Methods for treating psoriatic arthritis

Abstract

The present invention relates to a compound of formula I for treating psoriatic arthritis: #imgabs0# or a pharmaceutically acceptable salt thereof or a solvate or a salt of a solvate, a pharmaceutical composition containing them and a method of treatment using them, which is carried out by administering the compound of formula I.

Description

Field of the Invention

[0001] The present invention relates to the medical use of the compound of formula I of the present invention in treating psoriatic arthritis (PsA). The present invention also provides a method for treating and / or preventing PsA by administering the compound of formula I of the present invention.

[0002] background

[0003] Psoriatic arthritis (PsA) is an inflammatory form of arthritis that affects up to 30% of people with psoriasis. Psoriatic arthritis causes swelling, stiffness and pain in and around joints, nail changes and overall fatigue. Research shows that delaying treatment of PsA for as little as six months can lead to permanent joint damage. Early identification, diagnosis and treatment of PsA are critical to relieve pain and inflammation and help prevent joint damage. While many treatment options are available, few treatments are currently effective in relieving enthesitis and symptoms in the joints and skin.

[0004] In the fight against RA, Janus kinase (JAK) inhibitors have been developed. JAK is a cytoplasmic tyrosine kinase that can conduct cytokine signals from membrane receptors to STAT transcription factors. Four JAK family members have been described, namely JAK1, JAK2, JAK3 and TYK2. When cytokines bind to their receptors, JAK family members autophosphorylate and / or transphosphorylate each other, followed by STAT phosphorylation, and then migrate to the nucleus to regulate transcription. JAK-STAT intracellular signal transduction is used for interferon, most interleukins, and various cytokines and endocrine factors, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL (Vainchenker et al., 2008).

[0005] JAK1 is a target in the field of immunoinflammatory diseases. JAK1 heterodimerizes with other JAKs to transduce cytokine-driven proinflammatory signaling. Therefore, JAK1 inhibition is meaningful for immunoinflammatory diseases with pathologically related cytokines such as IL-6, IL-4, IL-9, IL-15, IL-21 or IFNγ, and other diseases driven by JAK-mediated signaling. WO2010 / 149769 (Menet and Smits, 2010) discloses a compound according to formula I, cyclopropanecarboxylic acid {5-[4-(1,1-dioxothiomorpholine-4-ylmethyl)phenyl]-[1,2,4]triazolo[1,5a]pyridine-2-yl}amide (Compound 1), and has the chemical structure shown below:

[0006]

[0007] Compound I is a potent and selective JAK1 inhibitor for the treatment of inflammatory disorders. Compound I is highly selective for inhibiting JAK1 among 451 unique kinase gene products tested in vitro. In a human whole blood assay, Compound I inhibited cytokine-induced STAT1 phosphorylation with a half-maximal inhibitory concentration (IC 50 ) values ​​were 629 nM and 17,453 nM for JAK1 and JAK2 mediated signaling, respectively, demonstrating a 27-fold selectivity for JAK1 over JAK2 in this assay. Compound I is therefore a JAK1 selective inhibitor.

[0008] In humans, Compound I is metabolized to a major metabolite, a compound of Formula II:

[0009]

[0010] This molecule also inhibits JAK1 signaling, but is about 20 times less potent than the parent compound and is enriched by about 10 times more. Although the efficacy of this metabolite is lower than that of the parent molecule, the overall exposure and peak plasma concentration in humans are higher than the levels in all tested animal species. Therefore, special pharmacology and toxicology studies have been carried out with compound II. The results of pharmacodynamic (PD) tests in healthy volunteers suggest that the clinical activity of compound I may be derived from the combination of the parent molecule and metabolites. The compound of formula II is described in WO2013 / 189771.

[0011] JAK inhibitors are being evaluated for the treatment of PsA. A phase III clinical trial of tofacitinib in patients with active psoriatic arthritis who had previously responded inadequately to conventional synthetic disease-modifying antirheumatic drugs showed an ACR20 response rate of 50% at month 3 when given at 5 mg and 61% at 10 mg, compared to 33% in the placebo group (Mease P. et al., NEJM 377; 16 1537-1550).

[0012] However, although JAK inhibitors are useful and effective molecules in treating inflammatory diseases, it is reported that the disadvantages of using these compounds include anemia, thrombocytopenia and neutropenia, hypercholesterolemia, and increased creatinine, all of which may be due to lack of selectivity, especially selectivity for JAK2 (O'Shea, JJ et al. 2013. Back to the Future: Oral targeted therapy for RA and other autoimmunediseases. Nat. Rev. Rheumatol. 9, 173-182; O'Shea, JJ, Plenge, R., 2012. JAKs and STATs in Immunoregulation and Immune-Mediated Disease. Immunity 36, 542-550). In contrast, selective JAK inhibition, especially JAK1 inhibition, can produce safe and effective therapeutic agents. (Yamaoka, K., 2016. Janus kinase inhibitors for rheumatoid arthritis. Curr. Opin. Chem. Biol. 32, 29–33).

[0013] Therefore, there remains a need in the art for additional drugs with better risk-benefit profiles for the treatment of PsA. SUMMARY OF THE INVENTION

[0015] The present invention relates to the discovery that Compound I has shown unexpectedly high potential in the treatment of psoriatic arthritis with a favorable benefit-risk profile. In a Phase IIa trial (Example 1 reported herein), an ACR20 of 80% was demonstrated after 16 weeks of treatment of patients with psoriasis with Compound I. Other specific findings will be apparent from the following description of the invention.

[0016] Therefore, the present invention provides a compound of formula I

[0017]

[0018] It is used for treating psoriatic arthritis and is orally administered daily at a dosage selected from 100-200 mg once a day or 50-100 mg twice a day.

[0019] In a specific embodiment, the compound of Formula I is administered as the sole active agent for the treatment of PsA.

[0020] In another embodiment, a compound of Formula I is provided for use in treating psoriatic arthritis, administered orally at a dosage selected from 100 or 200 mg once daily or 100 mg twice daily, wherein an ACR20 response is observed in at least 60, 70 or 80% of patients.

[0021] In another embodiment, a compound of Formula I is provided for use in treating psoriatic arthritis, administered orally at a dosage selected from 100 or 200 mg once daily or 100 mg twice daily, wherein an ACR50 response is observed in at least 30, 35 or 40% of patients.

[0022] In another embodiment, a compound of Formula I is provided for use in treating psoriatic arthritis, administered orally at a dose selected from 100 or 200 mg once daily or 100 mg twice daily, wherein a statistically significant ACR20 response is observed after the first week of treatment.

[0023] In another embodiment, a compound of Formula I is provided for use in treating psoriatic arthritis, administered orally at a dosage selected from 100 or 200 mg once daily or 100 mg twice daily, wherein a statistically significant ACR50 response is observed after the first week of treatment.

[0024] In another embodiment, a compound of Formula I is provided for use in treating psoriatic arthritis in a patient with entheseal inflammation.

[0025] In another embodiment, a compound of Formula I is provided for use in treating psoriatic arthritis in patients not previously exposed to bDMARDs, particularly anti-TNF drugs.

[0026] In another embodiment, a composition, such as a pharmaceutical composition, is provided, comprising Compound I according to any embodiment disclosed herein and a pharmaceutically acceptable vehicle.

[0027] In another aspect, there is provided a method of treating psoriatic arthritis comprising the step of orally administering to a human in need thereof a compound of formula I at a dosage selected from 100 or 200 mg once daily, or 100 mg twice daily.

[0028] In one embodiment, the method of treatment results in an ACR20 response in at least 60, 70, or 80% of patients. In another embodiment, the ACR20 response is statistically significant after week 1 of treatment.

[0029] In another embodiment, the method of treatment results in an ACR50 response in at least 30, 35, or 40% of patients. In another embodiment, the ACR50 response is statistically significant after week 1 of treatment.

[0030] In another embodiment, the patient undergoing said treatment has not been previously exposed to bDMARDs, particularly anti-TNF therapy.

[0031] In another embodiment, the patient undergoing said treatment displays signs and / or symptoms of entheseal inflammation. DETAILED DESCRIPTION OF THE INVENTION

[0033] The following terms are intended to have the meanings set forth below, and may be used to understand the description and intended scope of the present invention.

[0034] When describing the present invention that may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, unless otherwise indicated, the following terms (if any) have the following meanings. It should also be understood that when described herein, any portion defined below can be substituted with a variety of substituents, and the corresponding definitions are intended to include such substituted portions within the scope described below. Unless otherwise indicated, the term "substituted" should be defined as follows. It should be further understood that the terms "group" and "base" can be considered interchangeable when used herein.

[0035] The terms "a" and "an" herein may be used to refer to one or more (ie, at least one) of the grammatical objects of the article. As an example, "an analogue" refers to one or more than one analogue.

[0036] The terms "compound I", "compound according to formula I" or "compound of formula I" are used interchangeably to refer to a compound having structural formula I:

[0037]

[0038] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or equivalent in a country outside the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0039] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, these salts include: (1) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid (2) when the acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or a coordination compound with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. By way of example only, salts also include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; when the compound contains a basic functional group, it is a salt of a non-toxic organic or inorganic acid, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0040] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0041] "Solvate" refers to a compound form that is combined with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid, etc. The compounds of the present invention can be prepared, for example, in a crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and also include stoichiometric solvates and non-stoichiometric solvates. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be able to separate. "Solvate" covers solution phases and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0042] "Subject" includes humans. The terms "human," "patient," and "subject" are used interchangeably herein.

[0043] "Effective amount" refers to the amount of the compound of the present invention that is sufficient to affect the treatment of the disease when administered to a subject for the treatment of the disease. "Effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated.

[0044] "Prevent" or "preventing" refers to reducing the risk of acquiring or developing a disease or condition in a subject who may be exposed to a disease-causing agent or who is susceptible to the disease prior to the onset of the disease, i.e., resulting in the non-occurrence of at least one clinical symptom of the disease.

[0045] The word "prophylaxis" is related to "prevent" and refers to measures or methods intended to prevent rather than treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospitalized patients at risk of thrombosis due to reasons such as immobilization; and the administration of antimalarial drugs such as chloroquine before visiting geographic areas where malaria is prevalent or the risk of contracting malaria is high.

[0046] In one embodiment, "treatment" of any disease or disorder refers to ameliorating the disease or disorder (i.e., preventing the disease or reducing the manifestation, extent, or severity of at least one clinical symptom thereof). In another embodiment, "treatment" refers to improving at least one physical parameter, which may be unrecognizable to the subject. In yet another embodiment, "treatment" refers to regulating the disease or disorder physically (e.g., stabilizing recognizable symptoms), physiologically (e.g., stabilizing physical parameters), or both. In another embodiment, "treatment" involves slowing the progression of the disease.

[0047] For the purposes of the present invention, the terms "ACR20", "ACR50" and "ACR70" as used herein are scores indicating how much a patient's peripheral arthritis symptoms have improved according to the criteria established by the American College of Rheumatology (ACR). ACR scores represent percentages. An ACR20 score indicates that a person's arthritis symptoms have improved by 20%, an ACR50 score indicates that a person's arthritis symptoms have improved by 50%, and an ACR70 score indicates that a person's arthritis symptoms have improved by 70%. Specifically, in order to quantify the ACR20 score, a person must have at least 20% fewer joint tenderness (tender joint count TJC68 improved by at least 20% from baseline) and at least 20% fewer swollen joints (swollen joint count SJC66 improved by at least 20% from baseline). In addition, patients must show a 20% improvement in at least three of the following five areas: the patient's global (composite) assessment of their own disease activity (using a 0-100 mm visual analog scale (VAS)), the clinician's global assessment of the patient's disease activity (using a 0-100 mm VAS), the patient's assessment of their own PsA pain intensity (using a 0-100 mm VAS), their own assessment of physical function as measured by the HAQ-DI, and the results of a C-reactive protein (CRP) blood test (in mg / dL or mg / L). The ACR50 and ACR70 scores use the same criteria, but require improvements of 50% and 70%, respectively.

[0048] As used herein, "DAS28 (CRP)" refers to a clinical score from 2.0 to 10.0 that is used to measure a patient's disease activity and includes 28 tender and swollen joint counts, CRP measurements from blood analysis, and general health assessment using VAS. More details on the DAS28 (CRP) assay are provided in Example 1. DAS28 (CRP) values ​​below 2.6 indicate remission, DAS28 (CRP) values ​​between 2.6 and 3.2 indicate low disease activity, DAS28 (CRP) values ​​between 3.2 and 5.1 indicate moderate disease activity, and DAS28 (CRP) values ​​above 5.1 are associated with high disease activity (Wells et al., 2009 Ann. Rheum. Dis. 68, 954-960).

[0049] As used herein, the term "CRP" refers to C-reactive protein in serum and is an inflammatory marker. Specifically, guidelines for CRP are widely available and recommend a normal value of <0.5 mg / dL (Porter, 2011 The Merck Manual of Diagnosis and Therapy (Wiley)).

[0050] As used herein, the term "entheseal inflammation" refers to inflammation of the tendon's entheseal attachments, which is a typical feature of PsA and one of the characteristics that distinguishes it from rheumatoid arthritis.

[0051] As used herein, the term "SPARCC enthesitis index" refers to a clinical score performed after examining 16 peripheral sites (tendon bone attachments) for tenderness, the degree of tenderness is assessed by palpation, and a score of 0 (no tenderness) or 1 (tenderness) is assigned. The total enthesitis score is the sum of all site scores, up to a maximum of 16. The higher the score, the higher the enthesitis burden. (Maksymowych WP et al. Development and validation of the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index. Ann Rheum Dis 2009; 68: 948-53).

[0052] As used herein, the term "Leeds Enthesin Inflammation Index" or "LEI" refers to a clinical score after examining six sites for tenderness (of the tendon ends): two sites each at the lateral epicondyle of the humerus, the medial femoral condyle, and the insertion of Achilles tendon. The LEI score range is 0-6. The higher the score, the higher the enthesin inflammation load.

[0053] As used herein, the term "HAQ-ID" refers to the Health Assessment Questionnaire without Disability Index, which is a measure of a patient's physical function. HAQ-DI is a 20-question tool used to assess a person's difficulty in completing tasks in eight functional areas (B. Bruce and J. Fries, "The Stanford Health Assessment Questionnaire: dimensions and practical applications" Health Qual Life Outcomes, p. 1: 20, 2003). The total score of HAQ-DI ranges from 0 to 3, with higher scores indicating more severe functional impairment.

[0054] As used herein, the term "MDA" refers to minimal disease activity, which is a measure of disease remission. For the purposes of the present invention, a patient is classified as having achieved MDA if 5 of the following 7 criteria are met:

[0055] -TJC68≤1

[0056] -SJC66≤1

[0057] -PASI ≤ 1 or BSA ≤ 3%

[0058] - Patient's PsA pain intensity score composite assessment ≤ 15 (0-100 mm VAS)

[0059] - Patient's disease activity composite assessment ≤ 20 (0-100 mm VAS)

[0060] -HAQ-DI≤0.5

[0061] - SPARCC enthesin inflammation index ≤ 1

[0062] As used herein, the term "PASI" refers to the Psoriasis Area and Severity Index score and is an index used to represent the severity of psoriasis. It combines the severity (erythema, induration and desquamation) and the percentage of affected areas. More details on determining PASI are provided in Example 1. PASI scores represent changes relative to baseline. "PASI50" refers to the portion of patients who achieve a 50% improvement in PASI score when testing a treatment. "PASI75" refers to the portion of patients who achieve a 75% improvement in PASI score when testing a treatment. "PASI90" refers to the portion of patients who achieve a 90% improvement in PASI score when testing a treatment.

[0063] As used herein, the term "BSA" refers to body surface area and is an estimate of the percentage of the body affected by psoriasis. BSA < 3% is rated as a mild case of psoriasis, BSA 3-10% is rated as a moderate case of psoriasis, and BSA > 10% is rated as a severe case of psoriasis.

[0064] As used herein, the term "cDMARD" refers to conventional disease-modifying antirheumatic drugs. Typically, cDMARDs are synthetic drugs, also referred to as conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Specific examples of cDMARDs for the treatment of psoriatic arthritis include methotrexate, leflunomide, sulfasalazine, chloroquine, and hydroxychloroquine.

[0065] As used herein, the term "bDMARD" refers to a biological disease-modifying antirheumatic drug. A specific class of bDMARDS is tumor necrosis factor (TNF) inhibitors, also known as anti-TNF drugs, such as etanercept, adalimumab, infliximab, golimumab, certolizumab, or certolizumab pegol.

[0066] As used herein, the term "first "TNF patients" refers to patients who have not been previously exposed to anti-TNF drugs, such as anti-TNF monoclonal antibody therapy, or subjects who have been previously exposed to anti-TNF therapy (such as but not limited to infliximab, golimumab, adalimumab, certolizumab pegol and / or certolizumab pegol) at doses registered for the treatment of inflammatory disorders, and the treatment of the inflammatory disorder has been interrupted for at least 8 weeks prior to entering this study.

[0067] As used herein, the term "TNF-experienced patients" refers to patients who are receiving or have received anti-TNF drugs, such as anti-TNF monoclonal antibody treatment (such as but not limited to infliximab, golimumab, adalimumab, certolizumab pegol and / or certolizumab pegol) at the time of entry into this study and are no longer responding to such treatment.

[0068] As used herein, the term "anti-TNF drug" refers to a class of drugs used to treat inflammatory conditions, particularly rheumatoid arthritis (RA), psoriatic arthritis, juvenile arthritis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), ankylosing spondylitis, and psoriasis. TNF is a chemical produced by the immune system that causes inflammation in the body. In healthy individuals, excess TNF in the blood is naturally blocked, but in those inflammatory conditions, high levels of TNF in the blood lead to more inflammation and persistent symptoms. Specific examples of anti-TNF drugs include infliximab, golimumab, adalimumab, certolizumab pegol, and certolizumab pegol. Therefore, the term "anti-TNF therapy" refers to treatment by administering an anti-TNF drug.

[0069] The term "compounds of the present invention" and equivalent expressions encompass compounds of Formula I as described herein, including pharmaceutically acceptable salts and solvates, such as hydrates, and solvates of pharmaceutically acceptable salts, if the context permits. Similarly, reference to intermediates, whether or not they are claimed, is intended to include salts and solvates thereof, if the context permits.

[0070] The term "therapeutic effect" refers to an effect attributable to a particular or specific treatment, such as use of Compound I to treat psoriatic arthritis.

[0071] Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis, characterized by a heterogeneous musculoskeletal phenotype that involves multiple areas, including peripheral joints, the axial skeleton, tendon and ligament insertion sites (enthesitis), and the fingers (dactylitis). PsA occurs in approximately 30% of patients with psoriasis. In the majority of cases (75%), psoriasis precedes the joint disease, but in some cases (15%), the onset is synchronous, while in 10% of patients, arthritis precedes psoriasis. In the latter, unrecognized psoriasis may be found, or there may be a history of extensive guttate psoriasis in childhood or a strong family history.

[0072] PsA occurs with equal frequency in men and women. Arthritis in PsA typically involves distal joints and tends to distribute in a radial pattern, making it more likely that all of the same joints of a single finger are affected (dactylitis). The degree of erythema on the affected joints, the presence of asymmetric spinal involvement, the presence of entheseal inflammation, and lower levels of tenderness are also typical features of PsA. Since spondylitis is present in up to 40% of patients, PsA is also classified as a spondyloarthropathy. The extra-articular features observed in PsA are similar to those of other spondyloarthropathy and include mucosal lesions, iritis, urethritis, diarrhea, and aortic root dilatation and are associated with HLA-B27.

[0073] Traditionally, first-line treatment has consisted of nonsteroidal anti-inflammatory drugs (NSAIDs) and conventional disease-modifying antirheumatic drugs (cDMARDs), such as sulfasalazine (SSZ), methotrexate (MTX), and leflunomide (LEF). These drugs remain the mainstay of treatment, with limited access to biologics in this setting. The arrival of anti-tumor necrosis factor (TNF) drugs more than a decade ago significantly expanded the treatment armamentarium for PsA, leading to greatly improved outcomes for skin and joint disease. However, anti-TNF drugs do not work for all patients and may lose response over time, in part due to immunogenicity. Drugs with different mechanisms of action that target the interleukin (IL)-23 / IL-17 pathway, which promotes inflammation in the skin and joints, are now available, and more are being evaluated in clinical studies. These include the IL-12 / IL-23 inhibitors ustekinumab and tildrakizumab; the IL-23 inhibitor guselkumab; IL 17 receptor A inhibitors such as secukinumab and ixekizumab, the IL-17 receptor inhibitor brodalumab, the IL 17 receptor A / F inhibitor bimekizumab, and the phosphodiesterase E4 inhibitor apremilast. The therapeutic response to these new drugs has been most pronounced in psoriasis, resulting in marked plaque clearance; the results of these drugs in PsA are similar to those observed with anti-TNF drugs. IL-17 blockade is also effective in axial disease and inhibits radiological progression. The oral formulation apremilast provides modest responses in the skin and joints, has few safety signals, and is not indicated in patients who exhibit radiographic lesions or axial involvement.

[0074] Several key cytokines in the IL-23 / IL-17 pathway promote inflammatory signaling in the skin and joints through the Janus kinase (JAK) family of receptor-associated TYKs. Activated JAKs recruit and activate signal transducers and activators of transcription (STATs), which in turn drive gene transcription. Specific JAK-STAT activation depends on cytokine signals, which include IFN and its related cytokines, common γ-chain cytokines, and IL-6-type cytokines. Studies have shown that phospho-STAT3 (pSTAT3) and pSTAT1 expression are increased in psoriatic skin, and IFNγ, IL-6, and IL-22 have been shown to induce pSTAT1 or pSTAT3 in keratinocytes.

[0075] The present invention

[0076] The present invention provides a compound of the present invention for use in treating psoriatic arthritis, wherein the compound of the present invention is of Formula I:

[0077]

[0078] In one aspect, the compound of the invention according to any one of the embodiments described herein exists as a free base.

[0079] In one aspect, the compound of the invention according to any one of the embodiments described herein is a pharmaceutically acceptable salt. In a specific embodiment, the compound of the invention is present as a 1:1 maleate salt.

[0080] In one aspect, a compound of the invention according to any one of the embodiments described herein is a solvate of the compound.

[0081] In one aspect, the compound of the invention according to any one of the embodiments described herein is a solvate of a pharmaceutically acceptable salt of the compound. In a specific embodiment, the solvate of a pharmaceutically acceptable salt is a [compound of formula I: HCl: 3H2O] adduct.

[0082] It should be understood that the compounds of the present invention can be metabolized into biologically active metabolites. Active metabolites of compounds of formula I are described in WO2013 / 189771. In an alternative aspect, the compound of the present invention is a metabolite of a compound of formula I, and the metabolite is of formula II:

[0083]

[0084] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention, which is used to treat psoriatic arthritis when administered orally at a daily dose of 100 mg-250 mg, administered in one or two doses. In particular, the dose is selected from 50 mg twice daily (bid), 100 mg once daily (qd), 100 mg b.id and 200 mg qd.

[0085] In one embodiment, in aspects of the above uses and methods, the patient is not concurrently treated with another agent or medication for psoriatic arthritis.

[0086] In another embodiment, in aspects of the above uses and methods, the patient has had an inadequate response or is intolerant to one or more conventional disease modifying antirheumatic drugs (cDMARDs), such as methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine or chloroquine.

[0087] In an alternative embodiment, in aspects of the above uses and methods, the patient is concurrently treated with another agent for treating psoriatic arthritis, such as cDMARD therapy, such as treatment with methotrexate (e.g., up to 25 mg / week, oral or parenteral), leflunomide (e.g., up to 20 mg / day, oral), sulfasalazine (e.g., 3 g / day, oral), hydroxychloroquine (e.g., up to 400 mg / day) or chloroquine (e.g., up to 250 mg / day).

[0088] In another embodiment, in aspects of the above uses and methods, the patient is bDMARD treatment naive, particularly an anti-TNF drug.

[0089] In an alternative embodiment, in aspects of the above uses and methods, the patient was previously treated with a bDMARD, particularly an anti-TNF drug, and in particular, the patient had an inadequate or insufficient response to prior treatment with a bDMARD, such as an anti-TNF drug.

[0090] In another embodiment, the compounds of the invention are particularly useful for treating patients with psoriatic arthritis who exhibit signs and symptoms of entheseal inflammation. In another embodiment, such PsA patients suffer from entheseal inflammation as measured by the SPARCC Entheseal Inflammation Index. In an alternative embodiment, such PsA patients suffer from entheseal inflammation as measured by the Leeds Entheseal Inflammation Index (LEI score), e.g., a LEI score greater than 0.5 or greater than 1.0.

[0091] In a specific embodiment of the above-mentioned uses and methods in patients with psoriatic arthritis, ACR20 responses are observed in at least 50% of the patient population after 4 weeks of treatment. In particular, ACR20 responses are observed in at least 55%, at least 60% of the patient population after 4 weeks of treatment. In particular, ACR20 responses are observed after 8 weeks of treatment, after 12 weeks of treatment, or after 16 weeks of treatment. In particular, ACR20 responses are observed in at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83% of the patient population after 12 weeks of treatment. In particular, ACR20 responses of at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83% of the patient population are observed after 16 weeks of treatment.

[0092] In a specific embodiment of the above uses and methods in patients with psoriatic arthritis, an ACR50 response is observed in at least 30% of the patient population after 12 weeks of treatment. In particular, an ACR50 response is observed in at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45% of the patient population after 16 weeks of treatment.

[0093] In a specific embodiment of the above uses and methods in patients with psoriatic arthritis, an ACR70 response is observed in at least 10% of the patient population after 12 weeks of treatment. In particular, an ACR70 response is observed in at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25% of the patient population after 16 weeks of treatment.

[0094] In a specific embodiment of the above uses and methods in patients with psoriatic arthritis, the LEI score is reduced by at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8 or at least 1.9. In particular, more particularly, the LEI score is reduced by at least 1.5 after 16 weeks of treatment, after 12 weeks of treatment, after 8 weeks of treatment, and even more particularly after 4 weeks of treatment.

[0095] In a specific embodiment of the above uses and methods in patients with psoriatic arthritis, HAQ-DI (related to the patient's physical function) is reduced by at least 0.35, at least 0.40, at least 0.43, at least 0.44, at least 0.45, at least 0.46, at least 0.47, at least 0.48, at least 0.49, at least 0.50, at least 0.51, at least 0.52, at least 0.53, at least 0.54, at least 0.55 or at least 0.57 after treatment with Compound I. In particular, HAQ-DI is reduced by at least 0.40 points after 4 weeks of treatment. In particular, HAQ-DI is reduced by at least 0.45 points after 12 weeks of treatment. In particular, HAQ-DI is reduced by at least 0.45 points after 8 weeks of treatment. In particular, HAQ-DI is reduced by at least 0.50 points after 16 weeks of treatment.

[0096] In another embodiment of the above uses and methods in patients with psoriatic arthritis, Compound I is effective in reducing psoriasis skin manifestations, also known as psoriasis. Such effects are evaluated and quantified by the Psoriasis Area and Severity Index (PASI) (see Section 1.5.3). Further, the compounds of Formula I are used in PsA patients with psoriasis, such as patients with at least 3% of their body surface area covered by psoriasis. In an alternative embodiment, Compound I is used to improve the itch element of psoriasis.

[0097] In another embodiment of the above uses and methods in psoriatic arthritis patients, at least 15%, at least 17% or at least 20% of patients achieve MDA status after 16 weeks of treatment, or more specifically after 12 weeks of treatment. Example

[0098] The compounds of formula I of the present invention have been extensively described and data are disclosed in WO 2010 / 149769 (Menet and Smits, 2010). The synthesis of salts and suitable preparations are described in WO2015 / 117980, WO2015 / 117981 and PCT / US2018 / 022027.

[0099] Similarly, the compounds of formula II according to the present invention have been extensively described and data disclosed in WO 2013 / 189771 (Van't Klooster et al., 2013).

[0100] Example 1. Clinical Study - Treatment of Subjects with Moderately to Severely Active Psoriatic Arthritis (ClinicalTrials.gov Identifier: NCT03101670)

[0101] a. Research Purpose

[0102] The primary objective of this study was to evaluate the effect of Compound I compared with placebo on psoriatic arthritis as assessed by ACR20 after 16 weeks of treatment.

[0103] The secondary objectives of this study are to:

[0104] - To evaluate the effect of Compound I compared to placebo on:

[0105] Signs and symptoms of PsA, as assessed by MDA.

[0106] - Signs and symptoms of peripheral arthritis as assessed by ACR50 and ACR70 responses, DAS28 (CRP), SDAI, CDAI, EULAR, PsARC, Physician's and Patient's Global Assessment of Disease Activity, Patient's Global Assessment of PsA pain intensity, 66 / 68-joint counts, and CRP measurements.

[0107] - Psoriasis, as assessed by PASI, PASI50, PASI75, PASI90, and PASI100 (including body surface area [BSA]), clinician and patient global assessment of psoriasis, mNAPSI, and pruritus NRS.

[0108] • Enthesitis, as assessed by the SPARCC Enthesitis Index and the Leeds Enthesitis Index.

[0109] • Dactylitis, as assessed by LDI.

[0110] • Physical function, as assessed by the HAQ-DI.

[0111] • Fatigue and general quality of life as assessed by FACIT-Fatigue, SF-36 and PsAID.

[0112] -Evaluate the safety and tolerability of Compound I.

[0113] The exploratory objectives of this study are to:

[0114] - Evaluation of the effect of Compound I on spinal symptoms as assessed by BASDAI.

[0115] - Evaluation of the effects of Compound I on all aspects of PsA as assessed by PASDAS.

[0116] - Characterize the population PK and PD of Compound I and its active metabolite in this population.

[0117] 1.2 Study design

[0118] This is a multicenter, Phase 2, double-blind, placebo-controlled study in subjects with moderately to severely active PsA who have had an inadequate response to or are intolerant to conventional disease-modifying therapies. A total of approximately 124 subjects were randomized 1:1 to one of 2 treatment groups: Compound I 200 mg qd or matching placebo qd. Treatment groups were randomized and stratified according to current cDMARD use (yes or no) and prior anti-TNF drug use (yes or no).

[0119] 1.3 Study population

[0120] 1.3.1 Sample size

[0121] A sufficient number of subjects will be screened to ensure that approximately 124 moderate to severe PsA subjects will be randomized to either 200 mg Compound I or matching placebo.

[0122] 1.3.2 Selection criteria

[0123] Subjects who meet all of the following conditions are eligible to participate in this study:

[0124] 1. Male or female subjects aged ≥ 18 years on the date of signing the informed consent.

[0125] 2. Diagnosed with PsA at least 12 weeks before screening and currently meeting the classification criteria for psoriatic arthritis (CASPAR).

[0126] 3. Active PsA defined as ≥5 swollen joints (from 66 swollen counts [SJC]) and ≥5 tender joints (from 68 tender joint counts [TJC]) at screening and baseline (measurable dactylitis counts as a single swollen joint and, if tender, a single tender joint).

[0127] 4. Have a documented history of plaque psoriasis or current active plaque psoriasis.

[0128] 5. If using cDMARD therapy, subjects are only allowed to use one of the following drugs, and must have been taking it for 12 weeks before screening and at a stable dose (including stable route of administration) for at least 4 weeks before baseline:

[0129] - Up to 25 mg / week of oral or parenteral methotrexate (local standards of care must be followed when concurrently using folic acid or folinic acid supplements);

[0130] - Oral leflunomide up to 20 mg / day;

[0131] - Sulfasalazine 3 g / day orally;

[0132] - Up to 400 mg / day of hydroxychloroquine or 250 mg / day of chloroquine.

[0133] 6. If non-pharmacological therapies (including physical therapy) are used, they should remain stable during the screening process.

[0134] 7. Male and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use highly effective contraceptive methods.

[0135] 8. Females of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline.

[0136] 9. Able and willing to sign an Informed Consent Form (ICF) approved by the Independent Ethics Committee (IEC). Written consent must be provided before any screening evaluation begins. Subjects must have read and understood the ICF, must fully understand the requirements of the study, and must be willing to comply with all study visits and evaluations.

[0137] 1.3.3 Exclusion criteria

[0138] Subjects who meet one or more of the following conditions are not eligible for this study:

[0139] 1. Use any of the following treatments:

[0140] - Current use of high-potency opioid analgesics (e.g., methadone, hydromorphone, morphine, or oxycodone);

[0141] - Use of alkylating agents such as chlorambucil or cyclophosphamide at any time;

[0142] - Use of investigational or approved JAK inhibitors, including Compound I, at any time;

[0143] - Prior use of more than one TNF inhibitor at any time (including proposed biosimilars that have demonstrated efficacy equivalent to approved TNF inhibitors in clinical studies). Prior use of one TNF inhibitor is permitted with the following minimum washout period prior to screening:

[0144] i. Etanercept: 4 weeks

[0145] ii. Adalimumab, certolizumab pegol, golimumab: 8 weeks

[0146] iii. Infliximab: 12 weeks;

[0147] - Use at any time of any other investigational or approved biologic immunomodulator not listed above, including but not limited to: cytodepleting biologics (e.g., anti-CD20, CAMPATH, anti-CD4, anti-CD3), denosumab, anti-IL-6 (e.g., tocilizumab), anti-IL-17 (e.g., secukinumab, ixekizumab, brodalumab), anti-IL-12 / IL-23 (e.g., ustekimumab), anti-IL-23 (e.g., tildrakizumab, guselkumab), rituximab;

[0148] - Any intramuscular or intravenous corticosteroid treatment within 4 weeks prior to screening;

[0149] - Use of oral steroids at a dose of >10 mg / day of prednisone or prednisone equivalents or at an unstable dose for at least 4 weeks prior to baseline;

[0150] - Any therapy by intra-articular injection within 4 weeks prior to screening (e.g., corticosteroids, hyaluronate);

[0151] - Use of more than 1 NSAID or cyclooxygenase-2 (COX-2) inhibitor. If using an NSAID or COX-2 inhibitor, its dose must not exceed the maximum dose allowed by the local label and must be used at a stable dose for at least 2 weeks prior to baseline. In addition, subjects are allowed to take acetylsalicylic acid for cardiac prevention at a dose of ≤325 mg q.d.;

[0152] - Leflunomide, if discontinued less than 12 weeks prior to baseline or less than 4 weeks prior to baseline if a washout period (e.g., cholestyramine) had been performed;

[0153] - Any of the following systemic immunomodulatory treatments within 4 weeks prior to screening, including but not limited to: 6-mercaptopurine, azathioprine, cyclosporine or other calcineurin inhibitors (e.g., sirolimus, tacrolimus), dapsone, fumarate derivatives, gold therapy, MTX (if discontinued), mycophenolate mofetil, antimalarial drugs (e.g., hydroxychloroquine, chloroquine) (if discontinued), SSZ (if discontinued), apremilast, or thioguanine;

[0154] - Continuous use of prohibited psoriasis treatments / medications during the specified minimum washout period prior to baseline as follows:

[0155] iv. Oral retinoids (including tazarotene) or vitamin D analogs: 4 weeks

[0156] v. Light therapy (UVA or UVB), with or without psoralens, or self-treatment using a tanning bed or sunbath: 4 weeks

[0157] vi. Any topical therapy, including but not limited to: alpha or beta hydroxy acids, anthralin, corticosteroids (except mild-potency corticosteroids for the face, scalp, axilla, and genital areas), >3% salicylic acid preparations, retinoids including tazarotene, tar preps, or urea: 2 weeks;

[0158] - Treatment with any potent P-glycoprotein (P-gp) inducers (e.g., carbamazepine, clotrimazole, cyclosporine, dexamethasone, phenothiazines, phenytoin, retinoic acid, rifampicin, St. John's wort, and venlafaxine). Potent P-gp inducers need to be eliminated 3 weeks prior to baseline;

[0159] - Use of any investigational medication and / or device not already mentioned within 4 weeks or 5 half-lives prior to screening, whichever is longer.

[0160] 2. Known hypersensitivity to study drug components.

[0161] 3. Have undergone surgical treatment for PsA, including synovectomy and arthroplasty, in more than 3 joints and / or in the last 12 weeks prior to screening.

[0162] 4. History of major surgery (requiring local block or general anesthesia) within 12 weeks before screening or planned surgery during this study.

[0163] 5. Diagnosis of any systemic musculoskeletal disorder, such as systemic osteoarthritis, or systemic inflammation other than PsA, such as but not limited to RA, juvenile chronic arthritis, ankylosing spondylitis, reactive arthritis, IBD-related arthropathy, systemic lupus erythematosus, scleroderma, inflammatory myopathy, mixed connective tissue disease, overlap syndrome, or systemic vasculitis. Gout was allowed if the subject was well controlled on urate-lowering therapy and had no evidence of disease flare in the past year and current uric acid level <7.0 mg / dL.

[0164] 6. Very poor functional status or inability to perform self-care.

[0165] 7. Presence of active IBD requiring systemic or local therapy, current peptic ulcer disease, or past history of severe diverticulitis (ie, requiring hospitalization), or prior gastrointestinal perforation.

[0166] 8. Significant medical conditions, including but not limited to the following: uncontrolled hypertension (≥160 / 95 mmHg), congestive heart failure (New York Heart Association Class III or IV status), uncontrolled diabetes, cerebrovascular accident, myocardial infarction, unstable angina, unstable arrhythmia, or any other cardiovascular condition within 24 weeks prior to screening, which, in the opinion of the investigator, would put the subject at risk for participation in this study.

[0167] 9. History of malignant tumor or myelodysplastic or lymphoproliferative disease within 5 years before screening (except for fully treated basal cell carcinoma of the skin or cervical cancer in situ that has been treated without evidence of recurrence and has a lifetime incidence of no more than 3 times).

[0168] 10. History of bone marrow or organ transplantation.

[0169] 11. Untreated or inadequately treated active or latent TB infection (LTBI) based on any of the following findings:

[0170] - A positive QuantiFERON-TB Gold test result (Note: if the QuantiFERON-TB Gold test result is inconclusive, it may be repeated once; however, if the retest is inconclusive or positive, the subject is ineligible); or

[0171] - Chest radiograph (posterior-anterior view), taken within 12 weeks prior to or at screening, read by a qualified radiologist or pulmonologist, with evidence of current active TB or old inactive TB; or

[0172] - Symptoms suggestive of clinically overt TB disease within 12 weeks prior to first administration of study drug.

[0173] Subjects who are adequately treated for LTBI or active TB infection may be admitted to the study with the sponsor's approval; such treatment must be documented and is defined as:

[0174] i. Subjects who have previously received TB treatment, i.e., if the subject has previously completed adequate treatment for latent (36 weeks of an adequate course of isoniazid or other acceptable regimen and resides in a location with <5% primary multidrug-resistant TB infection rate) or active (acceptable multidrug regimen) TB, do not need to obtain the QuantiFERON-TB Gold test, but must obtain a chest radiograph if this has not been done within 12 weeks prior to screening or if the results are not available at the study site.

[0175] Subjects with newly identified LTBI were those with a newly identified positive diagnostic TB test result (defined as any positive QuantiFERON-TB Gold test or two separate QuantiFERON-TB Gold test indeterminate results) for whom active TB had been excluded, including a negative chest radiograph, and for whom appropriate LTBI treatment had been initiated for at least 4 weeks prior to the first study drug administration and was planned to continue during the study until completion if ongoing at the time of screening. Adequate treatment of LTBI was defined according to United States (US) Centers for Disease Control guidelines.

[0176] 12. Positive serology for human immunodeficiency virus (HIV) 1 or 2, hepatitis B virus (i.e., hepatitis B virus surface antigen [HBsAg] or core antibody [Ab] positive), or hepatitis C virus (HCV) (i.e., HCV Ab positive), or any history of infectious hepatitis due to any cause, excluding hepatitis A.

[0177] 13. History of invasive or opportunistic infection (e.g., listeriosis, pneumocystis, or histoplasmosis) or immunodeficiency syndrome.

[0178] 14. Active infection with clinical significance according to the investigator's judgment, or any infection requiring hospitalization or intravenous anti-infective medication within 30 days of screening, or any infection requiring oral anti-infective therapy within 14 days of screening.

[0179] 15. Current use of any therapy for chronic infections (e.g., Pneumocystis jiroveci, cytomegalovirus, herpes simplex, herpes zoster, and atypical mycobacteria).

[0180] 16. History of symptomatic herpes zoster or herpes simplex infection within 12 weeks prior to screening, or history of disseminated or complicated herpes zoster infection (e.g., multidermatomal, ocular, or central nervous system involvement) at any time.

[0181] 17. History of disseminated Staphylococcus aureus infection.

[0182] 18. History of infected joint prosthesis with the prosthesis still in place.

[0183] 19. Administration of live or attenuated vaccines within 12 weeks prior to baseline.

[0184] 20. History of drug or alcohol abuse within the past 2 years or evidence of current drug or alcohol abuse, in the opinion of the investigator.

[0185] 21. History of being admitted to an institution pursuant to administrative or court order, where applicable, national or local legislation.

[0186] 22. Pregnancy, breastfeeding, or planning to become pregnant at the time of joining this study or within 35 days after the last dose of study drug.

[0187] 23. Any condition, including unstable concomitant medical conditions or active fibromyalgia, that, based on the investigator's clinical assessment, makes the subject an unsuitable candidate for the study because it may confound the risk-benefit assessment.

[0188] 24. Any illness or condition that the investigator or sponsor believes may make it unlikely or impossible for the subject to complete the study or comply with the study procedures and requirements.

[0189] - Major blood loss (>450 mL) or any blood product transfusion within 12 weeks prior to baseline.

[0190] - Results of the following laboratory tests performed in the screening center laboratory meet any of the following criteria:

[0191] -Hemoglobin <8.5 g / dL (SI: <85 g / L);

[0192] - White blood cell count <3.0 x 103 cells / mm3 (SI: <3.0 x 109 cells / L);

[0193] - Neutrophils <1.5 x 103 cells / mm3 (SI: <1.5 x 109 cells / L);

[0194] - Lymphocytes <0.5 x 103 cells / mm3 (SI: <0.5 x 109 cells / L);

[0195] - Platelets <100 x 103 cells / mm3 (SI: <100 x 109 cells / L);

[0196] - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥1.5x ULN;

[0197] - Total bilirubin ≥ 2x ULN, except for subjects diagnosed with Gilbert's disease and clearly documented;

[0198] - Creatinine clearance <40 mL / min calculated by the Cockcroft-Gault equation.

[0199] 1.4 Efficacy evaluation

[0200] Efficacy evaluations were performed at baseline (Day 1) and at Weeks 1, 2, 4, 8, 12, 16 or at the Early Discontinuation Visit (EDV) if appropriate to assess signs and symptoms of PsA and peripheral arthritis, psoriasis, enthesitis, dactylitis, spondylitis, and physical function, unless otherwise indicated. Each component of the ACR response criteria was obtained at screening and throughout the study.

[0201] In addition, at baseline (Day 1) and at Weeks 4 and 16 (or EDV, if applicable), subjects were asked to complete the Fatigue Rating of Chronic Illness Therapy (FACIT-Fatigue) questionnaire, the 36-Item Short Form Health Survey (SF-36 survey), and the Functional Assessment of Psoriatic Arthritis Impact of Disease (PsAID) questionnaire.

[0202] 1.4.1 High-sensitivity serum C-reactive protein

[0203] Serum CRP was measured at the time points indicated in the study flow chart using the hsCRP test. Post-baseline CRP results were blinded to the investigator and sponsor until database lock.

[0204] 1.4.2 66 / 68-Joint Count

[0205] Each of the 66 joints will be evaluated for swelling (SJC66) and each of the 68 joints will be evaluated for tenderness (TJC68) at the time points described in the protocol.

[0206] A joint assessor who is adequately trained and experienced in performing joint assessments will be designated at each study site to perform all joint assessments. This joint assessor will preferably be a rheumatologist; however, if a rheumatologist is not available, it should be a healthcare provider with at least one year of experience in joint assessments. The assessor for each subject should be as consistent as possible throughout the study. In the event of the absence of the designated joint assessor, the designated joint assessor will be asked to identify an appropriate backup assessor to provide coverage.

[0207] 68 Tender joint counts should be performed by scoring the presence or absence of tenderness as assessed by pressure and manipulation of the joint during physical examination.

[0208] Synovial and / or soft tissue swelling, but without bony overgrowth, represented a positive result for the swollen joint count in 66 joints evaluated.

[0209] 1.4.3 Comprehensive evaluation of disease activity by clinicians

[0210] The subjects' arthritis disease activity was assessed globally by clinicians who had access to joint assessments (Section 1.4.2). A visual analog scale (VAS) was used to draw a vertical line and use a ruler to calculate the distance between the "no disease activity" anchor and the 10-cm line (in mm) with the end indicating "extreme disease activity" as a score of 0-100.

[0211] 1.4.4 Evaluation of inflammation at the onset and enthesis

[0212] Entheseal inflammation was assessed using the SPARCC Entheseal Inflammation Index. Tenderness at 16 body sites was assessed by palpation and scored as 0 (no tenderness) or 1 (tenderness). The total entheseal inflammation score was the sum of all site scores, with a maximum of 16. The higher the score, the higher the entheseal inflammatory burden.

[0213] In addition to the 16 sites used to evaluate enthesitis when evaluating the SPARCC Enthesitis Index, the medial femoral condyles (left and right) were evaluated and assessed in a similar manner to the other 16 sites to evaluate the Leeds Enthesitis Index (LEI).

[0214] 1.4.5 Evaluation of dactylitis

[0215] Dactylitis is assessed using the LDI by evaluating the size and tenderness of all fingers and toes. The LDI measures the ratio of the circumference of the affected digit to the circumference of the digit of the contralateral hand or foot using the Leeds Dactylometer. A dactylitic digit is defined as a minimum difference of 10%. If the contralateral digit is also dactylitic, a table of standardized values ​​based on population means is used to provide a comparison. The ratio of the circumference is multiplied by a binary tenderness score (0 for no tenderness and 1 for tenderness). The results for each finger with dactylitis are then added together to give a final score.

[0216] 1.4.6 Psoriasis Area and Severity Index (PASI) score, including body surface area (BSA)

[0217] The PASI score is used to measure the severity and extent of psoriasis. A representative area of ​​psoriasis is selected for each body region (head, arms, trunk, and legs). The intensity of erythema, induration, and scaling of psoriasis is rated as none (0), mild (1), moderate (2), severe (3), or very severe (4).

[0218] Total BSA in subjects involved in psoriasis was measured using a numerical score ranging from 0 to 100%, as assessed by the investigator.

[0219] 1.4.7 Comprehensive evaluation of psoriasis by clinicians

[0220] The clinician's global assessment of psoriasis can be used to determine the overall psoriasis lesions of the subject at a given time point. The clinician rated the subject's psoriasis disease activity using a 6-point scale (see 1.5.1 below) ranging from 0 (clear) to 5 (severe).

[0221] 1.4.8 Modified Nail Psoriasis Area and Severity Index (mNAPSI)

[0222] The mNAPSI will evaluate the severity of nail matrix psoriasis and nail bed psoriasis (Cassell S. et al. "The modified Nail Psoriasis Severity Index: validation of an instrument to assess psoriatic nail involvement in patients with psoriatic arthritis.", J Rheumatol., pp. 34(1): 123-9, 2007). Characteristics of nail matrix psoriasis include pitting, leukonychia, erythema in the nail arc shadow, and nail plate crumbling. Characteristics of the nail bed affected by psoriasis include oil-drop discoloration, onycholysis, nail bed hyperkeratosis, and splinter hemorrhages.

[0223] Each subject's nails were evaluated for the presence of features of nail matrix and nail bed psoriasis, taking into account the following anomalies and rules:

[0224] The following anomalies are ranked on a scale of 0-3:

[0225] - Onycholysis and oil droplets (salmon patch) skin discoloration (to be considered together).

[0226] -Depressed nail

[0227] -Nail plate peeling

[0228] The next 4 anomalies are scored simply by their presence or absence. A score of 1 indicates presence, while a score of 0 indicates absence:

[0229] - Leukonychia

[0230] - Erythema in the nail arc shadow

[0231] -Hyperkeratosis of the nail bed

[0232] -Linear bleeding

[0233] Each finger is scored between 0 and 14, and the total mNAPSI score ranges from 0 to 140.

[0234] 1.4.9 Comprehensive evaluation of the patient's disease activity

[0235] The subject's overall assessment of arthritis disease activity was recorded on a 0-100 mm VAS. A vertical line was drawn on the VAS and a ruler was used to divide the distance (in mm) between the start of the line and the mark on the 10-cm line into a score of 0-100. For the question "Considering all the ways that psoriasis affects you, how are you doing today?", a score of "0" means "very good" and 100 means "very bad".

[0236] 1.4.10 Comprehensive evaluation of patients’ psoriasis

[0237] The Patient's Global Assessment of Psoriasis is a single-item, patient-completed assessment using a 5-category scale ranging from "clear" (0 points - no psoriasis) to "severe" (4 points) and is used to assess the overall extent of psoriasis-related skin disease at a specific time point.

[0238] 1.4.11 Patients’ evaluation of PsA pain intensity

[0239] The patient's assessment of pain was made using a 0-100 mm VAS ranging from "no pain" to "unbearable pain" following the question "Please mark the worst pain you have had in your psoriatic arthritis today with a vertical bar (|) on the horizontal line." The length of the line from 0 to the patient's mark was recorded. This assessment should be completed prior to the joint examination. This pain score is also used to derive the ACR20 / 50 / 70.

[0240] 1.4.12 Health Assessment Questionnaire-Disability Index (HAQ-DI)

[0241] The HAQ-DI is used to monitor the subject's self-assessed physical function or disability. This 20-question instrument assesses how difficult it is for a person to complete tasks in eight areas of function (dressing, getting up, eating, walking, sleeping, hygiene, reaching, grip, performing tasks, and chores). Responses are rated on a 4-point Likert scale ranging from 0 (indicating no difficulty) to 3 (indicating an inability to perform tasks in that area). The need for assistive devices / devices or help from other people is also recorded. The total HAQ DI score ranges from 0 to 3, with higher scores indicating greater functional impairment.

[0242] 1.4.13 Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

[0243] Patient-reported disease activity in subjects was measured using BASDAI (Sieper J. et al., "The Assessment of SpondyloArthritisinternational Society (ASAS) handbook: a guide to assess spondyloarthritis." Ann Rheum Dis., pp. 68 Suppl 2: ii1-44, 2009). This is a 6-item index (fatigue, spinal pain, peripheral arthritis, entheseal inflammation, intensity and duration of morning stiffness), where each item is recorded as a 0 to 10 NRS. The total score ranges from 0 to 10, and a score of 4 or above indicates suboptimal control of the disease.

[0244] 1.4.14 Pruritus Numerical Rating Scale (Pruritus NRS)

[0245] At each study visit, subjects were asked to complete an evaluation of pruritus using a visual rating scale with numbered intervals (whole numbers). Subjects rated the intensity of pruritus based on a 24-hour recall period of the worst pruritus episode experienced during that interval. Subjects were asked to rate pruritus on a scale of 0 (no pruritus) to 10 (worst possible pruritus).

[0246] 1.4.15 Functional Assessment of Chronic Disease Therapy Fatigue Scale (FACIT-Fatigue)

[0247] The FACIT-Fatigue scale (4th edition) is used to measure the degree of fatigue an individual has experienced during daily activities in the past week. It consists of 13 questions with a 5-point Likert scale over a 7-day recall period, where 0 means "not at all" and 4 means "very much". The total score ranges from 0 to 52. The higher the score, the better the quality of life.

[0248] 1.4.16 36-Item Short Form Health Survey (SF-36)

[0249] Use the SF-36 (2nd edition, The Health Survey (HHS) evaluates the subjects' health-related quality of life with a recall period of 1 week. It consists of 36 questions belonging to 8 domains and divided into 2 parts:

[0250] - Physical health: 4 domains: physical function (10 items), role physical (4 items), bodily pain (2 items), and general sense of health (5 items).

[0251] - Mental Health: 4 domains: vitality (4 items), social functioning (2 items), roleemotional (3 items), and mental health (5 items).

[0252] The remaining items (Healthy Transitions) do not fall into the above areas and are kept separately.

[0253] These scores were rescaled from 0 to 100 (converting the lowest possible score to 0 and the highest possible score to 100), with higher scores indicating better quality of life.

[0254] 1.4.17 Psoriatic Arthritis Disease Impact Questionnaire (PsAID)

[0255] The PsAID questionnaire evaluates the impact of PsA on people's lives. For this study, the EULAR PsAID questionnaire PsAID9, which is used in clinical trials, was used. This is a 9-item questionnaire in which each item is scored between 0 and 10. All items are prioritized according to the importance of the health area they represent. The weight of each area is taken into account in the total PsAID score. Higher scores on the PsAID indicate a greater impact of the disease. Scores below 4 out of 10 are considered to be an acceptable state for the patient. Changes of 3 or more points are considered to be relevant absolute changes.

[0256] 1.5 Efficacy analysis

[0257] 1.5.1 ACR20 / 50 / 70

[0258] The signs and symptoms of peripheral arthritis were measured using ACR20 / 50 / 70. The ACR response is a measure of improvement in the Multiple Disease Evaluation Criteria.

[0259] A positive ACR20 response was defined as at least a 20% improvement from baseline in both swollen (SJC66) and tender (TJC68) joint counts and at least a 20% improvement in 3 or more of the following 5 criteria:

[0260] - Patient's global assessment of disease activity (0-100 mm VAS)

[0261] - Clinician's Global Assessment of Disease Activity (0-100 mm VAS)

[0262] -Patient's global rating of PsA pain intensity (0-100 mm VAS)

[0263] - Assessment of the patient's physical function as measured by HAQ-DI

[0264] -CRP in mg / dL or mg / L

[0265] Positive responses of ACR50 and ACR70 were derived from the definition of ACR20 but required at least 50% and 70% improvement, respectively.

[0266] Compound I achieved statistically significant differences in ACR20, ACR50, and ACR70 scores compared to placebo at Week 16. From Week 1 onwards, statistically significant differences were achieved in ACR20 and ACR50 compared to placebo.

[0267] Table 1-ACR20

[0268] 200 mg Compound I qd (n=65) Placebo qd (n=66) P-value Week 1 26.2％ 4.5％ 0.003 Week 2 33.8％ 15.2％ 0.0123 Week 4 61.5％ 18.2％ <0.0001 Week 8 67.7％ 28.8％ <0.0001 Week 12 83.1％ 36.4％ <0.0001 Week 16 80.0％ 33.3％ <0.0001

[0269] Table 2 - ACR50

[0270] 200 mg Compound I qd (n=65) Placebo qd (n=66) P-value Week 1 6.2％ 0％ 0.0364 Week 2 10.8％ 0％ 0.048 Week 4 20.0％ 0.83％ 0.0017 Week 8 32.3％ 4.23％ 0.0007 Week 12 41.5％ 7.34％ 0.0003 Week 16 47.7％ 8.44％ <0.0001

[0271] Table 3 - ACR70

[0272] 200 mg Compound I qd (n=65) Placebo qd (n=66) P-value Week 1 1.5％ 0％ 0.3055 Week 2 3.1％ 0％ 0.1448 Week 4 7.7％ 0.27％ 0.0830 Week 8 12.3％ 0.27％ 0.0125 Week 12 10.8％ 2.38％ 0.2968 Week 16 23.1％ 2.38％ 0.0037

[0273] On first use No significant differences were observed between patients on anti-TNF drugs and those who had previously received anti-TNF therapy.

[0274] 1.5.2 Minimum Disease Activity (MDA)

[0275] Disease activity in PsA will be measured using the MDA, a measure that indicates disease remission. The MDA is based on a composite score of 7 domains. A patient is classified as having achieved the MDA if 5 of the following 7 criteria are met:

[0276] -TJC68≤1

[0277] -SJC66≤1

[0278] -PASI ≤ 1 or BSA ≤ 3%

[0279] - Patient's PsA pain intensity global assessment score ≤ 15 (0-100 mm VAS)

[0280] - Patient's Global Assessment of Disease Activity ≤ 20 (0-100 mm VAS)

[0281] -HAQ-DI≤0.5

[0282] - SPARCC enthesin inflammation index ≤ 1

[0283] Table 4 - MDA

[0284] 200 mg Compound I qd (n=65) Placebo qd (n=66) P-value MDA Week 12 21.5％ 10.6％ 0.0691 MDA Week 16 23.1％ 9.1％ 0.0212

[0285] No significant differences were observed between patients who were first exposed to anti-TNF drugs and those who had previously received anti-TNF therapy.

[0286] 1.5.3 Psoriasis (PASI)

[0287] The four affected areas of head (h), upper limbs (u), trunk (t) and lower limbs (l) are scored using the three parameters erythema (E), induration (I) and desquamation (D), each graded on a severity scale of 0 to 4 (0 = none, 1 = mild, 2 = moderate, 3 = severe and 4 = very severe) (Section 1.4.6). The percentage of area involved is calculated as follows: 1 = less than 10% of the area; 2 = 10-29%; 3 = 30-49%; 4 = 50-69%; 5 = 70-89%; and 6 = more than 90%. The final formula for the PASI score is:

[0288] PASI=0.1x(Eh+Ih+Dh)x Ah+0.2x(Eu+Iu+Du)x Au+0.3x(Et+It+Dt)x At+0.4x(El+Il+Dl)x Al

[0289] Total PASI scores range from 0 (no disease) to 72 (maximal disease) but are considered unreliable when BSA is <3%. Therefore, PASI was analyzed only in the subpopulation of patients with psoriasis who had BSA ≥3% at baseline.

[0290] The following PASI parameters are available:

[0291] - Change from baseline in PASI

[0292] -PASI 50% improvement (PASI50)

[0293] -PASI 75% improvement (PASI75)

[0294] -PASI 90% improvement (PASI90)

[0295] -PASI 100% improvement or complete resolution of all disease (PASI 100)

[0296] Table 5 - PASI

[0297] 200 mg Compound I qd (n=42) Placebo qd (n=40) P-value PASI mean cfb W12 -5.5 -3.1 0.0427 PASI mean cfb W16 -6.3 -3.2 0.0070

[0298] Table 6-PASI75

[0299] 200 mg Compound I qd (n=42) Placebo qd (n=40) P-value PASI75 W12 33.3％ 12.5％ 0.0304 PASI75W16 45.2％ 15.0％ 0.0034

[0300] No significant differences were observed between patients who were first exposed to anti-TNF drugs and those who had previously received anti-TNF therapy.

[0301] 1.5.4 Enthesitis

[0302] Entheseal inflammation was assessed using the SPARCC Entheseal Inflammation Index and the Leeds Entheseal Inflammation Index (LEI). Entheseal inflammation was analyzed only in the subpopulation of subjects with entheseal inflammation (LEI>0) at baseline. Analyses focused on changes from baseline.

[0303] Compound I improved enthesin inflammation compared with placebo. Among the 85 patients (65%) with enthesin inflammation at baseline, the mean change from baseline at Week 16 was greater with filgotinib compared with placebo (LS mean difference -1.4 [95% CI -2.6 to -0.1], p = 0.0310) according to the SPARCC Enthesin Inflammation Index. There was no significant difference in the reduction of enthesin inflammation between the two groups (treatment difference 12% [-6.5 to 31.0], p = 0.1583).

[0304] When assessed by LEI, 76 (58%) patients had enthesin inflammation at baseline. The treatment effects are reported in Table 7. Enthesin inflammation was resolved in more patients receiving filgotinib than in those receiving placebo (treatment difference 26% [95% CI 4.0-45.1], p=0.0059).

[0305] Table 7 – LEI scores (change from baseline)

[0306] 200 mg Compound I qd (n=33) Placebo qd (n=43) P-value Week 4 -1.7 -0.5 0.0003 Week 8 -2.1 -0.9 0.0004 Week 12 -1.9 -1.0 0.0201 Week 16 -1.8 -0.7 0.0004

[0307] No significant differences were observed between patients who were first exposed to anti-TNF drugs and those who had previously received anti-TNF therapy.

[0308] 1.5.5 Physical function (HAQ-DI)

[0309] The HAQ-DI was scored on a scale of 0 to 3, and changes from baseline were reported. A decrease of at least 0.22 points from baseline was considered clinically meaningful.

[0310] HAQ-DI

[0311] 200 mg Compound I qd (n=33) Placebo qd (n=43) P-value Week 1 -0.19 -0.09 0.0781 Week 2 -0.30 -0.12 0.0078 Week 4 -0.44 -0.13 0.001 Week 8 -0.50 -0.13 <0.001 Week 12 -0.53 -0.28 0.0090 Week 16 -0.57 -0.28 0.0009

[0312] No significant differences were observed between patients who were first exposed to anti-TNF drugs and those who had previously received anti-TNF therapy.

Claims

1. Compounds of formula I: or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating patients diagnosed with psoriatic arthritis exhibiting clinical signs and symptoms of entheseal inflammation, wherein the compound is administered at a daily dose of 100-200 mg.

2. The use according to claim 1, wherein the compound is administered once a day (qd) or twice a day (bid).

3. The use according to claim 1, wherein the compound is administered for a period of at least 1, 2, 3, 4, 6, 8, 10, 12 or 16 weeks.

4. The use according to claim 1, wherein the treatment-induced therapeutic effect is characterized by an American College of Rheumatology (ACR) score of 20 of at least 70%, at least 75% or at least 80%.

5. The use according to claim 1, wherein the treatment-induced therapeutic effect is characterized by an American College of Rheumatology (ACR) score of at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45% of 50.

6. The use according to claim 1, wherein the patient diagnosed with psoriatic arthritis has a Leeds Enthesin Inflammatory Index (LEI) score greater than 0, greater than 0.5, or greater than 1.

0.

7. The use according to claim 6, wherein the treatment-induced therapeutic effect is characterized by a decrease in LEI score of at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8 or at least 1.

9.

8. The method of claim 1, wherein the treatment-induced therapeutic effect is characterized by a decrease in Health Assessment Questionnaire-Disability Index (HAQ-DI) score of at least 0.35, at least 0.40, at least 0.43, at least 0.44, at least 0.45, at least 0.46, at least 0.47, at least 0.48, at least 0.49, at least 0.50, at least 0.51, at least 0.52, at least 0.53, at least 0.54, at least 0.55 or at least 0.

57.

9. Use according to claim 4, 5 or 7, wherein the therapeutic effect is observed at the 12th week of treatment.

10. Use according to claim 4, 5 or 7, wherein the therapeutic effect is observed at the 16th week of treatment.

11. Use according to any one of claims 1 to 5, wherein the patient diagnosed with psoriatic arthritis exhibits greater than 3% body surface area (BSA) psoriasis.

12. The use according to any one of claims 1 to 8, wherein the patient is not concurrently receiving any other treatment for psoriatic arthritis, or, wherein the patient is not concurrently receiving any anti-TNF treatment.

13. The use according to claim 9, wherein the patient is not concurrently receiving any other treatment for psoriatic arthritis, or, wherein the patient is not concurrently receiving any anti-TNF therapy.

14. The use according to claim 10, wherein the patient is not receiving any other treatment for psoriatic arthritis at the same time, or, wherein the patient is not receiving any anti-TNF treatment at the same time.

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