Methods and compositions for treating inflammatory and autoimmune disorders of the skin

Abstract

The present invention provides methods and compositions for treating an inflammatory or autoimmune disorder selected from the group consisting of Sjogren's syndrome, neutrophilic eccrine hydradenitis, vitiligo, lichen planus, ophthalmic inflammation, acne, alopecia areata, Sweet syndrome, pyoderma gangrenosum, epidermolysis, and pustular psoriasis. In certain embodiments, the invention provides methods for treating one of the foregoing disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the present invention provides Compound 1 for use in treating one of the foregoing disorders.

Description

[0001] METHODS AND COMPOSITIONS FOR TREATING INFLAMMATORY AND AUTOIMMUNE DISORDERS OF THE SKIN

[0002] RELATED APPLICATIONS

[0003] This application claims priority to DK Application Nos. PA202470100, PA202470101, PA202470102, PA202470103, PA202470104, PA202470111, PA202470105, PA202470106, PA202470107, PA202470108 and PA202470109; each of which was filed April 9, 2024. The entire teachings of the above applications are incorporated herein by reference.

[0004] BACKGROUND

[0005] Chronic inflammatory skin disorders are common and range in severity from mild to severe. Some disorders of this type are associated with additional health complications. Such disorders can result from a variety of factors, including autoimmunity, genetics and environmental exposure. These disorders can produce itching, pain, and changes in skin appearance, and result in substantial psychological distress in those suffering from them. Current treatment for these disorders, including topical and systemic medications, are often unable to provide long term relief to patients. There is therefore a need for new medications for treating chronic inflammatory skin disorders that are effective in eliminating or significantly reducing the symptoms of these disorders and are safe to take over prolonged time periods.

[0006] SUMMARY OF THE INVENTION

[0007] The present invention provides methods and compositions for treating an inflammatory or autoimmune disorder selected from the group consisting of Sjogren’s syndrome, neutrophilic eccrine hydradenitis, vitiligo, lichen planus, ophthalmic inflammation, acne, alopecia areata, Sweet syndrome, pyoderma gangrenosum, epidermolysis, and pustular psoriasis. In certain embodiments, the invention provides methods for treating one of the foregoing disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound or a pharmaceutically acceptable salt thereof.

[0008] In certain embodiments, the present invention provides Compound 1 for use in treating one of the foregoing disorders.

[0009] In a first embodiment, the present invention provides compositions and methods for treating at least one symptom of Sjogren’s syndrome. In one embodiment, the invention provides a method for treating Sjogren’s syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0010] The invention further provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating at least one symptom of Sjogren’s syndrome.

[0011] In a second embodiment, the present invention provides compositions and methods for treating neutrophilic eccrine hidradenitis. In one embodiment, the invention provides a method for treating neutrophilic eccrine hidradenitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0012] The invention provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating neutrophilic eccrine hidradenitis.

[0013] In a third embodiment, the present invention provides compositions and methods for treating vitiligo. In one embodiment, the invention provides a method for treating vitiligo in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0014] The invention further provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating vitiligo.

[0015] In a fourth embodiment, the present invention provides compositions and methods for treating lichen planus. In one embodiment, the invention provides a method for treating lichen planus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0016] The invention further provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating lichen planus.

[0017] In a fifth embodiment, the present invention provides compositions and methods for treating Sweet syndrome. In one embodiment, the invention provides a method for treating Sweet syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0018] The invention further provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating Sweet syndrome.

[0019] In a sixth embodiment, the present invention provides compositions and methods for treating ophthalmic inflammation. In one embodiment, the invention provides a method for treating ophthalmic inflammation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0020] The invention further provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating ophthalmic inflammation.

[0021] In a seventh embodiment, the present invention provides compositions and methods for treating epidermolysis bullosa acquisita. In one embodiment, the invention provides a method for treating epidermolysis bullosa acquisita in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0022] The invention further provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating epidermolysis bullosa acquisita.

[0023] In an eighth embodiment, the present invention provides compositions and methods for treating alopecia areata. In one embodiment, the invention provides a method for treating alopecia areata in a subject in need thereof, comprising administering to the subject a therapeutically effective amount Compound 1, or a pharmaceutically acceptable salt thereof.

[0024] The invention further provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating alopecia areata. In a ninth embodiment, the present invention provides compositions and methods for treating pyoderma gangrenosum. In one embodiment, the invention provides a method for treating pyoderma gangrenosum in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0025] The invention further provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating pyoderma gangrenosum.

[0026] In a tenth embodiment, the present invention provides compositions and methods for treating acne. In one embodiment, the invention provides a method for treating acne in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0027] The invention further provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating acne.

[0028] In an eleventh embodiment, the present invention provides compositions and methods for treating pustular psoriasis. In one embodiment, the invention provides a method for treating pustular psoriasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0029] The invention further provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating pustular psoriasis.

[0030] BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings.

[0032] Figure l is a graph showing the concentrations of Compound 1 found in the biopsied tissues in subjects grouped according to their clinical response to Compound 1 therapy.

[0033] Figure 2 presents graphs of CCL5 RNA sequencing data in non-lesional and lesional skin biopsies from a patient diagnosed with Sjogren’s Syndrome.

[0034] Figure 3 presents graphs of CXCL10 RNA sequencing data in non-lesional and lesional skin biopsies from a patient diagnosed with Sjogren’s Syndrome.

[0035] Figure 4 presents graphs of CXCL13 RNA sequencing data in non-lesional and lesional skin biopsies from a patient diagnosed with Sjogren’s Syndrome. Figure 5 presents the Z-score of the expression of selected genes as measured by RNA sequencing in lesional skin biopsies from a patient diagnosed with alopecia areata.

[0036] Figure 6 presents differential expressed genes as measured by RNA sequencing in non-lesional and lesional skin biopsies from a patient diagnosed with pyoderma gangrenosum.

[0037] Figure 7 presents graphs of IL36G qPCR data in non-lesional and lesional skin biopsies from a patient diagnosed with pyoderma gangrenosum.

[0038] Figures 8 A and 8B each presents a graph of IL17A qPCR data in non-lesional and lesional skin biopsies from a patient diagnosed with pyoderma gangrenosum.

[0039] Figure 9 presents graphs of TNF qPCR data in lesional skin biopsies from a patient diagnosed with acne vulgaris.

[0040] Figure 10 presents the Z-score of the expression of selected genes as measured by RNA sequencing in non-lesional and lesional skin biopsies from a patient diagnosed with vitiligo.

[0041] Figure 11 presents graphs of IL6 qPCR data in non-lesional and lesional skin biopsies from three patients diagnosed with vitiligo.

[0042] Figure 12 presents graphs of IL23A qPCR data in non-lesional and lesional skin biopsies from three patients diagnosed with pustular psoriasis.

[0043] Figure 13 presents graphs of CXCL8 qPCR data in non-lesional and lesional skin biopsies from three patients diagnosed with pustular psoriasis.

[0044] Figure 14 presents the Z-score of the expression of selected genes as measured by RNA sequencing in non-lesional and lesional skin biopsies from a patient diagnosed with lichen planus.

[0045] Figures 15A and 15B each presents a graphs of TNF qPCR data in non-lesional and lesional skin biopsies from a patient diagnosed with lichen planus.

[0046] DETAILED DESCRIPTION OF THE INVENTION

[0047] The present invention relates to the use of Compound 1 in the treatment of certain inflammatory and autoimmune disorders. Compound 1 is a potent inhibitor of HSP90, and the synthesis and HSP90 inhibitory activity of Compound 1 are described in W02008 / 115719, the contents of which are incorporated by reference herein in their entirety. Sjogren’s syndrome

[0048] Sjogren syndrome (SS) is a chronic, multisystem autoimmune disease, characterized by chronic inflammation involving the exocrine glads. It may occur alone, or it may coexist with other systemic connective tissue disorders. The characteristic feature of SS is excrine glad dysfunction, leading to classic sicca symptoms of xerostomia (dry mouth) and xerophthakmia or keratoconjunctivitis sicca (dry eye). Cutaneous manifestations are common extragi andul ar features of SS (Roguedas AM et al. Clin Exp Rheumatol 2004, 22:632-636). The diagnosis of SS relies on a combination of clinical, serological, and functional tests and histopathological biomarkers.

[0049] The pathogenesis of SS remains largely unknown. However, genetic and epigenetic disposition, various environmental factors and hormones have been implicated in the pathogenesis of the disease. Recently, studies have shown that both innate and adaptive immunity contribute to the development of SS. Genomewide association studies (GWAS) have identified several susceptibility genes coding for different signalling pathways and involving different cytokines and chemokines. CCL5, CXCL10 and CXCL13 have among others been suggested as contributors to the pathogenesis of SS and therefore also potential treatment targets for SS (Hinrichs AC et al. Front Immunol 2022, 13:887972, Kim JW et al. Clinical and Experimental Medicine 2024, 24:133, Zhu T et al. Clin Rheumatol 2022, 41 :2791-2802).

[0050] The treatment of SS depends on the symptoms and are often non-pharmacological treatment aiming to relief symptoms such as dry mouth or dry eyes. However, also pharmaceutical drugs such as hydroxychloquine, corticosteroids and other immunosuppressive drugs are often used.

[0051] In certain embodiments, the present invention relates to methods and a compound for treating at least one symptom of Sjogren’s syndrome. In one embodiment, the invention provides a method of treating at least one symptom of Sjogren’s syndrome in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating at least one symptom of Sjogren’s syndrome.

[0052] In the methods and compounds for treating at least one symptom of Sjogren’s syndrome of the invention, the subject is preferably a human subject. The subject can have at least one symptom of Sjogren’s syndrome at any degree of severity. For example, the symptoms of Sjogren’s syndrome may affect one or more of the 12 domains defined by EULAR Sjogren’s syndrome activity index (ESSDAI; Seror, R. et al., RMD Open 2015; l :e000022). In certain embodiments, the symptoms of Sjogren’s syndrome in a subject may be e.g.: no, low, moderate or high level of activity of a symptom. For example, the subject can have at least one of mild, intermittent or severe fever; lymphadenopathy and / or splenomegaly of varying severity or current B-cell malignant proliferative disorder; small or major glandular or lachrymal swelling, arthralgias or synovitis in hands, wrists, ankles and feet accompanied by morning stiffness; Erythema multiforma or limited cutaneous vasculitis comprising e.g., urticarial vasculitis, or purpura limited to feet and ankle, or subacute cutaneous lupus, diffuse cutaneous vasculitis comprising e.g., urticarial vasculitis, urticarial vasculitis or diffuse purpura, or ulcers related to vasculitis; persistent cough due to bronchial involvement with no radiographic abnormalities on radiography or radiological HRCT evidence of interstitial lung disease with no breathlessness and normal lung function test, moderately or highly active pulmonary involvement, such as interstitial lung disease; renal disfunction, for example, mild, moderately or highly active renal involvement, such as tubular acidosis with or without renal failure or glomerular involvement with proteinuria and with or without haematuria; mild, moderately active or highly active myosis; mild, moderately or highly active PNS involvement shown by NCS such as axonal sensory-motor neuropathy with partial or full motor deficit or mild, moderate or severe ataxia; moderately and highly active CNS features, such as cranial nerve involvement of central origin, optic neuritis or multiple-sclerosis-like syndrome with or without motor deficit, cerebral vasculitis with cerebrovascular accident or transient ischaemic attack, seizures, transverse myelitis, lymphocytic meningitis; cytopenia of autoimmune origin with neutropenia; clonal component and / or hypocomplementemia and / or hypergammaglobulinemia or high IgG level; xerostomia (dry mouth); keratoconjunctivitis sicca (dry eye syndrome or dry eye); xeroderma (dry skin); joint pain; trouble sleeping; eye discomfort; muscle pain and / or brain fog. For example, the subject can have xerostomia (dry mouth), keratoconjunctivitis sicca (dry eye syndrome or dry eye), xeroderma (dry skin), joint pain, trouble sleeping, eye discomfort, muscle pain and / or brain fog.

[0053] Neutrophilic eccrine hydrandenitis

[0054] Neutrophilic eccrine hi dradenitis (NEH) is a distinctive dermatosis occurring in patients with malignancy or undergoing chemotherapy, however the exact aetiology is not known. One hypothesis suggests that neutrophilic accumulation around the eccrine cells is either caused by local chemotactic factors or secondary to abnormal neutrophil function. Another hypothesis suggests that NEH is a unique subtype of neutrophilic dermatosis, in which antineoplastic chemotherapy induces the differentiation of myeloid leukaemia blast cells into neutrophils. These leukaemia blasts are thought to disappear from circulation as they develop mature morphology and differentiated functional characteristics, which allows accumulation in other tissues like the eccrine glands. Chemotherapeutic agents are excreted via the eccrine sweat glands and may cause a local irritant reaction (Indian J Pharmacol. 2013 Jan-Feb; 45(1): 91-92. doi: 10.4103 / 0253-7613.106445).

[0055] The disorder is characterized by neutrophilic infiltrate around the eccrine glands and secretory coils and is associated with necrosis. Malignancies associated with NEH include acute myeloid leukaemia, acute myelomonocytic leukaemia, testicular carcinoma, Hodgkin’s and non-Hodgkin’s lymphoma, and osteogenic sarcoma. The most commonly indicated drugs that may cause NEH are cytarabine (an anti-epileptic drug), mitoxantrone, chlorambucil, zidovudine and acetaminophen. The clinical lesions are typically erythematous plaques, diagnosed by skin biopsy.

[0056] In certain embodiments, the present invention relates to methods and a compound for treating neutrophilic eccrine hidradenitis. In one embodiment, the invention provides a method of treating neutrophilic eccrine hidradenitis in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating neutrophilic eccrine hidradenitis.

[0057] In the methods and compounds for treating neutrophilic eccrine hidradenitis of the invention, the subject is preferably a human subject. The subject can have neutrophilic eccrine hidradenitis at any degree of severity.

[0058] Vitiligo

[0059] Vitiligo is an acquired, common autoimmune disease of the skin that causes depigmentation through T-cell-mediated progressive destruction of melanocytes, and it correlates with increased risk of other autoimmune diseases. Typically, vitiligo lesions are asymptomatic, white, non-scaly macules and patches with distinct margins in the skin, but it can also include the hair. Lesions usually appear with a symmetrical distribution. The disease can start at any site of the body, although the face, as well as acral and genital locations, are often the initial site. A number of patterns have been described but most can be grouped together (Fitzpatrick’s Dermatology 9th edition, ed’s.: Kang S, Magai M et al. Vol. 1, chapter 76). Clinical signs of lesional activity include confetti, trichrome, and inflammatory lesions, as well as koebnerization. Although vitiligo is not a life-threatening disease, it can cause significant social stigma and is often psychologically devastating for patients (Ezzedine K. et al. J Am Acad Dermatol 2015, 73, 883-885).

[0060] Vitiligo can begin at any age although it usually starts before the third decade of life. The prevalence of the disease is stated to be similar all over the world and estimated at 0.5% to 1% (Singh M. et al. Int J Dermatol 1985, 24: 233-235, Alikhan A. et al. J Am Acad Dermatol 2011, 65:473-491).

[0061] The pathogenesis of vitiligo is not fully understood, but it is an autoimmune disease of the skin where CD8+ T cells play a critical role serving as primary immune effectors that destroy melanocytes. Studies using human tissues and a mouse model of vitiligo have revealed that interferon (fFN)-y is a key cytokine in the pathogenic process (Frisoli ML et al. Annu Rev Immunol 2020, 26:621-648). Also other cytokines and chemokines such as e.g., interleukin (IL)-6 have been shown to be upregulated in both serum and skin samples from patients with vitiligo and suggested to play a critical role in the pathogenesis of the disease (Kargiin E et al. The Aging Male 2020, 23:1487-1492, Choudhary De A et al. Indian J Dermatol 2023, 68:67-72, Sushama S et al. J Cosmet Dermatol 2Q 9, 18:337-341, Singh M et al. Imm unol Invest 2022, 51 : 120-137).

[0062] Treatments for vitiligo include topical and oral immunosuppressants (including JAK inhibitors approved for vitiligo), phototherapy, surgery, and chemical depigmentation agents, and sometimes these treatment options are used in combination. Most of the treatments used for treating vitiligo were developed for other inflammatory skin diseases and several are therefore used off-label to treat vitiligo.

[0063] In certain embodiments, the present invention relates to methods and a compound for treating vitiligo. In one embodiment, the invention provides a method of treating vitiligo in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating vitiligo.

[0064] In the methods and compounds for treating vitiligo of the invention, the subject is preferably a human subject. The subject can have vitiligo with symptoms at any degree of severity. For example, the subject can have segmental vitiligo (where pale patches appear on one area of the body) or non-segmental vitiligo (NSV, in which pale patches appear symmetrically on the body).

[0065] Lichen planus

[0066] Lichen planus (LP) is an idiopathic T-cell-mediated, chronic, inflammatory disease that affects the squamous cell layer, including the skin and mucosal membranes (Carrozzo M et al. J Invest Dermatol 2004, 122:87-94, Fitzpatrick’s Dermatology 9th edition, ed’s.: Kang S, Magai M et al. Vol. 1, chapter 5). The world- wide prevalence of LP is approximately 1%. Many variations in the clinical presentation of LP have been described but in its most common form it presents with well-marginated, flat-topped, red-violet polygonal papules with a symmetrical distribution on the flexural aspects of the extremities. Thus, sites of involvement also include the scalp, oral and genital mucosa, nails and other parts of the body. Mucosal involvement in LP is debilitating, often a therapeutic enigma and due to its chronic recalcitrant course and persistent inflammation, it may function as a fertile ground for neoplastic disorders (Gonzalez-Moles MA et al. Oral Dis 2021, 27: 1908-1918). Frequently, it affects the oral cavity and more preferentially, women.

[0067] The etiology and pathogenesis of LP are not fully understood, although it is widely agreed that an immunological response is important in the process and studies have shown that T cell-mediated immune responses are closely related to the disease which eventually leads to the apoptosis of keratinocytes (Sugerman PB et al. Br J Dermatol 2000, 142:449- 456, Amirchaghmaghi M et al. J Clin Diagn Res 2016, 10:134-137). T cells, both CD4+and CD8+, accumulate in the dermis. These inflammatory cells, through the secretion of several cytokines, are responsible for the apoptosis of basal epidermal cells. Increased expression of several pro-inflammatory cytokines such as e.g. IFNy, TNF-a, IL-6 and IL- ip have been demonstrated in lesional LP tissue (Wang Y et al. J Oral Pathol Med 2020, 49:920-925, Chen JF et al. Clinical, Cosmetic and Investigational Dermatology 2022, 15: 1509-1516, Yin M et al. Biomedical Reports 2017, 6:571-575, Pietschke K et al. Exp Dermatol 2021, 30:262-270).

[0068] Albeit LP is clinically well defined, the disease still represents a therapeutic enigma and treatment of LP is often challenging and discouraging (Fitzpatrick’s Dermatology 9th edition, ed’s.: Kang S, Magai M et al. Vol. 1, chapter 5). Treatment involves skin-directed therapies such as corticosteroids, calcineurin inhibitors and phototherapy and also a number of systemic drugs including immunosuppressants such as e.g., azathioprine, methotrexate, cyclosporin and corticosteroids.

[0069] In certain embodiments, the present invention relates to methods and a compound for treating lichen planus. In one embodiment, the invention provides a method of treating lichen planus in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating lichen planus.

[0070] In the methods and compounds for treating lichen planus of the invention, the subject is preferably a human subject. The subject can have lichen planus with symptoms at any degree of severity. For example, the subject can have cutaneous lichen planus, or mucosal lichen planus. Cutaneous forms are those affecting the skin, scalp, and nails. Mucosal forms are those affecting the lining of the gastrointestinal tract (mouth, pharynx, esophagus, stomach, anus), larynx, and other mucosal surfaces including the genitals, peritoneum, ears, nose, bladder, and conjunctiva of the eyes.

[0071] Sweet syndrome

[0072] Sweet syndrome, also known as acute febrile neutrophilic dermatosis, is a rare skin disorder characterised by sudden onset of tender edematous and erythematous papules, nodules, and plaques, most often on the arms, face and neck, but also on, for example, the legs. Pustules may develop as well. Less commonly, oral or genital lesions may be observed. In some cases, neutrophils may develop in the subcutaneous fat. The above symptoms are commonly accompanied by fever and leukocytosis. Other manifestations of the syndrome can be, for example, headache; fatigue; arthralgia; and ophthalmologic manifestations such as inflammation of the conjunctiva or episclera.

[0073] Sweet syndrome can be idiopathic (classical Sweet syndrome (CSS)). Classical Sweet syndrome is commonly preceded by a gastrointestinal infection or upper respiratory tract infection and may be associated with an underlying inflammatory or autoimmune condition, such as lupus, Crohn’s disease, ulcerative colitis, or rheumatoid arthritis. It may as well be associated with pregnancy in women. In some cases, Sweet syndrome is associated with an underlying malignancy (malignancy-associated Sweet syndrome (MASS)), such as a hematologic or visceral malignancy, commonly a cancer. Furthermore, in some cases, Sweet syndrome is drug-induced (drug-induced Sweet syndrome). This is most common in patients that have undergone treatment with granulocyte-colony stimulating factors, but other medicines may be associated with drug- induced Sweet syndrome as well.

[0074] Sweet syndrome is often treated with systemic corticosteroids. Other systemic treatment options are oral treatment with colchicine or potassium iodide. Oral treatment with cyclosporine, indomethacin, clofazimine, or dapsone has been described as well. Local treatment with topical or intralesional corticosteroids may be effective for isolated lesions, either as monotherapy or in combination with another therapy.

[0075] The pathogenesis of Sweet syndrome has not yet been fully determined, but it is speculated that the cause may be multifactorial. However, neutrophil activation and infiltration are known to play key roles in the pathogenesis of Sweet syndrome. The present invention relates to methods and a compound for treating Sweet syndrome.

[0076] In certain embodiments, the present invention provides a method of treating Sweet syndrome in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating Sweet syndrome.

[0077] In the methods and compounds for treating Sweet syndrome of the invention, the subject is preferably a human subject. The subject can have Sweet syndrome with one or more symptoms at any degree of severity. The subject can have classical Sweet syndrome, malignancy-associated Sweet syndrome, or drug-induced Sweet syndrome.

[0078] Ophthalmic inflammation

[0079] Inflammatory ophthalmic indications include dry eye, uveitis and scleritis. Uveitis is inflammation of the uvea, scleritis is inflammation of the sclera. Such ophthalmic indications may be autoimmune conditions.

[0080] Treatment of such ophthalmic indications is often based on administration of steroids, e.g., injection or topical application of corticosteroids. Immunosuppressive medicaments may also be used if steroid treatment is not sufficient.

[0081] In certain embodiments, the present invention provides methods and a compound for treating ophthalmic indications, preferably inflammatory ophthalmic indications, in particular autoimmune ophthalmic diseases. In one embodiment, the invention provides a method of treating ophthalmic indications in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating ophthalmic indications.

[0082] In the methods and compounds for treating ophthalmic indications of the invention, the subject is preferably a human subject. The subject can have ophthalmic indications with symptoms at any degree of severity. For example, the subject can have dry eye, uveitis or scleritis.

[0083] Epidermolysis Bullosa Acquisita

[0084] Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering diseases of the skin and mucous membranes. Collagen is typically attacked, leading to skin detachment, weakened skin, sores and blisters in those suffering from the condition. Pharmaceutical treatment is uncommon, but some reports have suggested treatment via administration of steroids, e.g., injection or topical application of corticosteroids.

[0085] In certain embodiments, the present invention provides methods and a compound for treating epidermolysis bullosa acquisita. In one embodiment, the invention provides a method of treating epidermolysis bullosa acquisita in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating epidermolysis bullosa acquisita.

[0086] In the methods and compounds for treating epidermolysis bullosa acquisita of the invention, the subject is preferably a human subject. The subject can have epidermolysis bullosa acquisita with symptoms at any degree of severity. For example, the subject can have inflammatory or non-inflammatory EBA. Inflammatory variants of EBA include bullous pemphigoid (BP)-like EBA, mucous membrane pemphigoid (MMP)-like EBA, linear IgA bullous dermatosis (LABD)-like EBA, and Brunsting-Perry cicatricial pemphigoid-like EBA.

[0087] Alopecia areata

[0088] Alopecia areata (AA) is a common, inflammatory, nonscarring type of hair loss. It occurs in both genders equally and can affect every age group, although the incidence in younger age groups is higher. AA is found in approximately 0.1% to 0.2% of the general population and among the US population, the cumulative lifetime incidence of AA is estimated at 2% (Safavi K. Arch Dermatol 1992, 128:702, Mirzoyev SA et al J Invest Dermatol 2014, 134: 1141). Significant variations in the clinical presentation of AA are seen, but in its most common form it presents as small, well-circumscribed patches of hair loss on the scalp or other parts of the body. Of patients with AA, approximately 5% develop hair loss of their entire scalp hair (alopecia totalis) and approximately 1% develop loss of total body hair (alopecia universalis) (Fitzpatrick’s Dermatology 9th edition, ed’s.: Kang S, Magai M et al. Vol. 1, chapter 87). The unpredictable course of the disease also makes it a mental struggle and AA patients are more often associated with depression and anxiety compared to the healthy population.

[0089] The pathogenesis of AA is incomplete understood but the disease is thought to be an autoimmune disease with a possible hereditary component. Autoreactive cytotoxic CD8+ T cells, which affect hair follicle cycling with premature entry into the telogen phase are thought to play an important role. In addition, patients with AA have a higher prevalence of atopic dermatitis (AD) and vice versa, indicating that AA and AD have pathogenetic cascades in common. AA and AD are associated with genetically predisposed multi -factorial disorders. Exploration of the genetic co-drivers toward AA and AD was performed with Mendelian randomization with genome-wide association studies. The approach identified IL- 13 as one of the top associated single nucleotide polymorphisms. IL-13 has therefore also been suggested as a therapeutic target for AA (O’Hagan R et al. J Am Acad Dermatol 2023, 89:600-602, Oiso N Int J Dermatol 2024, 63:268-269). The effectiveness of anti-IL-13 treatment with tralokinumab for refractory AD and AA associated with AD has recently been demonstrated (Tavoletti G et al. Int J Dermatol 2024, 63:374-375).

[0090] Current management is guided by the degree of scalp and body involvement, with topical and intralesional corticosteroid injections as primarily first-line for mild cases and broad immunosuppressants as the mainstay for more severe cases. The treatment armamentarium also includes cryo therapy, several different topicals, photo(chemo) therapy. More recently, Janus kinase inhibitors (JAK) have been approved for the treatment of AA.

[0091] In certain embodiments, the present invention relates to methods and a compound for treating alopecia areata. In one embodiment, the invention provides a method of treating alopecia areata in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating alopecia areata. In the methods and compounds for treating alopecia areata of the invention, the subject is preferably a human subject. The subject can have alopecia areata with symptoms at any degree of severity. For example, the subject can have diffuse alopecia areata, alopecia areata monolocularis, alopecia areata multilocularis, alopecia areata totalis or alopecia areata universalis.

[0092] Pyoderma Gangrenosum

[0093] Pyoderma gangrenosum (PG) is an uncommon, chronic, recurrent, cutaneous ulcerative disease with a distinctive morphologic presentation. The initial lesion is often a pustule on an erythematous or violaceous base, an erythematous nodule, or a bulla. Lesions are expanding with ulcers presenting with necrotic undermined borders and with a purulent base. PG is a global disease that can occur at any age, but most commonly afflicts women between 20 and 50 years of age (Dermatology 5 ’th edition. Ed’s: Bolognia JL et al. vol 1, chapter 4, pp.457-461). Diagnosing PG can be challenging as there is no specific or laboratory tests or histopathologic features of the disease.

[0094] Although PG is most commonly thought to be a neutrophilic dermatosis, its pathophysiology is poorly understood. The dominant hypothesis is that altered innate immunity leads to systemic autoinflammation (Ahronowitz I et al. Am J Clin Dermatol 2012, 13: 191-211). The initial inflammatory events of PG are dominated by aberrant cytokine and chemokine expression, and gene expression analysis has revealed robust expression of T cell attractant chemokines CXCL9, CXCL10, CXCL11, and the cytokines IL8, 11.17. and IL36G (Ahronowitz I et al. Am J Clin Dermatol 2012, 13: 191-211). Other key proinflammatory cytokines such as TNF and ILla and have also been reported upregulated in lesional PG skin (Dermatology 5 ’th edition. Ed’s: Bolognia JL et al. vol 1, chapterchapter 4, pp.457-461).

[0095] There is neither a specific nor uniformly effective treatment for PG (Dermatology 5 ’th edition. Ed’s: Bolognia JL et al. vol 1, chapterchapter 4, pp.457-461). The therapeutic goals are to reduce the inflammatory process of the wound, thereby promoting healing and reducing pain. When delivered in adequate dosage, systemic corticosteroids have generally been the most predictable and effective medication but also other immunosuppressive drugs such as cyclosporine, TNF-a and IL- 12 / 23 inhibitors as well as JAK inhibitors are frequently used (Dermatology 5 ’th edition. Ed’s: Bolognia JL et al. vol 1, chapterchapter 4, pp.457-461). In certain embodiments, the present invention relates to methods and a compound for treating pyoderma gangrenosum. In one embodiment, the invention provides a method of treating pyoderma gangrenosum in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating pyoderma gangrenosum.

[0096] In the methods and compounds for treating pyoderma gangrenosum of the invention, the subject is preferably a human subject. The subject can have pyoderma gangrenosum with symptoms at any degree of severity. For example, the subject can have peristomal pyoderma gangrenosum, bullous pyoderma gangrenosum, vesicular-bullous pyoderma gangrenosum, pustular pyoderma gangrenosum, ulcerative pyoderma gangrenosum, superficial pyoderma gangrenosum or vegetative pyoderma gangrenosum.

[0097] Acne

[0098] Acne, also known as acne vulgaris, is a chronic inflammatory skin condition of the pilosebaceous unit. The clinical lesions are non-inflammatory open and closed comedones and / or papules, pustules, and nodules with varying degree of inflammation and depth. It mainly affects the face, upper part of the chest and the back.

[0099] Treatments for acne are available, such as lifestyle changes (e.g., by eating fewer simple carbohydrates), medications and medical procedures. Treatments may be applied directly to the affected skin, such as azelaic acid, benzoyl peroxide and salicylic acid. Antibiotics and retinoids are also available in various formulations that are applied to the skin topically or administered orally, however their use may be limited by emerging antibiotic resistance in the subject.

[0100] In certain embodiments, the present invention relates to methods and a compound for treating acne. In one embodiment, the invention provides a method of treating acne in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating acne.

[0101] HSP90 inhibition by Compound 1 has been shown to reduce the expression of TNF, IL-lb and IL-17A in cultured human keratinocytes in vitro (Ben Abdallah H et al. Front Immunol. 2023). TNF, IL-lb and IL-17A expression are upregulated in acne vulgaris. In the methods and compounds for treating acne of the invention, the subject is preferably a human subject. The acne can be, for example, acne vulgaris, comedonal acne, preputal acne, nodulocystic acne, acne conglobate, or acne fulminans. The subject can have at acne at any degree of severity. For example, the acne may be classified as mild, moderate or severe.

[0102] Pustular Psoriasis

[0103] Pustular psoriasis is a rare, chronic, inflammatory skin disorder. It is characterised by erythema and the formation of yellow or white pustules on the skin. The pustules show a sterile neutrophilic infiltrate. They can have different distribution patterns and can be localised or widespread. Different types of pustular psoriasis can be distinguished, depending on the location of the pustules and the clinical presentation. A distinction is normally made between generalised and localised pustular psoriasis.

[0104] Generalised pustular psoriasis (GPP) manifests with sudden widespread eruption of pustules. It may precede or follow episodes of plaque psoriasis, but not necessarily. The disorder is frequently associated with inflammatory polyarthritis and metabolic syndrome. Moreover, symptoms such as fever and arthralgia commonly accompany the formation of the pustules.

[0105] Subtypes of GPP include von Zumbusch subtype, Annular subtype, Exanthematic subtype, and Impetigo herpetiformis. Impetigo herpetiformis denotes GPP occurring during pregnancy, typically in the third trimester, but earlier onset may occur. The condition usually resolves after delivery. Characteristic initial symptoms are erythematous patches and plaques with grouped sterile pustules at the margin, predominantly in the mother’s flexural regions. The lesions usually spread to cover large areas of the body. Lesions may form as well in the oral cavity, on the tongue, and in the oesophagus.

[0106] The exact pathogenesis of GPP has not yet been fully determined, but the disorder appears to be associated with genetic factors and environmental risk factors. Dysregulation of the interleukin-36 pathway, which is key to regulating the innate immune system, has been found to play a central role in the pathogenesis of GPP.

[0107] Subtypes of localised pustular psoriasis include Acrodermatitis continua of Hallopeau and Palmoplantar pustular psoriasis (PPP). Acrodermatitis continua of Hallopeau causes pustules on the fingertips, toes, and / or on the nail beds that may sometimes spread up the arms and legs. Palmoplantar pustular psoriasis manifests with pustules on the palms, soles, or both. Both genetic factors and antigenic triggers appear to play a role in the pathogenesis of PPP. First-line local treatment of PPP includes topical administration of corticosteroids, often combined or alternated with synthetic vitamin D medication such as calcipotriene. Oral acitretin is a first-line option for systemic treatment. Alternative treatment options include phototherapy and oral methotrexate and cyclosporine. Recently, Spesolimab, an anti-IL36R monoclonal antibody, has been approved for the treatment of flares in adult patients with GPP.

[0108] In certain embodiments, the present invention relates to methods and a compound for treating pustular psoriasis. In one embodiment, the invention provides a method of treating pustular psoriasis in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The invention further relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating pustular psoriasis.

[0109] In the methods and compounds for treating Pustular psoriasis of the invention, the subject is preferably a human subject. The subject can have Pustular psoriasis at any degree of severity and any type or subtype of Pustular psoriasis, comprising, for example, generalised pustular psoriasis, localised pustular psoriasis, Zumbusch subtype, Annular subtype, Exanthematic subtype, Impetigo herpetiformis, Palmoplantar psoriasis, and Acrodermatitis continua of Hallopeau.

[0110] Pharmaeutical Compositions

[0111] Compound 1 or a pharmaceutically acceptable salt thereof is preferably administered in the form of a pharmaceutical composition comprising the therapeutic agent tionsand a pharmaceutically acceptable carrier, excipient or diluent. Suitable pharmaceutical compositions include a solid, semisolid or liquid preparation (tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, liquid, emulsion, suspension, syrup, injection, etc.). The pharmaceutical composition can be administered by any suitable means, including, without limitation, parenteral, intravenous, intramuscular, subcutaneous, implantation, oral, sublingual, buccal, nasal, pulmonary, transdermal, topical, vaginal, rectal, and transmucosal administrations or the like. Topical administration can involve the use of a cream, eye drops, a lotion, a gel, an ointment, an aerosol, a liquid, a liquid drop, an emulsion, or a suspension. A particularly preferred administration form is liquid drops, such as eye-drops, mouth-drops or nasal drops or sprays. In a preferred embodiment, the pharmaceutical composition is administered orally, for example, as a solid or a liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescent, powders, and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment of the present invention, the composition is formulated in a capsule. In another embodiment, the composition is formulated as a tablet.

[0112] Any inert excipient that is commonly used as a carrier or diluent may be used in the pharmaceutical compositions of the present invention, such as for example, a gum, a starch, a sugar, a cellulosic material, an acrylate, or mixtures thereof. A preferred diluent is microcrystalline cellulose. The compositions may further comprise a disintegrating agent (e.g., croscarmellose sodium) and a lubricant (e.g., magnesium stearate), and may additionally comprise one or more additives selected from a binder, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof. Furthermore, the compositions of the present invention may be in the form of controlled release or immediate release formulations.

[0113] For liquid formulations, pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, emulsions or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil. Solutions or suspensions can also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

[0114] In addition, the compositions may further comprise binders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers (e.g., tris-HCI., acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol, polyethylene glycol), a glidant (e.g., colloidal silicon dioxide), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosity increasing agents (e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., pol oxamers or pol oxamines), coating and film forming agents (e.g., ethyl cellulose, acrylates, polymethacrylates) and / or adjuvants.

[0115] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0116] It is especially advantageous to formulate oral compositions in unit dosage form for ease of administration and uniformity of dosage. “Unit dosage form”, as used herein, refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the unit dosage forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. Formulations of the invention intended for oral administration can include one or more permeation enhancers, including long chain fatty acids or salts thereof, such as decanoic acid and sodium decanoate.

[0117] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0118] The pharmaceutical composition of the invention is preferably suitable for oral administration and is most preferably in the form of a tablet. In one embodiment, the pharmaceutical composition is a tablet comprising Compound 1. In certain embodiments the tablet comprises Compound 1 in the form of the free base. In certain embodiments, the tablet comprises Compound 1 free base in an amount from 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg. Alternatively, the tablet comprises a pharmaceutically acceptable salt of Compound 1 in the foregoing amounts where these amounts represent free base equivalents. Preferably, the tablet comprises 0.5 mg, 1 mg, 5 mg, 20 mg, 50mg, 100 mg, 125 mg or 250 mg of Compound 1 free base. In certain embodiments, Compound 1 is administered orally, preferably in the form of a tablet, to the subject as the free base at a dose of 0.5 mg to 400 mg per day, preferably as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day. In certain embodiments, the pharmaceutically acceptable salt of Compound 1 is administered orally, preferably in the form of a tablet, to the subject at a free base equivalent dose of 200 mg to 300 mg per day, preferably at a free base equivalent dose of 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

[0119] The pharmaceutical composition of the invention is preferably suitable for topical administration and is most preferably in the form of a cream, eye drops, a lotion, a gel, an ointment, an aerosol, a liquid, a liquid drop, an emulsion, or a suspension. In one embodiment, the pharmaceutical composition is a cream or liquid drops comprising Compound 1. In certain embodiments, the cream or liquid drops comprise Compound 1 in the form of the free base. In certain embodiments, the cream or liquid drops comprise Compound 1 free base in an amount from 0.25 mg to 250 mg, from 0.5 mg to 225 mg, from 1 mg to 200 mg, from 1.5 mg to 175 mg, from 2 mg to 150 mg, from 2.5 mg to 125 mg, from 3 mg to 100 mg, from 4 mg to 75 mg, from 4.5 mg to 50 mg, from 5 mg to about 25mg. Preferably, the cream or liquid drops comprise 0.5 mg, 1 mg, 5 mg, 20 mg, 50mg, 100 mg, 125 mg or 250 mg of Compound 1 free base. In certain embodiments, Compound 1 is administered topically to the subject as a free base at a dose of 0.5 mg to 400 mg per day, preferably as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

[0120] The pharmaceutical composition can be administered daily or on a suitable schedule. In one embodiment, daily administration is repeated continuously for a period of several days to several years. Oral treatment may continue for between one week and the life of the patient. The administration can be continuous or intermittent, e.g., treatment for a number of consecutive days followed by a rest period.

[0121] The amount of the compound administered to the patient is preferably less than an amount that would cause toxicity in the patient. In certain embodiments, the amount of Compound 1 or pharmaceutically acceptable salt thereof that is administered to the patient is less than the amount that causes a concentration of the compound in the patient's plasma to equal or exceed the toxic level of the compound.

[0122] The dosing schedules described herein describe administration of Compound 1, which can be administered in the form of the free base or as a pharmaceutically acceptable salt. Any amount of Compound 1 administered in the dosing regimens described herein refers the amount of the free base form, or with respect to a pharmaceutically acceptable salt, the free base equivalent amount.

[0123] In certain embodiments, Compound 1 is administered at a dose of 0.5 mg to 400 mg per dosing day. In certain embodiments, Compound 1 is administered at a dose of 10 mg to 50, 100 or 200 mg per dosing day. In certain embodiments, Compound 1 is administered to the subject at a dose of 0.5 mg to 300 mg per dosing day, 25 mg to 275 mg per dosing day, 30 mg to 260 mg per dosing day or 250 mg per dosing day. In certain embodiments, Compound 1 is administered to the subject at a dose of 0.5 mg to 200 mg per dosing day, 20 mg to 175 mg per day, 20 mg to 150 mg per dosing day, 20 mg to 125 mg per dosing day, 20 mg to 100 mg per dosing day, or 20 mg to 50 mg per dosing day. In certain embodiments, Compound 1 is administered to the subject at a dose of 50 mg to 150 mg per dosing day, 60 mg to 140 mg per dosing day, 70 mg 130 mg per dosing day, 75 mg to 125 mg per dosing day, 80 mg to 120 mg per dosing day, 90 mg to 110 mg per dosing day or 100 mg per dosing day.

[0124] In certain embodiments, Compound 1 is administered to the subject at a dose of 150 mg to 300 mg per dosing day, 200 mg to 300 mg per dosing day, 225 mg to 275 mg per dosing day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per dosing day.

[0125] The term “dosing day”, as used herein, refers to a day on which Compound 1, in the form of the free base or a pharmaceutically acceptable salt, is administered to the subject. In certain embodiments, Compound 1 is administered to the subject daily. In other embodiments, Compound 1 is administered every other day. In certain embodiments, Compound 1 is administered to the subject three days per week, preferably on non- consecutive days, for example on Monday, Wednesday and Friday. The dose mentioned is the amount of drug per day and will correlate to the concentration of drug in the specific dosage format and the amount / area applied.

[0126] In certain embodiments, Compound 1 is initially administered to the subject at a loading dose of 0.5-250 mg per dosing day for a suitable period of time, such as 1-12 weeks, 2-10 weeks or 4 to 8 weeks. The loading dose is preferably administered daily. The loading dose can be followed by a reduced maintenance dose, for example any of the reduced dosing schedules and / or reduced doses per dosing day as described above. For example, Compound 1 can be administered at loading dose of 25-250 mg / dosing day for 4 to 8 weeks, followed by a maintenance dose of 0.5-200 mg per dosing day, provided that the maintenance dose is a lower dose per dosing day and / or dosed less frequently than the loading dose. In certain embodiments, the loading dose is 200 to 250 mg per day for 4 to 8 weeks and the maintenance dose is 25 to 200 mg per day, provided that the maintenance dose is lower than the loading dose.

[0127] Dosing of Compound 1 or a pharmaceutically acceptable salt thereof as described above can continue for any period of time and is preferably continued for at least 16 weeks or more. Preferably dosing continues as long as the subject is exhibiting clinical improvement in the signs and symptoms of ophthalmic indications.

[0128] Dosing of Compound 1 or a pharmaceutically acceptable salt thereof as described above can be interrupted by occasional periods of one or more days in which dosing is suspended, and then dosing can be continued either on a predetermined scheduled or upon return or worsening of ophthalmic indications signs and symptoms.

[0129] Response of a subject to the therapeutic methods of the present invention can be determined as is known in the art. For example, the subject can be evaluated according to the Physician’s Global Assessment (PGA) and / or Dermatology Life Quality Index (DLQI).

[0130] DEFINITIONS

[0131] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0132] Compound 1 can be formulated and administered in the methods of the invention as the free base or as a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid or inorganic acid. Examples of pharmaceutically acceptable nontoxic acid addition salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid lactobionic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, -toluenesulfonate, undecanoate, valerate salts, and the like.

[0133] As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration, such as sterile pyrogen-free water. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated.

[0134] The term “subject” as used herein refers to an animal. Preferably the animal is a mammal. Most preferably, the subject is a human.

[0135] The terms “therapeutically effective amount" and “effective amount” of a therapeutic agent refers to an amount of such agent which confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to treatment of ophthalmic indications. A therapeutically effective amount of an agent may be different when used as a single agent that when used in combination with one or more other agents. In addition, a therapeutically effective amount of an agent may depend on the specific combination of agents to be administered. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). Therapeutically effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.

[0136] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.

[0137] Upon improvement of a patient’s condition, a maintenance dose of a compound or composition of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0138] Preparation of Compound 1

[0139] Compound 1 can be prepared using the methods disclosed in published PCT Application No. W02008 / 115719, the contents of which are incorporated herein by reference in their entirety.

[0140] EXAMPLES

[0141] Example 1 Pharmacokinetic Studies of Compound 1

[0142] A 16-week treatment, randomized, double-blind, proof-of-concept study was designed to assess the safety and efficacy of Compound 1 compared to placebo in treating hi dradenitis suppurativa. Eligible subjects completed an up-to 4-week screening phase and sequentially be randomized 2: 1 to one of two cohorts, treatment cohort (n = 10) or placebo-control cohort (n = 5), in a 16-week treatment phase followed by a 4-week observational follow-up phase. In the 16-week treatment phase, subjects randomized to the treatment group receive 250 mg Compound 1 free base in the form of a tablet administered orally once daily. The 250 mg dose was selected based on the results of an earlier oncology trial conducted with doses in excess of 1000 mg / day as a safe minimal dose from which to conduct dose escalation if required. Subjects randomized to the placebo-control group receive placebo treatment once daily (microcrystalline cellulose, mannitol, crospovidone, Opadry II red, magnesium stearate, colloidal silicon dioxide).

[0143] The accumulation of Compound 1 in the skin of human hi dradenitis suppurativa subjects in the treatment cohort was determined. Snap frozen punch biopsies of non- lesional skin obtained at the week 16 visit showed high concentrations of Compound 1, indicating that Compound 1 accumulates in the skin. Figure l is a graph showing the concentrations of Compound 1 found in the biopsied tissues in subjects grouped according to their clinical response to Compound 1 therapy. The mean skin concentration following 16 weeks of treatment with Compound 1 was 7130 ng / mg, which is equivalent to 16.1 mM.

[0144] The skin accumulation found in this study was compared to plasma levels of Compound 1 determined in a previous study in healthy human volunteers. Six healthy male subjects were given a single oral dose of 250 mg Compound 1, and plasma samples were collected pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, 30, 36, 48, 72 and 96 hours after dosing. The results of this study are shown in the table below.

[0145] The Cmax for Compound 1 determined for the six subjects ranged from 19.42 ng / mL to 24.92 ng / mL, with a median of 20.3 ng / mL or 46 nM.

[0146] The results show that the accumulation of Compound 1 is approximately 100,000- fold higher in the skin than in the plasma following daily oral dosing at 250 mg. In addition, the observed skin concentrations exceed the ICso of Compound 1 for inhibition of HSP-90 (0.1 pM) by a factor of about 104. One of skill in the art would understand that a daily oral dose of Compound 1 which is significantly less than 250 mg, for example, as low as 1 mg per day, will result in sufficient skin accumulation of Compound 1 to inhibit HSP-90 in the skin and thereby treat atopic dermatitis.

[0147] Example 2 Effects of Compound 1 on Biopsied Skin of a Sjogren’s Syndrome Patient To investigate the effects of Compound 1 on inflammatory cytokines CCL5, CXCL10 and CXCL13 in the skin, 3 mm punch biopsies were taken from a volunteer SS patient. Biopsies consisted of one taken from non-lesional skin and two from lesional skin areas.

[0148] The biopsies were individually incubated in an apparatus to provide an air-liquid interface across each biopsy to mimic the skin orientation. The liquid used was a cell culture medium to which dimethylsulfoxide (DMSO, vehicle control) or Compound 1 (5 pM in DMSO) was added. Cultures were incubated for 24 hours before analysis to compare the relative gene expression. Reverse transcription of total RNA (20 ng) was performed using TaqMan® Reverse Transcription Reagents (Applied Biosystems, Foster City, CA, USA). For qPCR, the mastermix used was Platinum® qPCR Super-mix-UDG (Invitrogen by Life Technologies). Primers / probes from Thermo Fisher Scientific and as a reference gene for normalization human RPLPO were used (TaqMan Gene Expression assay, Thermo Fisher Scientific). Each gene was analyzed in triplets on the real-time qPCR machine Rotorgene 3000 (Corbett Research, Sydney, Australia). The relative gene expression levels were determined from a standard curve for each gene made from a 4- fold serial dilution.

[0149] The results of this study are shown in Figures 2-4. The expression of each cytokine was significantly reduced in lesional skin treated with Compound 1 compared to lesional skin treated with vehicle. Expression of CXCL10 and CXCL13 was also reduced by treatment of Compound 1 to levels significantly below those found for non-lesional skin.

[0150] Example 3 Effects of Compound 1 on Biopsied Skin of an Alopecia Areata Patient To investigate the effects of Compound 1 on inflammatory cytokines associated with alopecia areata in the skin, 3 mm punch biopsies were taken from a volunteer alopecia areata patient. Biopsies consisted of two from lesional skin areas. The biopsies were treated and gene expression was determined using the methods described in Example 2.

[0151] The results of this study are shown in Figure 5, which presents the Z-score of the expression of selected genes as measured by RNA sequencing in lesional skin biopsies treated with DMSO vehicle and Compound 1.

[0152] Example 4 Effects of Compound 1 on Biopsied Skin of Pyoderma Gangrenosum Patients

[0153] To investigate the effects of Compound 1 on inflammatory cytokines associated with pyoderma gangrenosum in the skin, 3 mm punch biopsies were taken from two volunteer pyoderma gangrenosum patients. Biopsies consisted of one from non-lesional skin and two from lesional skin areas per patient. The biopsies were treated and gene expression was determined using the methods described in Example 2.

[0154] The results of this study are shown in Figures 6-8. Figure 6 presents the Z-score of the expression of selected genes as measured by RNA sequencing in lesional skin biopsies treated with DMSO vehicle and Compound 1. Figure 6 presents differential expressed genes as measured by RNA sequencing in non-lesional and lesional skin biopsies from one of the patients and shows significant differences in gene expression between vehicle- treated and Compound 1- treated skin. Figure 7 is a graph of IL36G qPCR data in non- lesional and lesional skin biopsies from one of the patients. The lesional biopsy treated with Compound 1 showed a significant reduction in IL36G expression compared to both vehicle treated lesional biopsies and the non-lesional biopsy. Figures 8A and 8B are each a graph of IL17A qPCR data in non-lesional and lesional skin biopsies from one of the patients. In both patients the lesional biopsy treated with Compound 1 showed significantly reduced expression of IL17A compared to the vehicle-treated lesional biopsy.

[0155] Example 5 Effects of Compound 1 on Biopsied Skin of an Acne Vulgaris Patient To investigate the effects of Compound 1 on inflammatory cytokines associated with acne vulgaris in the skin, 3 mm punch biopsies were taken from the patient. Biopsies consisted of one from non-lesional skin and two from lesional skin areas. The biopsies were treated and gene expression was determined using the methods described in Example 2.

[0156] The results of this study are shown in Figure 9. The lesional biopsy treated with Compound 1 showed a significantly decreased TNF expression compared to lesional biopsy treated with DMSO vehicle.

[0157] Example 6 Effects of Compound 1 on Biopsied Skin of Vitiligo Patients

[0158] To investigate the effects of Compound 1 on inflammatory cytokines associated with vitiligo in the skin, 3 mm punch biopsies were taken from three vitiligo patients. The biopsies consisted of one from non-lesional skin and two from lesional skin areas per patient. The biopsies were treated and gene expression was determined using the methods described in Example 2.

[0159] The results of this study are shown in Figures 10 and 11. Figure 10 presents the Z- score of the expression of selected genes as measured by RNA sequencing in non-lesional and lesional skin biopsies from one patient. Figure 11 is a graph of IL6 qPCR data in the non-lesional and lesional skin biopsies from the three patients. The lesional biopsies treated with Compound 1 showed significantly decreased IL6 expression compared to lesional biopsies treated with DMSO vehicle and the non-lesional biopsies. Example 7 Effects of Compound 1 on Biopsied Skin of Pustular Psoriasis Patients

[0160] The effects of Compound 1 on gene expression in the skin of three pustular psoriasis patients were determined. 3 mm punch biopsies were taken from each patient. Biopsies consisted of one from non-lesional skin and two from lesional skin areas per patient. The biopsies were treated and gene expression was determined using the methods described in Example 2.

[0161] The results of this study are shown in Figures 12 and 13. Figure 12 is a graph of IL23A qPCR data in the non-lesional and lesional skin biopsies from the three patients. The lesional biopsies treated with Compound 1 showed significantly decreased IL23A expression compared to lesional biopsies treated with DMSO vehicle. Figure 13 is a graph of CXCL8 qPCR data in the non-lesional and lesional skin biopsies from the three patients. The lesional biopsies treated with Compound 1 showed significantly decreased CXCL8 expression compared to lesional biopsies treated with DMSO vehicle.

[0162] Example 8 Effects of Compound 1 on Biopsied Skin of Lichen Planus Patients

[0163] The effects of Compound 1 on gene expression in the skin of two lichen planar patients were determined. 3 mm punch biopsies were taken from each patient. Biopsies consisted of one from non-lesional skin and two from lesional skin areas. The biopsies were treated and gene expression was determined using the methods described in Example 2.

[0164] The results of this study are shown in Figures 14 and 15. Figure 14 presents the Z- score of the expression of selected genes as measured by RNA sequencing in non-lesional and lesional skin biopsies from one of the patients. Figure 15A and 15B are graphs of TNF qPCR data in the non-lesional and lesional skin biopsies from each of the two patients. The lesional biopsies treated with Compound 1 showed significantly decreased TNF expression compared to lesional biopsies treated with DMSO vehicle and non-lesional biopsies.

[0165] The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts, and scientific literature cited herein are hereby incorporated by reference. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A method for treating at least one symptom of Sj ogren’ s syndrome in a subj ect in need thereof, comprising administering to the subject a therapeutically effective amount ofor a pharmaceutically acceptable salt thereof.for use in the treatment of at least one symptom of Sjogren’s syndrome.

3. The method of claim 1, or the compound of claim 2, wherein the at least one symptom is selected from dryness of the mouth, dryness of the eyes, dryness of the skin, dryness of the nose, joint pain, trouble sleeping, eye discomfort, muscle pain and / or brain fog.

4. The method of claims 1 or 3, or the compound of claims 2-3, wherein Compound 1 is administered orally or topically to the subject.

5. The method or the compound of claim 4, wherein Compound 1 is administered orally to the subject as the free base at a dose of 0.5 mg to 400 mg per day.

6. The method or the compound of claim 5, wherein Compound 1 is administered orally to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

7. The method of claims 1 or 3-6, or the compound of claims 2-6, wherein a pharmaceutically acceptable salt of Compound 1 is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg per day.

8. The method or the compound of claim 7, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

9. The method of claims 1, 3-7, or the compound of claims 2-7, wherein Compound 1 or pharmaceutically acceptable salt thereof, is orally administered in the form of a tablet.

10. The method or the compound of claim 9, wherein the tablet comprises 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg free base equivalent amount of Compound 1 or a pharmaceutically acceptable salt thereof.

11. The method or the compound of claim 4, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered topically, e.g., in the form of a cream or liquid drops, such as eye-drops or nasal drops or spray.

12. The method or compound of claim 11, wherein Compound 1 is administered topically to the subject as a free base at a dose of 0.5 mg to 400 mg per day.

13. The method or compound of claim 12, wherein Compound 1 or pharmaceutically acceptable salt thereof, is topically administered in the form of a cream, eye drops, a lotion, a gel, an ointment, an aerosol, a liquid, a liquid drop, an emulsion, or a suspension.

14. The method or compound of claim 12, wherein Compound 1 is administered topically to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

15. A method for treating neutrophilic eccrine hidradenitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compoundor a pharmaceutically acceptable salt thereof.for use in the treatment of neutrophilic eccrine hidradenitis.

17. The method of claim 15, or the compound of claim 16, wherein Compound 1 is administered orally or topically to the subject.

18. The method or the compound of claim 17, wherein Compound 1 is administered orally to the subject as the free base at a dose of 0.5 mg to 400 mg per day.

19. The method or the compound of claim 18, wherein Compound 1 is administered orally to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

20. The method or the compound of any one of claims 15 and 17, wherein a pharmaceutically acceptable salt of Compound 1 is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg per day.

21. The method or the compound of claim 20, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

22. The method of any one of claims 15 and 18-21, or the compound of any one of claims 16-21, wherein Compound 1 or pharmaceutically acceptable salt thereof, is orally administered in the form of a tablet.

23. The method or the compound of claim 22, wherein the tablet comprises 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg free base equivalent amount of Compound 1 or a pharmaceutically acceptable salt thereof.

24. The method or the compound of claim 17, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered topically, e.g., in the form of a cream or liquid drops, such as eye-drops or nasal drops or spray.

25. The method or compound of claim 24, wherein Compound 1 is administered topically to the subject as a free base at a dose of 0.5 mg to 400 mg per day.

26. The method or compound of claim 25, wherein Compound 1 is administered topically to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

27. The method or compound of any one of claims 25-26, wherein Compound 1 or pharmaceutically acceptable salt thereof, is topically administered in the form of a cream, eye drops, a lotion, a gel, an ointment, an aerosol, a liquid, a liquid drop, an emulsion, or a suspension.

28. A method for treating alopecia areata in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1,or a pharmaceutically acceptable salt thereof.

29. Compound 1for use in the treatment of alopecia areata.

30. The method of claim 28, or the compound of claim 29, wherein the subject has diffuse alopecia areata, alopecia areata monolocularis, alopecia areata multilocularis, alopecia areata totalis or alopecia areata universalis.

31. The method of claim 28 or 30, or the compound of claim 29 or 30, wherein Compound 1 is administered orally or topically to the subject.

32. The method or the compound of claim 31, wherein Compound 1 is administered orally to the subject as the free base at a dose of 0.5 mg to 400 mg per day.

33. The method or the compound of claim 32, wherein Compound 1 is administered orally to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

34. The method of any one of claims 28 or 30-33 or the compound of any one of claims 29-33, wherein a pharmaceutically acceptable salt of Compound 1 is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg per day.

35. The method or the compound of claim 34, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

36. The method of any one of claims 28 and 30-34, or the compound of any one of claims 29-34, wherein Compound 1 or pharmaceutically acceptable salt thereof, is orally administered in the form of a tablet.

37. The method or the compound of claim 36, wherein the tablet comprises 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg free base equivalent amount of Compound 1 or a pharmaceutically acceptable salt thereof.

38. The method or the compound of claim 31, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered topically.

39. The method or compound of claim 38, wherein Compound 1 is administered topically to the subject as a free base at a dose of 0.5 mg to 400 mg per day.

40. The method or compound of claim 39, wherein Compound 1 or pharmaceutically acceptable salt thereof, is topically administered in the form of a cream, a lotion, a gel an ointment, an aerosol, a powder, a liquid, an emulsion, a suspension, or via transdermal patches or via iontophoresis devices.

41. The method or compound of claim 39, wherein Compound 1 is administered topically to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

42. A method for treating epidermolysis bullosa acquisita in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compoundor a pharmaceutically acceptable salt thereof.

43. Compound 1for use in the treatment of epidermolysis bullosa acquisita.

44. The method of claim 42, or the compound of claim 43, wherein the subject has inflammatory or non-inflammatory epidermolysis bullosa acquisita.

45. The method of claim 42 or 44, or the compound of claim 43 or 44, wherein Compound 1 is administered orally or topically to the subject.

46. The method or the compound of claim 45, wherein Compound 1 is administered orally to the subject as the free base at a dose of 0.5 mg to 400 mg per day.

47. The method or the compound of claim 46, wherein Compound 1 is administered orally to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

48. The method of any one of claims 42 and 44-47, or the compound of any one of claims 43-47, wherein a pharmaceutically acceptable salt of Compound 1 is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg per day.

49. The method or the compound of claim 48, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

50. The method of any one of claims 42 and 44-49, or the compound of any one of claims 43-49, wherein Compound 1 or pharmaceutically acceptable salt thereof, is orally administered in the form of a tablet.

51. The method or the compound of claim 50, wherein the tablet comprises 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg free base equivalent amount of Compound 1 or a pharmaceutically acceptable salt thereof.

52. The method or the compound of claim 45, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered topically.

53. The method or compound of claim 52, wherein Compound 1 is administered topically to the subject as a free base at a dose of 0.5 mg to 400 mg per day.

54. The method or compound of claim 53, wherein Compound 1 or pharmaceutically acceptable salt thereof, is topically administered in the form of a cream, a lotion, a gel an ointment, an aerosol, a powder, a liquid, an emulsion, a suspension, or via transdermal patches or via iontophoresis devices.

55. The method or compound of claim 53, wherein Compound 1 is administered topically to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

56. A method for treating Pustular psoriasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1,or a pharmaceutically acceptable salt thereof.for use in the treatment of Pustular psoriasis.

58. The method of claim 56, or the compound of claim 57, wherein the subject has a type or subtype of Pustular psoriasis, the type or subtype comprising generalised pustular psoriasis, localised pustular psoriasis, Zumbusch subtype, Annular subtype, Exanthematic subtype, Impetigo herpetiformis, Palmoplantar psoriasis, and Acrodermatitis continua of Hallopeau.

59. The method of any one of claims 56 and 58, or the compound of any one of claims 57 and 58, wherein Compound 1 is administered orally or topically to the subject.

60. The method or the compound of claim 59, wherein Compound 1 is administered orally to the subject as the free base at a dose of 0.5 mg to 400 mg per day.

61. The method or the compound of claim 60, wherein Compound 1 is administered orally to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

62. The method of any one of claims 56, 58 and 59, or the compound of any one of claims 57-59, wherein a pharmaceutically acceptable salt of Compound 1 is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg per day.

63. The method or the compound of claim 62, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

64. The method of any one of claims 56 and 58-63, or the compound of any one of claims 57-63, wherein Compound 1 or pharmaceutically acceptable salt thereof, is orally administered in the form of a tablet.

65. The method or the compound of claim 64, wherein the tablet comprises 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg free base equivalent amount of Compound 1 or a pharmaceutically acceptable salt thereof.

66. The method or the compound of claim 59, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered topically, e.g., in the form of a cream.

67. The method or compound of claim 66, wherein Compound 1 is administered topically to the subject as a free base at a dose of 0.5 mg to 400 mg per day.

68. The method or compound of claim 67, wherein Compound 1 is administered topically to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

69. The method or compound of claim 67 or 68, wherein Compound 1 or pharmaceutically acceptable salt thereof, is topically administered in the form of a cream, a lotion, a gel, an ointment, an aerosol, a powder, a liquid, a liquid drop, an emulsion, a suspension, via transdermal patches or via iontophoresis devices.

70. A method for treating vitiligo in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1,or a pharmaceutically acceptable salt thereof.for use in the treatment of vitiligo.

72. The method of claim 70, or the compound of claim 71, wherein the subject has segmental vitiligo or non-segmental vitiligo.

73. The method of claims 70 or 72, or the compound of claim 71 or 72, wherein Compound 1 is administered orally or topically to the subject.

74. The method or the compound of claim 73, wherein Compound 1 is administered orally to the subject as the free base at a dose of 0.5 mg to 400 mg per day.

75. The method or the compound of claim 74, wherein Compound 1 is administered orally to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

76. The method of any one of claims 70 or 72-76, or the compound of any one of claims 71-75, wherein a pharmaceutically acceptable salt of Compound 1 is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg per day.

77. The method or the compound of claim 76, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

78. The method of any one of claims 70 and 72-76, or the compound of any one of claims 71-76, wherein Compound 1 or pharmaceutically acceptable salt thereof, is orally administered in the form of a tablet.

79. The method or the compound of claim 78, wherein the tablet comprises 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg free base equivalent amount of Compound 1 or a pharmaceutically acceptable salt thereof.

80. The method or the compound of claim 73, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered topically.

81. The method or compound of claim 80, wherein Compound 1 is administered topically to the subject as a free base at a dose of 0.5 mg to 400 mg per day.

82. The method or compound of claim 81, wherein Compound 1 or pharmaceutically acceptable salt thereof, is topically administered in the form of a cream, a lotion, a gel an ointment, an aerosol, a powder, a liquid, an emulsion, a suspension, or via transdermal patches or via iontophoresis devices.

83. The method or compound of claim 81, wherein Compound 1 is administered topically to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

84. A method for treating Sweet syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1,or a pharmaceutically acceptable salt thereof.

85. Compound 1for use in the treatment of Sweet syndrome.

86. The method of claim 84, or the compound of claim 85, wherein the subject has classical Sweet syndrome, malignancy-associated Sweet syndrome, or drug-induced Sweet syndrome.

87. The method of any one of claims 84 or 86, or the compound of any one of claims 85 and 86, wherein Compound 1 is administered orally or topically to the subject.

88. The method or the compound of claim 87, wherein Compound 1 is administered orally to the subject as the free base at a dose of 0.5 mg to 400 mg per day.

89. The method or the compound of claim 88, wherein Compound 1 is administered orally to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

90. The method of any one of claims 84 and 86-87, or the compound of any one of claims 85-87, wherein a pharmaceutically acceptable salt of Compound 1 is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg per day.

91. The method or the compound of claim 90, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

92. The method of any one of claims 84 and 86-91, or the compound of any one of claims 85-91, wherein Compound 1, or pharmaceutically acceptable salt thereof, is orally administered in the form of a tablet.

93. The method or the compound of claim 92, wherein the tablet comprises 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg free base equivalent amount of Compound 1 or a pharmaceutically acceptable salt thereof.

94. The method or the compound of claim 87, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered topically, e.g. in the form of a cream or liquid drops, such as eye-drops or nasal drops or spray.

95. The method or compound of claim 94, wherein Compound 1 is administered topically to the subject as a free base at a dose of 0.5 mg to 400 mg per day.

96. The method or compound of claim 95, wherein Compound 1 is administered topically to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

97. The method or compound of any one of claims 95 and 96, wherein Compound 1 or pharmaceutically acceptable salt thereof, is topically administered in the form of a cream, eye drops, a lotion, a gel, an ointment, an aerosol, a powder, a liquid, a liquid drop, an emulsion, a suspension, transdermal patches or iontophoresis devices.

98. A method for treating lichen planus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1,or a pharmaceutically acceptable salt thereof.

99. Compound 1for use in the treatment of lichen planus.

100. The method of claim 98, or the compound of claim 99, wherein the subject has cutaneous lichen planus, or mucosal lichen planus.

101. The method of claim 98 or 100, or the compound of claim 99 or 100, wherein Compound 1 is administered orally or topically to the subject.

102. The method or the compound of claim 101, wherein Compound 1 is administered orally to the subject as the free base at a dose of 0.5 mg to 400 mg per day.

103. The method or the compound of claim 102, wherein Compound 1 is administered orally to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

104. The method of any one of claims 98 or 100-103, or the compound of any one of claims 99-103, wherein a pharmaceutically acceptable salt of Compound 1 is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg per day.

105. The method or the compound of claim 104, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

106. The method of any one of claims 98 and 100-104, or the compound of any one of claims 99-104, wherein Compound 1 or pharmaceutically acceptable salt thereof, is orally administered in the form of a tablet.

107. The method or the compound of claim 106, wherein the tablet comprises 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg free base equivalent amount of Compound 1 or a pharmaceutically acceptable salt thereof.

108. The method or the compound of claim 101, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered topically.

109. The method or compound of claim 108, wherein Compound 1 is administered topically to the subject as a free base at a dose of 0.5 mg to 400 mg per day.

110. The method or compound of claim 109, wherein Compound 1 or pharmaceutically acceptable salt thereof, is topically administered in the form of a cream, a lotion, a gel an ointment, an aerosol, a powder, a liquid, an emulsion, a suspension, or via transdermal patches or via iontophoresis devices.

111. The method or compound of claim 109, wherein Compound 1 is administered topically to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

112. A method for treating pyoderma gangrenosum in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1,or a pharmaceutically acceptable salt thereof.

113. Compound 1,for use in the treatment of pyoderma gangrenosum.

114. The method of claim 112, or the compound of claim 113, wherein the subject has peristomal pyoderma gangrenosum, bullous pyoderma gangrenosum, vesicular-bullous pyoderma gangrenosum, pustular pyoderma gangrenosum, ulcerative pyoderma gangrenosum, superficial pyoderma gangrenosum or vegetative pyoderma gangrenosum.

115. The method of any one of claims 112 or 114, or the compound of any one of claims 113 and 114, wherein Compound 1 is administered orally or topically to the subject.

116. The method or the compound of claim 115, wherein Compound 1 is administered orally to the subject as the free base at a dose of 0.5 mg to 400 mg per day.

117. The method or the compound of claim 116, wherein Compound 1 is administered orally to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

118. The method of any one of claims 112 or 114-117, or the compound of any one of claims 113-117, wherein a pharmaceutically acceptable salt of Compound 1 is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg per day.

119. The method or the compound of claim 118, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

120. The method of any one of claims 112 and 114-118, or the compound of any one of claims 113-118, wherein Compound 1 or pharmaceutically acceptable salt thereof, is orally administered in the form of a tablet.

121. The method or the compound of claim 120, wherein the tablet comprises 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg free base equivalent amount of Compound 1 or a pharmaceutically acceptable salt thereof.

122. The method or the compound of claim 115, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered topically.

123. The method or compound of claim 122, wherein Compound 1 is administered topically to the subject as a free base at a dose of 0.5 mg to 400 mg per day.

124. The method or compound of claim 123, wherein Compound 1 or pharmaceutically acceptable salt thereof, is topically administered in the form of a cream, a lotion, a gel an ointment, an aerosol, a powder, a liquid, an emulsion, a suspension, or via transdermal patches or via iontophoresis devices.

125. The method or compound of claim 123, wherein Compound 1 is administered topically to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

126. A method for treating acne in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1,or a pharmaceutically acceptable salt thereof.for use in the treatment of acne.

128. The method of claim 126, or the compound of claim 127, wherein the acne is mild, moderate or severe acne.

129. The method of any one of claims 126 and 128, or the compound of any one of claims 127-128, wherein the acne is acne vulgaris, comedonal acne, preputal acne, nodulocystic acne, acne conglobate, or acne fulminans.

130. The method of any one of claims 126 and 128-129, or the compound of any one of claims 127-129, wherein Compound 1 is administered orally or topically to the subject.

131. The method or the compound of claim 130, wherein Compound 1 is administered orally to the subject as the free base at a dose of 0.5 mg to 400 mg per day.

132. The method or the compound of claim 131, wherein Compound 1 is administered orally to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

133. The method of any one of claims 126 and 129-130, or the compound of any one of claims 127-130, wherein a pharmaceutically acceptable salt of Compound 1 is administered orally to the subject at a free base equivalent dose of 200 mg to 300 mg per day.

134. The method or the compound of claim 133, wherein the free base equivalent dose is 225 mg to 275 mg per day, 240 mg to 260 mg per day, 245 to 255 mg / day or 250 mg per day.

135. The method of any one of claims 126 and 128-134, or the compound of any one of claims 127-134, wherein Compound 1, or pharmaceutically acceptable salt thereof, is orally administered in the form of a tablet.

136. The method or the compound of claim 135, wherein the tablet comprises 0.5 mg to 500 mg, from 1 mg to 450 mg, from 10 mg to 350 mg, from 20 mg to 300 mg, from 40 mg to 275 mg, 50 mg to 260 mg or 250 mg free base equivalent amount of Compound 1 or a pharmaceutically acceptable salt thereof.

137. The method or the compound of claim 130, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered topically, e.g., in the form of a cream.

138. The method or compound of claim 137, wherein Compound 1 is administered topically to the subject as a free base at a dose of 0.5 mg to 400 mg per day.

139. The method or compound of claim 138, wherein Compound 1 is administered topically to the subject as the free base at a dose of 25 mg to 275 mg per day, 30 mg to 260 mg per day, 50 to 255 mg / day or 250 mg per day.

140. The method or compound of any one of claims 138-139, wherein Compound 1 or pharmaceutically acceptable salt thereof, is topically administered in the form of a cream, eye drops, a lotion, a gel, an ointment, an aerosol, a liquid, a liquid drop, an emulsion, or a suspension.

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