of the subject. For example, the draining fistula count of the subject is a count of the total number of draining fistulas of the subject. Further details regarding fistula count are provided in Kimball et al. Journal of the European Academy of Dermatology and Venereology 2016,30,989-994, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the fistula count (e.g., draining fistula count) of the subject before the administration period is ≦20. In some embodiments, the subject's fistula count (e.g., draining fistula count) prior to the administration period is 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.

[0110] In some embodiments, the method includes maintaining or reducing the fistula count (e.g., draining fistula count) of the subject during or after the administration period compared to the fistula count (e.g., draining fistula count) of the subject before the administration period. In some embodiments, the fistula count (e.g., draining fistula count) of the subject during or after the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% (including all values ​​and subranges therebetween)) lower than the fistula count (e.g., draining fistula count) of the subject before the administration period.

[0111] In one embodiment, reducing the fistula count comprises reducing the fistula count by 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, or about 15. In another embodiment, reducing the fistula count comprises reducing the fistula count by at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, or at least about 15. In a further embodiment, the fistula count is a draining fistula count.

[0112] In some embodiments of the method for treating HS, the subject achieves Hidradenitis Suppurativa Clinical Response (HiSCR) during or after the administration period. As used herein, a subject is said to have achieved HiSCRn if the subject exhibits at least n% reduction in total AN counts without an increase in skin abscess counts and without an increase in draining fistula counts during or after the administration period, respectively, compared to the subject's total AN counts, skin abscess counts, and draining fistula counts before the administration period. For example, a subject is said to have achieved "HiSCR50", "HiSCR75", or "HiSCR90" if the subject exhibits at least 50%, 75%, or 90% reduction in total AN counts without an increase in skin abscess counts and without an increase in draining fistula counts during or after the administration period, respectively, compared to the subject's total AN counts, skin abscess counts, and draining fistula counts before the administration period. Further details of the HiSCR assessment are provided in Kimball et al. Journal of the European Academy of Dermatology and Venereology 2016, 30, 989-994, the contents of which are incorporated herein by reference in their entirety.

[0113] In some embodiments of the methods for treating HS, the subject achieves a modified hidradenitis suppurativa clinical response (mHiSCR) during or after the administration period, defined as a ≧50% reduction in the total number of inflammatory nodules, abscesses, and draining fistulas, and a ≧50% reduction in the total number of draining fistulas, compared to the subject's total number of inflammatory nodules, abscesses, and draining fistulas, and the total number of draining fistulas, respectively, prior to the administration period.

[0114] In some embodiments, the methods of treating HS provided herein include reducing a Patient Global Assessment of Skin Pain (PGA-SP) score during or after the administration period, compared to the subject's PGA-SP score before the administration period. As used herein, PGA-SP score refers to a score assigned by a patient to rate their skin pain as the "worst" in the past 24-hour period using an 11-point numerical rating scale (i.e., NRS for skin pain), where 0 is no skin pain and 10 is the worst skin pain imaginable. Further details regarding PGA-SP are provided in Kimball et al., J Am Acad Dermatol, 2018, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the subject's PGA-SP score before the administration period is ≧3. In some embodiments, the subject's PGA-SP score before the administration period is 3, 4, 5, 6, 7, 8, 9, or 10.

[0115] In one embodiment, reducing the PGA-SP score comprises reducing the PGA-SP score by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, or about 9. In another embodiment, reducing the PGA-SP score comprises reducing the PGA-SP score by at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, or at least about 9.

[0116] In some embodiments, the subject's PGA-SP score during or after the administration period is reduced to 2, 1, or 0.

[0117] Reducing the subject's PGA-SP score during or after the administration period, in one embodiment, comprises reducing the PGA-SP score by at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% (including all values ​​and subranges therebetween)) compared to the subject's PGA-SP score before the administration period. In some embodiments, reducing the subject's PGA-SP score during or after the administration period comprises reducing the subject's PGA-SP score by at least about 10% compared to the subject's PGA-SP score before the administration period. In some embodiments, the subject's PGA-SP score during or after the administration period is reduced to 3 or less.

[0118] In some embodiments, the method of treating HS comprises reducing the subject's International Hidradenitis Suppurativa Severity Scale (IHS4) score during or after the administration period, compared to the subject's IHS4 score before the administration period. As used herein, IHS4 refers to the number of inflammatory nodules (multiplied by 1), plus the number of abscesses (multiplied by 2), plus the number of draining fistulas (multiplied by 4). A total IHS4 score of 3 or less represents mild (Stage I HS), 4-10 represents moderate (Stage II HS), and 11 or more represents severe disease (Stage III HS). Further details regarding the measurement of IHS4 are provided in Zouboulis et al. British Journal of Dermatology (2017) 177, pp1401-1409, the contents of which are incorporated herein by reference in their entirety.

[0119] In one embodiment of the method of treating HS, the subject has an IHS4 score of > 4 prior to the administration period. In a further embodiment, the subject has an IHS4 score of > 4 and < 10 prior to the administration period. In a further embodiment, the subject has an IHS4 score of > 11 prior to the administration period.

[0120] In some embodiments, the method of treating HS comprises reducing the subject's IHS4 score during or after the administration period by at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, including all values ​​and subranges therebetween) compared to the subject's IHS4 score before the administration period. In some embodiments, the method of treating HS comprises reducing the subject's IHS4 score during or after the administration period by at least about 10% compared to the subject's IHS4 score before the administration period. In some embodiments, the methods of treating HS comprise reducing the subject's IHS4 score to 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 during or after the administration period.

[0121] In one embodiment, reducing the IHS4 score comprises reducing the IHS4 score by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, or about 9. In another embodiment, reducing the IHS4 score comprises reducing the IHS4 score by at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, or at least about 9.

[0122] In one embodiment, the method of treating HS comprises reducing the subject's IHS4 score during or after the administration period from an HS Hurley stage III score to an HS Hurley stage II score.

[0123] In another embodiment, the method of treating HS comprises reducing the subject's IHS4 score during or after the administration period from an HS Hurley stage III score to an HS Hurley stage I score.

[0124] In yet another embodiment, the method of treating HS comprises reducing the subject's IHS4 score during or after the administration period from an HS Hurley stage II score to an HS Hurley stage I score.

[0125] In some embodiments, the method of treating HS according to the present invention comprises improving the Hurley stage of the subject's HS during or after the administration period, compared to the Hurley stage of the subject's HS before the administration period. Hurley stage is a severity classification of HS that was developed in 1989 and is widely used to determine HS severity (Hurley, Dermatologic surgery. New York: Marcel Dekker. 1989; 729:39; Ovadja et al., Br J Dermatol. 2019; 181(2):344-49, each of which is incorporated herein by reference in its entirety). In one embodiment, improving the Hurley stage of the subject's HS comprises reducing the severity of the subject's HS from Hurley stage III to Hurley stage II. In another embodiment, improving the Hurley stage of the subject's HS comprises reducing the severity of the subject's HS from Hurley stage III to Hurley stage I. In another embodiment, improving the Hurley stage of HS in a subject comprises reducing the severity of the subject's HS from Hurley stage II to Hurley stage I.

[0126] In some embodiments, the method of treating HS according to the present invention comprises reducing the subject's Hidradenitis Suppurativa Quality of Life (HiSQOL) score during or after the administration period, compared to the subject's HiSQOL score before the administration period. As used herein, HiSQOL refers to a Health-Related Quality of Life (HRQOL) measure specific to HS developed by the Hidradenitis Suppurativa Core Outcome Set International Collaboration (HISTORIC). The 17-item HiSQOL includes 4 symptom items, 8 activity adjustment items, and 5 psychosocial items. Item scores are summed to create a total range of 0 to 68, with higher scores indicating more severe impact on HRQOL and more severe disease. Further details regarding the measurement of HiSQOL are provided in Kirby et al., The Hidradenitis Suppurativa Quality of Life (HiSQOL) score: development and validation of a measure for clinical trials. Br J Dermatol. 2020 Aug;183(2):340-348, the contents of which are incorporated by reference in their entirety for all purposes. In some embodiments, the methods of treating HS comprise reducing the subject's HiSQOL score during or after the administration period by at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, including all values ​​and subranges therebetween), compared to the subject's HiSQOL score before the administration period. In one embodiment, reducing the HiSQOL score comprises reducing the HiSQOL score by about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, or about 65.In another embodiment, reducing the HiSQOL score comprises reducing the HiSQOL score by at least about 1, 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, at least about 50, at least about 55, at least about 60, or at least about 65.

[0127] In some embodiments, the method of treating HS according to the present invention comprises reducing the subject's Hidradenitis Suppurativa-Investigator Global Assessment (HS-IGA) score during or after the administration period compared to the subject's HS-IGA score before the administration period. HS-IGA is a clinical endpoint for measuring disease activity and response to treatment in patients with HS, which is based on the maximum count of abscesses, fistulas (draining and non-draining), and nodules (inflammatory and non-inflammatory) measured separately for the upper and lower body regions (Garg et al., Br J Dermatol. 2022;187(2):203-210, incorporated herein by reference in its entirety). HS-IGA is scored as a number between 0 and 5 based on the maximum lesion count for either the upper or lower body region, whichever is greater. Response to treatment is defined as a 2-point reduction (improvement) in HS-IGA score relative to baseline. In some embodiments, the method of treating HS comprises reducing the subject's HS-IGA score during or after the administration period by at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, including all values ​​and subranges therebetween) compared to the subject's HS-IGA score before the administration period. In one embodiment, reducing the HS-IGA score comprises reducing the HS-IGA score by about 1, about 2, about 3, about 4, or about 5. In another embodiment, reducing the HS-IGA score comprises reducing the HS-IGA score by at least about 1, at least about 2, at least about 3, at least about 4, or at least about 5. In a further embodiment, reducing the HS-IGA score comprises reducing the HS-IGA score by at least 2 points.

[0128] In some embodiments, the method of treating HS according to the present invention comprises reducing the subject's Dermatological Life Quality Index (DLQI) score during or after the administration period, compared to the subject's DLQI score before the administration period. The DLQI is a self-administered questionnaire designed to measure the health-related quality of life of adults (e.g., age >16 years) suffering from a skin disease (Finlay et al., Clin Exp Dermatol. 1994;19(3):210-6, incorporated herein by reference in its entirety). It consists of 10 questions regarding the assessor's perception of the impact of the skin disease on various aspects of the assessor's quality of life in the past week. Each question has four alternative answers: not at all, a little, a lot, or a lot, with corresponding scores of 0, 1, 2, and 3, respectively (irrelevant answers are scored as 0). The DLQI is the sum of scores ranging from 0 to 30. The higher the score, the greater the impairment in quality of life: 0-1=no impact, 2-5=little impact, 6-10=moderate impact, 11-20=very significant impact, 21-30=extremely significant impact. In some embodiments, the method of treating HS comprises reducing the subject's DLQI score during or after the administration period by at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, including all values ​​and subranges therebetween), compared to the subject's DLQI score before the administration period. In one embodiment, reducing the DLQI score comprises reducing the DLQI score by about 1, about 3, about 5, about 10, about 15, about 20, about 25, about 28, or about 30.In another embodiment, reducing the DLQI score comprises reducing the DLQI score by at least about 1, at least about 3, at least about 5, at least about 10, at least about 15, at least about 20, at least about 25, at least about 28, or at least about 30.

[0129] In some embodiments, the method of treating HS according to the present invention comprises reducing the subject's HS-Related Patient Global Assessment (HS-Related PtGA) score during or after the administration period compared to the subject's HS-Related PtGA score before the administration period. The HS-Related PtGA is a single-item questionnaire assessing how much HS has affected the participant's quality of life over the past seven days, with five response levels: not at all, slightly, moderately, very much, and extremely, with corresponding scores of 0, 1, 2, 3, and 4, respectively (Kirby et al., Br J Dermatol. 2021;184(4):681-87, incorporated herein by reference in its entirety). In some embodiments, the method of treating HS comprises reducing the subject's HS-related PtGA score during or after the administration period by at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, including all values ​​and subranges therebetween) compared to the subject's HS-related PtGA score before the administration period. In one embodiment, reducing the HS-related PtGA score comprises reducing the HS-related PtGA score by about 1, about 2, about 3, or about 4. In another embodiment, reducing the HS-associated PtGA score comprises reducing the HS-associated PtGA score by at least about 1, at least about 2, at least about 3, or at least about 4.

[0130] In some embodiments, the neutrophil count in a biological sample obtained from the subject prior to the administration period is greater than a control subject without HS. In some embodiments, the neutrophil count in a biological sample obtained from the subject prior to the administration period is at least about 1.2-fold (e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween) greater than a control subject without HS. In some embodiments, the neutrophil count in a biological sample obtained from the subject prior to the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% (including all values ​​and subranges therebetween)) higher than a control subject without HS.

[0131] In some embodiments, the methods of treating HS provided herein include reducing the number of neutrophils in a biological sample obtained from the subject during or after the administration period, compared to (a) the number of neutrophils in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the number of neutrophils in a corresponding biological sample obtained from a control subject, where the control subject has HS and has not been administered the composition. For example, in some embodiments, the neutrophil count in a biological sample obtained from the subject during or after the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% (including all values ​​and subranges therebetween)) lower than (a) the number of neutrophils in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the number of neutrophils in a corresponding biological sample obtained from a control subject, wherein the control subject has HS and has not been administered the composition.

[0132] In some embodiments, the level of SA100A7 (S100 calcium binding protein A7, also known as psoriasin) in a biological sample obtained from the subject prior to the administration period is increased compared to a control subject without HS. The level of "SA100A7" can refer to the level of protein expression of the SA1007 protein or the level of expression of the gene encoding SA1007. In some embodiments, the level of SA100A7 in a biological sample obtained from the subject prior to the administration period is at least about 1.2-fold (e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween)) higher than a control subject without HS. In some embodiments, the level of SA100A7 in a biological sample obtained from the subject prior to the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% (including all values ​​and subranges therebetween)) higher than a control subject without HS.

[0133] In some embodiments, a method of treating HS includes reducing the level of SA100A7 in a biological sample obtained from the subject during or after the administration period, compared to (a) the level of SA100A7 in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the level of SA100A7 in a corresponding biological sample obtained from a control subject, where the control subject has HS and has not been administered a composition comprising a compound of Formula (I). In some embodiments, the level of SA100A7 in a biological sample obtained from the subject during or after the administration period is reduced by at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, including all values ​​and subranges therebetween), compared to (a) the level of SA100A7 in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the level of SA100A7 in a corresponding biological sample obtained from a control subject, wherein the control subject has HS and has not been administered the composition.

[0134] In some embodiments, the level of myeloperoxidase (MPO) in a biological sample obtained from the subject prior to the administration period is increased compared to a control subject without HS. "Level of MPO" can refer to the level of protein expression of MPO protein or the level of expression of the gene encoding MPO. In some embodiments, the level of MPO in a biological sample obtained from the subject prior to the administration period is at least about 1.2-fold (e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween)) higher than a control subject without HS. In some embodiments, the level of MPO in a biological sample obtained from the subject prior to the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% (including all values ​​and subranges therebetween)) higher than a control subject without HS.

[0135] In some embodiments, the methods of treating HS provided herein include decreasing the level of MPO in the subject (as measured from a biological sample obtained from the subject) during or after an administration period, compared to (a) the level of MPO in the subject before the administration period, and / or (b) the level of MPO in a corresponding biological sample obtained from a control subject, the control subject having HS and not being administered a composition provided herein. In some embodiments, the decrease is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, including all values ​​and subranges therebetween).

[0136] In some embodiments, the level of peptidylarginine deiminase 4 (PAD4) in a biological sample obtained from a subject prior to the administration period is increased compared to a control subject without HS. "Level of PAD4" may refer to the level of protein expression of PAD4 protein or the level of expression of the gene encoding PAD4. In some embodiments, the level of PAD4 in a biological sample obtained from a subject prior to the administration period is at least about 1.2-fold (e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween)) higher than a control subject without HS. In some embodiments, the level of PAD4 in a biological sample obtained from the subject prior to the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% (including all values ​​and subranges therebetween)) higher than a control subject without HS.

[0137] In some embodiments, the methods of treating HS provided herein include reducing the level of PAD4 in a subject (e.g., from a biological sample obtained from the subject) during or after an administration period, compared to (a) the level of PAD4 in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the level of PAD4 in a corresponding biological sample obtained from a control subject, the control subject having HS and not being administered a composition provided herein. In some embodiments, the reduction is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, including all values ​​and subranges therebetween).

[0138] Peptidylarginine deiminase 4 (PAD4) promotes protein citrullination, such as histone citrullination. Thus, in some embodiments, the level of citrullinated peptides in a biological sample obtained from a subject before the administration period is increased compared to a control subject without HS. In some embodiments, the level of citrullinated peptides in a biological sample obtained from a subject before the administration period is at least about 1.2 times higher (e.g., about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 7.5 times, about 8 times, about 8.5 times, about 9 times, about 9.5 times, about 10 times, about 15 times, about 20 times, about 25 times, or about 30 times higher (including all values ​​and subranges therebetween)) than a control subject without HS. In some embodiments, the level of citrullinated peptides in a biological sample obtained from the subject prior to the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% (including all values ​​and subranges therebetween)) higher than a control subject without HS.

[0139] In some embodiments, the methods of treating HS provided herein include decreasing a level of a citrullinated peptide in a subject (i.e., from a biological sample obtained from the subject) during or after an administration period, as compared to (a) the level of the citrullinated peptide in the subject (i.e., from a corresponding biological sample obtained from the subject) before the administration period, and / or (b) the level of the citrullinated peptide in a corresponding biological sample obtained from a control subject, the control subject having HS and not being administered the composition. In some embodiments, the decrease is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, including all values ​​and subranges therebetween).

[0140] In some embodiments, the level of a cytokine, lipid mediator, or combination thereof in a biological sample obtained from the subject prior to the administration period is increased compared to a control subject without HS. In some embodiments, the level of a cytokine, lipid mediator, or combination thereof in a biological sample obtained from the subject prior to the administration period is at least about 1.2-fold (e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween) higher than a control subject without HS. In some embodiments, the level of a cytokine, lipid mediator, or combination thereof in a biological sample obtained from the subject prior to the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% (including all values ​​and subranges therebetween)) higher than a control subject without HS.

[0141] In some embodiments, the methods of treating HS provided herein include decreasing the level of a cytokine, lipid mediator, or combination thereof in a subject (i.e., from a biological sample obtained from the subject) during or after an administration period, as compared to (a) the level of the cytokine, lipid mediator, or combination thereof in the subject (i.e., from a corresponding biological sample obtained from the subject) before the administration period, and / or (b) the level of the cytokine, lipid mediator, or combination thereof in a corresponding biological sample obtained from a control subject, where the control subject has HS and has not been administered a composition provided herein. In some embodiments, the decrease is at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% (including all values ​​and subranges therebetween).

[0142] In some embodiments, the cytokine is a chemokine, hi some embodiments, the cytokine is IL-1, IL-36, IL-8, IL-17, TNF-alpha, or any combination thereof.

[0143] In some embodiments, the level of C-reactive protein (CRP) in a biological sample obtained from the subject prior to the administration period is increased compared to a control subject without HS. In some embodiments, the level of CRP in a biological sample obtained from the subject prior to the administration period is at least about 1.2-fold (e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween) higher than a control subject without HS. In some embodiments, the level of CRP in a biological sample obtained from the subject prior to the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% (including all values ​​and subranges therebetween)) higher than a control subject without HS.

[0144] In some embodiments, the subject in need of treatment is at risk of developing HS, hi some embodiments, the subject at risk of developing HS is or has been repeatedly exposed to tobacco smoke, has a family history of hidradenitis suppurativa, or a combination thereof.

[0145] In some embodiments, the subject in need of treatment is or has been repeatedly exposed to tobacco smoke. As used herein, "repeated exposure" to tobacco smoke refers to exposure that is frequent enough to be associated with, result in, or increase the risk of developing one or more adverse effects from inhaling tobacco smoke. Non-limiting adverse effects of inhaling tobacco smoke are cancer (e.g., lung cancer), coronary heart disease, respiratory infections, stroke, lung disease, diabetes, chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, tuberculosis, eye disease, immune dysfunction, and rheumatoid arthritis. In some embodiments, the subject is exposed to tobacco smoke at least once a month, for example, once every two weeks, once a week, every other day, every day, or several times a day. In some embodiments, the subject is an active smoker of tobacco-containing products, such as cigarettes. In some embodiments, the subject is passively exposed to tobacco smoke.

[0146] In some embodiments, HS is associated with the presence or development of one or more of acne, arthritis, diabetes, metabolic syndrome, inflammatory bowel disease, obesity, or any combination thereof.

[0147] In some embodiments, the level of DPP1 in a biological sample obtained from the subject is in the range of about 1 ng / mL to about 1000 ng / mL prior to the administration period. The present disclosure further provides a method of treating hidradenitis suppurativa in a subject in need thereof, the method comprising: (a) determining the level of DPP1 in a biological sample obtained from the subject; and (b) administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein. In some embodiments, the level of DPP1 determined in step (a), or the level of DPP1 in a biological sample obtained from the subject prior to the administration period, is in the range of about 1 ng / mL to about 1000 ng / mL, e.g., about 3 ng / mL, about 5 ng / mL, about 7 ng / mL, about 10 ng / mL, about 13 ng / mL, about 15 ng / mL, about 17 ng / mL, about 20 ng / mL, about 30 ng / mL, about 40 ng / mL, about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, about 100 ng / mL, about 150 ng / mL, about 160 ng / mL, about 170 ng / mL, about 180 ng / mL, about 200 ng / mL, about 250 ng / mL, about 260 ng / mL, about 270 ng / mL, about 280 ng / mL, about 300 ng / mL, about 350 ng / mL, about 360 ng / mL, about 370 ng / mL, about 380 ng / mL, about 390 ng / mL, about 40 ... g / mL, about 100 ng / mL, about 150 ng / mL, about 200 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, about 500 ng / mL, about 550 ng / mL, about 600 ng / mL, about 650 ng / mL, about 700 ng / mL, about 750 ng / mL, about 800 ng / mL, about 850 ng / mL, about 900 ng / mL, about 950 ng / mL, or about 1000 ng / mL (including all values ​​and subranges therebetween). In some embodiments, the level of DPP1 determined in step (a) or the level of DPP1 in a biological sample obtained from the subject prior to the administration period is within the range of about 5 ng / mL to about 20 ng / mL. In some embodiments, the level of DPP1 determined in step (a), or the level of DPP1 in a biological sample obtained from the subject prior to the administration period, is within the range of about 1 ng / mL to about 100 ng / mL. In some embodiments, the level of DPP1 refers to the level of total DPP1, including both active and inactive DPP1. In other embodiments, the level of DPP1 refers to the level of active DPP1.

[0148] In some embodiments, the level or activity of DPP1 determined in step (a), or the level or activity of DPP1 in a biological sample obtained from the subject prior to the administration period, is at least about 1.2-fold (e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween) higher than the level or activity of DPP1 in a healthy subject not having hidradenitis suppurativa.

[0149] In some embodiments, the level or activity of DPP1 determined in step (a), or the level or activity of DPP1 in a biological sample obtained from the subject prior to the administration period, is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 10 ... at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% (including all values ​​and subranges therebetween) higher.

[0150] In some embodiments, the activity of DPP1 in a biological sample obtained from the subject during or after the administration period is lower than (a) the activity of DPP1 in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the activity of DPP1 in a corresponding biological sample obtained from a control subject, where the control subject has hidradenitis suppurativa and has not been administered the composition. In some embodiments, the activity of DPP1 in a biological sample obtained from the subject during or after the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% (including all values ​​and subranges therebetween)) lower than (a) the activity of DPP1 in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the activity of DPP1 in a corresponding biological sample obtained from a control subject, wherein the control subject has hidradenitis suppurativa and has not been administered the composition.

[0151] In some embodiments, the level of DPP1 in a biological sample obtained from the subject during or after the administration period is lower than (a) the level of DPP1 in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the level of DPP1 in a corresponding biological sample obtained from a control subject, where the control subject has HS and has not been administered the composition. In some embodiments, the level of DPP1 in a biological sample obtained from the subject during or after the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% (including all values ​​and subranges therebetween)) lower than (a) the level of DPP1 in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the level of DPP1 in a corresponding biological sample obtained from a control subject, wherein the control subject has hidradenitis suppurativa and has not been administered the composition.

[0152] In some embodiments, DPP1 and its levels can be detected and / or quantified using methods such as, for example, Western blotting and enzyme activity assays. Further details are provided in Pham et al., Proc Natl Acad Sci 96(15):8627-32(1999), Chen et al., J.Med.Chem.64:11857-11885(2021), Hamon et al., J Biol Chem.291(16):8486-99(2016), and International Patent Application No. PCT / US2021 / 042199, the contents of each of which are incorporated herein by reference in their entirety.

[0153] In some embodiments, the level of neutrophil extracellular traps (NETs) in a biological sample obtained from the subject is in the range of about 1 ng / mL to about 1000 ng / mL prior to the administration period.The present disclosure further provides a method of treating hidradenitis suppurativa in a subject in need thereof, the method comprising: (a) determining the level of NETs in a biological sample obtained from the subject; and (b) administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein. In some embodiments, the level of NETs determined in step (a), or the level of neutrophil extracellular traps (NETs) in a biological sample obtained from the subject prior to the administration period, is in the range of about 1 ng / mL to about 1000 ng / mL, e.g., about 3 ng / mL, about 5 ng / mL, about 7 ng / mL, about 10 ng / mL, about 13 ng / mL, about 15 ng / mL, about 17 ng / mL, about 20 ng / mL, about 30 ng / mL, about 40 ng / mL, about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL , about 90 ng / mL, about 100 ng / mL, about 150 ng / mL, about 200 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, about 500 ng / mL, about 550 ng / mL, about 600 ng / mL, about 650 ng / mL, about 700 ng / mL, about 750 ng / mL, about 800 ng / mL, about 850 ng / mL, about 900 ng / mL, about 950 ng / mL, or about 1000 ng / mL (including all values ​​and subranges therebetween).

[0154] In some embodiments, the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject prior to the administration period, is at least about 1.2-fold (e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween) higher than the level of NETs in a healthy subject not having hidradenitis suppurativa.

[0155] In some embodiments, the level of NETs determined in step (a), or in a biological sample obtained from the subject prior to the administration period, is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 140%, at least about 150%, at least about 160%, at least about 180%, at least about 190%, at least about 200%, at least about 210%, at least about 220%, at least about 230%, at least about 240%, at least about 250%, at least about 260%, at least about 270%, at least about 280%, at least about 300%, at least about 350%, at least about 350%, at least about 360%, at least about 370%, at least about 380%, at least about 390%, at least about 40 ... at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% (including all values ​​and subranges therebetween) higher.

[0156] In some embodiments, the level of neutrophil extracellular traps (NETs) in a biological sample obtained from the subject during or after the administration period is lower than (a) the level of NETs in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the level of NETs in a corresponding biological sample obtained from a control subject, where the control subject has hidradenitis suppurativa and has not been administered the composition. In some embodiments, the level of NETs in a biological sample obtained from the subject during or after the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% (including all values ​​and subranges therebetween)) lower than (a) the level of NETs in a corresponding biological sample obtained from the subject prior to the administration period, and / or (b) the level of NETs in a corresponding biological sample obtained from a control subject, wherein the control subject has hidradenitis suppurativa and has not been administered the composition.

[0157] In some embodiments, the level of NETs is the level of circulating plasma NETs. In some embodiments, the level of NETs is determined by measuring DNA complexed with NET molecules such as myeloperoxidase (MPO-DNA) or neutrophil elastase (NE-DNA) using enzyme-linked immunosorbent assay (ELISA), by measuring the presence of citrullinated histones by fluorescence microscopy, detecting NET components by flow cytometry, detecting the localization of NET-associated molecules (NE, MPO, CitH3) to extracellular DNA by immunofluorescence, or using flow cytometry or confocal microscopy-based methods. Further details regarding determining the levels of NETs are provided in Arends et al., J. Vis. Exp. (143), e59150, (2019), Gal, et al., Sci Rep 10, 4320 (2020), and Thalin et al., Arteriosclerosis, Thrombosis, and Vascular Biology. 39, 1724-1738 (2019), each of which is incorporated by reference in its entirety for all purposes.

[0158] In some embodiments, the level of neutrophil serine protease (NSP) in a biological sample obtained from the subject is in the range of about 1 ng / mL to about 1000 ng / mL prior to the administration period. The present disclosure further provides a method of treating hidradenitis suppurativa in a subject in need thereof, the method comprising: (a) determining the level of NSP in a biological sample obtained from the subject; and (b) administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein. In some embodiments, the level of NSP determined in step (a), or the level of NSP in a biological sample obtained from the subject prior to the administration period, is in the range of about 1 ng / mL to about 1000 ng / mL, e.g., about 3 ng / mL, about 5 ng / mL, about 7 ng / mL, about 10 ng / mL, about 13 ng / mL, about 15 ng / mL, about 17 ng / mL, about 20 ng / mL, about 30 ng / mL, about 40 ng / mL, about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, or about 100 ng / mL. / mL, about 100ng / mL, about 150ng / mL, about 200ng / mL, about 250ng / mL, about 300ng / mL, about 350ng / mL, about 400ng / mL, about 450ng / mL, about 500ng / mL, about 550ng / mL, about 600ng / mL, about 650ng / mL, about 700ng / mL, about 750ng / mL, about 800ng / mL, about 850ng / mL, about 900ng / mL, about 950ng / mL, or about 1000ng / mL (including all values ​​and subranges therebetween). In the present disclosure, in some embodiments, the level of NSP refers to the level of total NSP, including both active and inactive forms of NSP. In other embodiments, the level of NSP refers to the level of the active form of NSP.

[0159] In some embodiments, the level or activity of the NSP determined in step (a), or the level or activity of the NSP in a biological sample obtained from the subject prior to the administration period, is at least about 1.2-fold (e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween) higher than the level or activity of the NSP in a healthy subject not having hidradenitis suppurativa.

[0160] In some embodiments, the level or activity of the NSP determined in step (a), or the level or activity of the NSP in a biological sample obtained from the subject prior to the administration period, is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 5 ... about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% (including all values ​​and subranges therebetween) higher.

[0161] In some embodiments, the activity of a neutrophil serine protease (NSP) in a biological sample obtained from the subject during or after the administration period is less than (a) the activity of the NSP in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the activity of the NSP in a corresponding biological sample obtained from a control subject, where the control subject has hidradenitis suppurativa and has not been administered the composition. In some embodiments, the activity of the NSP in a biological sample obtained from the subject during or after the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% (including all values ​​and subranges therebetween)) lower than (a) the activity of the NSP in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the activity of the NSP in a corresponding biological sample obtained from a control subject, wherein the control subject has HS and has not been administered the composition.

[0162] In some embodiments, the level of neutrophil serine protease (NSP) in a biological sample obtained from the subject during or after the administration period is lower than (a) the level of NSP in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the level of NSP in a corresponding biological sample obtained from a control subject, where the control subject has hidradenitis suppurativa and has not been administered the composition. In some embodiments, the level of the NSP in a biological sample obtained from the subject during or after the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, 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%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% (including all values ​​and subranges therebetween)) lower than (a) the level of the NSP in a corresponding biological sample obtained from the subject before the administration period, and / or (b) the level of the NSP in a corresponding biological sample obtained from a control subject, wherein the control subject has HS and has not been administered the composition.

[0163] In some embodiments, the NSP is a secreted NSP or an NSP in a cytoplasmic granule. In some embodiments, the NSP is a proform of the NSP. In some embodiments, the NSP is an active form of the NSP. In some embodiments, the NSP is a secreted proform of the NSP. In some embodiments, the NSP is neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), neutrophil serine protease 4 (NSP4), or any combination thereof. In some embodiments, the NSP is a cell surface localized NSP, an intracellular NSP, or a combination thereof. In some embodiments, the level of cell surface localized NSP or intracellular NSP is measured using flow cytometry.

[0164] In some embodiments, neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), or levels thereof may be detected and / or quantified using methods such as, for example, western blotting, ELISA assays, enzyme activity assays, or any combination thereof. Non-limiting examples of ELISA assays include ProteaseTag® Active NE Immunoassay, ProteaseTag® Active PR3 Immunoassay, and ProteaseTag® Active CatG Immunoassay from ProAxsis (Belfast, Northern Ireland). Non-limiting examples of activity assays include NE enzyme kinetic assay, PR3 enzyme kinetic assay, and CatG enzyme kinetic assay. In some embodiments, NSP4 and levels thereof may be detected and / or quantified using methods such as, for example, western blotting and enzyme activity assays. Further details are provided in Perera et al., PNAS 109:6229-6234 (2012), Perera et al., J Immunol 191:2700-2707 (2013), and Kasperkiewicz et al., PLoS One 10(7):e0132818 (2015), each of which is incorporated by reference in its entirety.

[0165] In some embodiments, the biological sample is sinus tissue, blood, serum, white blood cells (WBC), neutrophils, skin tissue, or any combination thereof. In one embodiment of the methods disclosed herein, the biological sample is skin tissue. In some embodiments, the skin tissue comprises tissue from one or more skin lesions, one or more skin abscesses, one or more fistulas (e.g., one or more draining fistulas), one or more fistulas, one or more skin scars, or combinations thereof. In further embodiments, the skin tissue comprises tissue from one or more fistulas. In further embodiments, the one or more fistulas comprise one or more draining fistulas.

[0166] The dosage of the compound of formula (I) varies depending on the compound used, the mode of administration, the desired treatment, and the type, symptoms, or severity of HS being treated. In some embodiments, the subject is administered a compound of formula (I) at a daily dosage of about 10 mg to about 100 mg, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg (including all values ​​and subranges therebetween) during the administration period. In some embodiments, the subject is administered a compound of formula (I) at a daily dosage of about 10 mg to about 40 mg. In one embodiment, the subject is administered a compound of formula (I) at a daily dosage of about 10 mg. In another embodiment, the subject is administered a compound of formula (I) at a daily dosage of about 40 mg. In one embodiment, the compound of formula (I) is brensocatib, or a pharma- ceutically acceptable salt thereof. In another embodiment, the compound of formula (I) is brensocatib.

[0167] In some embodiments, the daily dosage of the compound of Formula (I) during the administration period is in the range of 0.01 micrograms per kilogram of body weight (μg / kg) to 100 milligrams per kilogram of body weight (mg / kg), e.g., about 0.05 μg / kg, 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, 5 μg / kg, 10 μg / kg, 20 μg / kg, 30 μg / kg, 40 μg / kg, 50 μg / kg, 60 μg / kg, 70 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 120 μg / kg, 140 μg / kg, 160 μg / kg, 180 μg / kg, 190 μg / kg, 200 μg / kg, 210 μg / kg, 220 μg / kg, 230 μg / kg, 240 μg / kg, 250 μg / kg, 260 μg / kg, 270 μg / kg, 280 μg / kg, 290 μg / kg, 300 μg / kg, 310 μg / kg, 320 μg / kg, 330 μg / kg, 340 μg / kg, 350 μg / kg, 360 μg / kg, 370 μg / kg, 380 μg / kg, 390 μg / kg, 40 ... μg / kg, 90 μg / kg, 100 μg / kg, 200 μg / kg, 300 μg / kg, 400 μg / kg, 500 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 900 μg / kg, 1 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, or 100 mg / kg (including all values ​​and subranges therebetween).

[0168] In one embodiment, the composition comprising an effective amount of a compound of formula (I) is in an oral dosage form. In a further embodiment, the compound of formula (I) is administered in a dosage form of 10 mg to 50 mg, 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, a 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 10 mg, 25 mg, or 40 mg dosage form. In a further embodiment, the dosage form is administered once daily. In one embodiment, the compound of formula (I) is brensocatib, or a pharma- ceutically acceptable salt thereof. In another embodiment, the compound of formula (I) is brensocatib.

[0169] In some embodiments, the compound of formula (I) is brensocatib and is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 100 mg, e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg, including all values ​​and subranges therebetween. In some embodiments, the amount of brensocatib in the pharmaceutical composition is in the range of about 10 mg to about 40 mg. In some embodiments, the amount of brensocatib in the pharmaceutical composition is in the range of about 25 mg to about 40 mg. In some embodiments, the amount of brensocatib in the pharmaceutical composition is in the range of about 10 mg to about 25 mg. In some embodiments, the amount of brensocatib in the pharmaceutical composition is about 10 mg. In some embodiments, the amount of brensocatib in the pharmaceutical composition is about 40 mg. In further embodiments, the pharmaceutical composition is administered once daily during the administration period. In further embodiments, the pharmaceutical composition is administered orally during the administration period.

[0170] In the methods of treating HS provided herein, the pharmaceutical composition is administered by a suitable route of administration, including oral, enteral, mucosal, rectal, nasal, inhalation (e.g., via aerosol), buccal (e.g., sublingual), intravaginal, intrathecal, intraocular, transdermal, intrauterine (or intrauterine), parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular (including administration to skeletal muscle, diaphragm muscle, and / or cardiac muscle), intradermal, intrapleural, intracerebral, intraarticular, intravascular, or via injection), topical (e.g., to both cutaneous and mucosal surfaces, including airway surfaces, and transdermal administration), intralymphatic, etc., as well as direct injection into a tissue or organ (e.g., into the liver, skeletal muscle, cardiac muscle, diaphragm muscle, or brain). In some embodiments, administration is by injection into the central nervous system. In one embodiment, administration is via the enteral route, via the nasogastric (NG) tube.

[0171] In a preferred embodiment, the route of administration is oral. In a further embodiment, administration is oral once a day. In an even further embodiment, the pharmaceutical composition comprises 10 mg, 25 mg, or 40 mg of the compound of formula (I). In an even even further embodiment, the compound of formula (I) is brensocatib.

[0172] The length of the administration period in any given case may depend on the nature and severity of the condition being treated and / or prevented and may be determined by a physician, hi some embodiments, the administration period is about 6 months, about 12 months, about 18 months, about 24 months, or about 36 months.

[0173] In some embodiments, the administration period is about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 30 months, about 36 months, about 4 years, about 5 years, about 10 years, about 15 years, or about 20 years. In some embodiments, the compounds or compositions disclosed herein may be administered for about 24 weeks. In some embodiments, the compounds or compositions disclosed herein may be administered for about 52 weeks. In yet another embodiment, the administration period is at least about 30 days, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years, or at least about 20 years.

[0174] In some embodiments, the administration period for the methods provided herein is from about 6 months to about 20 years. In further embodiments, the administration period is from about 6 months to about 18 years, from about 6 months to about 16 years, from about 6 months to about 14 years, from about 6 months to about 12 years, from about 6 months to about 10 years, from about 6 months to about 8 years, from about 6 months to about 6 years, from about 6 months to about 4 years, or from about 6 months to about 2 years.

[0175] In some embodiments, the administration period for the methods provided herein is at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years. In another embodiment, the administration period for the methods provided herein is from about 30 days to about 180 days. In another embodiment, the administration period is from about 30 days to about 36 months, from about 30 days to about 30 months, or from about 30 days to about 24 months, or from about 30 days to about 18 months, or from about 30 days to about 12 months, or from about 30 days to about 6 months, or from about 6 months to about 30 months, or from about 6 months to about 36 months, or from about 6 months to about 24 months, or from about 6 months to about 18 months, or from about 12 months to about 36 months, or from about 12 months to about 24 months, or from about 18 months to about 36 months.

[0176] In one embodiment, the administration period is about 1 year to about 50 years. For example, in one embodiment, the administration period is about 1 year to about 40 years, about 1 year to about 30 years, about 1 year to about 25 years, about 1 year to about 20 years, about 1 year to about 15 years, about 1 year to about 10 years, about 1 year to about 5 years, about 1 year to about 3 years, about 1 year to about 2 years, about 2 years to about 15 years, about 2 years to about 10 years, about 2 years to about 8 years, about 2 years to about 5 years, about 2 years to about 4 years, or about 2 years to about 3 years.

[0177] In one embodiment, the subject is administered the pharmaceutical composition chronically, i.e., the subject is administered the composition for their entire life once treatment for HS is initiated.

[0178] The administration schedule, including the frequency of the dose, can be determined by a physician. In some embodiments, the composition can be administered to the subject once a day or more than once a day during the administration period. In some embodiments, the composition can be administered to the subject twice a day. In some embodiments, the composition can be administered to the subject every day, every other day, every third day, every fourth day, every fifth day, or every sixth day. In some embodiments, the composition can be administered to the subject every week, every other week, or every three weeks. In some embodiments, the pharmaceutical composition is administered at about the same time every day. In a preferred embodiment, the administration of the composition comprising an effective amount of a compound of formula (I) is performed once a day, and the composition is in an oral dosage form. In a further embodiment, the compound of formula (I) is brensocatib.

[0179] In a preferred embodiment, administration of the pharmaceutical composition is once daily during the administration period.

[0180] In another embodiment, administration is twice daily, hi another embodiment, administration is once weekly, twice weekly, three times weekly, four times weekly, five times weekly, or six times weekly.

[0181] The compounds of formula (I), or pharma- ceutically acceptable salts thereof, may be used by themselves or in conjunction with standard treatments administered by the treating physician. Any standard treatment agent may be used in combination with the compounds disclosed herein.

[0182] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered to the subject in combination with a second therapy. In some embodiments, the second therapy targets HS. In some embodiments, the second therapy is administered before, after, or simultaneously with administration of the pharmaceutical composition. In some embodiments, the second therapy comprises one or more of the following: antibiotics, steroids, biologics, hormones, retinoids, anti-inflammatory drugs, surgical intervention, or any combination thereof. In some embodiments, the antibiotic is applied topically. In some embodiments, the antibiotic is doxycycline, minocycline, clindamycin, rifampin, or any combination thereof. In some embodiments, the steroid is triamcinolone. In some embodiments, the biologic is an anti-TNF-alpha antibody. In some embodiments, the anti-TNF-alpha antibody is adalimumab, infliximab, or a combination thereof.

[0183] In some embodiments, the biologic agent is an IL-17 inhibitor, an IL-12 inhibitor, an IL-23 inhibitor, a JAK-1 inhibitor, or any combination thereof. In some embodiments, the hormone is an estrogen. In some embodiments, the anti-inflammatory agent is aspirin, ibuprofen, naproxen, celecoxib, indomethacin, ketorolac, diclofenac, ketoprofen, or any combination thereof.

[0184] As used herein, the term "administered in combination" is understood to mean that two (or more) different therapies are delivered to a subject while the subject is suffering from a disorder (such as HS), such that the effects of the therapies on the patient overlap at some point. In certain embodiments, there is an overlap in terms of administration, since the delivery of one treatment is still occurring when the delivery of the second begins. This may be referred to herein as "simultaneous" or "concurrent" delivery. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins, which may be referred to as "sequential" or "serial" delivery.

[0185] In some embodiments, the combination of the treatments makes the treatment more effective. For example, the second treatment is more effective. For example, the second treatment requires less treatment to achieve the same effect than when the second treatment is administered without the first treatment, or the second treatment reduces symptoms to a greater extent, or the first treatment achieves a similar condition. The effect of the two treatments may be partially additive, entirely additive, or greater than additive (synergistic).

[0186] As used herein, the compositions include an effective amount of any one or more of the compounds disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0187] The compounds of formula (I), or pharma- ceutically acceptable salts thereof, may be used on their own, but are generally administered in the form of a pharmaceutical composition in which the compound / salt of formula (I) (the active pharmaceutical ingredient (API)) is in a composition comprising a pharma- ceutically acceptable adjuvant, diluent, and / or carrier. In one embodiment, the pharmaceutical composition is one of the pharmaceutical compositions described in International Application Publication No. WO 2019 / 166626, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0188] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals-The Science of Dosage Form Designs", MEAulton, Churchill Livingstone, 2nd Ed. 2002 (incorporated herein by reference in its entirety for all purposes). Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical textbooks. See, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 20th edition, pub. Lippincott, Williams & Wilkins, 2000, and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.

[0189] Depending on the method of administration, the pharmaceutical composition may contain about 0.05 to about 99% by weight, e.g., about 0.05 to about 80% by weight, or about 0.10 to about 70% by weight, or about 0.10 to about 50% by weight of the API, all weight percentages being based on the total weight of the pharmaceutical composition. Unless otherwise stated herein, the API weight percentages provided herein are relative to the respective free base form of the compound of Formula (I).

[0190] In one embodiment, the pharmaceutical composition is an oral dosage form of a film-coated oral tablet. In another embodiment, the oral dosage form is an immediate release dosage form with rapid dissolution characteristics under in vitro test conditions. In one embodiment, the oral dosage form is administered once a day to reach the daily dosage disclosed herein. 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 oral dosage form is administered twice a day to reach the daily dosage disclosed herein.

[0191] In some embodiments, the compositions of the present disclosure are formulated using pharma- ceutically acceptable salts of the compounds of formula (I). Pharmaceutically acceptable salts include, for example, acid addition salts derived from inorganic acids, such as hydrochloric acid or phosphoric acid, or organic acids, such as acetic acid, oxalic acid, tartaric acid, mandelic acid, etc. In some embodiments, the salts can be derived from inorganic bases (e.g., sodium, potassium, ammonium, calcium, or ferric hydroxide), or organic bases (e.g., isopropylamine, trimethylamine, histidine, procaine), etc.

[0192] The present disclosure provides compositions comprising an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in the methods provided herein. Any of the compounds provided herein may be used in a composition for delivery via one of the methods provided herein.

[0193] In some embodiments, the composition is in a solid form such as a lyophilized powder, liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder suitable for reconstitution. In some embodiments, delivery vehicles such as liposomes, nanocapsules, microparticles, microspheres, lipid particles, vesicles, etc. may be used.

[0194] In some embodiments, the compositions disclosed herein further comprise at least one pharma- ceutically acceptable carrier, excipient, and / or vehicle, such as a solvent, buffer, solution, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents. In some embodiments, the pharma- ceutically acceptable carrier, excipient, and / or vehicle may comprise saline, buffered saline, dextrose, water, glycerol, sterile isotonic aqueous buffer, and combinations thereof. In some embodiments, the pharma- ceutically acceptable carrier, excipient, and / or vehicle comprises phosphate buffered saline, sterile saline, lactose, sucrose, calcium phosphate, dextran, agar, pectin, peanut oil, sesame oil, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, polyol (such as, for example, glycerol, propylene glycol, and liquid polyethylene glycol), or suitable mixtures thereof. In some embodiments, the compositions disclosed herein further contain minor amounts of emulsifying or wetting agents, or pH buffering agents.

[0195] In some embodiments, the compositions disclosed herein further comprise other conventional pharmaceutical ingredients such as preservatives or chemical stabilizers such as chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, parabens, ethyl vanillin, glycerin, phenol, parachlorophenol, or albumin. In some embodiments, the compositions disclosed herein may further comprise antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, or thimerosal, isotonic agents such as sugars or sodium chloride, and / or absorption delaying agents such as aluminum monostearate and gelatin.

[0196] In some embodiments, the amount of the compound of formula (I) present in the pharmaceutical composition depends on the mode of administration. In some embodiments, the pharmaceutical composition comprises about 0.05% by weight to about 99% by weight (percent by weight), for example, about 0.5% by weight, about 1% by weight, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, about 90% by weight, about 95% by weight, about 98% by weight, or about 99% by weight (including all values ​​and subranges therebetween). In some embodiments, the pharmaceutical compositions contain from about 0.05% to about 80% by weight, or from about 0.10% to about 70% by weight, or from about 0.10% to about 50% by weight of the active ingredient (a compound of formula (I)), all weight percentages being based on the total composition.

[0197] In some embodiments, the adjuvant, diluent or carrier present in the pharmaceutical composition is selected based on the mode of administration.For example, for oral administration, the compound of the present disclosure may be mixed with an adjuvant, diluent or carrier, such as lactose, saccharose, sorbitol, mannitol; starch, such as potato starch, corn starch or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; disintegrants, such as cellulose derivatives, and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets.When coated tablets are required, the cores prepared as described above may be coated with a suitable polymer that is dissolved or dispersed in water or easily volatile organic solvents.Alternatively, the tablets may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talcum, and titanium dioxide.

[0198] For the preparation of soft gelatin capsules, the compound of the present disclosure may be mixed with, for example, vegetable oil or polyethylene glycol.Hard gelatin capsules may contain granules of the compound using pharmaceutical excipients such as the excipients mentioned above for tablets.Also, liquid or semi-solid formulations of the compound of the present disclosure may be filled into hard gelatin capsules.

[0199] In some embodiments, the form of the pharmaceutical composition depends on the mode of administration.For example, 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 that has rapid dissolution characteristics under in vitro test conditions.

[0200] 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.

[0201] In one embodiment, the composition is an oral thin film or oral disintegrating film (ODF). When placed on the tongue, such a formulation hydrates through interaction with sputum and releases the active compound from the dosage form. In one embodiment, the ODF contains a film-forming polymer such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), pullulan, carboxymethylcellulose (CMC), pectin, starch, polyvinyl acetate (PVA), or sodium alginate.

[0202] Liquid preparations for oral administration may be in the form of syrups, solutions or suspensions. Solutions may contain, for example, the compound of the present disclosure, the balance being a mixture of sugar, ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, saccharin, and / or carboxymethylcellulose as a thickening agent. In addition, other excipients known to those skilled in the art may be used when preparing preparations for oral use.

[0203] The compounds of the present disclosure can be prepared in a variety of ways in a known manner.For example, in one embodiment, the compound of formula (I) is prepared according to the method described in U.S. Patent No. 9,522,894 (incorporated herein by reference in its entirety for all purposes).The pharmaceutical composition used in the method provided herein is prepared in one embodiment by one of the methods disclosed in International Application Publication No. 2019 / 166626, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0204] As provided throughout, in accordance with 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 stable at different temperatures and humidities, or may be stable at room temperature or in the presence of H 2 The salts may be advantageous due to one or more of their chemical or physical properties, such as desirable solubility in water, oil, or other solvents. In some cases, salts may be used to aid in the isolation or purification of the compounds of formula (I).

[0205] 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.

[0206] Depending on the number of charged functional groups and the valency of the cation or anion, there may be more than one cation or anion. For a review of suitable salts and pharma- ceutically acceptable salts suitable for use herein, see Berge et al. (1977). J.Pharm.Sci., 66, 1-19, or "Handbook of Pharmaceutical Salts: Properties, selection and use", P.H. Stahl, P.G. Vermuth, IUPAC, Wiley-VCH, 2002 (incorporated herein by reference in its entirety for all purposes). Compounds of formula (I) may form mixtures of their salts and co-crystal forms. It is also understood that the methods provided herein may use such salt / co-crystal mixtures of compounds of formula (I).

[0207] The salts and co-crystals may 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 resulting from hydrogen bonding).

[0208] In another embodiment of the method, the pharmaceutical composition administered to the patient comprises: (a) about 1 to about 30% by weight of a compound of formula (I) or a pharma- ceutically acceptable salt thereof; (b) about 45 to about 85 weight percent of a pharmaceutical diluent; and (c) about 6 to about 30 weight percent of a compression aid; and (d) about 1 to about 15% by weight of a pharmaceutical disintegrant; (e) about 0.00 to about 2% by weight of a pharmaceutical flow enhancer; and (f) about 1 to about 10% by weight of a pharmaceutical lubricant, The components add up to 100% by weight.

[0209] In a further embodiment, the compound of formula (I) is brensocatib. In one embodiment, brensocatib is polymorphic form A as disclosed in U.S. Pat. No. 9,522,894. In another embodiment, brensocatib is characterized by one of the X-ray powder diffraction patterns described in WO 2019 / 166626.

[0210] In some embodiments of the method, composition (A) comprises a compound of formula (I), e.g., brensocatib, in an amount of about 1 to about 25 weight percent, about 1 to about 20 weight percent, about 1 to about 15 weight percent, about 1 to about 10 weight percent, about 1 to about 5 weight percent, or about 1 to about 3 weight percent of the total weight of the composition.

[0211] In some embodiments of the method, composition (A) comprises a compound of formula (I), e.g., brensocatib, in an amount of about 1.5 to about 30 weight percent, about 1.5 to about 25 weight percent, about 1.5 to about 20 weight percent, about 1.5 to about 15 weight percent, about 1.5 to about 10 weight percent, or about 1.5 to about 5 weight percent of the total weight of the composition.

[0212] In some embodiments of the method, composition (A) comprises a compound of formula (I), e.g., brensocatib, in an amount of about 3 to about 30%, about 3 to about 25%, about 3 to about 20%, about 3 to about 15%, about 3 to about 10%, or about 3 to about 5% by weight of the total weight of the composition. In further embodiments, the compound of formula (I) is present in an amount of about 3 to about 10% by weight of the total weight of the composition. In further embodiments, the compound of formula (I) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0213] In some embodiments of the method, composition (A) comprises a compound of formula (I), e.g., brensocatib, in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt% of the total weight of the composition.

[0214] In some embodiments of the method, composition (A) comprises one or more pharmaceutical diluents selected from the group consisting of microcrystalline cellulose, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose, xylitol, and combinations of the foregoing. In one embodiment, composition (A) comprises two or more pharmaceutical diluents. In another embodiment, composition (A) comprises one pharmaceutical diluent. In a further embodiment, the pharmaceutical diluent is microcrystalline cellulose. Microcrystalline cellulose is a binder / diluent in oral tablet and capsule formulations and can be used in dry granulation, wet granulation, and direct compression processes.

[0215] In some embodiments of the method, composition (A) comprises one or more pharmaceutical diluents in an amount of about 45 to about 80%, about 45 to about 75%, about 45 to about 70%, about 45 to about 65%, about 45 to about 60%, or about 45 to about 55% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still further embodiments, the compound of formula (I) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0216] In some embodiments of the method, composition (A) comprises one or more pharmaceutical diluents in an amount of about 50 to about 85 weight percent, about 50 to about 75 weight percent, about 55 to about 85 weight percent, about 55 to about 70 weight percent, about 60 to about 85 weight percent, about 65 to about 85 weight percent, about 70 to about 85 weight percent, or about 75 to about 85 weight percent of the total weight of the composition. In further embodiments, the one or more pharmaceutical diluents are present in about 55 to about 70 weight percent of the total weight of the composition. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still further embodiments, the compound of formula (I) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0217] In some embodiments of the method, composition (A) comprises one or more pharmaceutical diluents in an amount of about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85% by weight of the total weight of the composition.

[0218] In some embodiments of the method, the one or more pharmaceutical diluents in composition (A) are microcrystalline cellulose. In other embodiments, the one or more pharmaceutical diluents include calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose, and xylitol.

[0219] In the present disclosure, the terms "disintegrant" and "disintegrants" are intended to be interpreted in the context of pharmaceutical formulation science. Thus, the disintegrant in composition (A) may be, for example, alginic acid, calcium alginate, calcium carboxymethylcellulose, chitosan, croscarmellose sodium, crospovidone, glycine, guar gum, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose, sodium starch glycolate, starch, or a combination thereof.

[0220] In some embodiments of the method, one or more disintegrants in composition (A) is sodium starch glycolate. In one embodiment, the amount of disintegrant present in composition (A) is 2% to 8% of the total weight of the composition. In further embodiments, the amount of disintegrant is about 2%, about 2.5%, about 3%, about 3.5%, about 4%, or about 4.5% by weight of the total weight of the composition. The physical properties of sodium starch glycolate, and therefore its effectiveness as a disintegrant, are affected by the degree of crosslinking, the degree of carboxymethylation, and purity.

[0221] In some embodiments of the method, the one or more pharmaceutical disintegrants in composition (A) include croscarmellose sodium.

[0222] In some embodiments of the method, composition (A) comprises one or more pharmaceutical disintegrants in an amount of about 2 to about 14%, about 2 to about 13%, about 2 to about 12%, about 2 to about 11%, about 2 to about 10%, about 2 to about 9%, about 2 to about 8%, about 2 to about 7%, about 2 to about 6%, about 2 to about 5%, about 3.5 to about 4.5% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical disintegrants are present in an amount of about 3.5 to about 4.5% by weight of the total weight of the pharmaceutical composition. In further embodiments, the one or more pharmaceutical disintegrants are sodium starch glycolate. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still further embodiments, the compound of formula (I) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0223] In this disclosure, the terms "glidant" and "gliding agent" are intended to be interpreted in the context of pharmaceutical formulation science. Thus, the glidant in composition (A) may be, for example, silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate, and talc.

[0224] Thus, in some embodiments of the method, one or more pharmaceutical glidants in composition (A) are selected from silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate, talc, or combinations of the foregoing. In one embodiment, the glidant is silicon dioxide. Its small particle size and large specific surface area provide desirable flow characteristics that are utilized to improve the flow properties of dry powders in many processes, such as tableting and capsule filling. Typical silicon dioxide concentrations for use herein range from about 0.05 to about 1.0% by weight. Porous silica gel particles may also be used as glidants, which may be advantageous for some formulations, with typical concentrations of 0.25 to 1%.

[0225] In some embodiments of the method, composition (A) comprises one or more pharmaceutical glidants in an amount of about 0.00 to about 1.75 wt%, about 0.00 to about 1.50 wt%, about 0.00 to about 1.25 wt%, about 0.00 to about 1.00 wt%, about 0.00 to about 0.75 wt%, about 0.00 to about 0.50 wt%, about 0.00 to about 0.25 wt%, or about 0.00 to about 0.20 wt% of the total weight of the composition. In further embodiments, the one or more pharmaceutical glidants comprise silicon dioxide. In further embodiments, the one or more pharmaceutical disintegrants are sodium starch glycolate. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still further embodiments, the compound of formula (I) in composition (A) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0226] In some embodiments of the method, composition (A) comprises one or more pharmaceutical glidants in an amount of about 0.05 to about 2%, about 0.05 to about 1.75%, about 0.05 to about 1.50%, about 0.05 to about 1.25%, about 0.05 to about 1.00%, about 0.05 to about 0.75%, about 0.05 to about 0.50%, about 0.05 to about 0.25%, or about 0.05 to about 0.20% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical glidants are present in an amount of about 0.05 to about 0.25% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical glidants comprise silicon dioxide. In further embodiments, the one or more pharmaceutical disintegrants are sodium starch glycolate. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still a further embodiment, the compound of formula (I) in composition (A) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0227] In some embodiments of the method, composition (A) comprises one or more pharmaceutical glidants in an amount of about 0.05 to about 2%, about 0.10 to about 2%, about 0.2 to about 2%, about 0.3 to about 2%, or about 0.40 to about 2% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical glidants comprise silicon dioxide. In further embodiments, the one or more pharmaceutical disintegrants are sodium starch glycolate. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still further embodiments, the compound of formula (I) in composition (A) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0228] In the present disclosure, the terms "lubricant" and "lubricants" as used herein are intended to be interpreted in the context of pharmaceutical formulation science. Thus, the lubricant may be, for example, calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenic acid esters of glycerin (e.g., a mixture of glyceryl bihenehate, tribehenin, and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin, and zinc stearate.

[0229] Thus, in some embodiments of the method, the one or more pharmaceutical lubricants in composition (A) are selected from the group consisting of calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenic acid esters of glycerin (e.g., a mixture of glyceryl bihenehate, tribehenin, and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin, and zinc stearate. In other embodiments, the one or more pharmaceutical lubricants are selected from the group consisting of calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenic acid esters of glycerin (e.g., a mixture of glyceryl bihenehate, tribehenin, and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, stearic acid, talc, tribehenin, and zinc stearate.

[0230] In some embodiments of the method, composition (A) comprises one or more pharmaceutical lubricants, and the lubricant is not sodium stearyl fumarate. In further embodiments, the compound of formula (I) in composition (A) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0231] In one embodiment of the method, composition (A) includes glycerol behenate as a lubricant.

[0232] In some embodiments of the method, the one or more pharmaceutical lubricants in composition (A) include glyceryl behenate, magnesium stearate, stearic acid, or a combination thereof.

[0233] In one embodiment of the method, the lubricant in composition (A) is glyceryl behenate, magnesium stearate, or a combination thereof.

[0234] In one embodiment of the method, the one or more pharmaceutical lubricants in composition (A) include sodium stearyl fumarate and / or one or more behenic acid esters of glycerin.

[0235] In some embodiments of the method, composition (A) comprises one or more pharmaceutical lubricants in an amount of about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 2% to about 10%, about 2.5% to about 10%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4.5%, or about 2.5% to about 4.5% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical lubricants in composition (A) are present in an amount of about 2.5 to about 4.5% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical lubricants in composition (A) are glycerol behenate. In further embodiments, the one or more pharmaceutical glidants in composition (A) comprise silicon dioxide. In a further embodiment, the one or more pharmaceutical disintegrants in composition (A) are sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents in composition (A) comprise microcrystalline cellulose. In yet a further embodiment, the compound of formula (I) in composition (A) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0236] In one embodiment of the method, the one or more pharmaceutical lubricants in composition (A) consist of sodium stearyl fumarate and / or one or more behenic acid esters of glycerin, or mixtures thereof.

[0237] In another embodiment of the method, the one or more pharmaceutical lubricants in composition (A) consist of sodium stearyl fumarate, glyceryl dibehenate, glyceryl behenate, tribehenin, or any mixture thereof.

[0238] In one embodiment of the method, the one or more pharmaceutical lubricants in composition (A) comprise sodium stearyl fumarate. In another embodiment, the one or more pharmaceutical lubricants in composition (A) consist of sodium stearyl fumarate.

[0239] In one embodiment of the method, the one or more pharmaceutical lubricants in composition (A) include one or more behenic acid esters of glycerin (i.e., one or more of glyceryl dibehenate, tribehenin, and glyceryl behenate).

[0240] In one embodiment of the method, the compression aid in composition (A) is dicalcium phosphate dihydrate (also known as dibasic calcium phosphate dihydrate) (DCPD). DCPD is used in tablet formulations as an excipient and as a source of calcium and phosphorus in dietary supplements.

[0241] In one embodiment of the method, composition (A) comprises a compression aid, such as DCPD, in an amount of about 10 to about 30%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, or about 24% by weight of the total weight of the composition, hi a further embodiment, the compression aid is present at about 20% by weight of the total weight of the composition.

[0242] In one embodiment of the method, composition (A) comprises a compression aid, such as DCPD, in an amount of about 10 to about 25%, about 10 to about 20%, about 10 to about 15%, about 15 to about 25%, or about 20 to about 25%, or about 18 to about 22% by weight of the total weight of the composition. In a further embodiment, the compression aid is present in about 18 to about 22% by weight of the total weight of the composition. In a further embodiment, the compression aid is DCPD. In a further embodiment, one or more pharmaceutical lubricants in composition (A) are glycerol behenate. In a further embodiment, one or more pharmaceutical glidants in composition (A) comprise silicon dioxide. In a further embodiment, one or more pharmaceutical disintegrants in composition (A) are sodium starch glycolate. In a further embodiment, one or more pharmaceutical diluents in composition (A) comprise microcrystalline cellulose. In still a further embodiment, the compound of formula (I) in the exemplary composition is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0243] In one embodiment of the method, the pharmaceutical composition administered to the patient comprises: (a) about 1 to about 30% by weight of a compound of formula (I) or a pharma- ceutically acceptable salt thereof; (b) about 55 to about 75 weight percent of a pharmaceutical diluent; (c) about 15 to about 25 weight percent of a compression aid; and (d) about 3 to about 5% by weight of a pharmaceutical disintegrant; (e) about 0.00 to about 1% by weight of a pharmaceutical flow enhancer; and (f) about 2 to about 6% by weight of a pharmaceutical lubricant, The components add up to 100% by weight.

[0244] In some embodiments of the method in which composition (B) is administered to a patient, the identity of the pharmaceutical diluent, compression aid, pharmaceutical disintegrant, pharmaceutical flow enhancer, and pharmaceutical lubricant in the composition may be one of those described above for composition (A). In other embodiments, the amount of the pharmaceutical diluent, compression aid, pharmaceutical disintegrant, pharmaceutical flow enhancer, and pharmaceutical lubricant in composition (B) may also be one of those described above for composition (A), so long as the amount falls within the corresponding broader ranges recited above for composition (B).

[0245] The pharmaceutical compositions disclosed herein, including compositions (A) and (B), may be in a solid dosage form suitable for oral administration to humans. For example, the pharmaceutical composition is a pharmaceutical tablet. The pharmaceutical tablet may be prepared using methods known to those skilled in the art, including, for example, the dry blend / direct compression process described in WO 2019 / 166626. In some embodiments, the pharmaceutical tablet comprises a tablet core, the tablet core comprises a pharmaceutical composition disclosed herein, and the tablet core has a coating. In some embodiments, the coating is a film coating. The film coating may be applied using conventional methods known to those skilled in the art. A functional coating may be used to provide protection against, for example, moisture ingress or degradation by light. Additionally, a functional coating may be used to modify or control the release of a compound of formula (I), such as brensocatib, from the composition. The coating may comprise, for example, about 0.2 to about 10% by weight of the total weight of the pharmaceutical composition, for example, about 0.2 to about 4% by weight, about 0.2 to about 3% by weight, about 1 to about 6% by weight, or about 2 to about 5% by weight of the total weight of the pharmaceutical composition. EXAMPLES

[0246] The present disclosure will be further illustrated by reference to the following examples, however, it should be noted that the examples, like the above-mentioned embodiments, are illustrative and should not be construed as limiting the scope of the present invention in any way.

[0247] Example 1 - A Phase 2b Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of the Efficacy and Safety of Brensocatinib in Adults with Moderate-to-Severe Hidradenitis Suppurativa Brensocatib, a compound of formula (I), is an orally reversible DPP1 inhibitor. DPP1 activates neutrophil serine proteases (NSPs), which are pro-inflammatory and generally destructive to surrounding tissues when released from neutrophils. Since neutrophils are the major leukocyte infiltrates in HS lesions, and neutrophil numbers and neutrophil extracellular traps (NETs) have been significantly associated with the severity of HS disease, inhibition of DPP1 activity by brensocatib in patients with moderate to severe HS is expected to lead to a reduction in the formation of active NSPs, thereby preventing the propagation of the inflammatory response and possibly the presence of NETs, ​​which are associated with local and systemic immune dysregulation. As a result, brensocatib treatment is expected to result in a clinically meaningful reduction in the number and severity of HS lesions (abscesses, tunnels (both draining and non-draining), and nodules (both inflammatory and non-inflammatory).

[0248] This example describes a Phase 2b randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of brensocatinib in adults with moderate to severe hidradenitis suppurativa. Brensocatinib is the international nonproprietary name for (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] . A total of approximately 204 eligible participants (≥18 to ≥75 years) will be randomized in a 1:1:1 ratio into three treatment arms, with approximately 68 participants per treatment arm, to receive once-daily oral doses of 10 mg brensocatib, 40 mg brensocatib, and matching placebo, respectively, for 16 weeks (Period 1), followed by a 36-week open-label extension period (Period 2), during which all participants will receive once-daily oral doses of 40 mg brensocatib. The treatment regimen will allow for background therapy for HS (e.g., topical over-the-counter antiseptic / antibacterial treatment, pre-study analgesics). Efficacy parameters included hidradenitis suppurativa clinical response (HiSCR), HiSCR75, hidradenitis suppurativa-investigator global assessment (HS-IGA), total AN count, draining tunnel count, HS flare, hidradenitis suppurativa severity score 4 (IHS4), cutaneous quality of life index (DLQI), and numeric rating scale for cutaneous pain (NRS). Safety parameters included adverse events (AEs), clinical laboratory results, vital sign measurements, 12-lead ECG measurements, and physical examination results. Adverse events of special interest (AESIs) included hyperkeratosis, periodontitis / gingivitis, and infections. Pharmacokinetic (PK) parameters included plasma concentrations of brensocatib.

[0249] Brensocatib oral tablets will be used in the study. The tablets are round, biconvex, brown, film-coated, and considered an immediate release dosage form. The tablets contain the equivalent of 10 mg or 40 mg of brensocatib drug substance and are identical in size and appearance. Each film-coated tablet contains the active ingredient of the brensocatib drug substance and the official ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, sodium starch glycolate, silicon dioxide, and glyceryl behenate. The corresponding placebo without active ingredient is a film-coated tablet identical in shape, size, and color to the brensocatib film-coated tablet.

[0250] Eligibility Criteria Table 1 below provides important inclusion criteria for the studies. [Table 1]

[0251] Test Design Figure 1 provides a schematic of the study design. In this Phase 2b randomized, double-blind, parallel-group, placebo-controlled, dose-ranging, multicenter study, approximately 204 adult male and female participants (≥18 to ≤75 years) with moderate-to-severe HS will be administered brensocatib once daily (QD) for up to 52 weeks. The study includes four study periods with efficacy and safety evaluations, as well as blood sample collection for PK / PD analyses conducted throughout the study.

[0252] Screening Period - Participant eligibility will be determined during a screening period of at least 7 weeks and up to 28 days (4 weeks).

[0253] Treatment Period 1 - Eligible participants will be randomized using a web-based automated response system (IWRS) to receive oral double-blind brensocatib 10 mg, brensocatib 40 mg, or placebo film-coated tablets QD for 16 weeks in a 1:1:1 ratio, approximately 68 participants per treatment group. Randomization will be stratified based on total IHS4 score (4-10 moderate vs. >11 severe), prior anti-tumor necrosis factor alpha (TNFα) treatment (yes vs. no), and participation in the pharmacodynamics (PD) histology substudy (yes vs. no). The PD histology substudy will include up to 30 evaluable participants (up to 10 per treatment group) at selected study sites, and tissue samples will be collected from active HS lesions at designated study visits in Period 1 and Period 2. Evaluable participants are considered participants who have received at least one dose of study treatment and have at least one interpretable pre-dose and one pre-dose tissue sample. The investigators (including clinicians providing treatment to participants), sponsor, and participants / healthcare providers will be blinded to the study treatment in Period 1.

[0254] Treatment Period 2 – Participants who complete study treatment in Period 1 will cross over directly into Period 2, during which all participants will receive open-label brensocatib 40 mg film-coated tablets orally QD for 36 weeks.

[0255] Follow-up Period - Participants will be followed for 4 weeks after the last dose of study treatment.

[0256] Throughout the study, participants will be permitted to use topical over-the-counter antiseptic / antimicrobial treatments (including HS wound dressings), the same stable regimen of pre-study analgesics for HS (i.e., ibuprofen, acetaminophen / paracetamol, and tramadol; opioid analgesics except tramadol will be prohibited), and the same stable regimen of pre-study oral antibiotics for HS (i.e., doxycycline and minocycline).

[0257] The total duration of study treatment will be approximately 52 weeks. Period 1 (double-blind treatment): 16 weeks Period 2 (open-label extension): 36 weeks

[0258] Participants randomized to brensocatinib in Period 1 will be exposed to brensocatinib for approximately 52 weeks (16 weeks in Period 1 and 36 weeks in Period 2). Participants randomized to placebo in Period 1 will be exposed to brensocatinib in Period 2 for approximately 36 weeks.

[0259] Study treatments are presented in Table 2 below. In both study periods, brensocatib or placebo film-coated tablets will be administered orally QD at approximately the same time each morning with water and with or without food. On study visit days, study treatment will be administered at the study site by study personnel. At the baseline visit (Day 1), study treatment will be administered after an overnight fast of at least 8 hours. [Table 2]

[0260] Result evaluation The study objectives and variables (evaluation items) are shown in Table 3. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0261] Efficacy evaluation 1.HS Lesion Count The HS lesions associated with each efficacy measure are presented in Table 4A. The number of abscesses, tunnels (both draining and non-draining), and nodules (both inflammatory and non-inflammatory) are recorded by anatomical region and used to programmatically derive the HiSCR, mHiSCR, HS-IGA, total AN count, HS flare, and IHS4, as defined in Table 5B. The anatomical regions include both the upper and lower body. The upper body includes the head, neck (anterior / posterior), chest / breast, axilla, abdomen, flank, and back. The lower body includes the abdomen, back, groin, genital / perineum, buttocks (buttocks, perianal, cleft), lower back, and thighs. The draining tunnel count is the sum of the draining tunnels recorded in the HS lesion count assessment. The Hurley stage is based on the assessment of these same lesions, but is programmatically derived (see Section 2). [Table 4] [Table 5]

[0262] 1.1. Hidradenitis Suppurativa Clinical Response (HiSCR) and Modified HiSCR HiSCR is a validated scale for assessing treatment response in the research setting, capturing the more acute phase of HS activity with inflammatory changes. HiSCR is a clinical endpoint for measuring response to treatment in patients with HS, defined by the status of three lesion types: abscesses, inflammatory nodules, and draining tunnels (Alikhan et al., J Am Acad Dermatol. 2019;81(1):76-90; Kimball et al., Br J Dermatol. 2014;171(6):1434-42; Kimball et al., J Eur Acad Dermatol Venereol. 2016;30(6):989-94). HiSCR is programmatically derived from HS lesion count assessment, and response to treatment based on HiSCR, HiSCR75, and HiSCR90 are relative to day 1 (baseline).

[0263] To assess the effect of treatment on drainage tunnel reduction, the HiSCR is modified to include a ≧50% reduction in the total number of drainage tunnels resulting in an mHiSCR score. Thus, a response to treatment based on the mHiSCR from day 1 (baseline) is defined as a ≧50% reduction in the number of inflammatory nodules, abscesses, and drainage tunnels, and a ≧50% reduction from day 1 (baseline) in the total number of drainage tunnels. The mHiSCR is programmatically derived from the HS lesion count assessment.

[0264] 1.2. Clinical Response of Hidradenitis Suppurativa - Investigator Global Assessment (HS-IGA) The HS-IGA is a clinical endpoint for measuring disease activity and response to treatment in patients with HS, which is based on the maximum count of abscesses, fistulas (draining and non-draining), and nodules (inflammatory and non-inflammatory), measured separately for the upper and lower body regions (Garg et al., Br J Dermatol. 2022;187(2):203-210). The HS-IGA is scored as a number between 0 and 5 based on the maximum lesion count for either the upper or lower body region, whichever is greater (Table 5). Response to treatment is defined as a 2-point reduction (improvement) in the HS-IGA score relative to baseline. Both regions are scored at each visit, and the maximum count from either region is used to determine the HS-IGA score, so the regions used for scoring may vary from one visit to the next. The HS-IGA score is programmatically derived from the HS lesion count assessment. [Table 6]

[0265] 1.3. Total abscess and inflammatory nodule counts and draining tunnel counts Total AN count is defined by the total number of abscesses and inflammatory nodules. Total AN count is programmatically derived from the HS lesion count assessment.

[0266] 1.4.HS Flare Evaluation HS flare is defined as a ≥25% increase in total AN counts with an absolute increase in total AN counts of ≥2 compared to baseline, programmatically derived from HS lesion count assessments. Although there is no consensus on an objective, measurable definition of HS flare, this measure has been developed to approximate a flare to a real-world clinical presentation and is used in the pivotal phase 3 PIONEER study of adalimumab in HS (van der Zee et al., J Eur Acad Dermatol Venereol. 2020;34(5):1050-56).

[0267] 1.5. International Hidradenitis Suppurativa Severity Score 4 (IHS4) The IHS4 is a clinical scoring system for dynamically assessing HS severity for use in both real-life and clinical research settings (Zouboulis et al., Br J Dermatol. 2017;177(5):1401-09). The IHS4 includes lesions that are palpable with inflammatory signs (i.e., abscesses, nodules, and draining tunnels) and is complementary to the HiSCR.

[0268] The IHS4 score (points) is programmatically derived from the HS lesion count assessment and is calculated as follows: (number of inflammatory nodules x 1) + (number of abscesses x 2) + (number of draining tunnels x 4). Mild HS: ≦3 points Moderate HS: 4~10 points Severe HS: ≥ 11 points

[0269] 2. Hurley Stage The Hurley stage is a severity classification of HS that was developed in 1989 and is widely used to determine HS severity (Hurley, Dermatologic surgery. New York: Marcel Dekker. 1989;729:39; Ovadja et al., Br J Dermatol. 2019;181(2):344-49). Hurley stage is determined for each affected anatomical region, as defined above. If there is more than one stage in a region, the worst stage in each region is recorded.

[0270] 3. Patient Reported Outcome Scale The patient-reported outcome measures selected for this study (i.e., DLQI, NRS for Cutaneous Pain, HS-related PtGA, and HiSQOL) are scales commonly used in HS clinical trials, and the DLQI, NRS for Cutaneous Pain, and HS-related PtGA are scales validated for use in dermatology, atopic dermatitis, and HS, respectively (Basra et al., Br J Dermatol. 2008;159(5):997-1035; Finlay et al., Clin Exp Dermatol. 1994;19(3):210-6; Kirby et al., Br J Dermatol. 2021;184(4):681-87; Newton et al., J Patient Rep Outcomes. 2019;3(1):42). In this study, the DLQI, NRS for Cutaneous Pain, HS-related PtGA, and HiSQOL patient-reported outcome measures will be administered at designated study visits using electronic devices.

[0271] 3.1. Skin Life Quality Index (DLQI) The DLQI is a self-administered questionnaire designed to measure the health-related quality of life of adults (e.g., >16 years old) affected by skin diseases (Finlay et al., Clin Exp Dermatol. 1994;19(3):210-6). It consists of 10 questions regarding the assessor's perception of the impact of the skin disease on various aspects of the assessor's quality of life during the past week. Each question has four alternative answers: not at all, a little, a lot, or a lot, with corresponding scores of 0, 1, 2, and 3, respectively (irrelevant answers are scored as 0). The DLQI is the sum of scores ranging from 0 to 30. The higher the score, the greater the impairment of quality of life: 0-1 = no impact at all, 2-5 = small impact, 6-10 = moderate impact, 11-20 = very large impact, and 21-30 = extremely large impact.

[0272] 3.2. Numerical Rating Scale (NRS) for Cutaneous Pain The NRS for Cutaneous Pain is a single-item self-reported severity of worst skin pain in the past 24 hours on an 11-point scale ranging from 0 ("no pain") to 10 ("the worst pain imaginable") (Newton et al., J Patient Rep Outcomes. 2019;3(1):42). Participants complete the NRS on an electronic device at the end of each day.

[0273] 3.3. HS-related Patient Comprehensive Assessment (HS-related PtGA) The HS-related PtGA is a single-item questionnaire assessing the extent to which HS has affected participants' quality of life over the past 7 days, with five response levels: not at all, slightly, moderately, very much, and extremely, with corresponding scores of 0, 1, 2, 3, and 4, respectively (Kirby et al., Br J Dermatol. 2021;184(4):681-87).

[0274] 3.4. Hidradenitis Suppurativa Quality of Life (HiSQOL) The HiSQOL is a valid and reliable measure of the impact of HS on health-related quality of life for use in clinical trials and has been shown to be highly correlated with the DLQI (Kirby et al., Br J Dermatol. 2020;183(2):340-48., Kursawe Larsen et al., J Eur Acad Dermatol Venereol. 2021;35(7):1577-81). Impacts measured include HS-related symptoms (pain, pruritus, drainage, fatigue, odor), limitations in performance of activities (daily activities, physical, sleep), and psychosocial effects (emotional, cognitive, desire). The HiSQOL is a 17-item instrument with a 7-day recall period. The 5-point item response scale of extremely, very much, moderately, slightly, or not at all corresponds to point values ​​of 4, 3, 2, 1, and 0, respectively. Some items had the additional options “I am unable to do that due to my HS” and / or “I don't usually do this and HS has not affected it,” with assigned point values ​​of 4 and 0, respectively.

[0275] Pharmacokinetic (PK) evaluation Approximately 6 mL blood samples will be collected for measurement of brensocatib plasma concentrations and PK analysis. PK sample collection time points include: on day 1, pre-dose, 1 hour (±5 minutes), 2 hours (±10 minutes), and 6 hours (±2 hours); 1 hour post-dose at weeks 2, 6, and 12 during period 1 and at weeks 24, 32, and 52 during period 2; Pre-dose at weeks 4, 8, and 16 during Period 1.

[0276] Individual PK parameters (e.g., maximum plasma concentration (C max ), time to maximum observed plasma concentration (T max ), and the area under the concentration-time curve from 0 to 24 hours after administration (AUC 24 ), elimination half-life (t 1 / 2 ), apparent total clearance of drug from plasma after extravascular administration (CL / F), and apparent volume of distribution after the terminal phase (Vd / F)) are assessed using population PK analysis. PK / PD relationships are also determined.

[0277] Pharmacological (PD) evaluation 1.PD Tissue Sub-Test The PD tissue substudy will be conducted at selected sites to characterize the effect of brensocatib on HS lesion pro-inflammatory markers and NETs. The substudy will include up to 30 evaluable participants (up to 10 per treatment group) at selected study sites from whom tissue samples will be collected from active HS lesions via punch biopsies on Day 1, Week 16 of Period 1, and Week 52 (end of treatment) of Period 2. Punch biopsies will be taken as close as possible to the previous biopsy site. Evaluable participants will be considered those who have received at least one dose of study treatment and have at least one interpretable pre-dose and one pre-dose tissue sample.

[0278] 2. Biomarkers Pharmacological blood samples are collected to evaluate the effect of brensocatinib compared to placebo and to evaluate the long-term effect of brensocatinib on NSP activity in blood. Biomarkers include NE, CatG, and PR3. Samples are collected at the following time points: Day 1; Weeks 2, 4, 6, 8, 12, and 16 during Period 1; Weeks 24, 32, and 52 during Period 2 (end of treatment), and Week 56 of the follow-up period (end of study).

[0279] Data analysis Primary efficacy endpoint The primary efficacy endpoint, responder status for achieving HiSCR at week 16, will be analyzed using logistic regression in the full analysis set (i.e., including all randomized participants). The model includes treatment arm and randomization stratification factors of total IHS4 score (4-10 moderate vs. >11 severe) and previous anti-TNF-α treatment (yes vs. no). Odds ratios for treatment comparisons (brensocatinib 10 mg vs. placebo, brensocatinib 40 mg vs. placebo, each with two-sided α = 0.05), 95% Wald confidence intervals, and corresponding p-values ​​from Wald chi-square tests are summarized.

[0280] Secondary efficacy endpoints For Period 1, secondary variables assessed as change from baseline at week 16 (i.e., total AN counts, draining tunnel counts, IHS4, and DLQI) or as mean daily change over week 16 (i.e., NRS for skin pain) will be analyzed using analysis of covariance (ANCOVA) models with conditions for treatment, stratification factors of total IHS4 score (4-10 moderate vs. >11 severe), and previous anti-TNF-α treatment (yes vs. no), respectively, and continuous fixed covariates for the corresponding baseline values. Secondary endpoints assessed as responder status at week 16 (i.e., achieving a ≥ 2 point reduction from baseline in HiSCR75, HS-IGA, and remaining free of HS flare) will be analyzed using logistic regression adjusted for treatment group, and randomization stratification factors of total IHS4 score (4-10 moderate vs. >11 severe) and previous anti-TNF-α treatment (yes vs. no), respectively.

[0281] No inferential analyses will be used for Period 2. All analyses will be descriptive. Frequency counts of responders will be determined for binary responder status endpoints at Week 52 (i.e., achieved a ≥ 2 point reduction from baseline in HiSCR, HiSCR75, HS-IGA, and remained free of HS flare). Descriptive statistics (n, mean, standard deviation (SD) , median, minimum, and maximum) will be determined for continuous endpoints assessed as change from baseline at Week 52 (i.e., total AN count, draining tunnel count, IHS4, and DLQI) or as mean daily change over Week 52 (i.e., NRS for skin pain).

[0282] For both Period 1 and Period 2, the baseline for the secondary endpoint change from baseline in mean daily NRS skin pain score over Week 16 or Week 52 is the average of the daily NRS skin pain scores collected over the week prior to randomization. If there are ≧4 measurements collected within 7 days prior to randomization, the baseline will be the average of these measurements, and if <4 measurements are collected, the baseline will be the average of the most recent 4 measurements prior to randomization.

[0283] Safety analysis Safety analyses will assess the frequency and severity of treatment-emergent adverse events (SAEs) and AESIs, changes from baseline in clinical laboratory results, vital signs, and ECGs. All safety analyses will be based on descriptive statistics.

[0284] PK plasma concentration analysis Plasma concentrations of brensocatib will be summarized by treatment group and time point using descriptive statistics. Plasma concentration data versus time will be plotted for individual participants as well as mean profiles on both linear and semi-log scales.

[0285] Population pharmacokinetic analysis Plasma brensocatib concentration data from this study will be used to develop a population PK model describing the PK of brensocatib in the HS population using a nonlinear mixed-effects modeling approach. This analysis will evaluate covariates (e.g., weight, age, sex, creatinine clearance, etc.) on brensocatib PK. The final population PK model will be used to estimate individual PK parameters (e.g., C max , T max , AUC 24 , vanishing t 1 / 2 , CL / F, and Vd / F).

[0286] Pharmacodynamic analysis Blood NSP activity (NE, CatG, PR3) will be used to determine the change from baseline and percent inhibition over time using baseline activity as a reference. The relationship between NSP inhibition and dose level will be investigated along with the relationship between NSP inhibition and clinical effect.

[0287] Pharmacokinetic (PK) / Pharmacodynamic (PD) Analysis Predicted brensocatib exposure from the final population PK model was used to estimate brensocatib exposure (e.g., AUC, C maxThe relationship between PK-PD and clinical efficacy (e.g., HiSCR, HiSCR75, HiSCR90, HS-IGA, etc.), safety (e.g., AESI, etc.), or blood NSP activity (e.g., NE, CatG, PR3) will be evaluated using statistical methods or modeling approaches. Based on the PK-PD relationship, the optimal brensocatinib exposure and dose / regimen for the treatment of patients with HS will be identified via simulation. * * * * * * *

[0288] All articles, publications, and patents cited herein are incorporated by reference as if each individual article, publication, or patent was specifically and individually indicated to be incorporated by reference, and are incorporated by reference herein to disclose and describe the methods and / or materials in connection with which the cited publications are incorporated. However, mention of any references, articles, publications, patents, patent publications, and patent applications cited herein is not, and should not be taken as, an admission or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country throughout the world.

[0289] The embodiments described and discussed herein are intended only to teach those of ordinary skill in the art the best way known to the inventor to make and use the invention. The embodiments of the invention described above can be modified and varied without departing from the invention, as will be understood by those of ordinary skill 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

1. A pharmaceutical composition for treating hidradenitis suppurativa (HS) in a subject in need thereof, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, R １ but, 【Chemistry 2】 and R ２ is hydrogen, F, Cl, Br, OSO ２ C １ - ３ Alkyl, or C １ - ３ is alkyl, R ３ is hydrogen, F, Cl, Br, CN, CF ３ , S.O. ２ C １ - ３ Alkyl, CONH ２ , or SO ２ NR ４ R ５ and R ４ and R ５ together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, or piperidine ring; or X is O, S, or CF ２ and Y is O or S; Q is CH or N; R ６ But C １－３ alkyl, １－３ The alkyl is optionally substituted with one, two, or three F and is substituted with OH, OC １－３ Alkyl, N(C １－３ alkyl) ２ optionally substituted by one substituent selected from the group consisting of cyclopropyl, cyclopropyl, and tetrahydropyran; R ７ is hydrogen, F, Cl, or CH ３ A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the HS is Hurley stage I HS, Hurley stage II HS, or Hurley stage III HS.

3. The pharmaceutical composition described in claim 1, wherein the pharmaceutical composition is administered to the subject over an administration period, and during or after the administration period, the subject's skin abscess and inflammatory skin nodule count (AN count) is reduced compared to the subject's AN count before the administration period.

4. The pharmaceutical composition is administered to the subject over a dosing period, and the subject exhibits one or more of the following therapeutic effects: (i) the subject experiences a reduced incidence of HS flares during or after the administration period compared to the subject's incidence of HS flares before the administration period; (ii) the subject's draining fistula count is reduced or maintained during or after the administration period compared to the subject's draining fistula count before the administration period. (iii) the subject's Patient Global Assessment of Cutaneous Pain (PGA-SP) score is reduced during or after the administration period compared to the subject's PGA-SP score before the administration period; (iv) the subject's International Hidradenitis Suppurativa Severity Scale (IHS4) score is reduced during or after the administration period compared to the subject's IHS4 score before the administration period; (v) the subject's Hidradenitis Suppurativa-Investigator Global Assessment (HS-IGA) score is reduced during or after the administration period compared to the subject's HS-IGA score before the administration period; (vi) the subject's Dermatological Quality of Life Index (DLQI) score during or after the administration period is reduced compared to the subject's DLQI score before the administration period; The pharmaceutical composition of claim 1.

5. The pharmaceutical composition is administered to the subject over a dosing period, such that the subject achieves one or both of the following: (i) a Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) during or after said administration period, wherein the HiSCR50 is at least a 50% reduction in total AN counts, no increase in skin abscess counts, and no increase in draining fistula counts, compared to the subject's total AN counts, skin abscess counts, and draining fistula counts, respectively, before said administration period; (ii) Hidradenitis Suppurativa Clinical Response 75 (HiSCR75) during or after said administration period, wherein the HiSCR75 is at least a 75% reduction in total AN counts, no increase in skin abscess counts, and no increase in draining fistula counts, compared to the subject's total AN counts, skin abscess counts, and draining fistula counts, respectively, before said administration period; The pharmaceutical composition of claim 1.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is an S,S diastereomer. 【Transformation 3】

7. R １ but, 【Chemistry 4】 and X is O, S, or CF ２ and Y is O or S; Q is CH or N; R ６ But C １－３ alkyl, １－３ The alkyl is optionally substituted with one, two, or three F and is substituted with OH, OC １－３ Alkyl, N(C １－３ alkyl) ２ optionally substituted by one substituent selected from the group consisting of cyclopropyl, cyclopropyl, and tetrahydropyran; R ７ is hydrogen, F, Cl, or CH ３ The pharmaceutical composition according to claim 6, wherein

8. R １ but, 【Transformation 5】 and X is O, S, or CF ２ and Y is O or S; R ６ But C １－３ alkyl, １－３ The alkyl is optionally substituted with one, two, or three F and is substituted with OH, OC １－３ Alkyl, N(C １－３ alkyl) ２ optionally substituted by one substituent selected from the group consisting of cyclopropyl, cyclopropyl, and tetrahydropyran; R ７ is hydrogen, F, Cl, or CH ３ The pharmaceutical composition according to claim 6, wherein

9. R １ but, 【Transformation 6】 The pharmaceutical composition according to claim 6, wherein

10. X is O and R ６ But C １－３ alkyl, and R ７ The pharmaceutical composition of claim 9, wherein is hydrogen.

11. R １ but, 【Transformation 7】 and X is O, R ６ But C １－３ alkyl, １－３ alkyl is optionally substituted with 1, 2, or 3 F; R ７ The pharmaceutical composition of claim 6, wherein is hydrogen.

12. 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-1)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (brensocatib). 【Transformation 8】 、 or a pharmaceutically acceptable salt thereof.

13. 7. The pharmaceutical composition of claim 6, wherein 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-1)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (brensocatib). 【Chemistry 9】

14. 14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is orally administered to the subject once daily.

15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition to be orally administered to the subject once daily contains about 10 mg, about 25 mg, about 40 mg, about 5 mg to about 50 mg, about 10 mg to about 40 mg, or about 10 mg to about 25 mg of the compound of formula (I).

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