Treatment of psoriasis using small molecule inhibitors of tumor necrosis factor alpha

Abstract

A treatment for psoriasis is provided herein, wherein a human subject is administered a daily dose of 400 mg of compound 1 or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] A treatment for psoriasis is provided herein, wherein the patient is administered a prescribed dose of a low-molecular-weight inhibitor of soluble tumor necrosis factor alpha. This is based on the results of a clinical trial that showed that treatment with the inhibitor over 28 days was effective, safe, and well-tolerated by participants with mild to moderate psoriasis. [Background technology]

[0002] Tumor necrosis factor alpha (TNFα) is a cytokine with multifaceted effects on both pathological and homeostatic processes. TNFα is thought to play a crucial pathophysiological role in psoriasis (see, e.g., Mease, Ann Rheum Dis (2004) 63:755-758), and TNFα antagonists form the basis of modern management of psoriasis.

[0003] TNFα is a member of the TNF superfamily of cytokines. It is produced by various cell types, particularly inflammatory cells. It is initially expressed as a transmembrane protein also known as membrane-bound TNFα (mTNFα). On the cell surface, mTNFα can be cleaved by TNFα-converting enzyme to produce soluble TNFα (sTNFα). Structurally, both mTNFα and sTNFα exist as homotrimers capable of binding to three congener receptors. This trimer engagement is essential for receptor multimerization and subsequent signal transduction. sTNFα primarily signals via tumor necrosis factor receptor 1 (TNFR1), which is expressed in most cell types. In contrast, mTNFα mostly engages with tumor necrosis factor receptor 2 (TNFR2). TNFR2 is primarily expressed on neurons, endothelial cells, and immune cells, and is particularly enriched in certain subpopulations of regulatory T cells (Tregs).

[0004] Functionally, sTNFα and mTNFα play distinct roles in pathological and homeostatic processes. TNFR1 engagement with sTNFα leads to the activation of pro-inflammatory and pro-apoptotic pathways, which play a central role in the effects of TNFα in certain autoimmune states. In contrast, mTNFα signaling contributes to various homeostatic functions, including tissue regeneration and cell survival. From an inflammatory perspective, mTNFα has been shown to enhance the function and proliferation of certain subsets of suppressor Tregs. TNFR2 agonism has also been shown to promote the death of autoreactive CD8+ T cells. Notably, mTNFα mice expressing only an indispensable form of TNFα have been generated to study the specific effects of mTNFα. In respiratory tuberculosis infection models, multiple studies have demonstrated reduced mortality and bacterial load in mTNFα mice compared to TNFα knockout mice. Similar results have been demonstrated in mouse infection models of Listeria monocytogenes, Mycobacterium bovis bacilli Calmette-Guerin, and Leishmania major.

[0005] Typically, the naturally occurring asymmetric trimer form of sTNFα, a transient intermediate, has a reduced ability to engage with TNFR1 (see, e.g., O'Connell et al., Nat Commun (2019) 10:5795-5806). Using analytical size exclusion, O'Connell et al. demonstrated the reduced ability of sTNFα and further showed that UCB-9260, a molecule with a tris-substituted benzimidazole structure, stabilizes the asymmetric sTNFα trimer in vitro and reduces TNFR1 signaling. In their study, Jurcat cells were treated with sTNFα, sTNFα pre-incubated with UCB-9260, or sTNFα pre-incubated with etanercept. As measured by Western blot analysis of kinases, receptor-interacting protein kinase 1 (RIP-1) ubiquitination, and nuclear factor kappa B (NF-κB) phosphorylation, TNFR1 signaling was reduced in both samples treated with etanercept and UCB-9260 compared to samples treated with sTNFα alone.

[0006] The compound used in the treatment of the present disclosure is (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidine-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazosin-5(14H)-one. The structure of this compound, compound 1, is shown below, and it has a pentacyclic core structure. [ka]

[0007] The synthesis of compound 1 is described in international patent application PCT / EP2018 / 060489 (published as international publication brochure 2018 / 197503), which also describes the compound as belonging to a class of human TNFα activity regulators useful for the treatment and / or prevention of a variety of conditions, including various inflammatory and autoimmune disorders, neurological and neurodegenerative disorders, pain and noxious disorders, cardiovascular disorders, metabolic disorders, ocular disorders and neoplastic disorders.

[0008] Psoriasis is a T-cell-mediated autoimmune disease with characteristics regulated by genetic susceptibility as well as environmental triggers. An inflammatory pathway involving the overproduction of the cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23) promotes the differentiation of the pathogenic T-cell response, resulting in the production of TNF and interleukin-17 (IL-17). These cytokines are integral parts of the TNF / IL-23 / IL-17 axis, which plays a role in maintaining inflammation in psoriatic skin (see, e.g., Bergen et al., Scand J Immunol. (2020) 92(4):e12946). Psoriasis is estimated to affect 1%–3% of the world's population. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] Historically, psoriasis has been treated with topical formulations (e.g., creams and ointments that may only have a emollient effect or contain activators such as steroids and / or vitamin D analogs), phototherapy, and systemic therapies (e.g., treatment with oral anti-inflammatory drugs such as methotrexate or immunosuppressants such as cyclosporine). More recently, biological therapies that inhibit TNFα, such as etanercept (Enbrel®, approved in the EU for the treatment of conditions including moderate and severe plaque psoriasis), have been developed. While biological therapies can be very effective, they carry the risk of immunogenicity, the development of neutralizing anti-drug antibodies, and side effects, some of which can be severe. These are typically administered by injection and may require medical management or monitoring. Therefore, there is an urgent need for novel psoriasis treatments that are effective, have an acceptable safety profile, and offer advantages in terms of ease of manufacture, storage, and suitability for oral administration. [Means for solving the problem]

[0010] This disclosure provides the results of a clinical trial in which Compound 1 was orally administered to patients with psoriasis. The results suggest that the treatment described herein is effective not only in reducing clinical symptoms but also in reducing the levels of inflammatory mediators involved in disease progression. No serious adverse effects were observed during the trial, no safety concerns based on vital signs, ECG, or laboratory results, and no signals of risk on liver function tests. No signs of risk of QTc prolongation were observed. This is considered to be the first successful clinical trial of a small molecule TNFα inhibitor in patients with psoriasis.

[0011] In a first aspect, the present disclosure relates to (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidine-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidaz[1,2-b][2,5]benzodiazosin-5(14H)-one (compound 1): [ka] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, for use in a method of treating psoriasis in a human subject, wherein the subject has mild to moderate psoriasis, and the method comprises administering a daily dose of approximately 400 mg of the compound (calculated as free base) to the subject.

[0012] In one embodiment, psoriasis is plaque psoriasis, for example, chronic plaque psoriasis.

[0013] In this embodiment, the severity of psoriasis in a subject is assessed using PASI scoring, and the subject has a total PASI score of 16 or less.

[0014] In this embodiment, the subject has a total PASI score of 10 or more.

[0015] In this embodiment, the subject has at least two lesions with a TLS score of 4 or higher (excluding the scalp).

[0016] In an embodiment, the compound is administered orally to a subject.

[0017] In an embodiment, the compound is administered in the form of an oral pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In an embodiment, the oral pharmaceutical composition is a tablet.

[0018] In an embodiment, the method comprises administering to the subject a dose of about 200 mg of the compound (calculated as the free base) twice a day.

[0019] In a further aspect, the present disclosure provides a method of treating psoriasis as defined above, wherein a therapeutically effective amount of compound 1 (or a pharmaceutically acceptable salt thereof) is administered to a human subject that needs it, and the therapeutically effective amount is a daily dose of about 400 mg (calculated as the free base).

[0020] In a further aspect, the present disclosure provides compound 1 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating mild to moderate psoriasis according to the method defined above, wherein the medicament is adapted to provide a daily dose of about 400 mg of the compound (calculated as the free base).

[0021] Further features and advantages of the compositions and methods disclosed herein will become apparent from the following detailed description.

Brief Description of the Drawings

[0022] [Figure 1] Shows the mean (±SEM) change in TLS score from baseline over 2 and 4 weeks of treatment in human subjects with psoriasis. The solid line with black circles is the placebo treatment arm and the dashed line with white circles is the compound 1 treatment arm. [Figure 2]This chart shows the mean (±SEM) change in total PASI score from baseline over 2-week and 4-week treatment periods in human subjects with psoriasis. The solid line with black circles represents the placebo treatment arm, and the dashed line with white circles represents the compound 1 treatment arm. [Figure 3] This graph shows the time-course ratio of serum levels of IL-17A, a systemic biomarker for psoriasis, from baseline (data represent geometric mean (× / ÷) geometric SEM). The light gray line (top) represents the placebo treatment arm, and the dark gray line (bottom) represents the compound 1 treatment arm. *P<0.05; **P=0.0001; ***P<0.0001. [Figure 4] This graph shows the time-course ratio of serum levels of IL-17F, a systemic biomarker for psoriasis, from baseline (data represent geometric mean (× / ÷) geometric SEM). The light gray line (top) represents the placebo treatment arm, and the dark gray line (bottom) represents the compound 1 treatment arm. *P<0.05; **P=0.0001; ***P<0.0001. [Figure 5] This graph shows the time-course ratio of serum levels of IL-22, a systemic biomarker for psoriasis, from baseline (data represent geometric mean (× / ÷) geometric SEM). The light gray line (top) represents the placebo treatment arm, and the dark gray line (bottom) represents the compound 1 treatment arm. *P<0.05; **P=0.0001; ***P<0.0001. [Figure 6] The percentage of patients who achieved a static investigator global assessment (sIGA) score category (determined as described herein) at baseline, week 2, and week 4 is shown. Each sIGA category is represented by a pair of bars, with the percentage of patients from the placebo arm (N=12) shown in the left bar (gray) and the percentage of patients from the treatment arm (compound 1, 200 mg BID; N=25) shown in the right bar (white). [Modes for carrying out the invention]

[0023] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. Any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but exemplary methods, apparatus and materials are described herein. All technical and patent publications referenced herein are incorporated herein by reference in their entirety.

[0024] The implementation of this disclosure will utilize conventional techniques in tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the scope of the skills in the art, unless otherwise instructed. For example, Michael R. Green and Joseph Sambrook, Molecular Cloning (4 th ed., Cold Spring Harbor Laboratory Press 2012); the series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; the series Methods in Enzymology (Academic Press, Inc., NY); MacPherson et al. (1991) PCR 1:A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical approach;Harlow and Lane eds.(1999)Antibodies,A Laboratory Manual;Freshney(2005)Culture of Animal Cells:A Manual of Basic Technique,5 thedition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Patent No. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); Herzenberg et al. eds (1996) Weir’s Handbook of Experimental Immunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3 rd edition (Cold Spring Harbor Laboratory Press (2002)); See Sohail (ed.) (2004) Gene Silencing by RNA Interference: Technology and Application (CRC Press).

[0025] All numerical specifications (e.g., pH, temperature, time, concentration, molecular weight, including ranges) are approximations that, where appropriate, vary by (+) or (-) in increments of, for example, 0.1 or 1.0. It should be understood that, although not necessarily explicitly stated, the term “approximately” is used before every numerical specification to indicate a conventional level of variability. For example, a numerical specification that is “approximately” a given value may vary by ±10% of that value, or conversely, this variation may be ±5%, ±2%, or ±1% of that value. For example, an amount of compound 1 or a pharmaceutically acceptable salt thereof defined as “approximately 400 mg (calculated as free base)” may be 360 ​​mg to 440 mg (calculated as free base), i.e., 400 mg ± 10%, or conversely, the variation may be ±5%, ±2%, or ±1% of the value. It should also be understood that, although not necessarily explicitly stated, the reagents described herein are merely illustrative, and their equivalents are known in the art.

[0026] As used herein and in the claims, the singular forms “one (a),” “one (an),” and “it” include multiple references unless otherwise clearly indicated by the context. For example, the term “inhibitor” includes multiple inhibitors, including mixtures thereof. Unless otherwise specified or made clear by the context, the term “or” as used herein is understood to be inclusive. The term “including” is used herein to mean the phrase “including, but not limited to,” and is used interchangeably with this phrase.

[0027] Where used herein, the terms “contains” or “includes” are intended to mean that a composition and method includes the enumerated elements but does not exclude other elements. “Essentially from” is intended, where used to define a composition and method, to mean excluding other elements that are essentially important to the purposes described. Thus, a composition essentially from the elements defined herein would not exclude isolation and purification methods and trace impurities from pharmaceutically acceptable carriers, such as phosphate-buffered saline, preservatives, etc. “Consists of” is intended to mean the exclusion of other components, other components beyond trace elements, and substantial method steps for administering the compositions of this disclosure or process steps for producing the compositions or achieving the intended results. Embodiments defined by each of these transitional terms are within the scope of this disclosure. The use of the term “contains” herein is intended to encompass both “essentially from” and “consists of.”

[0028] The terms "subject," "individual," and "patient" are used interchangeably in this specification and refer to human beings.

[0029] "Administering" is defined herein as a means of providing a drug (e.g., an active ingredient) or a composition containing a drug to a target in a manner that the drug is present within the target's body. Such administration may be by any route, but is not limited to oral administration. Pharmaceutical formulations are, of course, administered in a form appropriate to each route of administration. The compositions and methods of this disclosure typically involve enteral, for example, oral administration.

[0030] "Treating" or "treating" a disease includes: (1) inhibiting the disease, i.e., stopping or reducing the onset of the disease or its clinical symptoms; and / or (2) alleviating the disease, i.e., causing a regression of the disease or its clinical symptoms. "Preventing" or "preventing" a disease includes preventing the onset of clinical symptoms of the disease in patients who may be predisposed to the disease but have not yet experienced or shown symptoms of the disease.

[0031] The term "affected" in relation to the term "treatment" refers to a patient or individual diagnosed with a disease. The term "affected" in relation to the term "prevention" refers to a patient or individual susceptible to a disease. A patient may also be said to be "at risk of developing" the disease due to a family history of the disease or the presence of a disease-related gene mutation. A patient at risk of developing the disease has not yet developed all or some of the characteristic pathological features of the disease.

[0032] An “effective dose” or “therapeutic effective dose” is a quantity sufficient to produce a beneficial or desired result. An effective dose may be administered in one or more doses, applications, or dosages. Such delivery depends on many variables, including the duration for which individual dose units are used, the bioavailability of the therapeutic agent, and the route of administration. However, it is understood that a particular dose level of the therapeutic agent of this disclosure for any particular subject will depend on various factors, including, for example, the activity of the particular compound used, the subject’s age, weight, overall health status, sex, and diet, the timing of administration, the severity of the particular disorder being treated, and the form of administration. Typically, dose-response relationships from in vitro and / or in vivo studies can provide useful guidance regarding the appropriate dose for initial patient administration. Generally, it will be desirable to administer an amount of the compound effective in achieving a serum level corresponding to the concentration found to be effective in vitro. Determining these parameters is well within the scope of the art. These considerations, as well as effective formulations and administration procedures, are well known in the art and are described in standard texts. As used herein in accordance with this definition, the term “therapeutic dose” is a quantity sufficient to treat (e.g., improve) one or more symptoms associated with a disease or disorder described herein, ex vivo, in vitro, or in vivo.

[0033] As used herein, the term “pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical excipients, including phosphate-buffered saline, water and emulsions (e.g., oil / water emulsion or water / oil emulsion), and carriers such as various types of wetting agents. Pharmaceutical compositions may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co., 2000).

[0034] As used herein, the term “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid-added salt or pharmaceutically acceptable base-added salt of the compound herein that can be administered without causing any substantially undesirable biological effects or adverse interactions with any other components of the pharmaceutical composition in which it may be contained.

[0035] The mass (e.g., dose) of Compound 1 referred to herein corresponds to the mass of the compound calculated as free base unless otherwise specified. For example, a 400 mg dose of Compound refers to the amount of free base of Compound 1 or the amount of a salt of Compound 1 that provides an equivalent molar amount of Compound 1, which is referred to herein as the amount "calculated as free base".

[0036] The enumeration of embodiments relating to variables or aspects in this specification includes this embodiment as any single embodiment, or in combination with any other embodiment or part thereof.

[0037] Any composition or method provided herein may be combined with one or more other compositions and methods provided herein.

[0038] The following abbreviations are used in this specification. ADL activities of daily living Adverse events (AEs) AESI (Adverse Events of Particular Note) ALT (Alanine Aminotransferase) aPTT (Activated Partial Thromboplastin Time) AST (Aspartate Aminotransferase) BID twice a day (medication) BMI (Body Mass Index) BSA body surface area CI confidence interval CK Creatine Kinase COVID-19 (also known as SARS-CoV-2; Severe Acute Respiratory Syndrome Coronavirus-2) CPK creatine phosphokinase (e) CRF (Electronic) Case Report Form (hs)CRP (High Sensitivity) C-Reactive Protein CYP Cytochrome P450 DBP (Diast Blood Pressure) DNA (Deoxyribonucleic Acid) ECG (Electrocardiogram) ELISA enzyme-linked immunosorbent assay End of Service / End of Service (EoS) exam completed. FSH (Follicle-Stimulating Hormone) GGT (Gamma Glutamate Transferase) (β-)HCG (beta-) Human chorionic gonadotropin HCV (Hepatitis C virus) hERG (human etheragogo-related gene) HIV1 / HIV2 Human Immunodeficiency Virus 1 / 2 HR (Heart Rate) HRT (Hormone Replacement Therapy) ICF Informed Consent Form IL interleukins (e.g., IL-17A, IL-17F, IL-22) IMP Investigational Drug INR International Standardization Ratio LSm (Least Squares Mean) Mixed Model for Repeated Measures (MMRM) NCI-CTCAE Common Terminology Criteria for Adverse Events of the National Cancer Institute NIMP Non-investigational drug P-gp P-glycoprotein PASI Area and Severity Index (The following abbreviations are used in relation to PASI scoring: head (h), upper extremities (u), trunk (t), lower extremities (l), numerical score (A), erythema (E), hypertrophy / induration (I), and desquamation / scaling (D), where "Eh" represents erythema on the head and "It" represents induration on the trunk). PCR (polymerase chain reaction) PCSA potentially clinically significant abnormalities PCT Procalcitonin PD drug power PK (Pharmacokinetics) PT basic term QFT QuantiFERON-TB Gold Test QTcF Fridericia-corrected QT interval (QT interval = time between the start of the QRS complex and the end of the T wave) RNA (ribonucleic acid) RT retention time SAE (Serious Adverse Event) SBP (Systolic Blood Pressure) SD standard deviation SE standard error Standard error of the SEM mean sIGA Static Clinical Trial Principal Investigator Global Evaluation SOC major classification by organ SPF (Sun Protection Factor) TB Tuberculosis Adverse events that occurred during TEAE treatment TLS(S) Target Lesion Severity (Score) TNF(α) Tumor Necrosis Factor (Alpha) mTNFα membrane-bound TNFα sTNFα Soluble TNFα TNFR1 / TNFR2 Tumor Necrosis Factor Receptor 1 / 2 ULN normal upper limit XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0039] Hereinafter, specific embodiments of the Disclosure will be described with reference to the Preparations and Schemes, but it should be understood that such embodiments are merely illustrative and illustrate only a small fraction of the many possible specific embodiments that may represent the application of the principles of the Disclosure. Various modifications and alterations will be apparent to those skilled in the art in consideration of the interests of the Disclosure and will be deemed to be within the spirit and scope of the Disclosure as further defined in the appended claims.

[0040] This disclosure describes clinical trials conducted to evaluate the effects of Compound 1 on patients with mild and moderate psoriasis. Oral administration of 400 mg of Compound 1 per day was shown to be effective in improving clinical parameters in human patients, including the Psoriasis Area and Severity Index (PASI) score and the Targeted Lesion Severity (TLS) score. Improvements in psoriasis biomarkers, including serum levels of IL-17A, IL-17F, and IL-22, were also observed. No serious or severe adverse events were observed during the trials, nor were there any significant effects on cardiac parameters (e.g., QTcF interval) or hepatic parameters (e.g., AST, ALT, or bilirubin levels).

[0041] Therefore, a first aspect of this disclosure is (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidine-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazosin-5(14H)-one (i.e., compound 1): [ka] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, for use in a method of treating psoriasis in a human subject, wherein the subject has mild to moderate psoriasis, and the method comprises administering a daily dose of approximately 400 mg of the compound (calculated as free base) to the subject.

[0042] A related embodiment is a method for treating psoriasis in a human subject in need thereof, the subject having mild to moderate psoriasis, and the method comprising a therapeutically effective amount of (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidine-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazosin-5(14H)-one (i.e., compound 1): [ka] The present invention provides a method comprising administering a pharmaceutically acceptable salt thereof to a target, wherein the therapeutically effective dose is approximately 400 mg per day (calculated as free base).

[0043] Another related embodiment provides a compound for use in the manufacture of a drug for treating psoriasis in human subjects, the compound being (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidine-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazosin-5(14H)-one (i.e., compound 1): [ka] or a pharmaceutically acceptable salt thereof, the subject having mild to moderate psoriasis, and the drug is adapted to provide a daily dose of approximately 400 mg of the compound (calculated as free base) to the subject.

[0044] In one embodiment, psoriasis is plaque psoriasis. In another embodiment, psoriasis is chronic plaque psoriasis.

[0045] In one embodiment, the subject has mild psoriasis. In this embodiment, the disclosure provides a compound for use in a method of treating mild psoriasis in a human subject, wherein the compound is compound 1 or a pharmaceutically acceptable salt thereof, and the method comprises administering a daily dose of about 400 mg of the compound (calculated as free base) to the subject. In another embodiment, the subject has moderate psoriasis. In this embodiment, the disclosure provides a compound for use in a method of treating moderate psoriasis in a human subject, wherein the compound is compound 1 or a pharmaceutically acceptable salt thereof, and the method comprises administering a daily dose of about 400 mg of the compound (calculated as free base) to the subject.

[0046] In embodiments, the severity of psoriasis in a subject is assessed using PASI scoring, for example, as described herein (see also, e.g., the EMA Guidelines on clinical investigation of medicinal products indicated for the treatment of psoriasis, November 18, 2004). A subject may be classified as having mild to moderate psoriasis if they have a total PASI score of 16 or less. Thus, in one embodiment, a subject has a total PASI score of 16 or less. A subject may be classified as having mild psoriasis if they have a total PASI score of less than 10. Thus, in one embodiment, a subject has a total PASI score of less than 10. A subject may be classified as having moderate psoriasis if they have a total PASI score of 10 or more. Thus, in one embodiment, a subject has a total PASI score of 10 or more.

[0047] In this latter aspect, the disclosure provides a compound for use in a method of treating psoriasis in a human subject, wherein the compound is compound 1 or a pharmaceutically acceptable salt thereof, the subject has a total PASI score of 10 or more, and the method comprises administering a daily dose of about 400 mg of the compound (calculated as free base) to the subject. In the embodiment, the subject has a total PASI score of 10 or more and 16 or less.

[0048] In another aspect, the Disclosure provides a compound for use in a method of treating psoriasis in a human subject, wherein the compound is compound 1 or a pharmaceutically acceptable salt thereof, the subject has a total PASI score less than 10, and the method comprises administering a daily dose of about 400 mg of the compound (calculated as free base) to the subject.

[0049] In embodiments, the treatment results in a reduction of the total PASI score (e.g., compared to a baseline that may be assessed immediately before the start of treatment). In embodiments, the reduction is at least 1 point, e.g., about 1.5 points. In other embodiments, the reduction is at least 2 points, e.g., about 3 points. In embodiments, the reduction in the total PASI score is at least 15%, e.g., at least 25% or at least 35%. In embodiments, the reduction is achieved over a period of at least 2 weeks or at least 4 weeks. In embodiments, the treatment results in a reduction of about 1.5 points in the total PASI score over a period of about 2 weeks. In embodiments, the treatment results in a reduction of about 17% in the total PASI score over a period of about 2 weeks. In embodiments, the treatment results in a reduction of about 3 points in the total PASI score over a period of about 4 weeks. In embodiments, the treatment results in a reduction of about 35% in the total PASI score over a period of about 4 weeks. In one embodiment, the subject has a total PASI score of less than 10, and the treatment results in a reduction of approximately 21% in the total PASI score over a period of approximately two weeks and / or a reduction of approximately 34% in the total PASI score over a period of approximately four weeks. In another embodiment, the subject has a total PASI score of 10 or more, and the treatment results in a reduction of approximately 9% in the total PASI score over a period of approximately two weeks and / or a reduction of approximately 33% in the total PASI score over a period of approximately four weeks.

[0050] In embodiments, the presence (or severity) of psoriasis in a subject is assessed using TLS scoring, for example, as described herein (see also, e.g., Fredriksson et al., Dermatologica (1978) 157(4):238-244; and Czarnowicki et al., J Am Acad Dermatol. (2014) 71(5):954-959.e1). In embodiments, a subject has at least two lesions with a TLS score of 4 or higher (excluding the scalp). In embodiments, a subject has at least two lesions with a TLS score of 4 or higher (excluding the scalp) and also has a total PASI score of 16 or less.

[0051] In embodiments, treatment results in a reduction in the TLS score of one or more lesions (e.g., compared to a baseline that can be assessed immediately before the start of treatment). In embodiments, the TLS score is calculated as the average score from two lesions. In embodiments, the reduction is at least 1 point. In embodiments, the reduction is about 1 point. In other embodiments, the reduction is at least 1.5 points, e.g., about 2.5 points. In embodiments, the reduction is at least 15%, e.g., at least 35%. In embodiments, the reduction is achieved over a period of at least 2 weeks or at least 4 weeks. In embodiments, treatment results in a reduction of about 1 point in the TLS score over a period of about 2 weeks. In embodiments, treatment results in a reduction of about 17% in the TLS score over a period of about 2 weeks. In embodiments, treatment results in a reduction of about 2.5 points in the TLS score over a period of about 4 weeks. In embodiments, treatment results in a reduction of about 38% in the TLS score over a period of about 4 weeks. In one embodiment, the subject has a total PASI score of less than 10, and the treatment results in a reduction of approximately 21% of the TLS score over a period of approximately two weeks and / or a reduction of approximately 37% of the TLS score over a period of approximately four weeks. In another embodiment, the subject has a total PASI score of 10 or more, and the treatment results in a reduction of approximately 11% of the TLS score over a period of approximately two weeks and / or a reduction of approximately 40% of the TLS score over a period of approximately four weeks.

[0052] In embodiments, the presence (or severity) of psoriasis in a subject is assessed using sIGA scoring, for example, as described herein (see also, e.g., Langley et al., J Dermatolog. Treat. (2015) 26(1):23-31). A subject may be classified as having mild to moderate psoriasis by having an average sIGA score of less than 4.5 (e.g., the average calculated from the scoring of erythema, induration, and scaling, as described below). Thus, in one embodiment, a subject has an average sIGA score greater than 0.0 and less than 4.5, for example, an average sIGA score of 1.5 or greater and less than 3.5. In embodiments, a subject has an average sIGA score greater than 0.0 and less than 2.5, for example, an average sIGA score of 1.5 or greater and less than 2.5 (e.g., the subject is classified as having mild psoriasis). In embodiments, subjects have an average sIGA score of 2.5 or higher and less than 4.5, for example, an average sIGA score of 2.5 or higher and less than 3.5 (for example, a subject is classified as having moderate psoriasis). sIGA scoring can also be used in conjunction with other assessment scales, e.g., those described herein. Therefore, in embodiments, subjects have an average sIGA score less than 4.5 and have: (i) at least two lesions with a TLS score of 4 or higher (excluding scalp); (ii) a total PASI score of 16 or less; or (iii) at least two lesions with a TLS score of 4 or higher (excluding scalp) and a total PASI score of 16 or less. In embodiments, subjects have an average sIGA score less than 3.5, for example, an average sIGA score less than 2.5. Subjects may be classified as having mild to moderate psoriasis based on their overall sIGA score (e.g., an sIGA score translated to an integer between 0 and 5 as described below). Therefore, in one embodiment, the subject has an overall sIGA score of 1, 2, 3, or 4. In another embodiment, the subject has an overall sIGA score of 1 or 2, for example, an overall sIGA score of 2 (for example, the subject is classified as having mild psoriasis). In yet another embodiment, the subject has an overall sIGA score of 3 or 4, for example, an overall sIGA score of 3 (for example, the subject is classified as having moderate psoriasis).

[0053] In embodiments, the treatment results in a reduction in the mean sIGA score (e.g., compared to baseline). In embodiments, the reduction is achieved over a period of at least about two weeks or at least about four weeks. In embodiments, the treatment results in a reduction of at least about 0.3 in the mean sIGA score, e.g., at least about 0.6, 1.0, 1.3, or 1.6. In embodiments, the treatment results in a reduction of up to about 2.0 in the mean sIGA score, e.g., up to about 1.7, 1.4, or 1.0. In embodiments, the reduction is between about 0.3 and about 1.7. In embodiments, the treatment results in a reduction of about 0.3 to about 1.7 in the mean sIGA score, e.g., between about 0.6 and about 1.4, e.g., about 1.0, over a period of about two weeks. In embodiments, the treatment results in a reduction of about 0.3 to about 1.7 in the mean sIGA score, e.g., between about 0.6 and about 1.4, e.g., about 1.0, over a period of about four weeks. In one embodiment, the subjects have an average sIGA score of less than 3.5 after treatment, for example, an average sIGA score of about 2.5 or less than 1.5 after treatment. In another embodiment, the subjects have an average sIGA score of 0 to about 2.5, for example, 0 to about 1.5, over a period of at least about 2 weeks or at least about 4 weeks after treatment.

[0054] In an embodiment, the treatment results in a reduction in the overall sIGA score (e.g., compared to baseline). In an embodiment, the reduction is achieved over a period of at least two weeks or at least four weeks. In an embodiment, the treatment results in a reduction of at least one point in the overall sIGA score, e.g., a reduction of one point or more in the overall sIGA score. In an embodiment, the reduction is a reduction of one point. In an embodiment, the treatment results in a reduction of approximately one point in the overall sIGA score over a period of approximately two weeks. In an embodiment, the treatment results in a reduction of approximately one point in the overall sIGA score over a period of approximately four weeks. In an embodiment, the subject has an overall sIGA score of three or more after treatment, e.g., two or more after treatment or one or more overall sIGA scores after treatment. In an embodiment, the subject has an overall sIGA score of one or two after treatment over a period of at least approximately two weeks. In an embodiment, the subject has an overall sIGA score of one or two after treatment over a period of at least approximately four weeks. In this embodiment, the subject has an overall sIGA score of 1 after treatment over a period of at least 4 weeks.

[0055] In embodiments, the treatment results in a reduction in the level of one or more biomarkers of psoriasis in the subject, for example, a reduction in the levels of IL-17A, IL-17F, and / or IL-22 in the subject's blood (e.g., serum). In embodiments, the treatment results in a reduction in the level of IL-17A, for example, a reduction in the level of IL-17A in the subject's blood (e.g., serum). In embodiments, the treatment results in a reduction of at least about 0.05 pg / mL of serum IL-17A levels (compared to a baseline that may be assessed immediately before the start of treatment), for example, a reduction of at least about 0.15 pg / mL. In embodiments, the treatment results in a reduction of about 0.06 pg / mL of serum IL-17A levels over two weeks. In embodiments, the treatment results in a reduction of about 0.18 pg / mL of serum IL-17A levels over four weeks. In embodiments, the treatment results in a reduction of at least about 10%, for example, at least about 25%, of serum IL-17A levels (compared to a baseline that may be assessed immediately before the start of treatment). In embodiments, treatment results in a reduction of approximately 8% in serum IL-17A levels over two weeks. In embodiments, treatment results in a reduction of approximately 28% in serum IL-17A levels over four weeks. In embodiments, treatment results in a reduction in IL-17F levels, for example, in the subject's blood (e.g., serum). In embodiments, treatment results in a reduction of at least approximately 1.0 pg / mL in serum IL-17F levels (compared to a baseline that may be assessed immediately before the start of treatment), for example, a reduction of at least approximately 1.2 pg / mL. In embodiments, treatment results in a reduction of approximately 1.0 pg / mL in serum IL-17F levels over two weeks. In embodiments, treatment results in a reduction of approximately 1.3 pg / mL in serum IL-17F levels over four weeks. In embodiments, treatment results in a reduction of at least approximately 35%, for example, at least approximately 50% in serum IL-17F levels (compared to a baseline that may be assessed immediately before the start of treatment). In one embodiment, the treatment results in a reduction of approximately 39% in serum IL-17F levels over two weeks. In another embodiment, the treatment results in a reduction of approximately 52% in serum IL-17F levels over four weeks.In embodiments, the treatment results in a decrease in IL-22 levels, for example, a decrease in the level of IL-22 in the subject's blood (e.g., serum). In embodiments, the treatment results in a decrease of at least about 1.0 pg / mL of serum IL-22 levels, for example, at least about 1.5 pg / mL, compared to a baseline that may be assessed immediately before the start of treatment. In embodiments, the treatment results in a decrease of about 1.2 pg / mL of serum IL-22 levels over two weeks. In embodiments, the treatment results in a decrease of about 1.6 pg / mL of serum IL-22 levels over four weeks. In embodiments, the treatment results in a decrease of at least about 30%, for example, at least about 40%, of serum IL-22 levels, compared to a baseline that may be assessed immediately before the start of treatment. In embodiments, the treatment results in a decrease of about 34% of serum IL-22 levels over two weeks. In embodiments, the treatment results in a decrease of about 43% of serum IL-22 levels over four weeks.

[0056] In an embodiment, the subject at the start of treatment meets one or more (e.g., all) of the following criteria: (a) male or female (e.g., male) and aged 18 to 65 years; (b) a confirmed diagnosis of moderate to severe chronic plaque psoriasis defined as PASI 16 or less at least 6 months prior to screening; (c) at least two lesions with a TLS score of 4 or more (excluding the scalp); (d) good health status (excluding psoriasis) evaluated by a clinician based on, for example, medical history, physical examination, vital signs, ECG, clinical laboratory tests, and urine tests; (e) female and postmenopausal (e.g., no menstruation for 12 months without another medical cause - high FSH levels within the postmenopausal range are used to confirm postmenopausal status in women not using hormonal contraception or HRT) or sterilized (e.g., after surgical bilateral oophorectomy not associated with a history of cancer); (f) test parameters within normal ranges, for example, liver enzymes (ALT, AST) not exceeding ULN and GGT and a total bilirubin value of up to 1.5 ULN when related to normal conjugated bilirubin values; (g) normal vital signs after resting in the supine position for at least 10 minutes at the time of screening, for example, 90 mmHg ≤ systolic blood pressure (SBP) ≤ 140 mmHg, 45 mmHg ≤ diastolic blood pressure (DBP) ≤ 90 mmHg, and 50 beats per minute (bpm) ≤ heart rate (HR) ≤ 100 bpm; (h) standard 12-lead ECG parameters (e.g., within the following ranges: PR < 220 ms, QRS < 120 ms, QTcF ≤ 450 ms, 50 bpm < HR < 100 bpm) and a normal ECG tracing after resting in the supine position for 10 minutes; (i) a BMI of 18.0 to 35.0 kg / m 2 ² (weight 50.0 kg or more); and (j) male, use of contraception and consent not to provide sperm from the start of treatment until 2.5 months after the last dose.

[0057] In embodiments, the subjects at the start of treatment do not meet any (e.g., all) of the following criteria: (a) existing signs of skin atrophy, telangiectasia, or striae in the affected area; (b) current evidence of non-plaque form psoriasis (e.g., erythrodermic psoriasis, guttate psoriasis, or pustular psoriasis) or psoriatic arthritis; (c) current evidence or suspicion of drug-induced psoriasis (e.g., new onset or exacerbation of psoriasis caused by beta-blockers, calcium channel blockers, or lithium); (d) presence or history of drug hypersensitivity or allergic disease diagnosed and treated by a physician; (e) (f) any opportunistic infection within 6 months prior to the scheduled start of treatment; (g) any past gastrointestinal surgery or recent gastrointestinal disease (within 3 months prior to the scheduled start of treatment) that may affect the absorption of compound 1; (h) any drug or alcohol abuse within 12 months prior to the scheduled start of treatment; (e) any clinically significant, severe or unstable, acute or chronic progressive or uncontrolled infection or medical condition (including ongoing biologically proven SARS-CoV-2 infections and recurrent infections) or any condition that may affect the safety of the participant (e.g., SARS-CoV- Evidence of not having been adequately vaccinated against CoV-2; (i) blood donation (any amount) within two months prior to the scheduled start of treatment; (j) known allergy to local anesthetics; (l) use of systemic immunosuppressants within four weeks prior to the scheduled start of treatment; (k) any systemic nonbiological psoriasis therapy within four weeks prior to the scheduled start of treatment (including, but not limited to, psoralen and UVA therapy, cyclosporine, methotrexate, azathioprine, corticosteroids, apremilast, tofacitinib, oral retinoids, mycophenolate mofetil, and sirolimus); (i) blood donation (any amount) within two months prior to the scheduled start of treatment; (j) known allergy to local anesthetics; (l) use of systemic immunosuppressants within four weeks prior to the scheduled start of treatment; (k) any systemic nonbiological psoriasis therapy (including, but not limited to, psoralen and UVA therapy, cyclosporine, methotrexate, azathioprine, corticosteroids, apremilast, tofacitinib, oral retinoids, mycophenolate mofetil, and sirolimus) within four weeks prior to the scheduled start of treatment. (n) use of topical psoriasis therapy with phototherapy (including ultraviolet B or self-treatment with a tanning bed or therapeutic sunbathing), or psoralen; (m) use of topical corticosteroids (excluding hydrocortisone 1%), topical calcineurin inhibitors, or other topical preparations with immunomodulatory properties within two weeks prior to the scheduled start of treatment; (n) prior use of any biological preparation for the treatment of psoriasis; (o) administration of any live vaccine within three months of the scheduled start of treatment, any initial non-live vaccine within 30 days, or a non-live booster vaccine within 14 days;(p) Use of any anticoagulant within 3 months of the scheduled start of treatment or use of acetylsalicylic acid within 2 weeks prior to the scheduled start of treatment; (q) Use of a highly sensitive P-gp, CYP3A4, CYP1A1, or CYP1A2 substrate, each with a narrow therapeutic concentration range or high-risk indication; (r) Use of a potent or moderate inducer or inhibitor of CYP3A4 or P-gp within 30 days or 5 half-lives, whichever is longer, from the scheduled start of treatment (this includes grapefruit, grapefruit juice, or glycerin within 72 hours of the scheduled start of treatment). (i) Consumption of grapefruit-containing products; (s) Use of strong or moderate inducers of CYP1A1 / CYP1A2 within 30 days or 5 half-lives from the scheduled start of treatment, whichever is longer (this also includes excessive consumption of beverages containing xanthine bases, e.g., more than 4 cups or glasses per day); (t) Enrollment in or participation in any clinical trial or any other type of medical research involving IMP, and still being in an exemption period under applicable regulations; (u) History of tuberculosis and / or QuantiFERON-TB (v) Positive Gold test (QFT); (v) Positive hepatitis B surface antigen and / or hepatitis B core antibody or positive anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab); (w) Positive hepatitis C antibody (unless treatment has been successful) or untreated, negative hepatitis C virus (HCV) RNA by PCR; (x) Positive result on urine drug screening (e.g., for amphetamine / methamphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine or opioids); (y) Procalcitonin (PCT) >0.5 ng / ml (equivalent to >0.5 μg / L) with clinically apparent signs and symptoms of infection; and (z) Positive alcohol test.

[0058] This disclosure intends for compound 1 in salt form, for example, in the form of a pharmaceutically acceptable salt. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. PHStahl & C.G. Wermuth, Wiley-VCH, 2002. In embodiments, the compound is a pharmaceutically acceptable salt of compound 1. In embodiments, the compound is a pharmaceutically acceptable salt of compound 1, and the method involves administering a daily dose of the salt to a target, corresponding to 400 mg of free base, for example, to a BID of 200 mg. In other embodiments, the compound is the free base of compound 1. In embodiments, the compound is the free base of compound 1, and the method involves administering a daily dose of 400 mg, for example, to a BID of 200 mg.

[0059] In embodiments, the compound is administered orally to a subject. In embodiments, the compound is administered in the form of an oral pharmaceutical composition (e.g., dosage form) comprising compound 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be any such excipient known in the art, including, for example, those described in Remington's Pharmaceutical Sciences, Mack Publishing Co. (ARGennaro edit. 1985). The pharmaceutical composition of the compound may be prepared by conventional methods known in the art, for example, by mixing with one or more pharmaceutically acceptable excipients.

[0060] For oral administration, the pharmaceutical composition may take the form of, for example, tablets, lozenges, or capsules, prepared by conventional means using pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium glycolate) or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. In embodiments, the oral pharmaceutical composition is a tablet. Preparations for oral administration may be appropriately formulated to provide controlled release of the active compound, for example, using types of formulations known in the art.

[0061] In the embodiment, the treatment involves administering a dose of approximately 200 mg of the compound (calculated as free base) twice daily to the subject, for example, 200 mg of compound 1 in BID. In the embodiment, the compound is administered in the form of a tablet, for example, a tablet containing 50 mg of the compound (calculated as free base). In the embodiment, the treatment involves administering four tablets, each containing approximately 50 mg of the compound (calculated as free base), twice daily for a total daily dose of approximately 400 mg.

[0062] In embodiments, the treatment includes administering the compound or a pharmaceutically acceptable salt thereof to the subject, for example, before, during, or immediately after a meal, along with food. In embodiments, the treatment includes administering the compound or a pharmaceutically acceptable salt thereof to the subject independently of meals.

[0063] Accordingly, in one embodiment, the disclosure also provides a pharmaceutical composition comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In an embodiment, the pharmaceutical composition is adapted to provide a daily dose of about 400 mg of compound 1 or a pharmaceutically acceptable salt thereof (calculated as free base). In an embodiment, the pharmaceutical composition is adapted to provide a twice-daily dose of about 200 mg of compound 1 or a pharmaceutically acceptable salt thereof (calculated as free base). In an embodiment, the pharmaceutical composition provides compound 1 or a pharmaceutically acceptable salt thereof in one or more (e.g., 1, 2, or 4) unit doses. In an embodiment, the pharmaceutical composition provides a unit dose of about 200 mg of compound 1 or a pharmaceutically acceptable salt thereof (calculated as free base) for the purpose of administering, for example, two unit doses per day. In the embodiment, the pharmaceutical composition provides a unit dose of about 50 mg of compound 1 or a pharmaceutically acceptable salt thereof (calculated as a free base) for the purpose of administering, for example, eight unit doses per day, or for example, four unit doses twice a day.

[0064] This disclosure provides compound 1 or a pharmaceutically acceptable salt thereof for use in a method for treating psoriasis. It will be understood that this disclosure also provides a method for treating psoriasis as described herein, wherein a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof as described herein is administered to a human subject in need thereof. It will also be understood that this disclosure further provides compound 1 (or a pharmaceutically acceptable salt thereof) for use in the manufacture of a pharmacopoeia for treating psoriasis according to the method disclosed herein.

[0065] As generally described herein, the following non-limiting embodiments are provided to further illustrate the present disclosure. [Examples]

[0066] Example 1: Synthesis of (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidine-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazosin-5(14H)-one (compound 1) [ka] Compound 1 was prepared according to Example 6 of the international patent application PCT / EP2018 / 060489 (published as international publication brochure 2018 / 197503). Briefly, in the first step, cyclobutanone was reacted with 2-methyl-2-propanesulfinamide, followed by titanium(IV) isopropoxide to prepare N-(cyclobutylidene)-2-methylpropane-2-sulfinamide (intermediate 13), which was purified by flash chromatography. In the second step, 5-bromo-2-iodopyrimidine was cooled and treated with n-butyllithium, followed by intermediate 13, to obtain N-[1-(5-bromopyrimidine-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide (intermediate 14), which was purified by flash chromatography. In the third step, intermediate 14 was treated with MeOH / HCl, followed by isopropyl ether / MeOH, to obtain 1-(5-bromopyrimidine-2-yl)cyclobutanamine hydrochloride (intermediate 15). In the fourth step, intermediate 15 was treated with di-tert-butyl dicarbonate and triethylamine to obtain tert-butyl N-[1-(5-bromopyrimidine-2-yl)cyclobutyl]carbamate (intermediate 16). In the fifth step, (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazosin-5(14H)-one (prepared according to Example 11 of International Publication No. 2016 / 050975) was treated with potassium bis(trimethylsilyl)amide, followed by iodomethane, to obtain (7R,14R)-11-chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazosin-5(14H)-one (intermediate 3), which was purified by flash chromatography.In the sixth step, intermediate 3 was treated with tris(dibenzylideneacetone)dipalladium(O), XPhos, bis(pinacolato)diborone and potassium acetate, followed by 1,4-dioxane. Intermediate 16 was then added along with an aqueous tripotassium phosphate solution, followed by the addition of additional tris(dibenzylideneacetone)dipalladium(O), XPhos and an aqueous tripotassium phosphate solution to obtain tert-butyl(1-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazosin-11-yl]pyrimidine-2-yl}cyclobutyl) carbamate (intermediate 17), which was purified by flash chromatography. In the seventh step, intermediate 17 was treated with HCl in 1,4-dioxane, followed by treatment with an aqueous sodium hydroxide solution to obtain the title compound as a white amorphous solid. δ. H (400MHz,DMSO-d6)9.05(s,2H),8.32-8.22(m,1H),7.91-7.66(m,3H),7.62(dd,J 8.5,1.8Hz,1H),7.53-7.46(m,2H),6.31(d,J 7.1Hz,1H),5.26(d,J 7.2Hz,1H),3.52(dt,J 14.2,7.3Hz,1H),3.36(s,3H),2.84(d,J 13.8Hz,1H),2.63(dtd,J 11.5,5.6,2.5Hz,2H),2.38(s,2H),2.16-2.05(m,2H),2.04-1.91(m,1H),1.87-1.73(m,1H). LCMS(ES+APCI)[M-NH2] - 486.0, RT 1.66 min (Method 2 of International Publication No. 2018 / 197503). LCMS(ES+)[M+H] + 503.0, RT 1.71 min (Method 1 of International Publication No. 2018 / 197503 pamphlet).

[0067] Example 2: Clinical trial of compound 1 in patients with mild to moderate psoriasis Test design A double-blind, randomized, placebo-controlled phase 1 trial was conducted in participants with mild to moderate psoriasis. Participants were randomized in a 2:1 ratio to receive either compound 1 or placebo 200 mg twice daily (BID) (approximately 24 in the treatment group and 12 in the placebo group). The trial included a screening period of up to 4 weeks and a 4-week treatment period with compound 1 or placebo. Final visits were conducted 10 ± 3 days after the last administration of the investigational drug (IMP).

[0068] The primary objective of the study was to evaluate the safety, tolerability, and clinical efficacy of compound 1 at a 200 mg BID administered orally. The clinical effect of compound 1 compared to placebo was also evaluated in terms of the percentage change in PASI and TLS scores from baseline to weeks 2 and 4. The percentage change in PASI scores from baseline to week 4 was determined. TLS scores were also evaluated over the same period. The effect of compound 1 on psoriasis biomarkers was also evaluated. Blood samples collected at predetermined time points were processed, and serum levels of biomarkers, including interleukin (IL)-17A, IL-17F, and IL-22, were quantified using a highly sensitive method. IL-17A, IL-17F, and IL-22 are major cytokines released by Th17 cells. Plasma levels of compound 1 were measured to evaluate its pharmacokinetics in the study population.

[0069] Planned test group Participants were only eligible to be included in the study if they met all of the following inclusion criteria. I01. Male or female participants aged 18-65: I02. A confirmed diagnosis of chronic plaque-type psoriasis, diagnosed with mild to moderate severity as defined as PASI ≤16 at least 6 months prior to screening. I03. Participants must have at least two lesions, excluding the scalp, with a TLSS score of 4 or higher at both screening and baseline. I04. Participants must be in good health as determined by the principal investigator based on medical history, physical examination, vital signs, ECG, clinical tests, and urinalysis (excluding psoriasis). Only female participants who are postmenopausal or sterilized (e.g., after surgical bilateral ovariectomy not related to a history of cancer) may be included in the study. The postmenopausal state is defined as the absence of menstruation for 12 months without another medical cause. High FSH levels within the postmenopausal range are used to confirm the postmenopausal state in women not using hormonal contraception or HRT (based on local tests). I06. Test parameters within the normal range (or the defined screening threshold of the trial facility) at screening (except when the investigator considers the abnormality clinically irrelevant to the participant); however, liver enzymes (ALT, AST), GGT should not exceed the upper limit of the normal range. A total bilirubin value up to 1.5 times the upper limit of the normal range is acceptable only if it is associated with a normal conjugated bilirubin value. I07. Normal vital signs after at least 10 minutes of rest in the supine position at screening: - 90 mmHg ≤ systolic blood pressure (SBP) ≤ 140 mmHg. - 45 mmHg ≤ diastolic blood pressure (DBP) ≤ 90 mmHg. - 50 beats per minute (bpm) ≤ heart rate (HR) ≤ 100 bpm. I08. Standard 12 - lead ECG parameters after 10 minutes of rest in the supine position at screening are PR < 220 ms, QRS < 120 ms, QTcF ≤ 450 ms (Fridericia's QT correction formula, no retesting is permitted for screening and inclusion), 50 bpm < HR < 100 bpm, and within the range of a normal ECG tracing (except when the investigator considers the ECG tracing abnormality clinically irrelevant). I09. The participant's BMI is 18.0 - 35.0 kg / m 2 (and the weight is 50.0 kg or more). I10. Male participants should use contraception methods in accordance with local regulations regarding contraception methods for participants in clinical trials. Male participants should agree not to provide sperm until 2.5 months after the last dose of the study drug.

[0070] Participants were excluded from the study if any of the following criteria were met: E01. Pre-existing signs of skin atrophy, telangiectasia, or striae in the affected area. E02. Current evidence of non-plaque forms of psoriasis (e.g., erythrodermic psoriasis, guttate psoriasis, or pustular psoriasis), psoriatic arthritis. E03. Current evidence or suspicion of drug-induced psoriasis (e.g., new onset or exacerbation of psoriasis caused by beta-blockers, calcium channel blockers, or lithium). E04. Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician. E05. Opportunistic infections within 6 months prior to randomization (Day 1). E06. Any past gastrointestinal surgery or recent gastrointestinal disease (within 3 months prior to day 1 of enrollment) that could affect the absorption of the test drug. E07. History of drug or alcohol abuse within 12 months prior to administration (equivalent to more than 800 mL of regular beer or more than approximately 40 g of alcohol per day). E08. Evidence of any clinically significant, severe or unstable, acute or chronic progressive, uncontrolled infection or medical condition (including ongoing, biologically proven SARS-CoV-2 infections and recurrent infections) or any condition that, in the judgment of the principal investigator, could affect the safety of the participant (including participants who have not been adequately vaccinated against SARS-CoV-2 infection in accordance with local regulations). E09. Blood donation (any amount) within two months prior to inclusion. E10. Known allergies to local anesthesia. E11. Use of systemic immunosuppressants within 4 weeks of joining the study and throughout the study period. E12. Use of any of the following therapies within four weeks prior to baseline (Day 1): Systemic nonbiological psoriasis therapy (including, but not limited to): psoralen and ultraviolet A (PUVA) therapy, cyclosporine, methotrexate, azathioprine, corticosteroids, apremilast, tofacitinib, oral retinoids, mycophenolate mofetil, sirolimus; or phototherapy (including ultraviolet B [UVB] or self-treatment with a tanning bed or therapeutic sunbathing) or topical psoriasis therapy with psoralen. E13. Use of topical corticosteroids (excluding hydrocortisone 1%), topical calcineurin inhibitors, or other topical preparations with immunomodulatory properties within two weeks prior to randomization (Day 1). E14. Past use of any biological agent for the treatment of psoriasis. E15. Participants who have received any live vaccine within 3 months of initial IMP administration, any initial non-live vaccine within 30 days, or a non-live booster vaccine within 14 days, or who are scheduled to receive any vaccine during the study. E16. Use of any anticoagulant within 3 months prior to day 1 (acetylsalicylic acid within 2 weeks prior to day 1) or during the test. E17. Any participant receiving highly sensitive P-gp, CYP3A4, CYP1A1, and CYP1A2 substrates, each with a narrow therapeutic dose range or high-risk indication. E18. Any participant who, prior to enrollment, has received a potent or moderate inducer or inhibitor of CYP3A4 and P-gp within 30 days of screening or within 5 half-lives, whichever is longer. This includes consumption of grapefruit, grapefruit juice, or grapefruit-containing products within 72 hours of the start of administration of compound 1. E19. Any participant who, prior to enrollment, has been administered a strong or moderate inducer of CYP1A1 / CYP1A2 within 30 days of screening or within 5 half-lives, whichever is longer. This also includes excessive consumption of beverages containing xanthine bases (more than 4 cups or glasses per day). E20. Any participant who is enrolled in or participates in any other clinical trial or any other type of medical study, including (this or that) IMP, and who is still in an exemption period under applicable regulations. E21. History of tuberculosis and / or positive QuantiFERON-TB Gold test (QFT) at the time of screening. E22. Positive for hepatitis B surface antigen and / or hepatitis B core antibody, or positive for anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab). E23. If the participant is positive for hepatitis C antibodies (unless the participant has been successfully treated) or, if the participant is untreated, negative for hepatitis C virus (HCV) RNA by polymerase chain reaction (PCR) (in either case, eligibility will be considered with supporting documentation). E24. Positive results on urine drug screening during screening (amphetamine / methamphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, opioids). E25. Procalcitonin (PCT) levels greater than 0.5 ng / ml (equivalent to greater than 0.5 μg / L) in patients with clinically evident signs and symptoms of infection as determined by the principal investigator at the time of screening. E26. Positive alcohol test during screening.

[0071] Participants were instructed to avoid direct exposure to natural or artificial sunlight during the trial treatment and to wear protective clothing with a high sun protection factor (e.g., SPF ≥ 30), sunscreen, and lip balm when outdoors throughout the trial period.

[0072] Regarding diet and eating restrictions, as well as the consumption of caffeine, alcohol, and tobacco, the following was established: During participation in the study, participants were not to consume excessive amounts of beverages containing methylxanthine bases (e.g., coffee, tea, cola, chocolate, energy drinks) (more than 4 cups or glasses per day); from 72 hours (3 days) prior to enrollment until the end of participation in the study, participants were not to consume grapefruit, grapefruit juice, or grapefruit-containing products; from 48 hours prior to screening, participants were not to consume foods or beverages containing poppy seeds; smokers and non-smokers (by randomization list) could be enrolled in the study, with restrictions only on smokers who smoked more than 20 cigarettes per day; and from screening until the end of participation in the study, participants were not to consume excessive amounts of alcohol (i.e., no more than 800 mL of regular beer or an amount equivalent to approximately 40 g of alcohol per day).

[0073] Trial intervention Two trial interventions were used: Compound 1 and placebo. The Compound 1 intervention consisted of four tablets of Compound 1 (50 mg), or 200 mg BID, taken twice daily for four weeks. The placebo intervention consisted of four placebo tablets taken twice daily for four weeks. The tablets were administered orally.

[0074] The intervention was used in two arms of the trial. Arm 1 was the experimental arm, which included participants who received 200 mg of the compound in BID form over four weeks under feeding conditions. Arm 2 was the placebo arm, which included participants who received the corresponding placebo tablet over four weeks under feeding conditions.

[0075] Test evaluation and procedures The planned timings for all effectiveness evaluations were as shown in the activity schedule below.

[0076] [Table 1]

[0077] [Table 2]

[0078] a. If a participant discontinues treatment prematurely, the participant will be evaluated using safety and clinical response procedures planned for a 4-week treatment completion trial visit, including, if necessary, blood sampling for pharmacokinetic and pharmacodynamic assessment.

[0079] b. Time (hours / minute) is expressed relative to the last dose (T0H) of compound 1.

[0080] c. Since the results of the screening tests (especially the QuantiFERON-TB Gold test) are released at a time limit of at least one week after the blood sample is received in the laboratory, please schedule your visit accordingly.

[0081] d. Including vaccination history and tonsillitis / periodontitis occurring within the past four weeks.

[0082] On day 1 and at each hospital visit, participants were provided with a diary, which was then returned and checked by the principal investigator to verify IMP intake. Adverse events reported on days 8±2, 15±2, 22±2, and 29±1 were also reviewed.

[0083] f. Before administration.

[0084] g. Administration on days 1, 8, 15, and 22 will be performed at the study facility, and a standard hospital breakfast (moderate-fat meal) will be provided by the study facility before administration of the study drug (i.e., administration of the study drug approximately 5-15 minutes after the end of breakfast). However, the study drug may be taken at home immediately before, during, or immediately after a meal. The study drug should be administered with a glass of water (minimum 240 ml).

[0085] h In accordance with the opinion of the principal investigator and, where applicable, in accordance with national and local regulations, Covid-19 testing may be repeated during the study as needed, screening tests as nasopharyngeal swabs may be analyzed by PCR, PCR testing may be performed outside the study site, and novel Covid-19 tests may be used during the study in accordance with available scientific knowledge and / or recommendations of local health authorities.

[0086] i. Skin biomarkers from biopsy (RNA analysis) (3mm punch): Biopsies are optional for participants who consent and have visible psoriasis plaques in a suitable area for tissue biopsy, performed before the first administration (day 1) in both lesional and non-lesional areas, and at week 4 in lesional areas only.

[0087] j. Photography is optional. Details are provided in the photo reference manual.

[0088] k For detailed safety investigations, please refer to the safety section (Section 8.2).

[0089] l TLSS, PASI, and sIGA should, where possible, be completed by the same physician for each participant to ensure long-term comparisons and avoid bias.

[0090] m Before administration on day 28 (if the visit to the facility is on day 28): If the visit to the facility is on day 29 or 30, this should be the same administration time as the treatment period.

[0091] n Before administering IMP at night (8-12 hours after morning IMP administration).

[0092] For participants living far from the test facility, accommodation from day -1 to day 1 and / or from day 1 to day 2 is optional.

[0093] p ECG at 3 hours ± 1 hour after administration.

[0094] q A triple digital ECG, with at least one minute between every two repetitions, recorded within five minutes for all ECGs.

[0095] Medical history may include, but is not limited to, a history of surgery, psoriasis, tonsillitis, periodontitis, smoking status, or complications.

[0096] Covid-19 testing may be performed on day -1 for those staying from day -1 to day -1.

[0097] Note: If several items are performed simultaneously, the following order should be followed: ECG, vital signs, questionnaire, pharmacodynamics, blood sampling, meal (if applicable), drug administration; the precise timing of pharmacokinetic samples should be observed.

[0098] We assessed the severity and clinical effectiveness of the TLS score, an effective tool for evaluating psoriasis severity. This score consists of a total score of three clinical severity parameters (scaling, erythema, and plaque elevation / induration; each on a 5-point severity scale; graded 0=none, 1=mild, 2=mild, 3=moderate, and 4=severe), with the total score ranging from 0 to 12 points (see, e.g., Czarnowicki et al., J Am Acad Dermatol. (2014) 71(5):954-959.e1). The following assessment was used, with the TLS score calculated here as the sum of A+B+C (adapted from Fredriksson et al., Dermatologica (1978) 157(4):238-244).

[0099] [Table 3]

[0100] The PASI scoring system assesses psoriasis based on the body surface area (BSA) involvement of plaques and morphological characteristics (see, for example, EMA Guidelines on clinical investigation of medicinal products indicated for the treatment of psoriasis, November 18 th , 2004). BSA estimation was performed using the "palm" (i.e., the flat part of the subject's hand together with the thumb, excluding the fingers). The palm thus defined accounted for 1% of the total BSA. PASI combines the assessment of the following four body regions: head (h, 10%), upper limbs (u, 20%), trunk (t, 30%) and lower limbs (l, 40%). Using the palm to assess BSA (as described above), a numerical score (A) representing the proportion of involvement was assigned to the proportion of skin affected by psoriasis in each region: 1 (0 - 9%); 2 (10 - 29%); 3 (30 - 49%); 4 (50 - 69%); 5 (70 - 89%) and 6 (90 - 100%). Within each region, the severity of three signs, namely erythema (E), thickening / induration (I) and desquamation / scaling (D), was evaluated on a 5 - point scale: 0, none; 1, mild; 2, moderate; 3, severe; 4, very severe. PASI ranges from 0 to 72 and is calculated using the following formula. PASI = 0.1(Eh + Ih + Dh)Ah + 0.2(Eu + Iu + Du)Au + 0.3(Et + It + Dt)At + 0.4(El + Il + Dl)Al

[0101] The sIGA used in this study is a 6 - point ordinal scale used to assess the overall severity of the disease across the body, measured by the overall degree of induration, scaling and erythema of the subject's psoriasis lesions. For statistical analysis, scores of 0 - 5 from "none" to "very severe" were assigned to the scale respectively.

[0102] Scoring was assigned to subjects on a scale of 0 to 5 for each of the following: erythema, induration, and scaling. The mean sIGA score was calculated as the average of these individual scores, which was then converted to an overall sIGA score (an integer from 0 to 5) as shown in the table below.

[0103] [Table 4]

[0104] [Table 5]

[0105] The planned timings for all safety assessments are shown in the activity schedule table above.

[0106] A physical examination includes at least the following: cardiac and respiratory auscultation; peripheral arterial pulsation; pupils, knee, Achilles, and plantar reflexes; peripheral lymph node and abdominal examination.

[0107] Vital signs (HR, SBP, and DBP measured at least 10 minutes after lying supine and approximately 3 minutes after standing) and auricular body temperature were measured.

[0108] The following electrocardiogram data was recorded: A standard 12-lead ECG (safety ECG) was recorded using an electrocardiogram device in the supine position at least 10 minutes after the start of the study. Throughout the study, electrodes were placed in the same location for each ECG recording (e.g., the lead wire attachment points were visualized on transparent paper). Three consecutive ECGs were recorded, with at least one minute between each of the two repetitions, and within a 5-minute interval for all ECGs. Each ECG consisted of a 10-second simultaneous recording of 12 leads, which yielded the following results: - A single 12-lead ECG (50 mm / s, 10 mm / mV) printout including the participant's date, time, and number, the investigator's signature, and at least three composites for each lead, including heart rate, PR, QRS, QT, and QTc autocorrected assessments (by ECG device). The principal investigator's medical findings and autocorrects were recorded in the eCRF. This printout was kept at the site. A second printout was also made as needed. - Digital storage to enable final further reading by the ECG central laboratory: Each digital file is identified by theoretical time (day and time Dxx Txx Hxx), actual date and real-time (recording time), sponsor study code, participant number (i.e., 3 digits), and site and country codes, where applicable. Digital records, data storage, and transmission (whenever required) must comply with all applicable regulatory requirements (i.e., FDA 21 Federal Regulatory Code [CFR], Part 11).

[0109] Laboratory tests (for blood samples, starting at least 10 hours after fasting) included the following: Hematology: Red blood cell count, hematocrit, hemoglobin, white blood cell count with white blood cell percentage (neutrophils, eosinophils, basophils, monocytes, and lymphocytes), platelets. ·Biochemistry: - Plasma / serum electrolytes: sodium, potassium, chloride, calcium, - Liver function: AST, ALT, alkaline phosphatase, GGT, total bilirubin and conjugate bilirubin, - Renal function: Urea, creatinine, - Metabolism: glucose, albumin, total protein, total cholesterol, triglycerides, - Potential myotoxicity: CK, - International normalized ratio (INR) and activated partial thromboplastin time (aPTT), - C-reactive protein (CRP) levels were assessed by independent investigators not involved in the study to protect blinding of the study. CRP values ​​were provided to the investigator by the independent investigator when medically necessary. - Procalcitonin levels at screening, week 2, and endoscopy (EOS). • QuantiFERON-TB Gold (QFT) trial.

[0110] For female participants, serum β-HCG testing was required at screening, on day 1, and on day 29 ± 1. Urine pregnancy tests were performed at screening, on day 1, and on day 29 ± 1. For postmenopausal women, plasma or serum FSH was tested only at screening.

[0111] The urine test included specific gravity, protein, glucose, blood, bilirubin, urobilinogen, white blood cells, ketones, nitrite, and pH: If any of the dipstick parameters were abnormal, quantitative urine analysis was performed. If protein and / or red blood cells were positive, microscopic analysis was performed by the local laboratory.

[0112] Urine drug screening was performed for amphetamine / methamphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, and opioids (only at the time of screening).

[0113] Serological tests included hepatitis B antigen, anti-hepatitis B core antibody (anti-HBc Ab), hepatitis C antibody, and anti-HIV1 and anti-HIV2 antibodies.

[0114] A 15 mL (or three 5 mL) blood sample was collected in a tube with a dry red cap, left upright at room temperature for 30 minutes, and then centrifuged at approximately 1500 g for 10 minutes at 4°C. The serum was then transferred to three storage tubes, immediately capped, and frozen upright at 20°C. This sample is used to ensure that pre-administration baseline values ​​are available for parameters not previously evaluated (e.g., serology) in case of any unforeseen safety issues. If this sample is not used, the principal investigator will discard it after approval by the sponsor.

[0115] In accordance with the opinion of the principal investigator and, where applicable, national and local regulations, COVID-19 testing may be repeated during the trial as needed. The initial screening test was a nasopharyngeal swab analyzed by PCR.

[0116] Other assessments included body weight (kg), auricular temperature, and alcohol breath test (only during screening).

[0117] Note: If vital signs, ECG, and blood samples, as well as skin biopsies, are scheduled to occur on day 1 concurrently with IMP administration and / or meals, these should be performed before IMP intake and / or meals. In addition, blood PK samples should be collected before administration and 3 hours after administration at scheduled visits (days 1, 15±2, and 29±1). All other safety, pharmacodynamic, and clinical response assessments scheduled for weeks 2 and 4 should be performed near (before or after) administration.

[0118] Adverse events (AEs) were reported by participants or observed by the principal investigator and were defined as follows: An adverse medical event (AE) is any adverse medical event in a patient or clinical trial participant that is temporarily related to the use of a trial intervention, regardless of whether it is considered to be related to the trial intervention. Note: Therefore, an adverse event (AE) may be any undesirable or unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) that is time-related to the use of the trial intervention.

[0119] Events that satisfy the definition of AE: • Any abnormal clinical laboratory results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiographic scan, vital signs measurement) that are considered clinically significant (i.e., worsening from baseline) in the medical and scientific judgment of the principal investigator, including those unrelated to the progression of the underlying disease, e.g., - Symptomatic, and / or - Those who require either orthodontic treatment or consultation, and / or - Anything that leads to discontinuation or modification of IMP, and / or - Those that meet the severity criteria, and / or - What is defined as AESI. • Exacerbation of a chronic and / or intermittent pre-existing condition, including an increase in the frequency or intensity of the condition. • A new condition may have existed before the start of the trial, but is detected or diagnosed after the trial intervention is administered. • Signs, symptoms, or clinical complications suggestive of a drug-drug interaction. • Signs, symptoms, or clinical complications suggestive of an overdose of either the trial intervention or the concomitant medication. Lack of efficacy or failure of expected pharmacological action itself is not reported as an AE or SAE. Such cases are captured in efficacy evaluations. However, signs, symptoms, and / or clinical complications resulting from a lack of efficacy are reported as AEs or SAEs if they meet the definition of an AE or SAE.

[0120] Events that do not fit the definition of AE: Any clinically significant abnormal laboratory findings or other abnormal safety assessments related to an underlying medical condition, except when judged by the principal investigator to be more severe than expected for the participant's condition. • The disease / disorder being studied, or the expected progression, signs, or symptoms of the disease / disorder being studied (except in cases where the condition is more severe than expected for the participant). • Medical or surgical procedures (e.g., endoscopy, appendectomy): The conditions leading to such procedures are adverse events (AEs). • Situations in which no unforeseen medical accidents occurred (social hospitalization and / or hospitalization for convenience). • Daily fluctuations in pre-existing or discovered medical conditions or conditions at the start of the study are expected and should not worsen.

[0121] A serious adverse event (SAE) is an adverse medical event that meets one or more of the following criteria at any dose:

[0122] A) To cause death.

[0123] B) It threatens life. Note: In the definition of "serious," the term "life-threatening" refers to an event in which a participant was at risk of death at the time of the event, and does not refer to an event in which death was possible if the event was severe.

[0124] C) The participant may require hospitalization or extension of an existing hospitalization. Generally, hospitalization means that a participant is admitted to a hospital or emergency ward (usually including at least an overnight stay) for observation and / or treatment that was not appropriate in a physician's clinic or outpatient setting. Complications that occur during hospitalization are AEs. An event is serious if the complication prolongs hospitalization or meets any other significant criteria. An AE should be considered serious if there is doubt as to whether hospitalization occurred or was necessary. Hospitalization for the selective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

[0125] D) Causes permanent or significant disability / incapacity. - The term disability refers to a substantial impairment of a person's ability to perform normal daily living functions. - This definition is not intended to include experiences of relatively minor medical significance, such as uncomplicated headaches, nausea, vomiting, diarrhea, influenza, and accidental injuries (e.g., a sprained ankle), that interfere with or may interfere with daily living activities but do not constitute substantial disruption.

[0126] E) Congenital anomaly / birth defect.

[0127] F) This is a medically important event: - Medical and scientific judgment should be used to determine whether priority reporting is appropriate in other circumstances, such as a significant medical event that does not immediately threaten life or lead to death or hospitalization but could endanger the participant, or a significant medical event that could require medical or surgical intervention to prevent any of the other outcomes listed in the definition above. - Note: Examples of such events include allergic bronchospasm, hematological mismatch, seizures, asymptomatic ALT elevation of ALT > 3 × ULN + total bilirubin > 2 × ULN or > 10 × ULN, onset of drug dependence or substance abuse, suicide attempt or any event suggestive of suicide, syncope, loss of consciousness (unless documented as a result of blood tests), or intensive care in the emergency room or at home for bullous skin rash.

[0128] The principal investigator will assess the severity of each AE and SAE reported during the trial and assign it to one of the following categories (according to NCI-CTCAE):

[0129] • Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observation only; no intervention indicated.

[0130] Grade 2: Moderate; minimal local or non-invasive interventions indicated; age-appropriate limitations in instrumental activities of daily living (ADL). Instrumental ADLs include preparing meals, shopping for groceries or clothing, using the telephone, and managing money.

[0131] Grade 3: Severe or medically significant but not immediately life-threatening; indicated hospitalization or prolonged hospitalization; incapacitation; limitations in self-care ADL. Self-care ADL refers to bathing, dressing and undressing, self-feeding, toilet use, medication administration, and not being bedridden.

[0132] Grade 4: Life-threatening consequences; order for emergency intervention.

[0133] Grade 5: Death related to adverse events (AEs).

[0134] An event was defined as "critical" if it met at least one of the predefined outcomes, as described in the SAE definition, and not "critical" if it was assessed as severe.

[0135] Where possible, a diagnosis or single syndrome was reported instead of symptoms. The principal investigator specified the date of onset, severity, actions taken for IMP, corrective treatment / therapy administered, additional examinations performed (e.g., if photographs of skin lesions were required), outcome, and the investigator's opinion on whether the AE was reasonably likely to have been caused by IMP.

[0136] All AEs (serious or non-serious) were collected at the points specified in the activity schedule above, from the time the Informed Consent Form (ICF) was signed until the End of Study (EOS). All SAEs and AESIs were recorded and reported immediately, in no case exceeding 24 hours, to the sponsor or nominee. The principal investigator submitted updated SAE data to the sponsor within 24 hours of its availability. After the end of study participation, the principal investigator was not obligated to proactively collect information regarding AEs or SAEs. However, if the principal investigator became aware of an SAE, including death, at any point after the participant's withdrawal from the study and determined that the event was reasonably related to the study intervention or participation in the study, the principal investigator was required to promptly notify the sponsor.

[0137] Care was taken to avoid bias when detecting AEs and / or SAEs. Free-form, uninducing oral questioning of participants was the preferred method for inquiring about the occurrence of AEs.

[0138] From the signing of the informed consent form to the completion of the trial as defined by the protocol, all adverse events (AEs), regardless of severity or association with an IMP / non-investigational drug (NIMP), were recorded on the corresponding page or screen of the case report form of the enrolled participant. For participants ineligible for screening, recording in the case report form was performed only if a SAE occurred during the screening period or if any screening procedure exposed the participant to a safety risk (e.g., administration of any substance as prior treatment or for phenotypic testing, performance of an invasive trial, or prolonged treatment interruption).

[0139] To ensure participant safety, the principal investigator took appropriate measures to monitor all adverse events (AEs) until clinical recovery was complete, laboratory results returned to normal or progression stabilized, or until death. This may mean that monitoring continued beyond the last planned visit in accordance with the protocol, and additional investigations may be requested by the monitoring team.

[0140] If treatment is discontinued prematurely, participants will be evaluated using the procedures planned for the end-of-study visit, which will include pharmacokinetic samples where appropriate as defined by the protocol.

[0141] Abnormalities in tests, vital signs, or ECG were recorded as AEs in the eCRF in the following cases: • If it is symptomatic, and / or • When either corrective treatment or consultation is required, and / or If it results in discontinuation or modification of IMP / NIMP, and / or if the severity criteria are met, and / or if it is defined as an AESI.

[0142] Pregnancies occurring in the female partners of male participants enrolled in the study were eligible as SAEs only if they met one of the severity criteria. If a female participant became pregnant, the IMP was discontinued. If a pregnancy occurred during the screening phase, it was reported only if it met one of the severity criteria. Follow-up of pregnancies was mandatory until the outcome was determined. When a pregnancy was reported, the principal investigator recorded the pregnancy information in the appropriate form and submitted it to the sponsor within 24 hours of becoming aware of the female participant.

[0143] Cardiovascular events were reported if they met the AE / SAE criteria. Events with fatal outcomes were reported as SAEs.

[0144] Particularly noteworthy adverse events (AESIs) are AEs (serious or non-serious) of scientific and medical concern specific to the IMP or program, for which continuous monitoring by the principal investigator and prompt notification to the sponsor may be appropriate. Such events may require further investigation to determine and understand their characteristics. AESIs may be added, modified, or excluded during the trial by amendments to the protocol.

[0145] In the case of AESI in this trial, in accordance with the SAE notification guidelines, if the severity criteria were not met, the sponsor was immediately notified using the corresponding screen in the eCRF (i.e., within 24 hours).

[0146] • ALT increased by >3 × ULN.

[0147] • QT prolongation (QTcF ≥ 500 milliseconds [ms]) and / or delta-QTc change from baseline > 60 ms (12-lead ECG). If the QTc interval prolongation (automatically measured) was ≥ 500 ms, as confirmed by manual reading by the principal investigator or a physician delegated by the principal investigator using the Fridericia formula to correct for QT, the participant was placed under special monitoring. Administration of the investigational drug was discontinued and appropriate blood samples were collected. Subsequently, the participant's subsequent ECG monitoring was performed regularly and clinically reliable until the QTc interval returned to a safe value determined by the principal investigator in agreement with the sponsor.

[0148] • Photosensitivity (Grade 2 or higher AE due to sun exposure).

[0149] ·pregnancy.

[0150] Symptomatic overdose. - An IMP overdose (accidental or intentional) is defined as an event suspected by the principal investigator or voluntarily reported by the participant (not based on a systematic number of tablets) that is at least twice the intended dose within the intended therapeutic interval, as adjusted according to the investigational drug.

[0151] In particular, asymptomatic overdose should be reported as a standard adverse event (AE).

[0152] Once participants were enrolled in the clinical trial, the following laboratory abnormalities were monitored, documented, and managed.

[0153] • Neutrophil count <1500 / mm³ 3 Characterized by being, or neutropenia due to an ethnic group (recorded as an AE only if at least one of the above criteria is met).

[0154] • Platelet count <100,000 / mm³ 3Thrombocytopenia, characterized by being confirmed regardless of the presence or absence of bleeding (recorded as AE only when at least one of the above criteria was met).

[0155] · Increase in ALT. Patients with 3ULN < ALT ≤ 5ULN and total bilirubin ≤ 2ULN were monitored. If total bilirubin > 2ULN or ALT > 5ULN, the IMP was discontinued.

[0156] · Acute kidney injury characterized by a persistent increase from baseline creatinine at the lower of either 0.3 mg / dL (about 26.4 μmol / L) or 30% (recorded as AE only when at least one of the above criteria was met).

[0157] · CPK increase suspected to be of non - cardiac origin and not related to strenuous physical activity, identified by muscle symptoms or systematic evaluation and characterized by CPK > 3ULN (suspicion of rhabdomyolysis was recorded as AE only when at least one of the above criteria was met, and the increase in CPK was recorded as AE only when at least one of the above criteria was met).

[0158] Blood samples were processed for the analysis of IL - 17A, IL - 17F, and IL - 22 in serum samples by a high - sensitivity method. Samples were collected according to the above activity schedule.

[0159] Results - Patient demographics and baseline characteristics A total of 38 participants were randomized, with 26 exposed to compound 1 and 12 to placebo. All 36 participants completed the trial. Two participants who received compound 1 at a 200 mg BID withdrew due to adverse events (AEs) (one on day 8 and one on day 15) and were replaced to complete the pharmacodynamic population of 36 participants. Safety data are available for all 38 participants, clinical response data are available for 37 participants (only one of the two dropouts had one post-baseline PD assessment on day 15), and biomarker data are available for all 38 participants (two dropouts had post-baseline biomarker assessments on day 8 and only one on day 15).

[0160] Thirty-eight male participants with comparable demographic characteristics were enrolled (demographics are summarized in Table 1 below). The median age was 43, more specifically 42.5 (range 21–64 years), and the median BMI was 26.2 kg / m². 2 The range was 21.0–32.7. All participants had a confirmed diagnosis of chronic plaque psoriasis (at least 6 months prior to screening) and presented with at least two lesions with a TLS score of ≥4 at screening and baseline. The mean (±SD) baseline TLS score was approximately 7.0, more specifically 7.01 (±1.54), and the mean PASI at baseline was 8.6, more specifically 8.58 (±3.40). In total, 13 out of 38 participants (34.2%) had a total PASI score of ≥10 (moderate psoriasis). In total, 25 out of 38 participants (65.8%) had a total PASI score <10 (mild psoriasis). Participants were prohibited from using any systemic or topical psoriasis therapy except for the use of up to 1% topical hydrocortisone, and treatment with 1,25-dihydroxyvitamin D analogs could be maintained at a stable dose until the end of the study if initiated 6 months prior to day 1. Nevertheless, none of the participants used any of the permitted treatments during the trial.

[0161] [Table 6]

[0162] Results - Clinical response based on TLS score TLS scores were assessed at baseline, 2 weeks, and 4 weeks. Table 2 below shows the least squares mean (LSm) ± standard error (SE) and least squares mean difference (ΔLSm; compound 1-placebo) ± standard error (SE) for each treatment, accompanied by a 90% confidence interval (CI) for the rate of improvement from baseline in TLS scores (calculated as the mean of TLS score values ​​collected from two lesions) at weeks 2 and 4.

[0163] [Table 7]

[0164] The results in Table 2 were obtained using a mixed model for repeated measures (MMRM).

[0165] Figure 1 shows the mean (±SEM) change in TLS score from baseline over time. The placebo-treated arm (solid line with black circles) shows a mean decrease of approximately 1.25 points at week 4, while the compound 1-treated arm (dashed line with white circles) shows a mean decrease of approximately 2.5 points over the same period.

[0166] Table 3 below shows the mean (±SEM) improvement rate from baseline in TLS scores (calculated as the mean of TLS score values ​​collected from two lesions) at weeks 2 and 4 in a patient population with PASI < 10 (mild) or PASI ≥ 10 (moderate) at baseline.

[0167] [Table 8]

[0168] The results in Table 3 are derived from standard descriptive analysis. (1) N=3, (2) N=15

[0169] Based on the observed data, the difference in the mean improvement rate of TLS scores at week 4 between compound 1 and placebo was estimated to be 17.7% (90% CI [5.0%; 30.5%]).

[0170] Results - Clinical response based on PASI score PASI scores were assessed at baseline, 2 weeks, and 4 weeks. Table 4 below shows the LSm (±SE) and ΔLSm (compound 1-placebo) for each treatment, with 90% confidence intervals (CI) for the percentage improvement from baseline in the total PASI score at weeks 2 and 4.

[0171] [Table 9]

[0172] The results in Table 4 were obtained using MMRM.

[0173] Figure 2 shows the mean (±SEM) change in total PASI score from baseline over time. The placebo treatment arm (solid line with black circles) shows a mean decrease of approximately 1.25 points at week 4, while the compound 1 treatment arm (dashed line with white circles) shows a mean decrease of approximately 3.0 points over the same period.

[0174] Table 5 below shows the mean (±SEM) improvement rate from baseline in total PASI score at weeks 2 and 4 in a patient population with PASI < 10 (mild) or PASI ≥ 10 (moderate) at baseline.

[0175] [Table 10]

[0176] The results in Table 5 are derived from standard descriptive analysis. (1) N=3, (2) N=15

[0177] Based on observed data, the difference in the mean improvement rate of total PASI score at week 4 between compound 1 and placebo was estimated to be 19.4% (90% CI [6.3%; 32.5%]). The improvement in PASI score after 4 weeks of treatment with compound 1 was clinically significant and consistent with the improvement in TLS score in mild to moderate psoriasis.

[0178] Overall, compound 1 at 200 mg BID showed significant improvement in total PASI scores at week 2 (17.73% vs. 4.12%, p=0.005) and week 4 (35.09% vs. 15.71%, p=0.009) (mean improvement from baseline, p-value for one-sided study at 5% significance level). Consistently, there was a clear improvement in TLS scores from baseline to week 2 (17.06% vs. 6.29%, p=0.032) and week 4 (38.18% vs. 20.44%, p=0.012). Individual analyses of patients with mild (PASI<10) or moderate (PASI≧10) psoriasis showed improvement at week 2 (mild: 20.9%; moderate: 10.9%) and week 4 (mild: 37.0%; moderate: 39.7%), regardless of disease severity.

[0179] Results - Clinical response based on sIGA score The sIGA score was evaluated as described herein. As shown in Table 6 below, the percentage of patients who achieved at least one severity level improvement in the sIGA score measured at week 4 compared to baseline sIGA measurements was 58.3% in the treatment arm compared to 0% in the placebo group.

[0180] [Table 11]

[0181] Figure 6 shows the severity of psoriasis in patients, as measured by the sIGA score, in the treatment arm compared to the placebo arm at baseline, week 2, and week 4.

[0182] Overall, compound 1 at 200 mg BID showed a clinically significant change in sIGA score after 4 weeks of treatment compared to placebo.

[0183] Conclusions regarding clinical response While milder disease forms typically result in more subtle therapeutic changes, compound 1 demonstrated a rapid and statistically significant improvement in psoriasis severity as early as week 2 compared to placebo, and this improvement persisted until week 4.

[0184] The mean least squares (LS) difference in the rate of improvement in TLS scores between compound 1 and placebo was 10.77% at week 2 and 17.74% at week 4, suggesting an overall improvement in TLS scores with compound 1 compared to placebo. A comparison of the mean LS difference in the rate of improvement in TLS scores between the treatment arm and the placebo arm at week 2 (mild: 20.9%; moderate: 10.9%) and week 4 (mild: 37.0%; moderate: 39.7%) shows improvement in TLS scores regardless of disease severity. The mean LS difference in the rate of improvement in total PASI scores at week 2 (13.61%) and week 4 (19.38%) also shows an overall improvement in psoriasis severity with compound 1 compared to placebo. In the compound 1 group versus placebo group, higher rates of improvement in PASI scores were observed in both subcategories at week 2 (mild: 21.2% vs. 4.8%, more specifically 21.24% vs. 4.80%; moderate: 9.3% vs. 3.5%, more specifically 9.31% vs. 3.54%) and week 4 (mild: 33.8% vs. 14.3%, more specifically 33.83% vs. 14.26%; moderate: 33.2% vs. 19.9%, more specifically 33.19% vs. 19.88%).

[0185] The treatment arm showed significant improvement from baseline in total PASI score compared to the placebo arm at week 2 (17.73% vs. 4.12%, p=0.005) and week 4 (35.09% vs. 15.71%, p=0.009). Clear improvement in TLS score was observed in the treatment arm compared to the placebo arm at week 2 (17.06% vs. 6.29%, p=0.032) and week 4 (38.18% vs. 20.44%, p=0.012). At week 4, the proportion of patients achieving improvement in at least one severity level in sIGA was 58.3% in compound 1 compared to no effect (0%) in the placebo group. The study also demonstrated that, compared to the placebo group, a higher proportion of patients receiving compound 1 showed improvement in sIGA scores from baseline "moderate" disease to "mild" or "nearly absent" at weeks 2 and 4. Patients in the placebo group showed an increase in sIGA from "mild" to "moderate."

[0186] Results - Pharmacokinetics The mean pre- and post-administration plasma concentrations of compound 1 were consistent with similar values ​​observed in previous studies with the same dose in healthy participants. Mean pre-administration plasma levels of compound 1 remained similar from day 8 to day 29, indicating that a steady state was achieved and maintained. Plasma concentrations of compound 1 were below the limit of quantification in the placebo group.

[0187] Results - Adverse Events Treatment-induced adverse events (TEAEs) were reported in 7 out of 12 participants (58.3%) in the placebo group and in 24 out of 26 participants (92.3%) in the compound 1 treatment group. There were no serious AEs (SAEs), severe TEAEs, or particularly noteworthy AESIs. Under compound 1 200 mg BID, there were two TEAEs that resulted in permanent discontinuation of the study intervention in two participants: one participant dropped out on day 15 due to nausea assessed by the investigator as drug-related, and the other participant dropped out on day 8 due to an elevated CPK (grade 2) assessed by the investigator as not drug-related and associated with increased physical activity, with CPK levels returning to baseline levels after 7 days.

[0188] The most frequent TEAEs by major organ system classification (SOC) were neurological disorders [4 patients (33.3%) in the placebo group and 19 patients (73.1%) in the compound 1 treatment group], gastrointestinal disorders [2 patients (16.7%) in the placebo group and 8 patients (30.8%) in the compound 1 treatment group], and infection and invasiveness [4 patients (33.3%) in the placebo group and 4 patients (15.4%) in the compound 1 treatment group]. The most frequent TEAEs by basic vocabulary (PT) were taste disorders [0 patients (0%) in the placebo group and 16 patients (61.5%) in the compound 1 treatment group] and headache [4 patients (33.3%) in the placebo group and 8 patients (30.8%) in the compound 1 treatment group]. All TEAEs were grade 1 or grade 2 in severity, and all participants recovered completely.

[0189] There were few potentially clinically significant abnormalities (PCSAs) in vital signs, ECG, and laboratory parameters scattered across the placebo and compound 1 treatment groups. All were deemed clinically insignificant by the principal investigator. There were no QTcF changes >60 msec and / or QTcF >480 msec from baseline. One participant under compound 1 200 mg BID had a QTcF >450 msec (459 msec) on a single occasion on day 8, with a QTcF change of 33 msec from baseline (baseline QTcF value was 426 msec). There were no PCSAs for ALT increase, and two participants under compound 1 200 mg BID had total bilirubin increases of >1.5 ULN on a single occasion on day 8 (1.67 ULN, baseline value was 1.5 ULN) and day 15 (1.56 ULN, baseline value was 1.3 ULN), respectively.

[0190] In summary, no serious adverse events, severe TEAEs, or AESIs were reported.

[0191] Conclusions regarding pharmacodynamics, pharmacokinetics, and safety Compound 1, a specific inhibitor of TNFR1 signaling, demonstrated consistent clinical efficacy over a 4-week treatment period. A 28-day dose of 200 mg BID of Compound 1 was safe and well-tolerated by participants with mild to moderate psoriasis, with no serious adverse events (AEs), severe treatment-induced AEs, or AESIs reported.

[0192] The observed plasma concentrations of compound 1 were consistent with pharmacokinetic data previously obtained in healthy participants. Based on the mean pre-administration plasma concentration, steady state was achieved within the first week and maintained until the end of treatment.

[0193] Results - Biomarker Analysis As described above, peripheral blood samples collected at predetermined time points were processed to quantify serum levels of psoriasis biomarkers, including IL-17A, IL-17F, and IL-22. IL-17A and IL-17F levels were quantified using a single-molecule counting sandwich immunoassay (SMCxPro®, see also Milpore-Hwang et al., Methods (2019) 158:69-76). IL-22 levels were quantified using a single-molecule array ELISA (SIMOA®, see also Myriad RBM-Rissin et al., Anal Chem (2011) 83(6):2279-2285). Statistical analysis was based on geometric mean ratios to baseline, and a t-test between two samples at a 5% significance alpha level was used to calculate p-values. Table 7 below shows the changes in biomarker levels summarized using descriptive statistics (mean, standard error of mean [SEM]) for each treatment and time point.

[0194] [Table 12]

[0195] Compared to placebo, compound 1 achieved a rapid and significant reduction in serum IL-22 levels by week 2 (0.66 vs. 1.24; p=0.0001), which decreased further by week 4 (0.57 vs. 1.20; p<0.0001). IL-17F levels were substantially reduced in treated patients at both week 2 (0.61 vs. 0.92; p=0.0795) and week 4 (0.48 vs. 1.00; p=0.0025) compared to the placebo group. A gradual decline was observed in IL-17A levels from baseline to week 2 (0.92 vs. 1.30; p=0.1066) and week 4 (0.72 vs. 1.10; p=0.0859). Figures 3 to 5 show the evolution of biomarkers (IL-17A, IL-17F, and IL-22) from baseline to week 4, respectively. The decrease in cytokine secretion correlated with a statistically significant clinical improvement in PASI compared to placebo in patients treated with compound 1 (week 2 (17.73% vs. 4.12%, p=0.005) and week 4 (35.09% vs. 15.71%, p=0.009)).

[0196] Conclusions regarding biomarker levels In patients with mild to moderate psoriasis, serum levels of IL-17A, IL-17F, and IL-22 were substantially reduced after 4 weeks of treatment with compound 1. The reduction in biomarkers correlated with the observed clinical improvement in patients treated with compound 1.

[0197] Overall conclusions from clinical trials Findings from this Phase 1 trial demonstrated that compound 1, a specific TNFR1 signaling inhibitor, is safe, well-tolerated, clinically effective, and produces a sustained clinical response in mild to moderate psoriasis over a 4-week treatment period.

[0198] Although this disclosure has been described in conjunction with the embodiments described above, it should be understood that the above description and examples are intended to illustrate, and not limit, the scope of this disclosure. Other aspects, advantages and modifications within the scope of this disclosure will be apparent to those skilled in the art in which this disclosure relates.

[0199] In addition, if a feature or aspect is described in terms of the Markush group, a person skilled in the art will recognize that such feature or aspect is also described in terms of any individual member or subgroup of a member of the Markush group.

[0200] All publications, patent applications, patents, and other references referred to herein are expressly incorporated by reference to the same extent as if each were incorporated individually by reference. In the event of any conflict, including definitions, this specification shall prevail.

Claims

1. (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidine-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidaz[1,2-b][2,5]benzodiazosin-5(14H)-one (compound 1): 【Chemistry 1】 A compound for use in a method of treating psoriasis in a human subject, which is a pharmaceutically acceptable salt thereof, wherein the subject has mild to moderate psoriasis, and the method comprises administering to the subject a daily dose of about 400 mg of the compound (calculated as free base).

2. The compound for use according to claim 1, wherein the psoriasis is plaque psoriasis, for example, chronic plaque psoriasis.

3. The severity of psoriasis in the subject is assessed using PASI scoring, and the subject has a total PASI score of 16 or less, the compound for use according to claim 1 or 2.

4. The subject is a compound for use according to any one of claims 1 to 3, having a total PASI score of 10 or more.

5. The compound for use according to any one of claims 1 to 4, wherein the subject has at least two lesions with a TLS score of 4 or higher (excluding the scalp).

6. A compound for use according to any one of claims 1 to 5, which is administered orally to the subject.

7. The compound for use according to any one of claims 1 to 6, administered in the form of an oral pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

8. The compound for use according to claim 7, wherein the oral pharmaceutical composition is a tablet.

9. The compound for use according to any one of claims 1 to 8, comprising administering a dose of approximately 200 mg of the compound (calculated as free base) to the subject twice daily.

10. A method for treating psoriasis according to any one of claims 1 to 9, wherein a therapeutically effective amount of compound 1 (or a pharmaceutically acceptable salt thereof) is administered to a human subject in need thereof, the therapeutically effective amount being a daily dose of about 400 mg (calculated as free base).

11. Compound 1 or a pharmaceutically acceptable salt thereof for use in the manufacture of an agent for treating mild to moderate psoriasis according to the method of any one of claims 1 to 9, wherein the agent is adapted to provide a daily dose of about 400 mg of the compound (calculated as free base).

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