TYK2 inhibitors and their uses

Abstract

Compounds, compositions thereof, and administration protocols for the inhibition of TYK2 and their methods of use for the treatment of inflammatory disorders, including psoriasis and psoriatic arthritis, are described.

Description

[Technical field]

[0001] Claiming priority This application claims priority to U.S. Provisional Patent Application No. 63 / 269,943, filed March 25, 2022, U.S. Provisional Patent Application No. 63 / 371,033, filed August 10, 2022, and U.S. Provisional Patent Application No. 63 / 490,664, filed March 16, 2023, each of which is incorporated by reference in its entirety.

[0002] Technical Field The present invention relates to methods of administering non-receptor tyrosine protein kinase 2 (TYK2) inhibitors, such as N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridine]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 1), and its use to treat inflammatory disorders, such as psoriasis and psoriatic arthritis. [Background technology]

[0003] Protein kinases constitute a large family of structurally related enzymes responsible for the control of various signaling processes within cells. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Nearly all kinases contain a similar catalytic domain of 250-300 amino acids. These kinases can be classified into families according to the substrates they phosphorylate (e.g., protein tyrosines, protein serine / threonines, lipids, etc.).

[0004] Generally, protein kinases mediate intracellular signaling by effecting phosphoryl transfer from nucleoside triphosphates to protein acceptors involved in signaling pathways. These phosphorylation events act as molecular on / off switches that can modulate or regulate the biological function of target proteins. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, UV radiation, bacterial endotoxins, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), interleukin-12 (IL-12), interleukin-23 (IL-23), and tumor necrosis factor alpha (TNF-α)), and growth factors (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell growth, migration, differentiation, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

[0005] Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events, including, but not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, some cancers, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases.

[0006] TYK2 catalyzes the phosphorylation of STAT proteins downstream of a number of cytokine receptors, including type I interferon receptors, IL-12 receptors, and IL-23 receptors. Activation of TYK2-dependent receptors by their cytokine ligands activates STAT-dependent transcriptional and cellular functional responses that are specific to the receptor and cell type in which TYK2 is expressed. Cytokine signaling pathways regulated by TYK2 play important roles in several immune-mediated disorders. The cytokine IL-12 is essential for the development of type 1 T helper cells (Th1), which produce interferon-gamma, the main effector molecule in systemic autoimmune disorders, such as systemic lupus erythematosus. The cytokine IL-23 is central to the expansion and survival of Th17 cells and innate lymphoid cells, both of which have been shown to play important pathogenic roles in autoimmunity. Stimulation of IL-23 promotes the production of key proinflammatory cytokines by Th17 cells, including IL-17A, IL-17F, and IL-22, all of which are important effector molecules for the pathogenesis of conditions such as psoriasis, psoriatic arthritis, and ankylosing spondylitis. Inhibition of TYK2 is predicted to impact multiple immune-mediated disorders through its effects on the IL-23 / Th17 / Th22 axis, IL-12-mediated Th1 function, and type I interferon-driven regulation of multiple immune pathways and cell types. Thus, there remains a need to find TYK2 inhibitors that are useful as therapeutic agents. The present disclosure fulfills this need, and also provides other related advantages. Summary of the Invention

[0007] Certain TYK2 inhibitors have been found to be suitable for oral administration to patients to treat inflammatory disorders (e.g., psoriasis, psoriatic arthritis, or inflammatory bowel disease (IBD), such as ulcerative colitis or Crohn's disease). Thus, in one embodiment, a method for treating psoriasis, psoriatic arthritis, ulcerative colitis, Crohn's disease, or inflammatory bowel disease in a patient in need of treatment can include administering to the patient a therapeutically effective amount of a TYK2 inhibitor (e.g., compound 1) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. Compound 1 has the following structure: [ka]

[0008] Compound 1 has the IUPAC name N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

[0009] In some embodiments, the mean decrease in the Psoriasis Area Severity Index (PASI) can be up to about 50% (e.g., about 30%, about 47% or about 48%), or the mean decrease in the Psoriasis Area Severity Index (PASI) can be about 25% to about 50%. The mean decrease in the Psoriasis Area Severity Index (PASI) can be about 50% to 75% or about 75% to 100%.

[0010] In some embodiments, the Physician Global Assessment (PGA) may be 0 or 1, or the Physician Global Assessment (PGA) may be 0.

[0011] In some embodiments, the Dermatology Life Quality Index (DLQI) score can be reduced by about 1 to about 3 points, about 3 to about 6 points, about 6 to about 9 points, about 9 to about 12 points, about 12 to about 15 points, about 15 to about 18 points, about 18 to about 21 points, about 21 to about 24 points, about 24 to about 27 points, or about 27 to about 30 points.

[0012] In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by more than about 5 points or from about 6 to about 9 points.

[0013] In some embodiments, the patient's Body Surface Area (BSA) can be reduced by between about 1 to about 10 percentage points, about 10 to about 20 percentage points, about 20 to about 30 percentage points, about 30 to about 40 percentage points, about 40 to about 50 percentage points, about 50 to about 60 percentage points, about 60 to about 70 percentage points, about 70 to about 80 percentage points, about 80 to about 90 percentage points, or about 90 to about 100 percentage points.

[0014] In some embodiments, the reduction in pain on the Numeric Rating Scale (NRS) can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0015] In some embodiments, the reduction in pruritus Numeric Rating Scale (NRS) can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0016] In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 can be about 1% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100%.

[0017] In some embodiments, the patient may have psoriasis vulgaris, which may be moderate to severe plaque psoriasis vulgaris.

[0018] In some embodiments, the patient may have psoriasis and psoriatic arthritis.The patient may have psoriatic arthritis.

[0019] In some embodiments, the method is capable of achieving at least an American College of Rheumatology (ACR) 20 response.

[0020] In some embodiments, the method achieves improvement in tender joint count, swollen joint count, patient global assessment of psoriatic arthritis, patient global pain assessment of psoriatic arthritis, physician global assessment of psoriatic arthritis, Health Assessment Questionnaire Disability Index (HAQ-DI) score, dactylitis count, Leed's Enthesitis Index, Minimal Disease Activity, Disease Activity Index for Psoriatic Arthritis (DAPSA) at week 12, or achieves a Psoriasis Area Severity Index (PASI)-75, or achieves a physician's static global assessment of 0 or 1 with at least a 2 point improvement from baseline at week 12, in subjects with 3% or more Body Surface Area (BSA) with psoriatic lesions on day 1.

[0021] In some embodiments, the method can achieve improvement in circulating cytokines and / or inflammatory biomarkers, improvement in 36-Item Short Form Health Survey, improvement in Functional Assessment of Chronic Illness-Fatigue, improvement in Disease Activity Score 28 and high sensitivity C-reactive protein (hsCRP), improvement in Psoriatic Disease Activity Score at 12 weeks of treatment, improvement in Psoriatic Arthritis Response Criteria at 12 weeks of treatment, a mean reduction in Psoriasis Area Severity Index (PASI) of 25% or more, or improvement in BSA with psoriatic lesions at 12 weeks, or improvement in Physician's Global Assessment of Psoriasis at 12 weeks of treatment.

[0022]

[0023] In another aspect, a method of inhibiting interferon gamma (IFNγ) production can include administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, or a composition thereof. In some embodiments, the method is associated with improvement in a PASI, such as those described above and elsewhere herein.

[0024] In some cases, the disclosed methods of administering Compound 1 and uses thereof that achieve certain pharmacokinetic parameters of the disclosure have particular advantages in treating psoriasis and psoriatic arthritis. For example, in some embodiments, the plasma T max is about 3 hours to about 6 hours, or the plasma t 1 / 2 However, it lasts from about 17 hours to about 37 hours.

[0025] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose of up to about 200 mg (e.g., about 20 mg to about 100 mg).In other embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient at a dose of about 2 mg, about 5 mg, about 10 mg, about 15 mg, or about 30 mg.

[0026] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient once a day or multiple times a day. In other embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered to the patient daily for 2 to 4 weeks. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered for at least 2 weeks or at least 4 weeks, for example, until the patient's psoriasis or psoriatic arthritis improves. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered chronically to treat the patient. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered orally to the patient (e.g., a human).

[0027] In some embodiments, the patient can have a PASI of at least about 12 prior to the administration.

[0028] In some embodiments, the patient can have a PGA of at least about 3 prior to the administration.

[0029] In some embodiments, the patient can have a BSA of at least about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% prior to administration.

[0030] In some embodiments, the psoriasis does not include erythrodermic psoriasis, pustular psoriasis, predominantly guttate psoriasis, or drug-induced psoriasis.

[0031] In some embodiments, serum Cmax can be about 25ng / ml to about 50ng / ml, about 50ng / ml to about 100ng / ml, about 100ng / ml to about 125ng / ml, about 125ng / ml to about 150ng / ml, about 150ng / ml to about 175ng / ml, about 175ng / ml to about 200ng / ml, about 200ng / ml to about 225ng / ml, about 225ng / ml to about 250ng / ml, about 250ng / ml to about 275ng / ml, or about 275ng / ml to about 300ng / ml.

[0032] In another aspect, a method of treating moderate to severe plaque psoriasis in a patient in need of treatment is provided, comprising administering a therapeutically effective amount of Compound 1 in a daily dose of about 5 mg to about 30 mg.

[0033] In another aspect, there is provided the use of Compound 1, or a pharma- ceutically acceptable salt thereof, in the treatment of psoriasis or psoriatic arthritis.

[0034] These and other aspects of the present disclosure will be evident from and elucidated with reference to the following detailed description. [Brief description of the drawings]

[0035] [Figure 1] FIG. 1 is a schematic diagram showing the study diagram of Example 4. [Diagram 2] FIG. 1 is a schematic diagram showing the study diagram of Example 5. [Diagram 3] 1 shows a graph depicting the relative selectivity of maximum drug concentration (CMAX) versus IC50 for JAK1 / 3 based on PK modeling of duravacitinib and Compound 1. Note: Compound 1 data is IC50 for pSTAT in PBMCs relative to TYK2, values ​​for JAK are >50,000ng / mL. [Figure 4] A graph showing relative TYK2 inhibition levels is shown and is modeled based on Phase 1a data and has not been evaluated in a 1:1 study. Note: Compound 1 data shows an IC50 of 25 ng / mL in hWB and a slope of 1. [Diagram 5] 1 is a graph showing pharmacodynamic data from a Phase 1a study of Compound 1, based on inhibition of IFN-gamma. [Figure 6] 1 shows images and data showing that Compound 1 reduced epidermal thickness and abolished expression of biomarker K16 in patients across three dosing cohorts at 4 weeks (17 patients evaluated). [Figure 7] Figure 1 shows a graph demonstrating that 28 days of treatment with Compound 1 reduced RNA expression levels of key cytokines and the psoriasis gene signature in lesional skin. Quantification of mRNA from skin biopsy specimens showed decreased expression of several psoriasis-associated genes by RT-PCR (including KRT16, IL17A, IL17F and IL22) and up to 50% improved expression of the dermal transcriptome in lesional skin previously associated with psoriasis through microarray analysis (p less than 0.001 compared to placebo treatment). [Figure 8] Schematic showing X-ray crystallographic results of compound 1 bound to the JH2 domain of TYK2 (top) and molecular docking studies of compound 1 bound to the JH2 domain of JAK1 (bottom). [Figure 9] Figure 1 shows a graph demonstrating that Compound 1 inhibited disease activity in a dose-related manner in the adjuvant-induced arthritis (AIA) rat efficacy model. Adjuvant was injected on day 0. Baseline ankle diameters were measured on day 9. Ankle diameter measurements were taken daily on days 12-20. Terminal necropsy and paw weights were taken on day 20. Compound 1 was administered daily for 20 days. Compound 1 exposure was assessed on day 19. Baseline IC50 / 90 lines (upper panel) represent inhibitory concentrations in a rat whole blood TYK2-dependent IFNα-induced IP10 assay. Concentration-dependent inhibition of TYK2-dependent IL12-induced INFγ production was also observed in rats (not shown). [Figure 10] Graphs showing steady-state exposure (plasma concentration) of compound 1 administered to mice treated with anti-CD40 (top panel) and colon weight and colon histology of the mice (bottom panel). [Figure 11] Graphs showing the pharmacokinetics of Compound 1 measured in healthy volunteers (PO, QD) (Study 101 and Study 104). Peak mean plasma concentrations at median Tmax were 4-6 hours on Days 1 and 14. Cmax and AUC0-24h increased approximately dose-proportionally from 5 to 75 mg. Oral T1 / 2 was consistent across doses, ranging from 16.5 to 30.7 hours. Accumulation rates for Cmax and AUC were 2.2-2.9-fold and 2.5-3.2-fold, respectively. [Figure 12] 1 shows graphs depicting steady-state plasma concentrations of Compound 1 based on steady-state exposures from the 20 mg and 35 mg cohorts of Study 101 (Example 1), the 5 mg cohort of Study 102 (Example 2), and the 50 mg cohort of Study 104. The IC50 / 90 baseline represents the inhibitory concentration in a human whole blood TYK2-dependent IFNα-induced IP10 assay. The 35 mg and 50 mg doses correspond to the IC90 at 24 hours. [Figure 13] 1 is a graph showing the proportion of patients who achieved PASI 75 at week 12 in the mITT analysis set of the study in Example 4. [Figure 14] 1 is a graph showing the percentage of patients who achieved PASI 75, PASI 90, and PASI 100 at week 12 in the study of Example 4. [Figure 15] 1 is a graph showing the percentage of patients who achieved PGA 0 / 1 at 12 weeks in the study of Example 4. [Figure 16A] Figure 16A is a graph showing the mean DLQI scores at baseline and week 12 for patients in the study of Example 4. Figure 16B is the change from baseline in DLQI at week 12. [Figure 16B] Same as description for Figure 16A. [Figure 17A]17A-17E are graphs showing blood parameters and CPK at weeks 0, 1, 2, 4, 8, 12, and 16. FIG. 17A is neutrophil count (ANC). FIG. 17B is lymphocyte count (ALC). FIG. 17C is hemoglobin. FIG. 17D is platelets. FIG. 17E is creatine kinase (CPK). [Figure 17B] Same as described in Figure 17A. [Figure 17C] Same as described in Figure 17A. [Figure 17D] Same as described in Figure 17A. [Figure 17E] Same as described in Figure 17A. [Figure 18A] Figures 18A-E are graphs showing liver and kidney parameters. Figure 18A is alanine aminotransferase (ALT). Figure 18B is aspartate aminotransferase (AST). Figure 18C is (total) bilirubin. Figure 18D is creatine. Figure 18E is estimated glomerular filtration rate (eGFR). [Figure 18B] Same as described in Figure 18A. [Figure 18C] Same as description for Figure 18A. [Figure 18D] Same as description for Figure 18A. [Figure 18E] Same as description for Figure 18A. [Figure 19A] Figures 19A-19E are graphs showing lipid parameters: Figure 18A is (total) cholesterol; Figure 19B is triglycerides; Figure 19C is HDL cholesterol; Figure 19D is LDL cholesterol; and Figure 19E is LDL / HDL ratio. [Figure 19B] Same as described in Figure 19A. [Figure 19C] Same as described in Figure 19A. [Figure 19D] Same as described in Figure 19A. [Figure 19E] Same as described in Figure 19A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS TYK2 is an essential mediator of signaling through IL-23, IL-12, and type I interferon receptors and is a validated therapeutic target in psoriasis and psoriatic arthritis. Compound 1 is a highly selective allosteric TYK2 inhibitor that has been tested in three placebo-controlled Phase 1 studies: Studies 1 and 2 (healthy volunteers (HV) treated for 2 weeks with single doses (5-200 mg, N=5 or 6 in each of 6 groups, placebo N=6) and multiple doses (20 mg-100 mg daily, N=6 in each of 4 groups, placebo N=4 in each of 2 groups)) and Study 3 (patients with moderate to severe psoriasis treated daily for 4 weeks (5 mg, 10 mg, or 30 mg, N=21 combined, placebo N=5)).

[0037] Compound 1 has also been tested in a randomized, double-blind, placebo-controlled Phase 2b study in moderate to severe psoriasis (Example 4: 2 mg QD (N=50), 5 mg QD (N=52), 15 mg QD (N=53), 30 mg QD (N=52), placebo (N=52)). Compound 1 has also been tested in a randomized, multicenter, double-blind, placebo-controlled, multiple-dose Phase 2b study in subjects with active psoriatic arthritis (Example 5: 5 mg QD, 15 mg QD, and 30 mg QD).

[0038] Disclosed herein is compound 1, an oral, allosteric, selective TYK2 inhibitor for the treatment of psoriasis, psoriatic arthritis, and other inflammatory and autoimmune diseases. Currently, there are no approved TYK2 inhibitors, and compound 1 is the most selective TYK2 inhibitor currently in clinical development. Furthermore, the selectivity of compound 1 and its potential to provide higher levels of TYK2 inhibition for longer periods with once-daily (QD) dosing may provide clinical and ultimately commercial advantages over other TYK2 inhibitors in development. TYK2 is a member of the Janus kinase (JAK) family of kinases, a class of intracellular signaling proteins that regulate chronic inflammation in inflammatory and autoimmune diseases. Inhibition of JAKs may be effective in treating inflammatory and autoimmune diseases, but may also pose on-target safety issues by modulating diverse cytokine pathways. As a result, JAK inhibitors have been established as oral therapeutics for a number of inflammatory and autoimmune diseases, but their clinical utility is limited by the increased risk of infection and other side effects, resulting in the U.S. Food and Drug Administration (FDA) mandating boxed warnings and dosing restrictions as part of their labeling. Designing selective JAK inhibitors and dosing protocols that directly and specifically inhibit the intended kinase function is challenging due to the structural similarity between the catalytic sites (orthosteric or JH1 sites) in the JAK catalytic domain for drug targeting. Based on human genetic data and growing clinical evidence on the selectivity of allosteric TYK2 inhibitors, the present approach of selective allosteric inhibition of TYK2 provides an optimal balance of achieving potent efficacy while potentially avoiding safety concerns associated with broad inhibition of JAK for the treatment of multiple inflammatory and autoimmune diseases.

[0039] Across three Phase I trials, Compound 1 was rapidly absorbed (T max The increase in exposure was approximately dose-proportional, with a median half-life (t 1 / 2) ranged from 17 to 37 hours. Drug potency was tested in ex vivo assays with cytokine induction using whole blood samples. Treatment with compound 1 resulted in faster inhibition of interferon gamma (IFNγ) production, and increasing exposure correlated with increased IFNγ inhibition. No serious adverse events (SAEs) or deaths were observed. Adverse events (AEs) observed included acneiform dermatitis, papular rash, aphthous ulcers, headache, and diarrhea. Laboratory abnormalities occurring in more than one subject with Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2 included neutropenia, lymphopenia, elevated creatine phosphokinase levels, and elevated nonfasting triglycerides. Exploratory efficacy in patients with psoriasis showed improvement at all doses tested (mean reduction in Psoriasis Area Severity Index (PASI) was 30% at 5 mg, 47% at 10 mg, and 48% at 30 mg vs. 26% with placebo). The TYK2 inhibitors described herein are delivered orally at the doses and schedules described herein.

[0040] In a Phase 2b study of psoriasis vulgaris, the percentage of patients who achieved PASI 75 was 5.8% for placebo, 18.0% for the 2 mg dose, 44.2% for the 5 mg dose, 67.9% for the 15 mg dose, and 67.3% for the 30 mg dose. See Figure 13. Further results and discussion are in Example 4 below.

[0041] In the following disclosure, certain specific details are given to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail so as not to unnecessarily obscure the description of the embodiments. Unless otherwise required by context, throughout the following specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," should be construed in an open and inclusive sense, i.e., "including, but not limited to." Furthermore, the headings provided herein are for convenience only and do not interpret the scope and meaning of the claimed invention.

[0042] Throughout this specification, reference to "one embodiment," "some embodiments," or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. That is, the appearance of the phrases "in one embodiment," "in some embodiments," or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Moreover, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in the sense of "and / or" unless the context clearly dictates otherwise.

[0043] In one aspect, a method for treating psoriasis, psoriatic arthritis, ulcerative colitis, Crohn's disease or inflammatory bowel disease (IBD) in a patient in need of such treatment includes administering to the patient a therapeutically effective amount of Compound 1, [ka] or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0044] In some embodiments, the administration occurs daily for a period of about 1 day to about 7 days, about 1 week to about 3 weeks, about 3 weeks to about 6 weeks, about 6 weeks to about 9 weeks, about 9 weeks to 12 weeks, about 12 weeks to about 15 weeks, or about 15 weeks to about 18 weeks.

[0045] In some embodiments, the method is for the treatment of psoriasis and / or psoriatic arthritis.

[0046] In some embodiments, the method is for the treatment of psoriasis vulgaris, eg, moderate to severe plaque psoriasis vulgaris.

[0047] In some embodiments, the mean reduction in Psoriasis Area Severity Index (PASI) is 25% or greater.

[0048] In some embodiments, the mean reduction in Psoriasis Area Severity Index (PASI) is about 35% or greater.

[0049] In some embodiments, the mean reduction in Psoriasis Area Severity Index (PASI) is about 45% or greater.

[0050] In some embodiments, the mean reduction in Psoriasis Area Severity Index (PASI) is about 25% to 50%.

[0051] In some embodiments, the mean reduction in Psoriasis Area Severity Index (PASI) is about 50% to 75%.

[0052] In some embodiments, the mean reduction in Psoriasis Area Severity Index (PASI) is about 75% to 100%.

[0053] In some embodiments, the Physician Global Assessment (PGA) is 0, 1, or 2.

[0054] In some embodiments, the Physician Global Assessment (PGA) is 0 or 1.

[0055] In some embodiments, the Physician Global Assessment (PGA) is 0.

[0056] In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 1 to about 3 points, about 3 to about 6 points, about 6 to about 9 points, about 9 to about 12 points, about 12 to about 15 points, about 15 to about 18 points, about 18 to about 21 points, about 21 to about 24 points, about 24 to about 27 points, or about 27 to about 30 points.

[0057] In some embodiments, the Dermatology Life Quality Index (DLQI) score can be reduced by greater than about 5 points.

[0058] In some embodiments, the Dermatology Life Quality Index (DLQI) score can be reduced by about 6 to about 9 points.

[0059] In some embodiments, the patient's Body Surface Area (BSA) decreases by some percentage points between about 1 to about 10 percentage points, about 10 to about 20 percentage points, about 20 to about 30 percentage points, about 30 to about 40 percentage points, about 40 to about 50 percentage points, about 50 to about 60 percentage points, about 60 to about 70 percentage points, about 70 to about 80 percentage points, about 80 to about 90 percentage points, or about 90 to about 100 percentage points.

[0060] In some embodiments, the reduction in pain numerical rating scale (NRS) is about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0061] In some embodiments, the reduction in pruritus Numeric Rating Scale (NRS) is about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0062] In some embodiments, the rate of inhibition of IFNγ production by induction of IL-12 / 18 is about 1% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100%.

[0063] In some embodiments, the patient has both psoriasis and psoriatic arthritis.

[0064] In some embodiments, the patient has psoriasis but does not have psoriatic arthritis.

[0065] In some embodiments, the psoriasis is moderate to severe.

[0066] In some embodiments, the psoriatic arthritis is moderate to severe.

[0067] In some embodiments, the patient has psoriatic arthritis.

[0068] In some embodiments, the method achieves at least an American College of Rheumatology (ACR) 20 response.

[0069] In some embodiments, the method provides an ACR20 response after about 12 weeks of treatment. In some embodiments, the method provides an ACR50 response. In some embodiments, the method provides an ACR70 response. In some embodiments, the method provides an ACR50 or ACR70 response after about 12 weeks of treatment. In some embodiments, the method provides an ACR20 response after 18 weeks. In some embodiments, the method provides an ACR50 response after 18 weeks. In some embodiments, the method provides an ACR70 response after 18 weeks. In some embodiments, the ACR response is measured after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, or 30 weeks. ACR20 is a composite measure defined as a 20% improvement in both tender joint count (68) and swollen joint count (66), as well as a 20% improvement in three of five measures: Patient Global Assessment of Psoriatic Arthritis, Physician Global Assessment of Psoriatic Arthritis, Patient Pain Scale, History of Disability Questionnaire (i.e., HAQ-DI), and acute phase reactants (i.e., erythrocyte sedimentation rate [ESR] or hsCRP). In some embodiments, improvement in acute phase reactants is measured by hsCRP. In some embodiments, such improvement is measured relative to the patient's baseline score before treatment began.

[0070] In some embodiments, the method achieves improvement in tender joint count, swollen joint count, Patient Global Assessment of Psoriatic Arthritis, Patient Global Assessment of Psoriatic Arthritis Pain, Physician Global Assessment of Psoriatic Arthritis, Health Assessment Questionnaire Disability Index (HAQ-DI) score, dactylitis count, Leed's Enthesitis Index, Minimal Disease Activity, Disease Activity Index for Psoriatic Arthritis (DAPSA) at Week 12, or achieves a Psoriasis Area Severity Index (PASI)-75, or a Physician's Static Global Assessment of 0 or 1 with at least a 2 point improvement from baseline at Week 12 in subjects with 3% or more Body Surface Area (BSA) with psoriatic lesions on Day 1.

[0071] In some embodiments, the method improves tender joint count. In some embodiments, the method improves swollen joint count. In some embodiments, the method improves the patient's global assessment of psoriatic arthritis. In some embodiments, the method improves the patient's global assessment of psoriatic arthritis by about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50, or by about 1-5, 2-8, 2-15, 2-25, 3-9, 5-10, 5-20, 5-30, 7-12, 8-15, 10-20, 15-25, 20-30, 25-45, or 30-50. In some embodiments, the method improves the patient's global assessment of psoriatic arthritis pain. In some embodiments, the method improves the patient's global assessment of psoriatic arthritis pain by about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50, or by about 1-5, 2-8, 2-15, 2-25, 3-9, 5-10, 5-20, 5-30, 7-12, 8-15, 10-20, 15-25, 20-30, 25-45, or 30-50. In some embodiments, the method improves the physician's global assessment of psoriatic arthritis pain. In some embodiments, the method improves the Physician's Global Assessment of Psoriatic Arthritis by about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50, or by about 1-5, 2-8, 2-15, 2-25, 3-9, 5-10, 5-20, 5-30, 7-12, 8-15, 10-20, 15-25, 20-30, 25-45, or 30-50. In some embodiments, the method improves the Health Assessment Questionnaire Disability Index (HAQ-DI) score. In some embodiments, the method improves the dactylitis count. In some embodiments, the method improves the Leed's Enthesitis Index. In some embodiments, the method improves the Minimal Disease Activity. In some embodiments, the method improves the Disease Activity Index for Psoriatic Arthritis (DAPSA).A DAPSA score of 5-14 represents low disease activity. A score less than 4 represents remission. Thus, in some embodiments, the method achieves a DAPSA score of 5-14, 4, or less than 4. In some embodiments, the method improves Psoriasis Area Severity Index (PASI)-75. In some embodiments, the method improves Psoriasis Area Severity Index (PASI)-75 after about 12 weeks of treatment, and the patient has 3% or more Body Surface Area (BSA) with psoriasis lesions on day 1 of treatment. In some embodiments, the method improves at least 2 points from baseline, for example with a Physician's Static Global Assessment of 0 or 1 after about 12 weeks of treatment. In some embodiments, the improvement is achieved after 6 weeks of treatment. In some embodiments, the improvement is achieved after 18 weeks of treatment. In some embodiments, the improvement is achieved after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, or 30 weeks.

[0072] In some embodiments, the method achieves improvement in circulating cytokines and / or inflammatory biomarkers, improvement in 36-Item Short Form Health Survey, improvement in Functional Assessment of Chronic Illness-Fatigue, improvement in Disease Activity Score 28 and high sensitivity C-reactive protein (hsCRP), improvement in Psoriatic Disease Activity Score at 12 weeks of treatment, improvement in Psoriatic Arthritis Response Criteria at 12 weeks of treatment, a mean reduction in Psoriasis Area Severity Index (PASI) of 25% or more, or improvement in psoriatic lesional BSA at 12 weeks or improvement in Physician's Global Assessment of Psoriasis at 12 weeks of treatment.

[0073] In some embodiments, the method improves circulating cytokines and / or inflammatory biomarkers. In some embodiments, the biomarkers include K16. In some embodiments, the biomarkers include expression of KRT16, IL17A, IL17F, or IL22. In some embodiments, the method improves the 36-Item Short Form Health Survey as described herein. In some embodiments, the method improves Functional Assessment of Chronic Illness-Fatigue. In some embodiments, the method improves Disease Activity Score 28 and high sensitivity C-reactive protein (hsCRP). In some embodiments, the method improves Psoriatic Disease Activity Score at week 12 of treatment. In some embodiments, the method improves Psoriatic Arthritis Response Criteria at week 12 of treatment. In some embodiments, the method improves PASI, for example at week 12 of treatment, in subjects who had 3% or more BSA with psoriatic involvement on day 1. In some embodiments, the method improves psoriatic BSA at week 12 in subjects who had 3% or more BSA with psoriatic lesions on day 1. In some embodiments, the method improves Physician's Global Assessment of Psoriasis, for example at week 12. In some embodiments, the improvement is achieved after 6 weeks of treatment. In some embodiments, the improvement is achieved after 18 weeks of treatment. In some embodiments, the improvement is achieved after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, or 30 weeks.

[0074] In one embodiment, a method for inhibiting interferon gamma (IFNγ) production in a patient includes administering to the patient a therapeutically effective amount of Compound 1, [ka] or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0075] In some embodiments, the patient has psoriasis.

[0076] In some embodiments, the patient has psoriatic arthritis.

[0077] In some embodiments, the psoriasis is moderate to severe.

[0078] In some embodiments, the psoriatic arthritis is moderate to severe.

[0079] In some embodiments, the plasma T max This is achieved in about 3 to 6 hours.

[0080] In some embodiments, the plasma t 1 / 2 is achieved in about 17 to about 37 hours.

[0081] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered to the patient at a dose of up to about 200 mg.

[0082] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered to the patient at a dose of about 20 mg to about 100 mg.

[0083] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered to the patient at a dose of about 2 mg, about 5 mg, about 10 mg, about 15 mg, or about 30 mg.

[0084] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered to the patient as a single dose.

[0085] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered to the patient in multiple doses.

[0086] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered to the patient daily for two weeks.

[0087] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered to the patient daily for four weeks.

[0088] In some embodiments, Compound 1 is administered orally to the patient.

[0089] In some embodiments, the patient is a human.

[0090] In some embodiments, the patient has a PASI of at least about 12 prior to the administration.

[0091] In some embodiments, the patient has a PGA of at least about 3 prior to the administration.

[0092] In some embodiments, the patient has a BSA of at least about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% prior to administration.

[0093] In some embodiments, the psoriasis does not include erythrodermic psoriasis, pustular psoriasis, predominantly guttate psoriasis, or drug-induced psoriasis.

[0094] In some embodiments, serum C maxabout 25ng / ml to about 50ng / ml, about 50ng / ml to about 100ng / ml, about 100ng / ml to about 125ng / ml, about 125ng / ml to about 150ng / ml, about 150ng / ml to about 175ng / ml, about 175ng / ml to about 200ng / ml, about 200ng / ml to about 225ng / ml, about 225ng / ml to about 250ng / ml, about 250ng / ml to about 275ng / ml, or about 275ng / ml to about 300ng / ml.

[0095] In one aspect, a method for treating moderate to severe plaque psoriasis in a patient in need of such treatment comprises administering to the patient a therapeutically effective amount of Compound 1: [ka] at a daily dose of about 5 mg to about 30 mg.

[0096] In one embodiment, the compound 1 [ka] or a pharma- ceutically acceptable salt thereof can be used to treat psoriasis or psoriatic arthritis.

[0097] The compounds described herein include those described generally herein and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes described herein, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, the general principles of organic chemistry are covered in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0098] As used herein, the term "about" refers to within 20% of a given value. In some embodiments, the term "about" refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

[0099] As used herein, the term “Compound 1” refers to N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2′-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide having the formula: [ka] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is in an amorphous form. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is in a crystalline form.

[0100] "Aliphatic" or "aliphatic group," as used herein, refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation but is not aromatic, having one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0101] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system having at least one bridge, i.e., saturated or partially unsaturated carbocyclic or heterocyclic. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or an atom or valence bond, connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system (except hydrogen) that is attached to three or more skeletal atoms. In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups shown below, where each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents as defined for aliphatic groups. Additionally or alternatively, any of the substitutable nitrogens of the bridged bicyclic group are optionally substituted. Exemplary bridged bicyclic groups include: [ka]

[0102] The term "lower alkyl" refers to any straight or branched chain C 1-4 refers to an alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0103] The term "lower haloalkyl" refers to a straight or branched chain C alkyl group substituted with one or more halogen atoms. 1-4 Refers to an alkyl group.

[0104] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (nitrogen in any oxidized form, sulfur, phosphorus, or silicon, the quaternization of any basic nitrogen, or a substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (including as in N-substituted pyrrolidinyl)).

[0105] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0106] As used herein, "a bivalent C 1-8 (or C 1-6 The term "hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains that are straight or branched, as defined herein.

[0107] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more of the methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those groups described below for substituted aliphatic groups.

[0108] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms have been replaced with a substituent. Suitable substituents include those groups described below for substituted aliphatic groups.

[0109] The term "halogen" means F, Cl, Br, or I.

[0110] The term "aryl" used alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and in which each ring in the system contains 3 to 7 ring members. The term "aryl" may also be used synonymously with the term "aryl ring". In certain embodiments, "aryl" refers to an aromatic ring system that may bear one or more substituents, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0111] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, 6, 10, or 14 pi electrons shared in a cyclic arrangement, and, in addition to carbon atoms, 1 to 5 heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, where, unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions are independently optionally substituted.

[0112] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably 1-4, heteroatoms as defined above. The term "nitrogen" when used in reference to a ring atom of a heterocycle includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or . + It may be NR (as in N-substituted pyrrolidinyl).

[0113] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0114] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to include rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0115] As described herein, compounds may include "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more of the hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a given group, the substituents may be either the same group or different groups at all positions. The combinations of substituents envisioned and described in the present invention are preferably those that result in the formation of stable compounds or chemically feasible compounds. The term "stable," as used herein, refers to a compound that is substantially unchanged when subjected to conditions that allow for the production, detection, and, in certain embodiments, the recovery, purification, and use of the compound for one or more of the purposes disclosed herein.

[0116] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen, -(CH2), 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, -(CH2) 0-4 Ph (optionally substituted with R°), -(CH2) 0-4 O(CH2) 0-1 Ph (optionally substituted with R°), -CH=CHPh (optionally substituted with R°), -(CH2) 0-4 O(CH2) 0-1 -pyridyl (optionally substituted with R°), -NO2, -CN, -N3, -(CH2) 0-4 N(R°)2, -(CH2) 0-4 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2) 0-4N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2) 0-4 N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -N(R°)C(NR°)N(R°) 2、 -(CH2) 0-4 C(O)R°, -C(S)R°, -(CH2) 0-4 C(O)OR°, -(CH2) 0-4 C(O)SR°, -(CH2) 0-4 C(O)OSiR°3, -(CH2) 0-4 OC(O)R°, -OC(O)(CH2) 0-4 SR°, -SC(S)SR°, -(CH2) 0-4 SC(O)R°, -(CH2) 0-4 C(O)NR°2, -C(S)NR°2, -C(S)SR°, -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2) 0-4 SSR°, -(CH2) 0-4 S(O)2R°, -(CH2) 0-4 S(O)2OR°, -(CH2) 0-4 OS(O)2R°, -S(O)2NR°2, -(CH2) 0-4 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR°)R°, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -OP(O)R°2, -OP(O)(OR°)2, -SiR°3, -(linear or branched C 1-4 alkylene)ON(R°)2, or -(linear or branched C 1-4 alkylene)C(O)ON(R°), where each R° is optionally substituted as defined below and is independently hydrogen, C 1-6 Aliphatic group, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, when R° is present independently 2 times, it may be joined with the intervening atom(s) to form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be optionally substituted as defined below.

[0117] Suitable monovalent substituents for R° (or the ring formed by R° together with the intervening atoms when R° is present independently) are independently halogen, -(CH2), 0-2 R ● , -(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 S.R. ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(linear or branched chain C 1-4 Alkylene)C(O)OR ● , or -SSR ● and each R ●is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently represents C 1-4 Aliphatic group, -CH2Ph, -O(CH2) 0-1 or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0118] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S- is mentioned, R * Each independently occurring group is hydrogen, C which may be substituted as defined below. 1-6 An "optionally substituted" group is selected from an aliphatic group, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbon atoms of the "optionally substituted" group include -O(CR * 2) 2-3 O- and R * Each independently occurring group is hydrogen, C which may be substituted as defined below. 1-6 It is selected from an aliphatic group, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0119] R * Suitable substituents for the aliphatic group include halogen, -R ● , -(Halo R● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, where R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently represents C 1-4 Aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0120] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † The following R † are independently hydrogen, C which may be substituted as defined below 1-6 an aliphatic group, an unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, regardless of the above definitions, R † When there are 2 independently occurring, R† together with the intervening atom(s) form an unsubstituted 3-12 membered mono- or bicyclic saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0121] R † Suitable substituents for the aliphatic groups are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and the respective R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently represents C 1-4 Aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0122] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharma- ceutically acceptable non-toxic acid addition salts are the salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic or malonic acids, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of the salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0123] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include the sodium, lithium, potassium, calcium, magnesium salts, and the like. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0124] Unless otherwise specified, a structure depicted herein is also intended to include all isomers of that structure (e.g., enantiomers, diastereomers, and geometric (or conformational) forms), such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention, are within the scope of the invention. Unless otherwise specified, all tautomers of the compounds of the invention are within the scope of the invention. In addition, unless otherwise specified, a structure depicted herein is also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the invention may be prepared by replacing hydrogen with deuterium or tritium, or by mixing the isomers of the compounds of the invention with isotopically enriched atoms. 13 C-enriched carbon or 14 It is within the scope of the invention to include the replacement of carbon with C-enriched carbon. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the invention. In certain embodiments, the warhead moiety R of provided compounds is 1 contains one or more deuterium atoms. In certain embodiments, ring B of provided compounds can be substituted with one or more deuterium atoms.

[0125] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits TYK2 with measurable affinity. In certain embodiments, an inhibitor has an IC 50 and / or the binding constant is less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0126] The terms "measurable affinity" and "measurably inhibit," as used herein, mean that there is a measurable change in TYK2 protein kinase activity between a sample containing a compound or composition thereof described herein and TYK2 protein kinase, and a corresponding sample containing TYK2 protein kinase in the absence of said compound or composition thereof.

[0127] As used herein, the "Dermatology Life Quality Index" or DLQI is a simple, 10-question, validated questionnaire that has been used in over 40 different skin conditions. See Finlay AY, Khan GK. "Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use," Clin Exp Dermatol. 1994;19(3):210-216, the entire disclosure of which is incorporated herein by reference in its entirety.

[0128] "Body Surface Area" as used herein refers to the percentage of surface area covered by psoriasis. A "percentage point" decrease refers to the amount by which the percentage of surface area decreases after treatment. For example, a 7 percentage point decrease would account for a decrease from 57% BSA to 50% BSA.

[0129] "Numerical rating scale" (NRS), as used herein, refers to a scale of 1 to 10 on which a patient scores their symptoms (e.g., pain or itch), with 10 being the worst distress imaginable and 0 being no distress at all.

[0130] "C max ", as used herein, is the highest (or peak) serum concentration that a drug achieves in a given area or test site of the body after administration of the drug and before a second administration.

[0131] "SDD" as used herein refers to a pharmaceutical formulation (e.g., a formulation of Compound 1 or a pharma- ceutically acceptable salt thereof) that is a spray-dried formulation. The formulation may include a compound of the present disclosure and hypromellose acetate succinate (HPMCAS). In one embodiment, the HMPCAS is HPMCAS-M, where "M" indicates (acetyl content 7.0%-11.0%, succinoyl content 10%-14%). The use of spray drying to produce powders from fluid feedstocks is well known, with applications ranging from milk powder to bulk chemicals and pharmaceuticals. See U.S. Pat. No. 4,187,617 and Mujumbar et al., 91 Drying, pages 56-73 (1991). It is also known to use spray drying to form amorphous solid dispersions of drugs and concentration-enhancing polymers. See European Patent Applications Nos. 0 901 786, 1 027 886, 1 027 887, 1 027 888, and PCT Applications Nos. WO 00 / 168092 and WO 00 / 168055, each of which is incorporated herein by reference. A typical spray drying apparatus includes a drying chamber, an atomizing means for atomizing a solvent-containing liquid fed to the drying chamber, a source of heated drying gas directed to the drying chamber, and a dried product recovery means for separating the dried product from the cooled drying gas and vaporized solvent stream after it leaves the drying chamber. Examples of such apparatus include Niro Models PSD-1, PSD-2, and PSD-4 (Niro A / S, Soeborg, Denmark).

[0132] "TPGS" or "vitamin E TPGS" as a descriptor of a pharmaceutical formulation of a compound of the present disclosure, as used herein, refers to a pharmaceutical formulation (e.g., a pharmaceutical formulation of Compound 1 or a pharma- ceutically acceptable salt thereof) that includes the following components: (a) an active compound; (b) one or more diluents (e.g., microcrystalline cellulose); (c) one or more solubilizers (e.g., D-α-tocopherol polyethylene glycol succinate [vitamin E TPGS]); and (d) one or more binders (e.g., povidone). The formulation may be prepared using a granulation process (e.g., wet granulation). "Granulation," as used herein, refers to a process that produces larger or smaller granules or particles of a substance or mixture of substances. This process may also remove fine particles and improve flowability within the formulation. Both wet granulation and / or dry granulation may be used. Dry granulation is performed using only a combination of granules without the need for any liquid. Slugging involves using a tablet press to form larger tablets of varying weights due to the poor flowability of the formulation, and then passing the resulting slugs through a granulator, where they are broken down into granules and then compressed again into the final granules.

[0133] 3. Exemplary compounds: According to one aspect, a method of treating an inflammatory disorder (e.g., psoriasis or psoriatic arthritis) in a patient in need of such treatment can include administering a therapeutically effective amount of a TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof. In some embodiments, the method includes administering up to 100 mg of a TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, in a single dose or in multiple doses (e.g., divided doses).

[0134] US Patent No. 11,046,698 (incorporated herein by reference in its entirety) describes certain therapeutically beneficial compounds. Such compounds include Compound 1. Compound 1 is referred to as I-908 in US Patent No. 11,046,698, and its synthesis, properties, and uses in treating various diseases and disorders are described in detail. Numerous other TYK2 inhibitors are described in US Patent No. 11,046,698, and those inhibitors may be used in the methods of the present disclosure. Thus, in some embodiments, the TYK2 inhibitor is one of those described in US Patent No. 11,046,698.

[0135] In certain embodiments, the TYK2 inhibitor used in the disclosed methods is an inhibitor of formula I: [ka] or a pharma- ceutically acceptable salt thereof, R 3 -C(O)NH2, -C(O)NHR 3A , -C(O)N(R 3A )2, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being 5B is replaced by R 5 is hydrogen or -L 1 -R 5A and R 6 is hydrogen, R A Or R B or or R 5 and R 6 together with the intervening atoms form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being selected from R 5A and n R C is replaced by R 7 are hydrogen, halogen, -NH2, -NHR 7AOr -NHC(O)R 7A or or R 6 and R 7 together with the intervening atoms form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring comprising p R C is replaced by L 1 is a covalent bond or a bivalent C which may be saturated or unsaturated and linear or branched 1-4 a hydrocarbon chain, one or two of the methylene units of the chain being optionally and independently -C(R 5B )2-, -CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; R 3A and R 7A are each independently R B and each of them is q R C is replaced by R 5A and each R 5B are each independently R A or R B and each of them is R C is replaced by Each R A are independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R; Each R B is independent, C 1-6an aliphatic group, a phenyl, a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R C are independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R, or an optionally substituted group; 1-6 a group selected from an aliphatic group, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or an optionally substituted group; C 1-6 a group selected from an aliphatic group, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, together with intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each hydrogen bonded to a carbon can be optionally and independently replaced by deuterium; Each of m, n, p, q, and r is independently 0, 1, 2, 3, or 4.

[0136] In some embodiments, the TYK2 inhibitor used in the disclosed methods is compound 1a [ka] or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0137] In some embodiments, the TYK2 inhibitor used in the disclosed methods is Compound 1, [ka] or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0138] The compounds and compositions described herein are generally useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods described herein is TYK2.

[0139] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors and type I and type III interferon receptors and is activated by these receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitin)), and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF).Velasquez et al.,“A protein kinase in the interferon α / β signaling pathway,”Cell(1992)70:313、Stahl et al.,“Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components,”Science(1994)263:92、Finbloom et al.,“IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes,”J.Immunol.(1995)155:1079、Bacon et al.,“Interleukin 12(IL-12)induces tyrosine phosphorylation of Jak2 and Tyk2:differential use of Janus family kinases by IL-2 and IL-12,”J.Exp.Med.(1995)181:399、Welham et al.,“Interleukin-13 signal transduction in lymphohemopoietic cells:similarities and differences in signal transduction with interleukin-4 and insulin,”J.Biol.Chem.(1995)270:12286、Parham et al.,“A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit,IL-23R,”J.Immunol.(2002)168:5699。Activated TYK2 then phosphorylates additional signaling proteins, such as STAT family members, including STAT1, STAT2, STAT4, and STAT6.

[0140] TYK2 activation by IL-23 has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. Duerr et al., "A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene," Science (2006) 314:1461-1463. TYK2, as a downstream effector of IL-23, is also involved in psoriasis, ankylosing spondylitis, and Behcet's disease. Cho et al., “Genomics and the multifactorial nature of human auto-immune disease,” N. Engl. J. Med (2011) 365: 1612-1623; Cortes et al., “Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci,” Nat. Genet. (2013) 45(7): 730-738; Remmers et al., “Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease,” Nat. Genet. (2010) 42: 698-702. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Strange et al., “A genome-wide association study identifies a new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1,” Nat. Genet. (2010) 42:985-992. TYK2 knockout or TYK2 inhibition with tyrphostin significantly reduces dermatitis induced by both IL-23 and IL-22.Ishizaki et al., “Tyk2 is a therapeutic target for psoriasis-like skin inflammation,” Intl. Immunol. (2013), doi:10.1093 / intimm / dxt062.

[0141] TYK2 is also involved in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucus hypersecretion are mediated by IL-13-induced TYK2 activation (which in turn activates STAT6). Zhang et al., “Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2 / STAT6 pathway,” FASEB J. (2012) 26:1-11.

[0142] Reduced TYK2 activity protects joints from collagen antibody-induced arthritis (a model of human rheumatoid arthritis). Mechanistically, reduced TYK2 activity reduces T h 1 / T h The production of 17-related cytokines, matrix metalloproteinases, and other important inflammatory markers was reduced. Ishizaki et al., “Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice,” Intl. Immunol. (2011) 23(9):575-582.

[0143] TYK2 knockout mice were completely resistant to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) and showed a lack of CD4 T cell infiltration in the spinal cord compared to controls, suggesting that TYK2 is essential for pathogenic CD4-mediated disease development in MS. Oyamada et al., “Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis,” J. Immunol. (2009) 183: 7539-7546. This supports previous studies that have linked increased expression of TYK2 to MS susceptibility. Ban et al., “Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor,” Eur J. Hum. Genet. (2009) 17: 1309-1313. Loss-of-function mutations in TYK2 result in reduced neuronal demyelination and increased remyelination, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0144] TYK2 is the only signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced footpad thickness induced by methylated BSA injection, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0145] Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder) showed a strong and significant correlation between loss-of-function mutations in TYK2 and reduced prevalence of SLE in families with affected members. Sigurdsson et al., “Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus,” Am. J. Hum. Genet. (2005) 76:528-537. Genome-wide association studies of individuals from an SLE cohort versus an unaffected cohort showed a significant correlation between the TYK2 locus and SLE. Graham et al., “Association of NCF2, IKZF1, IRF8, IFiH1, and TYK2 with Systemic Lupus Erythematosus,” PLoS Genetics (2011) 7(10): e1002341.

[0146] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice showed reduced cytotoxic T cell responses and accelerated tumor development. However, these effects were associated with efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors may be highly suitable for the treatment of autoimmune disorders or graft rejection. Although other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 has been suggested as a better target than other members, as it is involved in more or less closely related signaling pathways, resulting in fewer off-target effects than other members. Simma et al.“Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance,”Cancer Res.(2009)69:203-211.

[0147] However, contrary to the reduced tumor surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 via STAT1-mediated signaling by TYK2 to maintain cancer cell survival through upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Specific activating mutations in TYK2 that promote cancer cell survival include mutations in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required for improved cancer cell survival, as conversion did not occur with TYK2 enzymes characterized by kinase-dead mutations (M978Y or M978F) in addition to an activating mutation (E957D). Sanda et al. “TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia,” Cancer Disc. (2013) 3(5):564-577.

[0148] That is, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10-dependent and / or BCL2-dependent tumors, such as 70% of adult T-cell leukemia cases. Fontan et al. “Discovering What Makes STAT Signaling TYK in T-ALL,” Cancer Disc. (2013) 3: 494-496.

[0149] TYK2-mediated STAT3 signaling has also been shown to mediate amyloid-β (Aβ) peptide-induced neuronal cell death. After Aβ administration, decreased phosphorylation of STAT3 by TYK2 reduced neuronal cell death, and increased phosphorylation of STAT3 was observed in postmortem brains of Alzheimer's patients. Wan et al. “Tyk / STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease,” J.Neurosci.(2010)30(20):6873-6881.

[0150] Inhibition of the JAK-STAT signaling pathway is also involved in hair growth and reversal of hair loss associated with alopecia areata. Xing et al., “Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition,” Nat. Med. (2014) 20: 1043-1049; Harel et al., “Pharmacologic inhibition of JAK-STAT signaling promotes hair growth,” Sci. Adv. (2015) 1 (9): e1500973.

[0151] Thus, compounds that inhibit the activity of TYK2 would be beneficial, particularly those that have selectivity over JAK2. Such compounds should provide a pharmacological response that successfully treats one or more of the conditions described herein without the side effects associated with inhibition of JAK2.

[0152] Although TYK2 inhibitors are known in the art, there remains a need to provide new inhibitors with more effective or beneficial pharmacologic properties, such as compounds with improved activity, selectivity over other JAK kinases (particularly JAK2) and ADMET properties (absorption, distribution, metabolism, excretion and / or toxicity). That is, in some embodiments, inhibitors of TYK2 can exhibit selectivity over JAK2.

[0153] The activity of the compounds described herein, or variants thereof, as TYK2 inhibitors may be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of either the phosphorylation activity and / or subsequent functional consequences, or ATPase activity, of activated TYK2 or variants thereof. Alternative in vitro assays quantify the ability of the inhibitor to bind to TYK2. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex, and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by performing a competition experiment in which a novel inhibitor is incubated with TYK2 bound to a known radioligand. Representative in vitro and in vivo assays useful for assaying TYK2 inhibitors include, for example, assays described and disclosed in the documents incorporated herein by reference in their entirety. Detailed conditions for assaying the compounds described herein, or variants thereof, as inhibitors of TYK2 are provided in the Examples below and in US 11,046,698, incorporated herein by reference.

[0154] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder as described herein, or one or more of its symptoms. In some embodiments, treatment may be administered after one or more symptoms have manifested. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may continue after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0155] The compounds provided are inhibitors of TYK2 and are therefore useful for treating one or more diseases associated with the activity of TYK2 or its mutants. Thus, in certain embodiments, a method for treating a TYK2-mediated disorder can comprise administering to a patient in need of treatment a compound described herein or a pharma- ceutically acceptable composition thereof.

[0156] As used herein, the term "TYK2-mediated" disorders, diseases and / or conditions, as used herein, refers to any disease or other deleterious condition in which TYK2 or a variant thereof is known to play a role. Accordingly, another embodiment relates to treating or reducing the severity of one or more diseases in which TYK2 or a variant thereof is known to play a role. Such TYK2-mediated disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-related disorders.

[0157] In some embodiments, a method of treating one or more disorders, the disorders being selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a disorder associated with transplantation, the method comprising administering to a patient in need of treatment a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutical acceptable salt thereof.

[0158] In some embodiments, the disorder is an autoimmune disorder, hi some embodiments, the disorder is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis (e.g., plaque psoriasis), Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0159] In some embodiments, the disorder is an inflammatory disorder, hi some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis (e.g., plaque psoriasis), psoriatic arthritis, hepatomegaly, Crohn's disease, ulcerative colitis, or inflammatory bowel disease.

[0160] In some embodiments, a method of treating psoriasis (e.g., plaque psoriasis) or psoriatic arthritis in a patient in need of treatment can include administering a TYK2 inhibitor described herein (e.g., compound 1), or a pharma- ceutical acceptable salt thereof.

[0161] In some embodiments, a method of treating psoriasis (e.g., plaque psoriasis) in a patient in need of treatment can include administering a TYK2 inhibitor described herein (e.g., compound 1), or a pharma- ceutically acceptable salt thereof.

[0162] In some embodiments, a method of treating psoriatic arthritis in a patient in need of treatment can include administering a TYK2 inhibitor described herein (e.g., compound 1), or a pharma- ceutically acceptable salt thereof.

[0163] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments, the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, or essential thrombocytosis.

[0164] In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0165] In some embodiments, the disorder is a neurological disorder, hi some embodiments, the neurological disorder is Alzheimer's disease.

[0166] In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0167] In some embodiments, the disorder is associated with transplantation. In some embodiments, the disorder is associated with transplantation is transplant rejection or graft-versus-host disease.

[0168] In some embodiments, the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disorder is associated with type I interferon signaling. In some embodiments, the disorder is associated with IL-10 signaling. In some embodiments, the disorder is associated with IL-12 signaling. In some embodiments, the disorder is associated with IL-23 signaling.

[0169] The compounds described herein are also useful for treating inflammatory or allergic conditions of the skin, such as psoriasis (e.g., plaque psoriasis), contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0170] The compounds described herein may also be used to treat other diseases or conditions, e.g., diseases or conditions that have an inflammatory component, e.g., diseases and conditions of the eye, e.g., ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal keratoconjunctivitis, diseases affecting the nose, including allergic rhinitis, as well as autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic thrombocytopenia, and other conditions. sprue, autoimmune inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disorders, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome).For example, idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous diseases, endometriosis, leptospirosis renal disease, glaucoma, retinal diseases, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic and exercise-induced), acute lung disorders, acute respiratory distress. Distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, eye allergies, silica-induced disease, COPD (damage, airway inflammation, bronchial hyperresponsiveness, remodeling or reduction in disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopy dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, sweat gland abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis The composition may also be used to treat inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, including inflammatory bowel disease, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0171] In some embodiments, the inflammatory disease that can be treated according to the methods described herein is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

[0172] In some embodiments, the inflammatory disease that can be treated according to the methods described herein is T h 1 or T h In some embodiments, the disease is mediated by T h The 17 mediated disease is selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0173] In some embodiments, the inflammatory disease that can be treated according to the methods described herein is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, eye conditions such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, and diseases affecting the nose, such as allergic rhinitis.

[0174] Furthermore, the present invention may provide the use of a compound as defined herein or a pharma- ceutically acceptable salt thereof, or a hydrate or solvate thereof, for the preparation of a medicament for the treatment of an autoimmune, inflammatory or proliferative disorder, or a disorder commonly occurring in connection with transplantation.

[0175] Without wishing to be bound by any particular theory, it is believed that the proximity of the inhibitory compound or the pendant moiety of the inhibitory compound to the water of interest promotes the displacement or destruction of that water by the inhibitory compound or the pendant moiety of the inhibitory compound, in some embodiments, the water molecule that is displaced or destroyed by the inhibitory compound or the pendant moiety of the inhibitory compound is an unstable water molecule.

[0176] In certain embodiments, the method utilizes a complex comprising TYK2 and an inhibitor, where at least one of the labile waters of TYK2 is replaced or disrupted by the inhibitor, hi some embodiments, at least two selected labile waters are replaced or disrupted by the inhibitor.

[0177] 5. Pharmacokinetics / Pharmacodynamics In some embodiments, the present disclosure provides a method of administering a TYK2 inhibitor (e.g., Compound 1) to a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, or a composition thereof, to achieve a particular pharmacokinetic parameter. In some embodiments, the disclosed methods and uses of administering Compound 1 to achieve a particular pharmacokinetic parameter of the present disclosure are advantageous for treating diseases, such as inflammatory disorders, as described herein. Such diseases include psoriasis and psoriatic arthritis.

[0178] In some embodiments, the plasma T of a TYK2 inhibitor (e.g., Compound 1) is max is achieved for up to about 10 hours, e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours, or any range of times generated by using two of the above times as endpoints. max is achieved in about 1 to about 10 hours, about 1 to about 9 hours, about 2 to about 10 hours, about 2 to about 9 hours, about 3 to about 10 hours, about 3 to about 9 hours, about 4 to about 10 hours, about 4 to about 9 hours, about 5 to about 10 hours, about 5 to about 9 hours, about 6 to about 10 hours, about 6 to about 9 hours, about 7 to about 10 hours, about 7 to about 9 hours, about 8 to about 10 hours, about 9 to about 10 hours, or about 8 to about 9 hours. In some embodiments, the plasma T max is achieved in up to about 3 hours. In some embodiments, the plasma T max is achieved in up to about 4 hours. In some embodiments, the plasma T maxis achieved in up to about 5 hours. In some embodiments, the plasma T max is achieved in approximately 6 hours.

[0179] In some embodiments, the plasma T of a TYK2 inhibitor (e.g., Compound 1) is max is achieved in about 1 hour to about 4 hours, about 2 hours to about 5 hours, about 3 hours to about 6 hours, about 4 hours to about 7 hours, about 5 hours to about 8 hours, about 6 hours to about 9 hours, or about 7 hours to about 10 hours. In some embodiments, the plasma T max This is achieved in about 3 to 6 hours.

[0180] In some embodiments, the plasma t 1 / 2 is achieved for up to about 50 hours, e.g., about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 25 hours, 26 hours, about 27 hours, about 28 hours, about 29 hours, about 30 hours, about 31 hours, about 32 hours, about 33 hours, about 34 hours, about 35 hours, 36 hours, about 37 hours, about 38 hours, about 39 hours, about 40 hours, about 41 hours, about 42 hours, about 43 hours, about 44 hours, about 45 hours, 46 hours, about 47 hours, about 48 hours, about 49 hours, or about 50 hours, or any range of times generated by using two of the above times as endpoints. In some embodiments, the plasma t 1 / 2 is achieved in up to about 17 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 18 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 19 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 20 hours. In some embodiments, the plasma t 1 / 2is achieved in up to about 21 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 22 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 23 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 24 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 25 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 26 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 27 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 28 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 29 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 30 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 31 hours. In some embodiments, the plasma t 1 / 2 In some embodiments, the plasma t 1 / 2 is achieved in up to about 33 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 34 hours. 1 / 2 is achieved in up to about 35 hours. In some embodiments, the plasma t 1 / 2 is achieved in up to about 36 hours. In some embodiments, the plasma t 1 / 2 is achieved in approximately 37 hours.

[0181] In some embodiments, the plasma t 1 / 2 is achieved in about 10 to 30 hours, about 12 to 32 hours, about 14 to 34 hours, about 16 to 36 hours, about 18 to 38 hours, about 20 to 40 hours, or about 22 to 42 hours. In some embodiments, the plasma t 1 / 2 is achieved in approximately 17 to 37 hours.

[0182] In some embodiments, the disclosure provides a method of administering a TYK2 inhibitor (e.g., Compound 1) to a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, to achieve a particular pharmacodynamic result.

[0183] In some embodiments of the methods and uses disclosed herein, administration of a TYK2 inhibitor (e.g., Compound 1) rapidly inhibits interferon gamma (IFNγ) production, with increased exposure correlating with improved IFNγ inhibition. In some embodiments, a method of inhibiting IFNγ production in a patient can comprise administering to the patient a TYK2 inhibitor (e.g., Compound 1) described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0184] In some embodiments, the disclosed methods and uses of administering compound 1 include a mean reduction in Psoriasis Area Severity Index (PASI) of up to about 100% or up to about 90%, such as up to about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%, or any of the ranges of percentages created by using two of the above percentages as endpoints. The PASI score is a tool used to measure the severity and extent of psoriasis and is well known to those skilled in the art. In some embodiments, the mean reduction in Psoriasis Area Severity Index (PASI) is up to about 50%. In some embodiments, the mean reduction in Psoriasis Area Severity Index (PASI) is up to about 75%. In some embodiments, the mean reduction in Psoriasis Area Severity Index (PASI) is up to about 90%. In some embodiments, the mean reduction in Psoriasis Area Severity Index (PASI) is up to about 100%. In some embodiments, the mean reduction in Psoriasis Area Severity Index (PASI) is about 30%, about 47%, or about 48%.

[0185] In some embodiments, the disclosed methods and uses result in an average reduction in PASI of at least 25%. In some embodiments, the disclosed methods and uses result in an average reduction in PASI of at least 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, or 65% or more. In some embodiments, the disclosed methods and uses provide an average reduction in PASI of about 26-65%, 26-60%, 26-55%, 26-50%, 26-45%, 26-40%, 26-35%, 26-30%, 27-65%, 27-65%, 27-60%, 27-55%, 27-50%, 27-45%, 27-40%, 27-35%, 27-30%, 28-65%, 28-65%, 28-60%, 28-55%, 28-50%, 28-45%, 28-40%, 28-35%, 28-30%, 29-65%, 29-65%, 29-60% , 29~55%, 29~50%, 29~45%, 29~40%, 29~35%, 30~65%, 30~60%, 30~55%, 30~50%, 30~45%, 30~40%, 30~35%, 35~65%, 35~60%, 35~55%, 35~50%, 35~45%, 35~40%, 40~65%, 40~60%, 40~55%, 40~50%, 40~45%, 45~65%, 45~60%, 45~55%, 45~50%, 50~65%, 50~65%, 50~60%, 50~55%, 55~65%, or 55~60%.

[0186] In some embodiments, the average reduction in Psoriasis Area Severity Index (PASI) is between about 50% and 75%. In some embodiments, the average reduction in Psoriasis Area Severity Index (PASI) is between about 75% and 100%.

[0187] In some embodiments, the disclosed methods and uses result in a statistically significant (p<0.05) improvement in PASI across a patient population with an inflammatory disease, such as psoriasis or psoriatic arthritis.

[0188] In some embodiments, the patient has a PASI of at least about 12 prior to administration. In some embodiments, the patient has a PASI of about 10 to about 20 prior to administration. In some embodiments, the patient has a PASI of about 20 to about 30 prior to administration. In some embodiments, the patient has a PASI of about 30 to about 40 prior to administration. In some embodiments, the patient has a PASI of about 40 to about 50 prior to administration. In some embodiments, the patient has a PASI of about 50 to about 60 prior to administration. In some embodiments, the patient has a PASI of about 60 to about 72 prior to administration.

[0189] In some embodiments, the Physician Global Assessment (PGA) is 0, 1, or 2. In some embodiments, the Physician Global Assessment (PGA) is 0 or 1. In some embodiments, the Physician Global Assessment (PGA) is 0.

[0190] In some embodiments, the patient has a PGA of 1 prior to administration. In some embodiments, the patient has a PGA of 2 prior to administration. In some embodiments, the patient has a PGA of 3 prior to administration. In some embodiments, the patient has a PGA of 4 prior to administration. In some embodiments, the patient has a PGA of 5 prior to administration.

[0191] In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 1 to about 3 points, about 3 to about 6 points, about 6 to about 9 points, about 9 to about 12 points, about 12 to about 15 points, about 15 to about 18 points, about 18 to about 21 points, about 21 to about 24 points, about 24 to about 27 points, or about 27 to about 30 points. In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 1 to about 3 points. In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 3 to about 6 points. In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 6 to about 9 points. In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 9 to about 12 points. In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 12 to about 15 points. In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 15 to about 18 points. In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 18 to about 21 points. In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 21 to about 24 points. In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 24 to about 27 points. In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 27 to about 30 points.

[0192] In some embodiments, the Body Surface Area (BSA) of a patient affected by psoriasis is reduced by between about 1 and about 10 percentage points, between about 10 and about 20 percentage points, between about 20 and about 30 percentage points, between about 30 and about 40 percentage points, between about 40 and about 50 percentage points, between about 50 and about 60 percentage points, between about 60 and about 70 percentage points, between about 70 and about 80 percentage points, between about 80 and about 90 percentage points, or between about 90 and about 100 percentage points. In some embodiments, the Body Surface Area (BSA) of a patient affected by psoriasis is reduced by between about 1 and about 10 percentage points. In some embodiments, the Body Surface Area (BSA) of the patient is reduced by between about 10 and about 20 percentage points. In some embodiments, the Body Surface Area (BSA) of the patient is reduced by between about 20 and about 30 percentage points. In some embodiments, the patient's Body Surface Area (BSA) decreases by between about 30 and about 40 percentage points. In some embodiments, the patient's Body Surface Area (BSA) decreases by between about 40 and about 50 percentage points. In some embodiments, the patient's Body Surface Area (BSA) decreases by between about 50 and about 60 percentage points. In some embodiments, the patient's Body Surface Area (BSA) decreases by between about 60 and about 70 percentage points. In some embodiments, the patient's Body Surface Area (BSA) decreases by between about 70 and about 80 percentage points. In some embodiments, the patient's Body Surface Area (BSA) decreases by between about 80 and about 90 percentage points.In some embodiments, the patient's Body Surface Area (BSA) decreases by between about 90 and about 100 percentage points.

[0193] In some embodiments, the patient has at least about 10% BSA affected by psoriasis prior to administration, e.g., about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100%. In some embodiments, the patient has about 10% to about 20% BSA affected prior to administration. In some embodiments, the patient has about 20% to about 30% BSA prior to administration. In some embodiments, the patient has about 30% to about 40% BSA prior to administration. In some embodiments, the patient has about 40% to about 50% BSA prior to administration. In some embodiments, the patient has about 50% to about 60% BSA prior to administration. In some embodiments, the patient has about 60% to about 70% BSA prior to administration. In some embodiments, the patient has about 70% to about 80% BSA prior to administration. In some embodiments, the patient has about 80% to about 90% BSA prior to administration. In some embodiments, the patient has about 90% to about 100% BSA prior to administration.

[0194] In some embodiments, the reduction in the Numeric Rating Scale for Pain (NRS) is about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the reduction in the Numeric Rating Scale for Pain (NRS) is about 1. In some embodiments, the reduction in the Numeric Rating Scale for Pain (NRS) is about 2. In some embodiments, the reduction in the Numeric Rating Scale for Pain (NRS) is about 3. In some embodiments, the reduction in the Numeric Rating Scale for Pain (NRS) is about 4. In some embodiments, the reduction in the Numeric Rating Scale for Pain (NRS) is about 5. In some embodiments, the reduction in the Numeric Rating Scale for Pain (NRS) is about 6. In some embodiments, the reduction in the Numeric Rating Scale for Pain (NRS) is about 7. In some embodiments, the reduction in the Numeric Rating Scale for Pain (NRS) is about 8. In some embodiments, the reduction in the Numeric Rating Scale for Pain (NRS) is about 9. In some embodiments, the reduction in the Numeric Rating Scale for Pain (NRS) is about 10.

[0195] In some embodiments, the reduction in the Numeric Rating Scale (NRS) for itch is about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the reduction in the Numeric Rating Scale (NRS) for itch is about 1. In some embodiments, the reduction in the Numeric Rating Scale (NRS) for itch is about 2. In some embodiments, the reduction in the Numeric Rating Scale (NRS) for itch is about 3. In some embodiments, the reduction in the Numeric Rating Scale (NRS) for itch is about 4. In some embodiments, the reduction in the Numeric Rating Scale (NRS) for itch is about 5. In some embodiments, the reduction in the Numeric Rating Scale (NRS) for itch is about 6. In some embodiments, the reduction in the Numeric Rating Scale (NRS) for itch is about 7. In some embodiments, the reduction in the Numeric Rating Scale (NRS) for itch is about 8. In some embodiments, the reduction in the Numeric Rating Scale (NRS) for itch is about 9. In some embodiments, the reduction in the Numeric Rating Scale (NRS) for itch is about 10.

[0196] In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 is about 1% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100%. In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 is about 1% to about 10%. In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 is about 10% to about 20%. In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 is about 20% to about 30%. In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 is about 30% to about 40%. In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 is about 40% to about 50%. In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 is about 50% to about 60%. In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 is about 60% to about 70%. In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 is about 70% to about 80%. In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 is about 80% to about 90%. In some embodiments, the inhibition rate of IFNγ production by induction of IL-12 / 18 is about 90% to about 100%.

[0197] In some embodiments, the psoriasis does not include erythrodermic psoriasis, pustular psoriasis, predominantly guttate psoriasis, or drug-induced psoriasis.

[0198] In some embodiments, serum C maxIn some embodiments, the serum C is about 25 ng / ml to about 50 ng / ml, about 50 ng / ml to about 100 ng / ml, about 100 ng / ml to about 125 ng / ml, about 125 ng / ml to about 150 ng / ml, about 150 ng / ml to about 175 ng / ml, about 175 ng / ml to about 200 ng / ml, about 200 ng / ml to about 225 ng / ml, about 225 ng / ml to about 250 ng / ml, about 250 ng / ml to about 275 ng / ml, or about 275 ng / ml to about 300 ng / ml. max In some embodiments, the serum C max In some embodiments, the serum C max In some embodiments, the serum C max In some embodiments, the serum C max In some embodiments, the serum C max In some embodiments, the serum C max In some embodiments, the serum C max In some embodiments, the serum C max to approximately 250ng / ml to approximately 300ng / ml.

[0199] 6. Dosing and Schedule In some embodiments, the methods and uses described herein, e.g., in treating an inflammatory disorder (e.g., psoriasis and psoriatic arthritis) in a patient in need thereof, are carried out by administering a therapeutically effective amount of a TYK2 inhibitor (e.g., Compound 1), e.g., up to 200 mg, in one or multiple doses (e.g., orally). In some embodiments, the TYK2 inhibitor is administered once, twice, three times, four times, five times, six times, seven times, or eight times per day. In some embodiments, the method comprises administering (e.g., orally), in one or more doses, any of the following amounts in the range of about 2 to about 200 mg, e.g., about 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 145 mg, 150 mg, 160 mg, 170 mg, 185 mg, 190 mg, 195 mg, or about 200 mg, or a range of amounts generated by using two of the above amounts as endpoints. For example, oral dosages can contain 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg of a TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof per dosage form.

[0200] In some embodiments, the methods include administering (e.g., orally) in a single dose or in multiple doses in the range of about 2 to about 200 mg / dose daily, e.g., about 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 145 mg, 150 mg, 160 mg, 170 mg, 185 mg, 190 mg, 195 mg, or about 200 mg.

[0201] In some embodiments, the method includes administering about 2 to about 200 mg, about 2 mg to about 10 mg, about 15 mg to about 20 mg, about 25 mg to about 30 mg, about 35 mg to about 40 mg, about 45 mg to about 50 mg, about 60 mg to about 70 mg, about 80 mg to about 90 mg, about 100 mg to about 110 mg, about 120 mg to about 130 mg, about 140 mg to about 150 mg, about 150 mg to about 160 mg, about 170 mg to about 185 mg, about 190 mg to about 200 mg, about 5 mg to about 30 mg, about 1 This includes administering (e.g., orally) in the ranges of 0 mg to about 30 mg, about 10 mg to about 50 mg, about 10 mg to about 100 mg, about 25 mg to about 50 mg, about 25 mg to about 100 mg, about 25 mg to about 200 mg, about 30 mg to about 50 mg, about 30 mg to about 100 mg, about 40 mg to about 50 mg, about 40 mg to about 100 mg, about 50 mg to about 100 mg, about 75 mg to about 100 mg, about 75 mg to about 200 mg, about 100 mg to about 200 mg, about 125 mg to about 150 mg, or about 150 mg to about 200 mg. Any specific dosage within each of the ranges in this paragraph is contemplated. For example, "about 2 mg to about 10 mg" includes about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. Any non-integer doses between these ranges are also contemplated, for example, the range "about 2 mg to about 10 mg" includes values ​​such as about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, etc.

[0202] Any of the doses in the previous paragraph may be administered once, twice, three times, or four times during the day. For example, a 2 mg dose may be administered by administering a 1 mg dose, followed by a second 1 mg dose after a certain time lapse to reach a 2 mg dose. In a further example, a 2 mg dose may be administered by administering 0.5 mg, taking a time lapse, administering a second 0.5 mg dose, taking a time lapse, administering a third 0.5 mg dose, taking a time lapse, and administering a fourth 0.5 mg dose during the day to reach a total dose of 2 mg for that day.

[0203] Thus, in some embodiments, administering 2 mg of Compound 1 includes administering 1 mg, waiting a set time period, and administering a second 1 mg dose. In some embodiments, administering 5 mg of Compound 1 includes administering 2.5 mg, waiting a set time period, and administering a second 2.5 mg dose. In some embodiments, administering 10 mg of Compound 1 includes administering 5 mg, waiting a set time period, and administering a second 5 mg dose. In some embodiments, administering 15 mg of Compound 1 includes administering 7.5 mg, waiting a set time period, and administering a second 7.5 mg dose. In some embodiments, administering 30 mg of Compound 1 includes administering 15 mg, waiting a set time period, and administering a second 15 mg dose. The set time period may be determined by the clinician and is subject to the metabolism of the individual patient. In some embodiments, the determined elapsed time period is from about 2.5 hours to about 5 hours, from about 5 hours to about 7.5 hours, from about 7.5 hours to about 10 hours, from about 10 hours to about 12.5 hours, from about 12.5 hours to about 15 hours, from about 15 hours to about 17.5 hours, from about 17.5 hours to about 20 hours, from about 20 hours to about 22.5 hours, or from about 22.5 hours to about 24 hours.

[0204] In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of up to 2 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of up to 5 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of up to 10 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of up to 15 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of up to 20 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of up to 25 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of up to 30 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of up to 35 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of up to 40 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of up to 45 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of up to 50 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of about 5 mg to about 30 mg, e.g., about 5 mg, about 10 mg, or about 30 mg. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof is administered (e.g., orally) to the patient at a dose of about 10 mg to about 40 mg.In some embodiments, the TYK2 inhibitor (eg, compound 1), or a pharma- ceutically acceptable salt thereof, is administered (eg, orally) to the patient at a dose of about 25 mg to about 50 mg.

[0205] As shown in light of the preclinical data described herein, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered to the patient on a suitable dosing schedule to reversing the disease as desired with minimal side effects. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharmaceutical composition thereof is administered to the patient once daily (QD) for a period of about 1 day to about 7 days, about 1 week to about 3 weeks, about 3 weeks to about 6 weeks, about 6 weeks to about 9 weeks, about 9 weeks to 12 weeks, about 12 weeks to about 15 weeks, or about 15 weeks to about 18 weeks. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharmaceutical composition thereof is administered to the patient once daily (QD) for 2 weeks, 4 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, or 18 weeks.

[0206] In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered to a patient in a single daily dose of 2-200 mg for two weeks. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharmaceutical composition thereof is administered to a patient in multiple daily doses of 20-200 mg for two weeks. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or a pharmaceutical composition thereof is administered to a patient in a daily dose of 2 mg, 5 mg, 10 mg, 15 mg, or 30 mg for two, four, six, nine, twelve, fifteen, or eighteen weeks.

[0207] 7. Mixtures and combinations Pharmaceutically acceptable compositions The compounds and compositions according to the methods described herein may be administered using any amount and any route of administration effective to treat or reduce the severity of any of the disorders disclosed herein. The exact amount required will vary from subject to subject, depending on the race, age, and general condition of the subject, the severity of the infection, the particular drug, its method of administration, and the like. The compounds described herein are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete pharmaceutical unit appropriate for the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions described herein will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the specific compound used, the specific composition used, the age, weight, general health, sex, and diet of the patient, the time of administration, route of administration, and excretion rate of the specific compound used, the duration of the treatment, the drugs used in combination or with the specific compound used, and similar factors well known in the medical field.

[0208] According to another embodiment, the composition can include a compound as described herein or a pharma- ceutically acceptable derivative thereof and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition as described herein is such that it is effective to measurably inhibit TYK2 protein kinase or a variant thereof in a biological sample or a patient. In certain embodiments, the amount of the compound in the composition as described herein is such that it is effective to measurably inhibit TYK2 protein kinase or a variant thereof in a biological sample or a patient. In certain embodiments, the compositions as described herein are formulated for administration to a patient in need of such a composition. In some embodiments, the compositions as described herein are formulated for oral administration to a patient.

[0209] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0210] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0211] "Pharmaceutically acceptable derivatives" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound described herein that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound described herein, or an inhibitory active metabolite or residue thereof.

[0212] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of TYK2 protein kinase or a variant thereof.

[0213] The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, intracisternally, intraperitoneally, nasally, buccally, vaginally or via an implanted reservoir. In certain embodiments, the compounds described herein may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, one or more times per day to produce the desired therapeutic effect. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic acceptable parenteral diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

[0214] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other injectable sterile medium prior to use.

[0215] In order to prolong the effect of the compounds described herein, it is often desirable to slow the absorption of the compounds injected subcutaneously or intramuscularly. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on the size and crystalline form of the crystals. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with living tissue.

[0216] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at ambient temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity releasing the active compound.

[0217] For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful for the preparation of injectables, since they are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms, including emulsions and suspending agents. Other surfactants commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms, such as Tween, Span, and other emulsifiers or bioavailability enhancers, may also be used for formulation purposes.

[0218] The pharma- ceutically acceptable compositions described herein may be orally administered in any of the acceptable oral dosage forms, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, odorants, flavorings or colorings can also be added.

[0219] Alternatively, the pharma- ceutically acceptable compositions described herein may be administered in the form of suppositories for rectal administration.These suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug.Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0220] The solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders ... The composition is mixed with a glycerol monostearate, a glycerol monostearate, a sorbent, a sorbent mixture, and a mixture of these. The composition is mixed with a glycerol monostearate, ... These dosage forms may optionally contain opacifying agents and may also be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0221] The pharma- ceutically acceptable compositions described herein may be administered topically, especially when the therapeutic target includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0222] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0223] The provided pharma- ceutically acceptable compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers for topical application. Other topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Carriers for topical administration of the compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the provided pharma- ceutically acceptable compositions may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma- ceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and, if necessary, with any necessary preservatives or buffers. Absorption enhancers can also be used to increase the amount of compound that penetrates the skin. The rate can be controlled by either providing a rate-controlling membrane (for example, as in topically applied transdermal patches) or dispersing the compound in a polymer matrix or gel.

[0224] The pharmacy acceptable compositions provided may be formulated for ophthalmic use as micronized suspensions in isotonic, pH-adjusted, sterile saline, or preferably as solutions in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, the pharmacy acceptable compositions may be formulated for ophthalmic use in an ointment, such as petrolatum.

[0225] The pharma- ceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation.Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0226] Most preferably, the pharma- ceutically acceptable compositions described herein are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharma- ceutically acceptable compositions described herein are administered without food. In other embodiments, the pharma- ceutically acceptable compositions described herein are administered with food.

[0227] The amount of the compounds described herein that may be combined with a carrier material to provide a composition in a single dosage form may vary depending on the host being treated, the particular mode of administration, etc. Preferably, the compositions provided should be formulated to allow a dosage of 0.01-100 mg / kg body weight / day of the inhibitor to be administered to a patient receiving these compositions.

[0228] Liquid dosage forms for oral administration may be used, including, but not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0229] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend on the specific compound in the composition.

[0230] Depending on the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions described herein. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0231] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0232] Examples of agents that may be combined as described herein include, but are not limited to, agents for treating Alzheimer's disease, such as Aricept® and Excelon®, agents for treating HIV, such as ritonavir, agents for treating Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine, agents for treating multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone, agents for treating asthma, such as albuterol and Singulair®, agents for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol, anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine, immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine, neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents, agents for treating cardiovascular disease such as beta-blockers, AC E inhibitors, diuretics, nitrates, calcium channel blockers, and statins, drugs to treat liver disease such as corticosteroids, cholestyramine, interferons, and antivirals, drugs to treat blood disorders such as corticosteroids, anti-leukemia agents, and growth factors, drugs that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., metabolic degradation inhibitors) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir), and drugs to treat immune deficiency disorders such as gamma globulins.

[0233] In certain embodiments, the combination therapy described herein or a pharma- ceutically acceptable composition thereof is administered in combination with a monoclonal antibody or a siRNA drug.

[0234] These additional agents may be administered separately from the combination therapy provided as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds described herein in a single composition. When these two active agents are administered as part of a multiple dose regimen, they may be delivered simultaneously, sequentially, or within a period of one another, usually within 5 hours of the other.

[0235] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the invention. For example, the combinations described herein may be administered simultaneously or sequentially with another therapeutic agent, either in separate unit dosage forms or together in a single unit dosage form.

[0236] The amount of additional therapeutic agent present in the compositions described herein will not be greater than the amount that would normally be administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will range from about 50% to 100% of the amount that would normally be present in a composition containing that agent as the only therapeutically active agent.

[0237] In one embodiment, the composition can include a compound of formula I and one or more additional therapeutic agents. The therapeutic agents can be administered together with the compound of formula I, or before or after the administration of the compound of formula I. Suitable therapeutic agents are described in more detail below. In certain embodiments, the compound of formula I can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0238] In another embodiment, a method for treating psoriasis and / or psoriatic arthritis can include administering to a patient in need of treatment a compound of Formula I (e.g., Compound 1) and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biologics, including, for example, clobetasol, methotrexate, Humira®, Stelara®, triamcinolone, ustekinumab, adalimumab, Cosentyx®, Remicade®, Taltz®, Skyrizi®, Tremfya®, etanercept, Ilumya®, Avsola®, guselkumab, Inflectra®, ixekizumab, Renflexis®, risankizumab, secukinumab, tildrakizumab, fluocinonide, triamcinolone, Elocon®, calcipotriene, mometasone, Clobex®, Dovonex®, prednisone, desonide, hydrocortisone, Soriatane®. , Taclonex®, Tazorac®, Acitretin®, Cyclosporine®, Betamethasone, Betamethasone / Calcipotriene, Halobetasol, Temovate®, Kenalog®, Kenalog-40®, Neoral®, Desoximetasone®, Fluocinonide-E®, Otrexup®, Trexall®, Coal Tar, Enstilar®, Fluocinolone, Tazarotene, Topicort®, Calcitriol, Cortizone-10®, Dexamethasone, Kenalog-10®, Locoid®, Methylprednisolone, Prednisolone, Rasuvo®, RediTrex®, Taclonex Scalp®, Tacrolimus, Triderm®, Vanos®, Vectical®, Acthar®, Ala-Cort®, Ala-Scalp®, Ala-ScalpHP®, Alclometasone, Ammonium Lactate / Halobetasol, Aquanil HC®, Aristocort A®, Aristocort R®, Aristospan®, Beta HC®, Bioelements Immediate Comfort®, Caldecort®, Cinolar®, Clinacort®, Cloderm®, Cordran®, Cordran Tape®, Cortizone-5®, Dermarest Plus Anti-Itch®, Dermovate®, Dermtex HC®, Diflorasone, Flurandrenolide, Gengraf®, Halog®, Infliximab, Itch-X Lotion®, Locoid Lipocream®, NuCort®, Olux®, Olux-E®, Oxsoralen-Ultra®, Pandel®, Psoriasin®, Sarnol-HC®, Sernivo®, Synalar®, Texacort®, Trianex®, Tritocin®, U-Cort®, Abrilada®, Amcinonide, Amjevita®, Ammonium Lactate / Urea, Analpram-HC®, Analpram E®, Anthraforte®, Anthralin, Anthrascalp®, Apexicon®, ApexiCon E®, Balnetar®, Betatar Gel®, Brodalumab, Bryhali®, Calcitrene®, Capex®, Carb-O-Lac5®, Carb-O-Lac HP®, Clobevate®, Clocortolone, Clodan®, Coal Tar / Salicylic Acid / Sulfur, Coal Tar / Salicylic Acid, Cordran SP®, Cormax®, CormaxScalp®, Corticotropin, Cutar®, Cyclocort®, Cyltezo®, Derma-Smoothe / FS®, Derma-Smoothe® / FS (Body Oil), Derma-Smoothe® / FS (Scalp), Dermatop®, Desonate®, DesOwen®, DHS Tar Shampoo®, Doak Tar®, Dritho-Scalp®, Drithocreme®, Duobrii®, Elta Tar®, Embeline®, Embeline E®, Epifoam®, Estar®, Fototar®, HPActhar Gel®, Hadlima®, Halcinonide, Halobetasol / Tazarotene, Halonate®, HC Pram®, Hulio®, Hydrocortisone / Pramoxine, Hydroxyurea, Hyrimoz®, Impoyz®, Ionil T®, Ixifi®, Kalosar®, Kerasal Ultra 20®, LoKara®, Medotar®, Methoxsalen, MG217 Medicated Tar®, Neutrogena T® / Skin, Neutrogena T® / Gel, Nolix®, Novacort®, Oxipor VHC®, Pramosone®, Prednicarbate, Proctofoam HC®, RA Acne®, Resinol®, Resorcinol, Scytera®, Siliq®, Sorilux®, Synalar Ointment®, Tarsum®, Theraplex T®, Tovet®, Ultralytic®, Ultralytic2®, Ultravate®, Verdeso®, Wynzora®, Yusimry®, Zithranol®, and Zithranol-RR®.

[0239] In another embodiment, a method for treating an inflammatory disease, disorder, or condition can include administering to a patient in need of treatment a compound of Formula I and one or more additional therapeutic agents. Such additional therapeutic agents can be small molecules or recombinant biological agents, including, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Ulor). ic®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as aurothioglucose (Solganal®), aurothiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or are Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), as well as “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol ( Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), "anti-IL-6" agents such as tocilizumab (Actemra®),Diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), rubicone, cyclosporine ... Prostones (Amitiza®), laxatives such as milk of magnesia, polyethylene glycols (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®). , metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®), , and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®,Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epiv), ir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as Examples include amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivir®). vus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®);or any combination thereof.

[0240] In another embodiment, the method of treating rheumatoid arthritis comprises administering to a patient in need of treatment a compound of Formula I and nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials, such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts, such as aurothioglucose (Solganal®), aurothiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), or the like. ®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and adalimumab (Delta®). This may include administering one or more additional therapeutic agents selected from limumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), and "anti-IL-6" agents such as tocilizumab (Actemra®).

[0241] In some embodiments, a method of treating osteoarthritis can comprise administering to a patient in need of treatment a compound of Formula I and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies, such as tanezumab.

[0242] In some embodiments, the method of treating cutaneous lupus erythematosus or systemic lupus erythematosus comprises administering to a patient in need of treatment a compound of Formula I and a combination of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials, such as hydroxychloroquine, benzodiazepine, benzodiazepine, benzocaine, benzoyl peroxide ... Treatment may include administering one or more additional therapeutic agents selected from flucloxin (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants, such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0243] In some embodiments, a method of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease can include administering to a patient in need of treatment a compound of Formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®, and anticholinergic or antispasmodic agents such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0244] In some embodiments, the method of treating asthma comprises administering to a patient in need of treatment a compound of Formula I and an inhaled steroid such as Singulair®, a beta-2 agonist such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic agent such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), an inhaled corticosteroid such as prednisone, prednisolone, beclomethasone dipropionate ( and one or more additional therapeutic agents selected from: Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0245] In some embodiments, the method of treating COPD comprises administering to a patient in need of treatment a compound of Formula I and a beta-2 agonist such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic agent such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), a methylxanthine such as theophylline (Theo- Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®.

[0246] In another embodiment, a method of treating a hematological malignancy can comprise administering to a patient in need of treatment a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0247] In another embodiment, a method of treating a solid tumor can comprise administering to a patient in need of treatment a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0248] In another embodiment, a method of treating a hematological malignancy can comprise administering to a patient in need of treatment a compound of Formula I and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma" Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0249] In another embodiment, a method of treating diffuse large B-cell lymphoma (DLBCL) can comprise administering to a patient in need of treatment a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0250] In another embodiment, a method of treating multiple myeloma comprises administering to a patient in need of treatment a compound of Formula I and one or more additional therapeutic agents selected from bortezomib (Velcade®) and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).

[0251] In another embodiment, a method of treating or lessening the severity of a disease can comprise administering to a patient in need thereof a compound of Formula I and a BTK inhibitor, including, but not limited to, inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic thyroiditis, and / or inflammatory bowel disease. Sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated cerebrospinal meningitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerular nephropathy, endometriosis, interstitial Other conditions that may be causing symptoms include: cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, dust mites, or cockroach umbrellas), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, ulcerative colitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, sweat gland abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis,proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders, e.g., diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone lymphoma, Marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of the bone and joints (including but not limited to rheumatoid arthritis, seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease)), venous pulmonary arthritis, pulmonary pulmonary edema ... Stroke, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases, thromboembolic disorders (e.g., myocardial infarction, angina, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, cerebral infarction, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis), pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, clotting pulmonary circulation, pulmonary embolism, pulmonary edema, pulmonary edema, pulmonary malformation ...Selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0252] In another embodiment, a method of treating or lessening the severity of a disease can comprise administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenerative disorder, an angiogenesis disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), a liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0253] In another embodiment, a method of treating or lessening the severity of a disease can comprise administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, the disease being a benign or malignant tumor, carcinoma, or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, abdomen, stomach tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone, or thyroid, a sarcoma, glioblastoma, neuroblastoma, multiple myeloma, or a cancer of the gastrointestinal tract, particularly colon carcinoma or colorectal adenoma, or Diseases including head and neck tumors, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, epithelial plasma neoplasms, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinomas, large cell carcinomas, non-small cell lung cancers, lymphomas (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dacros disease, and Bannayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is aberrantly activated, asthma of any type or origin (intrinsic (non-albuminuria) asthma, both allergic (hypertensive) and extrinsic (allergic) asthma, including mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection), acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, chronic obstructive airways disease or chronic obstructive pulmonary disease (COPD, COAD or COLD) (including chronic bronchitis or chronic bronchitis-associated dyspnea, emphysema, and exacerbation of airway hyperresponsiveness as a result of other medications, especially other inhaled medications), bronchitis of any type or origin ( bronchitis of any kind or origin (including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or elongated bronchitis), pneumoconiosis (inflammatory disease of the lungs, whether chronic or acute, often accompanied by airway obstruction and resulting from repeated inhalation of dust, generally of an occupational nature, including, for example, aluminum lung disease, anthracosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tobacco poisoning and byssinosis), Löffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infestation (including tropical eosinophilia),Bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomas and eosinophil-related disorders affecting the airways (caused by drug reactions), psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca , and vernal conjunctivitis, diseases affecting the nose (including allergic rhinitis), and inflammatory diseases involving an autoimmune reaction or having an autoimmune component or etiology (autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, Dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca, and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, and Glomerulonephritis (with or without nephrotic syndrome (including, for example, idiopathic nephrotic syndrome or minimal change nephropathy)), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic cerebral infarction and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.

[0254] In some embodiments, a method of treating or lessening the severity of a disease can include administering to a patient in need thereof a compound of Formula I and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0255] In some embodiments, a method of treating or reducing the severity of a disease can include administering to a patient in need thereof a TYK2 pseudokinase (JH2) domain binding compound and a TYK2 kinase (JH1) domain binding compound. In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the JH2 binding compound is a compound of formula I. Other suitable JH2 domain binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1 domain binding compounds include those described in WO2015131080A1, each of which is incorporated herein by reference in its entirety.

[0256] According to one embodiment, a method of inhibiting protein kinase activity in a biological sample can include contacting said biological sample with a compound described herein, or a composition comprising said compound.

[0257] According to another embodiment, a method of inhibiting the activity of TYK2 or a mutant thereof in a biological sample can comprise contacting said biological sample with a compound described herein or a composition comprising said compound. In certain embodiments, a method of irreversibly inhibiting the activity of TYK2 or a mutant thereof in a biological sample can comprise contacting said biological sample with a compound described herein or a composition comprising said compound.

[0258] In another embodiment, methods are described for selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In some embodiments, the compounds described herein are more than 2-fold selective over JAK1 / 2 / 3. In some embodiments, the compounds described herein are more than 5-fold selective over JAK1 / 2 / 3. In some embodiments, the compounds described herein are more than 10-fold selective over JAK1 / 2 / 3. In some embodiments, the compounds described herein are more than 50-fold selective over JAK1 / 2 / 3. In some embodiments, the compounds described herein are more than 100-fold selective over JAK1 / 2 / 3.

[0259] The term "biological sample" as used herein includes, but is not limited to, cell culture medium or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0260] Inhibiting the activity of TYK2 (or a variant thereof) in a biological sample is useful for a variety of purposes known to those of skill in the art, including, but not limited to, blood transfusion, organ transplantation, biological sample storage, and biological assays.

[0261] Another embodiment method of inhibiting protein kinase activity in a patient can include administering to the patient a compound described herein, or a composition comprising said compound.

[0262] According to another embodiment, a method of inhibiting the activity of TYK2 or a mutant thereof in a patient can comprise administering to the patient a compound described herein, or a composition comprising said compound. According to certain embodiments, a method of reversibly or irreversibly inhibiting one or more activities of TYK2 or a mutant thereof in a patient can comprise administering to the patient a compound described herein, or a composition comprising said compound. In other embodiments, a method of treating a disorder mediated by TYK2 or a mutant thereof in a patient in need of treatment can comprise administering to the patient a compound described herein, or a pharma- ceutically acceptable composition thereof. Such disorders are described in detail herein.

[0263] Depending on the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions described herein. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0264] The compounds described herein may be used in combination with other therapeutic compounds to provide benefits. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active compounds, alkylating compounds, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, antitumor antimetabolites, platin compounds, compounds that target / reduce protein or lipid kinase activity, and further angiogenesis inhibitor compounds, compounds that target, reduce or inhibit protein or lipid phosphatase activity, gonadorelin agonists, antiandrogens, methionine aminopeptidase inhibitors. agents, matrix metalloproteinase inhibitors, bisphosphonates, biological response modifiers, antiproliferative antibodies, heparanase inhibitors, inhibitors of Ras oncogenic isoforms, telomerase inhibitors, proteasome inhibitors, compounds for use in the treatment of hematological malignancies, compounds which target, reduce or inhibit the activity of Flt-3, Hsp90 inhibitors, e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma These include, but are not limited to, temozolomide (Temodal®), kinesin spindle protein inhibitors such as SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx), MEK inhibitors such as ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer), and leucovorin.The term "aromatase inhibitors" as used herein relates to compounds that inhibit estrogen production, for example the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, in particular atamestane, exemestane and formestane, and nonsteroids, in particular aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is sold under the trade name Aromasin™. Formestane is sold under the trade name Lentaron™. Fadrozole is sold under the trade name Afema™. Anastrozole is sold under the trade name Arimidex™. Letrozole is sold under the trade name Femara™ or Femar™. Aminoglutethimide is sold under the trade name Orimeten™. The combinations described herein can include a chemotherapeutic agent that is an aromatase inhibitor, which is particularly useful in the treatment of hormone receptor positive tumors, such as tumors of the breast.

[0265] The term "antiestrogen" as used herein refers to a compound that antagonizes the action of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex®. Raloxifene hydrochloride is sold under the trade name Evista®. Fulvestrant can be administered under the trade name Faslodex®. The combinations described herein can include a chemotherapeutic agent that is an antiestrogen, which is particularly useful for treating estrogen receptor positive tumors, such as breast tumors.

[0266] The term "antiandrogen" as used herein refers to any substance capable of inhibiting the biological action of male hormones, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[0267] The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the polymeric camptothecin conjugate PNU-166148. For example, irinotecan can be administered in its marketed form, for example, under the trade name Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[0268] The term "topoisomerase II inhibitors" as used herein includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and rosoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is sold under the trade name Etopophos™. Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name Acriblastin™ or Adriamycin™. Epirubicin is sold under the trade name Farmorubicin™. Idarubicin is sold under the trade name Zavedos™. Mitoxantrone is sold under the trade name Novantron.

[0269] The term "microtubule activator" refers to microtubule stabilizing compounds, microtubule destabilizing compounds and microtubule polymerization inhibitors, including, but not limited to, taxanes, such as paclitaxel and docetaxel, vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine, discodermolide, colchicine, and epothilones, and derivatives thereof. Paclitaxel is sold under the trade name Taxol™. Docetaxel is sold under the trade name Taxotere™. Vinblastine sulfate is sold under the trade name Vinblastin RP™. Vincristine sulfate is sold under the trade name Farmistin™.

[0270] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin™. Ifosfamide is sold under the trade name Holoxan™.

[0271] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0272] The term "antineoplastic antimetabolites" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is sold under the trade name Xeloda™. Gemcitabine is sold under the trade name Gemzar™.

[0273] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum, and oxaliplatin. For example, carboplatin can be administered in the form as it is marketed, e.g., under the trade name Carboplat™. For example, oxaliplatin can be administered in the form as it is marketed, e.g., under the trade name Eloxatin™.

[0274] The term "compounds which target / reduce protein or lipid kinase activity or protein or lipid phosphatase activity or further angiogenesis inhibitory compounds" as used herein includes inhibitors of protein tyrosine kinases and / or serine and / or threonine kinases or lipid kinase inhibitors, such as a) compounds which target, reduce or inhibit the activity of platelet derived growth factor receptors (PDGFRs), e.g. compounds which target, reduce or inhibit the activity of PDGFRs, in particular b) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFRs); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), for example compounds which target, reduce or inhibit the activity of IGF-IR, in particular compounds which inhibit the kinase activity of the IGF-I receptor or compounds which inhibit the kinase activity of the IGF-I receptor or Antibodies targeting the extracellular domain of the growth factor, d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors, e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family, f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase, g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, e.g. imatinib, h) PDGFR family i) compounds which target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is a member of the c-Kit receptor tyrosine kinase family, for example compounds which target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds which inhibit the c-Kit receptor, for example imatinib, i) compounds which target, reduce or inhibit the activity of members of the c-Abl family, their gene fusion products (for example BCR-Abl kinase) and mutants, for example compounds which target or reduce the activity of c-Abl family members and their gene fusion products,j) compounds which target, reduce or inhibit the activity of protein kinase C (PKC) and members of the Raf family of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, members of the PI3K, SYK, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK) (e.g. staurosporin, such as midostaurin); Examples of further compounds include UCN-01, safingol, BAY43-9006, bryostatin 1, perifosine, irmofosine, RO318220 and RO320432, GO6976, lsis3521, LY333531 / LY379196, isoquinoline compounds, FTI, PD184352 or QAN697 (P13K inhibitors), or AT7519 (CDK inhibitors)), k) compounds that target, reduce or inhibit the activity of protein tyrosine kinases (e.g. compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate (Gleevec™), tyrphostins, e.g. Tyrphostin A23 / RG-50810, AG99, Tyrphostin AG213, Tyrphostin AG1748, Tyrphostin AG 490, Tyrphostin B44, Tyrphostin B44(+) enantiomer, Tyrphostin AG 555, AG494, Tyrphostin AG556, AG957, and Adafostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester, NSC680410, Adafostin); l) targeting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants;Compounds that reduce or inhibit (e.g. compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, in particular compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4, or that bind to EGF or EGF-related ligands, CP358774, ZD1839, ZM105180, trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OS I-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, as well as 7H-pyrrolo-[2,3-d]pyrimidine derivatives), m) compounds which target, reduce or inhibit the activity of the c-Met receptor, for example compounds which target, reduce or inhibit the activity of c-Met, in particular compounds which inhibit the kinase activity of the c-Met receptor, or antibodies which target the extracellular domain of c-Met or which bind to HGF, n) one or more compounds that target, reduce or inhibit the kinase activity of the above JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) (including, but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib); o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K) (including, but not limited to, ATU-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib), and q) compounds that target, reduce or inhibit the signaling action of the Hedgehog protein (Hh) or Smoothened receptor (SMO) pathways, including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (salidegib),These include, but are not limited to,

[0275] The term "PI3K inhibitor", as used herein, includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to, PI3K alpha, PI3K gamma, PI3K delta, PI3K beta, PI3K-C2 alpha, PI3K-C2 beta, PI3K-C2 gamma, Vps34, p110-alpha, p110-beta, p110-gamma, p110-delta, p85-alpha, p85-beta, p55-gamma, p150, p101, and p87. Examples of PI3K inhibitors useful in the methods described herein include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0276] The term "BTK inhibitor", as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0277] The term "SYK inhibitors", as used herein, includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0278] The term "Bcl-2 inhibitors", as used herein, includes compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's Pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof, see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of In some embodiments, the Bcl-2 inhibitor is a small molecule drug. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0279] Further examples of BTK inhibitor compounds and conditions treatable by such compounds in combination with the compounds described herein can be found in WO2008039218 and WO2011090760, which are incorporated by reference in their entireties.

[0280] Further examples of SYK inhibitor compounds and conditions treatable by such compounds in combination with the compounds described herein can be found in WO2003063794, WO2005007623, and WO2006078846, the entireties of which are incorporated herein by reference.

[0281] Further examples of PI3K inhibitor compounds and conditions treatable by such compounds in combination with the compounds described herein can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, the entireties of which are incorporated by reference herein.

[0282] JAK inhibitor compounds and conditions treatable by such compounds in combination with the compounds described herein can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entireties of which are incorporated by reference herein.

[0283] Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, e.g., a mechanism unrelated to the inhibition of protein or lipid kinases, such as thalidomide (Thalomid™) and TNP-470.

[0284] Examples of proteasome inhibitors useful for use in combination with the compounds described herein include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0285] Compounds which target, decrease or inhibit the activity of protein or lipid phosphatases are eg inhibitors of phosphatase 1, phosphatase 2A or CDC25, eg okadaic acid or a derivative thereof.

[0286] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, γ-tocotrienol or δ-tocotrienol.

[0287] The term cyclooxygenase inhibitors as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenyl acetic acids and derivatives, such as celecoxib (Celebrex™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenyl acetic acids, such as lumiracoxib, which is 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid.

[0288] The term "bisphosphonates" as used herein includes, but is not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is sold under the trade name Didronel™. Clodronic acid is sold under the trade name Bonefos™. Tiludronic acid is sold under the trade name Skelid™. Pamidronic acid is sold under the trade name Aredia™. Alendronic acid is sold under the trade name Fosamax™. Ibandronic acid is sold under the trade name Bondranat™. Risedronic acid is sold under the trade name Actonel™. Zoledronic acid is sold under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0289] The term "heparanase inhibitors" as used herein refers to compounds that target, reduce or inhibit the degradation of heparin sulfate. This term includes, but is not limited to, PI-88. The term "biological response modifiers" as used herein refers to lymphokines or interferons.

[0290] The term "inhibitor of oncogenic isoform of Ras" such as H-Ras, K-Ras or N-Ras, as used herein, refers to a compound that targets, reduces or inhibits the oncogenic activity of Ras, such as "farnesyltransferase inhibitors", for example, L-744832, DK8G557 or R115777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of telomerase. Compounds that target, reduce or inhibit the activity of telomerase are particularly compounds that inhibit telomerase receptor, such as telomestatin.

[0291] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of methionine aminopeptidase. Compounds that target, reduces or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0292] The term "proteasome inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of the proteasome. Compounds that target, reduces or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™) and MLN341.

[0293] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) as used herein includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC683551), BMS-279251, BAY12-9566, TAA211, MMI270B or AAJ996.

[0294] The term "compounds for use in the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R), interferons, 1-β-D-arabinofuransylcytosine (ara-c) and busulfan, ALK inhibitors, which are compounds that target, reduce or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[0295] Compounds which target, decrease or inhibit the activity of the FLT-3R-like tyrosine kinase receptor are in particular compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0296] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90, compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are in particular compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives, other geldanamycin-related compounds, radicicol and HDAC inhibitors.

[0297] The term "antiproliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, Erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, provided that they exhibit the desired biological activity.

[0298] For the treatment of acute myeloid leukemia (AML), the compounds described herein can be used in combination with standard leukemia therapy, particularly in combination with therapy used in the treatment of AML. In particular, the compounds described herein can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful in the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412. In some embodiments, the method of treating AML associated with ITD and / or D835Y mutations can include administering the compounds described herein together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), staurosporine derivatives (e.g., midostaurin or lestaurtinib), sorafenib, tanzutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitor is selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[0299] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue, which is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogues hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, reduce or inhibit the activity of histone deacetylase (HDAC) inhibitors, for example, sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and compounds disclosed in US6,552,065, including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, particularly the lactate salt. Somatostatin receptor antagonists, as used herein, refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Approaches that damage tumor cells refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and below means ionizing radiation that occurs either as electromagnetic waves (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy and is known in the art. Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1, pp. 248-275 (1993).

[0300] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binders" as used herein refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitors" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are in particular hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0301] In particular, these compounds, proteins or monoclonal antibodies of VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharma- ceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate, Angiostatin™, Endostatin™, anthranilic acid amide, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers, such as Macugen, FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI4610), and bevacizumab (Avastin™).

[0302] Photodynamic therapy, as used herein, refers to therapy that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0303] Angiogenesis inhibitory steroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11α-hydrocortisone, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0304] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0305] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists, biological response modifiers, preferably lymphokines or interferons, antisense oligonucleotides or oligonucleotide derivatives, shRNA or siRNA, or miscellaneous compounds, or compounds with other or unknown mechanisms of action.

[0306] The compounds described herein are also useful as combination therapeutic compounds, in particular in the treatment of obstructive or inflammatory airway diseases, e.g., in combination with other drug substances, e.g., anti-inflammatory, bronchodilatory or antihistamine drug substances, e.g., as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. The compounds described herein may be mixed with the other drug substances in a pharmaceutical composition, or may be administered separately, before, simultaneously with or after the other drug substances. Thus, the combination of the compounds described herein with anti-inflammatory, bronchodilatory, antihistamine or antitussive drug substances as described above, the compounds described herein and the drug substances may be present in the same pharmaceutical composition or in different pharmaceutical compositions.

[0307] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, non-steroidal glucocorticoid receptor agonists, LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL284, ONO4057, SB209247, LTD4 antagonists such as montelukast and zafirlukast, PDE4 inhibitors such as cilomilast (Ariflo®, GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allophylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID (trademark) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxitropium bromide, tiotropium salts and CHF4226 (Chiesi), as well as glycopyrrolate.

[0308] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine and fexofenadine hydrochloride, acrivastine, astemizole, azelastine, ebastine, epinastine, mizolastine and terfenadine.

[0309] Other useful combinations of the compounds described herein with anti-inflammatory agents are with antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0310] The structures of the active compounds, identified by code number, generic name or trade name, can be obtained from the current edition of the standard compendium "The Merck Index", or from databases such as Patents International (eg IMS World Publications).

[0311] The compounds described herein may be used in combination with known therapeutic processes, such as administration of hormones or radiation. In certain embodiments, the compounds provided are used as radiosensitizers, particularly in the treatment of tumors that are poorly sensitive to radiation therapy.

[0312] The compounds described herein can be administered alone or in combination with one or more other therapeutic compounds, with possible combination therapy taking the form of a fixed combination, a compound described herein and one or more other therapeutic compounds administered at different times or independently of each other, or a fixed combination administered in combination with one or more other therapeutic compounds.The compounds described herein can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof, particularly for the treatment of tumors, or in addition.Long-term therapy is also possible in the context of other therapeutic strategies, as described above, such as adjuvant therapy.Other possible treatments are those to maintain the patient's condition after tumor regression, or even after chemopreventive therapy, for example in patients at risk.

[0313] These additional agents may be administered as part of a multiple dose regimen separately from the composition containing the compound of the present invention. Alternatively, these agents may be part of a single dosage form mixed together with the compounds described herein in a single composition. When administered as part of a multiple dose regimen, these two active agents may be delivered simultaneously, sequentially, or within a period of time from the other, usually within 5 hours of the other.

[0314] As used herein, the terms "combination", "combined" and related terms refer to simultaneous or sequential administration of therapeutic agents. For example, the compounds described herein may be administered simultaneously or sequentially with another therapeutic agent, either in separate unit dosage forms or together in one unit dosage form. Thus, one unit dosage form may include the compounds described herein, the additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0315] The amounts of any of the compounds of the invention and additional therapeutic agents (in compositions containing additional therapeutic agents, as described above) that may be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions described herein should be formulated so that a compound of the invention can be administered at a dosage of between 0.01-100 mg / kg body weight / day.

[0316] In those compositions that include an additional therapeutic agent, the additional therapeutic agent and the compound described herein may act synergistically. Thus, the amount of additional therapeutic agent in such compositions will be less than that required for monotherapy using only that therapeutic agent. In such compositions, the additional therapeutic agent may be administered at a dosage of 0.01 to 1,000 μg / kg body weight / day.

[0317] The amount of additional therapeutic agent present in the compositions described herein will not be greater than the amount that would normally be administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will range from about 50% to 100% of the amount that would normally be present in a composition containing that agent as the only therapeutically active agent.

[0318] The compounds described herein or pharmaceutical compositions thereof may be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, are used to eliminate restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects may be prevented or mitigated by pre-coating the device with a pharma- ceutically acceptable composition that includes a kinase inhibitor. An implantable device coated with the compounds described herein is another embodiment. EXAMPLES

[0319] As shown in the examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedures. The general methods are shown to synthesize the specific compounds described herein, but it will be apparent that the general methods below and other methods known to those skilled in the art are applicable to all compounds and substances, and their respective subclasses and species of compounds, as described herein. Additional compounds described herein may be prepared by methods substantially similar to those described in the examples, and methods known to those skilled in the art. The TYK2 inhibitors described herein (e.g., compound 1) can be prepared by methods known to those skilled in the art, such as those described in US11,046,698, the contents of which are incorporated herein by reference in their entirety.

[0320] Example 1: Safety and Tolerability in Healthy Subjects (Study 101) Study 101 was a randomized, single-center, double-blind, placebo-controlled, single- and multiple-ascending dose study in healthy subjects aged 18-55 years. The study investigated single ascending doses (SAD) of 5 mg, 20 mg, 75 mg, 100 mg, and 200 mg, and multiple ascending doses (MAD) of 20 mg and 35 mg once daily for 14 days. An additional open-label cohort was also included to evaluate the comparative bioavailability of two drug formulations, the original d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) formulation and a novel spray-dried dispersion (SDD) formulation, and to assess the PK of a single oral dose of the SDD formulation of Compound 1 under fed and fasted conditions in healthy subjects. The SDD formulation has been used in clinical trials of Compound 1.

[0321] The study enrolled 47 participants (healthy volunteers) in single-dose cohorts (35 treated with Compound 1 ranging from 5 mg to 200 mg, 12 treated with placebo). Compound 1 treatment was generally safe and well tolerated. A total of 14 of the 35 participants treated with Compound 1 (40%) experienced at least one treatment-emergent adverse event (TEAE), compared with 3 of the 12 participants treated with placebo (25%). The most common AEs associated with Compound 1 treatment were dermatitis acneiform / papular rash and aphthous stomatitis, which were mild in severity and did not lead to discontinuation of treatment. There were no deaths, serious or severe AEs, or AEs leading to discontinuation of the study or study drug in either active or placebo-treated participants. No adverse trends were noted in safety laboratory tests, ECGs, vital signs, or physical examination findings.

[0322] The study enrolled 16 participants (healthy volunteers) in multiple-dose cohorts (12 treated with either 20 mg or 35 mg of Compound 1 daily for 2 weeks, 4 treated with placebo daily for 2 weeks). Compound 1 treatment was generally safe and well tolerated. A total of 12 (100%) of the 12 participants treated with Compound 1 experienced at least one TEAE during the study period, compared with 2 (50%) of the 4 participants who received placebo. The most common TEAE observed by preferred term (in 2 or more subjects) was dermatitis acneiform, reported in 8 subjects treated with Compound 1 (all 6 who received 20 mg daily for 2 weeks, and 2 who received 35 mg). Papular rash was reported in 3 subjects treated with 35 mg of Compound 1. All events of dermatitis acneiform or papular rash were considered drug-related. All were mild in intensity, resolved within 1-2 weeks of onset, and did not require discontinuation of treatment. Two subjects in the 20 mg group and one in the 35 mg group experienced aphthous ulcers, all of whom also experienced acneiform dermatitis. All events were considered drug-related. None of these events were observed in the placebo group. There were no deaths, serious or severe AEs, or AEs leading to discontinuation of the study. One participant in the 20 mg group discontinued treatment due to atrial fibrillation associated with hyperthyroidism, but completed study follow-up. The event was considered unrelated to study drug and was not serious. No adverse trends were noted in safety laboratory tests, ECGs, vital signs, or physical examination findings.

[0323] Of the six subjects enrolled in the open-label cohort, only one TEAE of herpes labialis was observed in one subject (16.7%) following a single dose of 35 mg Compound 1 (SDD formulation) under fasting conditions. This TEAE was mild in severity and was deemed by the investigator to be unrelated to Compound 1. This event was also the TEAE of particular interest and resolved prior to study termination. No SAEs were observed, and no subjects had a TEAE leading to discontinuation during the study period.

[0324] Pharmacokinetic Results: In this study, absorption of Compound 1 was generally rapid in SAD cohorts 1-6 and MAD cohorts 7 and 8, with mean peak plasma concentrations observed at a median time to maximum concentration (Tmax) of 3-5 hours post-dose. In SAD cohort 9, periods 1 and 2, Compound 1 (TPGS and SDD formulations, respectively) was administered to fasted subjects, with Tmax similar to other SAD cohorts and observed at a median time of 4-5 hours post-dose. In SAD cohort 9, period 3, Compound 1 (compound as SDD formulation) was administered to fed subjects, with Tmax observed at a median time of 8 hours post-dose, with individual values ​​ranging from 8 to 24 hours post-dose.

[0325] In cohorts 1-3 (5 mg, 20 mg, and 75 mg doses of Compound 1), the mean maximum concentration (Cmax) increased roughly dose-proportionally.

[0326] Cmax was (21.6-237.4 ng / mL, or an 11-fold increase with a 15-fold increase in dose) with moderate intersubject variability (coefficient of variation [CV] 20-28%). max The mean increased at less than dose-proportional levels (232.5–250 mg / mL) and showed some degree of between-subject variability (CV 35–57%).

[0327] Similarly, in cohorts 1-3 (5 mg, 20 mg, and 75 mg doses of compound 1), the mean area under the plasma concentration versus time curve (AUC0-inf) from time 0 to infinity increased roughly dose-proportionally (589.4-8369.8 hr*ng / mL, or a 14-fold increase in AUC0-inf for a 15-fold increase in dose). In the 100 mg and 150 mg doses (cohorts 5 and 4), the mean AUC0-inf increased at less than dose-proportional levels (10744.9 hr*ng / mL and 12190.8 hr*ng / mL, respectively). Exposure in cohort 6 (200 mg dose) did not increase further, with a mean AUC0-inf of 9015 hr*ng / mL. In single-dose cohorts 1–6, the percentage of extrapolated area under the concentration-time curve (AUC%) was moderate, ranging from 9.9 to 30.9%.

[0328] Repeated daily doses of 20 mg (cohort 7) or 35 mg (cohort 8) for 14 days showed max The accumulation ratios of 2.6 and 2.2, respectively, and the areas under the plasma concentration versus time curve from time 0 to the end of the treatment period (AUC0-tau) were 2.9 and 2.4, respectively. After repeated dosing at 20 mg or 35 mg, the minimum concentration (C min ) were 82.7 ng / mL and 169.9 ng / mL, respectively.

[0329] Across single-dose cohorts 1-6 and repeat-dose cohorts 7 and 8, terminal half-lives (t1 / 2) were consistent across dose levels tested and ranged from 17.1 to 37.4 hours.

[0330] In cohort 9, periods 1 and 2, the comparative bioavailability of the TPGS formulation (used to formulate Compound 1 for administration in cohorts 1-8) versus the SDD formulation was evaluated following a single 35 mg dose to fasted subjects. Overall, there was a significant increase in C after single administration of Compound 1 in either the TPGS or SDD formulations. max(112.3ng / mL and 148ng / mL, respectively) and AUC 0-inf Exposure was similar as assessed by the calculated oral bioavailability (F%) of the SDD formulation compared to the TPGS formulation (3146.3 hr*ng / mL and 4027.5 hr*ng / mL, respectively (calculated relative oral bioavailability (F%) of the SDD formulation compared to the TPGS formulation was 128%). The possible effect of food on exposure was evaluated in cohort 9, period 2 (fasted, SDD formulation) and period 3 (fed, SDD formulation). Overall, exposure was similar in the two periods and the ratios of pharmacokinetic parameters in fed to fasted subjects were both C max (0.91), A.U.C. 0-inf (1.07), the area under the plasma concentration versus time curve from time 0 to the last measurable concentration (AUC 0-last , 1.02) and t1 / 2 (0.95), which were close to 1. Thus, no food effect was observed in this study.

[0331] Overall, renal excretion of the parent drug was a low but measurable percentage (%) of the total dose of Compound 1, with the percentage of the dose excreted in urine (FE%) ranging from 0.37 to 1.89% of the dose. Therefore, based on this study, renal excretion may contribute to the elimination of the parent drug, but is predicted to be a relatively minor route of elimination. Renal clearance (CLr) ranged from 0.06 to 0.30 L / hr.

[0332] Pharmacodynamic Results: The PD effects of treatment in this study were assessed using an ex-vivo immunoassay that measured the amount of TYK2-dependent interferon gamma (IFNγ) produced by whole blood samples stimulated with the cytokines IL-12 and IL-18 at baseline (pre-dose) and after treatment. Increasing exposure to Compound 1 led to greater reductions in IFNγ, confirming robust effects of this compound on biological endpoints relevant to the pathogenesis of several autoimmune diseases.

[0333] Physiologically relevant IC20s were performed to assess the relative risk of JAK1 / 3 inhibition for duravacitinib and compound 1. 50 We modeled the peak concentration of each compound achieved in human studies relative to the level of inhibition. Figure 3 shows the JAK1 / 3 IC of deuclavacitinib and Compound 1 in human cells (peripheral blood monocytes, or PBMCs). 50 The fold selectivity with respect to inhibitory concentration is shown. Based on published PK data from the Phase 1a clinical trial of deuclavacitinib, deuclavacitinib administered at 12 mg once daily had peak concentrations achieved (approximately 120 ng / ml) and an IC of approximately 370 ng / ml for JAK1 / 3 pSTAT inhibition. 50 A 4-fold difference was observed between the concentrations of deuclavacitinib and compound 1. Based on the PK data from our Phase 1a clinical trial, without wishing to be bound by theory, the difference for compound 1 is believed to be more than 50-fold, with peak concentrations of approximately 320 ng / ml after 30 mg administered once daily. We have not performed a head-to-head comparison of preclinical or clinical studies of deuclavacitinib and compound 1. Therefore, we cannot draw a comparison between the data provided by BMS for deuclavacitinib and the data we observed for compound 1.

[0334] Without wishing to be bound by theory, the inventors believe that improved TYK2 inhibition over a 24-hour period may increase responses in patients with inflammatory and autoimmune diseases that require higher levels of cytokine regulation, particularly those with ulcerative colitis and Crohn's disease. In a Phase 2b study of deuclavacitinib administered at 6 mg once daily in moderate to severe ulcerative colitis, deuclavacitinib did not achieve the primary endpoint of clinical remission at 12 weeks, or the secondary endpoints of clinical response using modified Mayo score, nor endoscopic response and histological improvement. BMS is currently conducting a second study of deuclavacitinib in ulcerative colitis, which will include a higher dose. Based on the PK data observed in our Phase 1a clinical trial, shown below, we believe that Compound 1 at the dose tested may be able to increase TYK2 inhibition over a 24 hour period compared to Duke Lavacitinib at the dose tested in the Phase 2b study, which we believe supports further evaluation of Compound 1 in ulcerative colitis. See Figure 4.

[0335] Based on the PK data from a Phase 1a clinical trial of deucelavacitinib and similar data from our Phase 1a clinical trial, we have demonstrated that TYK2 inhibition also has an IC 50 According to our modeling, shown in Figure 4, 6 mg of deuclavacitinib once daily (the dose used in the Phase 3 study of deuclavacitinib in psoriasis and the Phase 2b study of deuclavacitinib in ulcerative colitis) increased TYK2 IC 50 Based on this model, it appears that Compound 1 at 5 mg and 30 mg administered once a day can maintain the TYK2 IC50 for 24 hours. Furthermore, in this model, the 30 mg dose of Compound 1 achieved approximately the IC 75 The state of IC is realized 24 hours a day. 90 This state was realized for several hours per day.

[0336] Without wishing to be bound by theory, the PK and pharmacodynamic (PD) data from our Phase 1a study suggest that compound 1 may offer increased dosing flexibility for JAK1 / 3 inhibition given its broad therapeutic index. Based on publicly available information, BMS has not explored doses higher than 12 mg twice daily in any of its patient studies for any indication. As shown in Figure 5, our PK and PD data from our Phase 1a study showed a good linear response between dose levels and blood drug levels and a robust response, including dose-dependent inhibition of the cytokine IFNy, which is regulated by TYK2 signaling. Based on PD data (IC in human leukocytes) 50 The predicted effective dose range (through concentrations above 0.01 mg) was 3 to 30 mg once daily.

[0337] Example 2: Safety and Tolerability in Subjects with Psoriasis (Study 102) This study was a Phase 1, randomized, multicenter, double-blind, placebo-controlled, multiple-ascending dose study of Compound 1 in subjects with moderate to severe plaque psoriasis. The goal of this study was to provide preliminary evidence of safety, tolerability, pharmacokinetics, pharmacodynamics, and early efficacy in the moderate to severe plaque psoriasis population.

[0338] A total of 26 subjects were enrolled in this study and randomized to be treated daily with either placebo (N=5) or one of three doses of Compound 1 (N=21) for a total duration of 28 days. Dose levels were 5mg (N=8), 10mg (N=7), or 30mg (N=6). TPGS formulation was used for the 5mg dose level, and SDD formulation was used for the 10mg and 30mg dose levels. Food intake was not restricted except during study procedures during outpatient visits.

[0339] Efficacy Results: This study provided exploratory efficacy data (PASI, static PGA [sPGA]) for psoriasis. The study had a small sample size (25 subjects contributed efficacy data) and treatment duration was limited to 28 days. The efficacy analysis set included a total of 25 subjects (N=8 5 mg, N=7 10 mg, N=5 30 mg, N=5 placebo) with PASI and / or sPGA data on Days 1 and 28. For these 25 subjects, efficacy data were complete and no imputation for missing data was required. PGA assessments were performed according to Table 1. [Table 1] Treatment with Compound 1 demonstrated a dose-dependent trend towards reduced disease severity with a 30% reduction in mean PASI score at Day 28 compared to Day 1 in the 5 mg group (mean PASI decreased from 15.4 on Day 1 to 10.9 on Day 28), 47% in the 10 mg group (mean PASI decreased from 18.2 on Day 1 to 9.6 on Day 28), and 48% in the 30 mg group (mean PASI decreased from 20.0 on Day 1 to 10.4 on Day 28), compared to a 26% reduction in placebo (mean PASI decreased from 13.5 on Day 1 to 10.0 on Day 28). PASI-50 was achieved by 13% (1 / 8) of patients in the 5 mg group, 57% (4 / 7) of patients in the 10 mg group, and 40% (2 / 5) of patients in the 30 mg group, compared with 0% (0 / 5) of patients in the placebo group. PASI-75 was achieved in 1 subject (1 / 5, 20%) in the 30 mg group but not in the other groups. The same subject also achieved PASI 90. Treatment with Compound 1 also improved sPGA scores compared to placebo, with one subject in the 30 mg cohort achieving an sPGA of 1 (very mild disease) at Day 28.

[0340] Safety Results: Treatment with Compound 1 was generally safe and well tolerated. No deaths or serious AEs were observed. TEAEs were observed in 38% (3 / 8) of subjects receiving Compound 1 at 5 mg, 57% (4 / 7) of subjects receiving Compound 1 at 10 mg, and 67% (4 / 6) of subjects receiving Compound 1 at 30 mg, compared with 20% (1 / 5) of subjects receiving placebo. All TEAEs were mild (grade 1) or moderate (grade 2) in intensity in subjects treated with Compound 1 at 30 mg, except for one severe (grade 3) adverse event of neutropenia, which led to discontinuation of treatment. This event was observed on day 8 of treatment, and study drug was discontinued on day 12. On day 15, 3 days after treatment was stopped, the subject's neutrophil count was normal.

[0341] Grade 3 neutropenia was the only adverse event constituting grade 2 or higher hematologic toxicity observed in the study. The adverse event was considered related to study drug but was not serious. No events of acneiform dermatitis, papular rash, or aphthous ulcers were reported in the study. No clinically significant changes were noted in vital signs, physical examination results, or ECGs. One subject in the 30 mg cohort received only one dose of study drug and was discontinued after day 1 due to a positive TB test. This subject was included in the safety analysis set but not the efficacy analysis.

[0342] Pharmacokinetic Results: In this study, absorption of Compound 1 was generally rapid in cohorts 1-3 (5-30 mg once daily), with mean peak plasma concentrations observed at a median of 3-4 hours after dosing. At doses of 5 mg-30 mg, mean Cmax generally increased somewhat more than dose-proportionally under steady-state conditions (i.e., on day 28 of dosing), with Cmax increasing 8-fold with a 6-fold increase in dose. Similarly, observed exposures over time, AUC0-tau, increased more than dose-proportionally, with AUC0-tau increasing 11-fold with a 6-fold increase in dose. Due to the small sample size and the large intersubject variability observed in the study (CVs of 55-111% for Cmax and 47-269% for AUC0-tau), the poor dose-proportionality observed may not be of pharmacokinetic or pharmacological relevance. In this study, the accumulation rates observed between days 1 and 28 were consistent with those obtained in previous studies in healthy volunteers.

[0343] Risks: No important risks were identified from Study 101 in healthy volunteers or Study 102 in subjects with moderate to severe plaque psoriasis.

[0344] In comparison, a third-party clinical trial of Otezla® reported a mean PASI reduction of 37% at 4 weeks in a Phase 3 study of Otezla® at 30 mg twice daily in patients with moderate to severe psoriasis. No mean PASI reduction was reported with deuclavacitinib, and BMS did not conduct a Phase 1b study with deuclavacitinib. Compound 1 showed exploratory signals of clinical activity in our 4-week Phase 1b study, which we believe are consistent with the 4-week results of deuclavacitinib and guselkumab (an anti-IL-23 monoclonal antibody) in their Phase 2b studies. In those studies, clinical responses increased substantially from week 4 to week 12. At the dose range used in the Phase 3 studies of deuclavacitinib and guselkumab, responses increased 3-4 fold at 12 weeks compared to 4 weeks. Thus, we believe that in our ongoing Phase 2b study in moderate to severe psoriasis, we may see an increased clinical response rate with Compound 1 at 12 weeks, as measured by PASI score.

[0345] PD Marker Results: We believe that PD markers from skin punch biopsy specimens support an exploratory signal of clinical activity of compound 1 (consistent with the signal expected from an allosteric TYK2 inhibitor). Skin PD markers are assessed based on changes in epidermal thickness (via hematoxylin and eosin, or H&E staining) and the presence of type I keratin K16 hyperproliferation marker. K16 expression is upregulated in psoriasis and downregulated as psoriasis improves. As seen in Figure 6, compound 1 reduced epidermal thickness and eliminated K16 biomarker expression in patients across three dosing cohorts at 4 weeks (17 patients were evaluated).

[0346] As shown in Figure 7, 28 days of treatment reduced RNA expression levels of key cytokines and the psoriasis gene signature in lesional skin. Methods: mRNA from skin biopsy specimens was isolated and assessed for targeted gene expression (RT-PCR) or global gene expression (microarray). Microarray analysis assessed differential gene expression between baseline lesional and non-lesional samples (psoriasis transcriptome, PSTR) and between baseline lesional and day 28 lesional samples (compound 1 response). The gene set that was significantly differentially expressed (FC≧2, p-value<0.05) between lesional and non-lesional baseline skin biopsy specimens (PSTR) showed significant overlap with several published datasets of genes that were differentially expressed between psoriasis lesional and non-lesional skin. Results: Quantification of mRNA from skin biopsy specimens suggested decreased expression of several psoriasis-associated genes (e.g., KRT16, IL17A, IL17F, and IL22) by RT-PCR and up to 50% improved expression of the skin transcriptome (p<0.001 vs. placebo treatment) in lesional skin, previously associated with psoriasis, through microarray analysis. These results support further development of Compound 1 in psoriasis. Significant improvements were seen after 28 days of treatment with Compound 1 at all doses in genes that were up- or down-regulated in published psoriasis skin datasets. Numbers in parentheses are (number of Nimbus PSTR probe sets overlapping with the indicated dataset / total number of probe sets in dataset). Improvement is assessed as the mean percent change (± standard error) in expression of overlapping probe sets relative to baseline non-lesional expression (***p<0.001 comparing treatment group with placebo).

[0347] Example 3: Phase 1 Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Study of Compound 1 in Healthy Volunteers (Study 104) overview Rationale: In a previous study (Study 101), two cohorts of healthy participants received Compound 1 at doses of 20 mg or 35 mg daily for 2 weeks. Treatment was generally safe and well tolerated, with no serious or severe adverse events reported. The study was designed to continue dose escalation in healthy participants to define a relatively broad dose range to help select doses for future studies in patients with psoriasis and other autoimmune diseases. Nonclinical pharmacology, toxicology, and pharmacokinetic (PK) studies, as well as previous clinical data, support the proposal to study multiple doses of Compound 1 in healthy participants. [Table 2]

[0348] Overall Design This study was a Phase 1, randomized, double-blind, placebo-controlled, multiple-dose study of Compound 1 in healthy participants.

[0349] The study population consisted of healthy male and / or non-childbearing female participants aged 18-65 years. There were two multiple-dose cohorts (Cohort 1 and Cohort 2) of eight healthy participants who received a daily dose of Compound 1 (N=6) or placebo (N=2) for 2 weeks. Study participants were admitted to the CRU on day -1. Participants remained confined to the CRU until all scheduled procedures were completed, until day 22, after which they were discharged if medically appropriate. Safety testing, blood sampling for PK, blood sampling for PD, and adverse event assessments were performed according to the Schedule of Activities (SoA).

[0350] Cohort 2 was not enrolled until the PI and sponsor determined that adequate safety and tolerability had been demonstrated in Cohort 1.

[0351] Patients were asked about possible COVID-19 exposure / symptoms, and PCR testing for COVID-19 was performed at the screening visit and on day -1, with samples sent to a central laboratory. Patients with a positive PCR test at screening or on day -1 were considered screen-ineligible. Participants who developed symptoms consistent with COVID-19 infection after dosing were subjected to PCR testing and, if the result was positive, were removed from the study. This was recorded as an adverse event. Disclosure Statement: This is a two-cohort, group sequential, interventional study that is blinded to sponsors, participants, and investigators.

[0352] Number of participants: There were approximately 16 participants randomized to the intervention study and 16 evaluable participants (8 per cohort).

[0353] Intervention group and duration: Sixteen participants will receive either the active study drug or a placebo at the doses defined below. [Table 3]

[0354] The screening period was approximately 28 days. Participants were confined to the CRU from day -1 to day 22. Treatment was administered daily for 14 days, and a safety follow-up visit was scheduled before discharge from the CRU on day 22. Total duration of study participation was approximately 50 days.

[0355] Stopping Rules for Dose Escalation The decision to progress from Cohort 1 to the next higher dose in Cohort 2 was made jointly by the sponsor and PI following consideration of all valid blinded safety / tolerability data (e.g., AEs, clinical laboratory results, physical examination results, vital signs, and safety ECGs) through Day 15, as well as PK data, for at least 6 participants in Cohort 1. Together, the sponsor and PI decided whether to continue the study as planned, to continue the study with additional safety evaluations, to continue the study at a dose different from that planned for Cohort 2, or to discontinue dose escalation.

[0356] Dose escalation was stopped if at least two participants in a cohort met any of the following criteria attributable to study drug: -Drug-related SAE Drug-related grade 3 or higher toxicity

[0357] Dose escalation was stopped if even one participant at a given dose level met any of the following criteria attributable to study drug: 1. There is evidence of drug-induced liver injury (DILI)

[0358] If evidence suggestive of treatment-related SAEs, grade ≥3 AEs, and / or DILI was observed, PK samples were collected and the sponsor notified. At the discretion of the PI, the corresponding participant's treatment assignment may be unblinded to determine if the event was related to Compound 1 and met the discontinuation criteria. Any unblinding of participants to treatment was documented.

[0359] Where applicable, full written reasons for study termination were provided to the IRB. The study was monitored by the study team.

[0360] Rationale for Dosage Compound 1 has previously been investigated in the first human study (Study 101) in healthy volunteers at single and two repeat dose levels (SAD and MD). Single doses of 5 mg to 200 mg and multiple doses of 20 mg or 35 mg daily for 2 weeks were generally safe and well tolerated. No serious or severe AEs or AEs leading to treatment discontinuation were observed. The most common adverse effect was in the form of skin rash, i.e., acneiform dermatitis, observed in 7 of 17 subjects (41%) receiving a single dose of 100 mg or more and in 8 of 12 subjects (67%) receiving repeat doses. Although these events were common, all were mild in intensity, resolved within 1-2 weeks, even in the repeat dose group, and required limited or no intervention or discontinuation of treatment.

[0361] In single dose cohorts using the TPGS formulation, overall exposure to Compound 1 increased approximately dose-proportionally from 5 mg to 75 mg and at less than dose-proportional levels from 100 mg to 200 mg. Overall, exposure was similar following single doses of Compound 1 in either the TPGS or SDD formulations. Similar oral exposures were observed whether Compound 1 was administered in the fed or fasted state using the SDD formulation.

[0362] In the repeated dose cohorts using the TPGS formulation, moderate accumulation of Compound 1 was observed at the 20 mg and 35 mg daily dose levels, with no significant difference in C max and AUC 0-tau At steady state, the accumulation ratio was less than 3 for both treatments. max was approximately 207 ng / mL, and AUC last was approximately 3160hr*ng / mL. When 35 mg was administered daily for 2 weeks, the corresponding C max The value is approximately 325 ng / mL, and the AUC lastThe AUC exposure level achieved at the higher dose tested, i.e., 35 mg, was approximately 8-9 times lower than the NOAEL determined in 28-day repeated-dose toxicity studies in monkeys and rats, respectively.

[0363] The study investigated two additional repeat doses to expand the range of doses tested: 50 mg in cohort 1 and up to 100 mg in cohort 2. The SDD formulation was used in this study. The predicted exposure levels after 2 weeks of daily administration of 50 mg and 100 mg doses are expected to be approximately 7-8 (50 mg) and 3-4 (100 mg) lower than the NOAEL determined in 28-day repeat dose toxicity studies in monkeys and rats, respectively.

[0364] Nonclinical pharmacology, toxicology and pharmacokinetic (PK) studies, historical clinical data, and modeling data from 50 mg and 100 mg doses support the proposed study of multiple doses of Compound 1 in healthy participants, with 50 mg as the initial dose tested.

[0365] Check-in Procedure (Day -1) All participants returned to the CRU in the morning of Day -1. Inclusion and exclusion criteria were reviewed to ensure participants continued to meet all entry criteria. A second COVID-19 PCR test was also performed and samples were sent to a central laboratory. After the PCR test was performed, participants remained in an isolation area until test results were known later that day. Participants who did not meet all inclusion criteria or met any of the exclusion criteria (including a positive COVID-19 test) on Day -1 were considered screen-ineligible.

[0366] Other participants who met the entry criteria at screening also returned to the CRU to complete day -1 activities. If these other participants were not randomized because the target number of participants per cohort had been met, they were still eligible for subsequent cohorts. If these other participants enrolled in the study the day after their initial day -1 assessment, they did not need to repeat the day -1 testing.

[0367] Treatment and monitoring period Pre-treatment assessment results were obtained in the morning of Day 1. Once all baseline assessments were completed, participants were randomized.

[0368] Participants received Compound 1 or placebo in a blinded manner, administered orally in the morning on day 1 and daily thereafter for a total of 14 days. Safety and tolerability were assessed through monitoring during the treatment period, including vital signs, clinical laboratory tests, 12-lead ECG, and AEs. Blood samples for PK and PD assessments, and urine samples for metabolite profiling, were collected at the time points listed. Cardiodynamic monitoring was also performed.

[0369] Safety Follow-up Visits / Early Discontinuation A safety follow-up visit was performed on day 22 prior to discharge.

[0370] Safety and tolerability were assessed through monitoring including vital signs, clinical specimen tests, 12-lead ECG, and AEs.

[0371] In the event of early discontinuation, the procedures listed in the SoA for the safety follow-up visit must be followed; however, blood samples for PK assessment were also collected. After the early discontinuation visit, the participant must return to the site for the safety follow-up visit within 7 days of the last dose of study drug.

[0372] Meal Schedule On day -1, meals and / or snacks were provided ad libitum.

[0373] Participants were required to fast overnight for at least 8 hours before receiving study medication, and then continuously fast for at least 4 hours on the first day only.

[0374] Water (except for water provided with dosing) was restricted from 1 hour before until 1 hour after dosing, but was available ad libitum at all other times. Other fluids were allowed as part of standard meals and / or snacks, but were restricted at all other times throughout the entire restraint period.

[0375] Duration of detention Participants were held at the CRU for 22 days.

[0376] Inclusion criteria Participants were eligible for inclusion in the study only if they met all of the following criteria: age 1. Participants must be between 18 and 65 years of age (inclusive) at the time of signing the informed consent. Participant types and disease characteristics 2. Participants who are medically healthy volunteers, as deemed by the PI, with no clinically significant medical history, physical examination results, specimen profile, vital signs, or ECG at Screening and Day -1. All specimen test results must be generally within normal ranges as defined by the CRU laboratory. 3. Non-smoker (defined as an individual who has not used any nicotine-containing products, including cigarettes and e-cigarettes, for at least 3 months prior to dosing) body weight 4. Body mass index (BMI) between 18 and 35 kg / m at screening and clinic admission. 2 In the range (inclusive) sex 5. Men or women of non-childbearing potential. Male participants and their female partners must use two methods of contraception during the study: one method considered highly effective (failure rate <1% per year) as defined in the CTFG guidelines (CTFG 2014) and one barrier method when engaging in sexual intercourse. After receiving the last dose, male participants and their partners must continue to use contraception and abstain from sperm donation for 90 days. Female participants must be either surgically infertile or menopausal (confirmed by FSH testing) at least 6 months prior to screening. Informed consent 6. Able to provide signed informed consent, including compliance with the requirements and limitations listed in the Informed Consent Document (ICF) and this protocol.

[0377] Exclusion criteria Participants were excluded from the study if they met any of the following criteria: Condition 1. Any acute or chronic medical condition, including laboratory abnormalities (>Grade 1) or electrocardiogram (ECG) abnormalities, or psychiatric illness that would prevent the participant from signing the informed consent document, place the participant at unacceptable risk if they were to participate in the study, or confound their ability to interpret data derived from the study. Participants with evidence of mild active infection (e.g., upper respiratory, urinary tract, gastrointestinal infection) at screening may return for rescreening after full resolution of symptoms and completion of an appropriate course of treatment. 2. Female participants of childbearing potential 3. Hepatitis B, Hepatitis C, or human immunodeficiency virus seropositivity (HBsAg positive, HCV Ab positive, or HIV Ab positive) 4. Have a positive PCR test for COVID-19 at screening or at the Day -1 visit, or have been suspected of having COVID-19 infection within 10 days of the screening visit, or have had previous contact with another person diagnosed with or under investigation for COVID-19 within 10 days of screening. However, subjects in Cohort 1 who test positive for COVID-19 during screening may be rescreened for Cohort 2 after completing an appropriate quarantine period per CDC guidelines. Subjects with previous COVID-19 infection (based on clinical symptoms or clinical specimen testing), who have recovered from symptoms, test negative for COVID-19 antigen by PCR, and have no residual symptoms may be screened for study inclusion if deemed appropriate by the PI. 5. Participant with any surgical or medical condition that may affect the absorption, distribution, metabolism, or excretion of study drug 6. Blood pressure <90 / 40mmHg or >140 / 90mmHg at screening 7. Heart rate <40 bpm or >99 bpm at screening 8. QTcF (Fridericia corrected) interval >450 msec for men and >470 msec for women at screening, or a history of long QT syndrome 9.Has had a blood transfusion (including whole blood, platelets, or plasma) or significant blood loss within 56 days prior to dosing, or is scheduled for a blood transfusion within 30 days of the last study drug dose 10. Inability to tolerate oral administration 11. History of solid or hematological malignancies (including premalignant conditions, e.g., myelodysplastic syndrome or lymphoproliferative disorder) within the past 5 years (excluding past history of localized basal or squamous cell carcinoma of the skin that has been surgically removed with no evidence of recurrence, successfully treated ductal carcinoma in situ, and successfully treated carcinoma in situ) Previous / concomitant medications, supplements, or procedures 12.Participants who have received any vaccine, including COVID-19, within 28 days of administration. 13. Participant has used a systemic prescription medication within 30 days of dosing (or within 5 half-lives of dosing with concomitant therapy, whichever is longer) or has used an over-the-counter medication, herbal medicine, vitamin supplement, or topical medication within 14 days of dosing. Self-limited use of medications (e.g., Tylenol) may be considered an exception if approved by the PI and sponsor. 14.Participants who are scheduled to undergo elective medical procedures during the study. 15. Participants who are involved in recreational drug use or have a positive drug screen test at screening 16. Participants who test positive for cotinine Previous / contemporary clinical trial experience 17.Participant who has received an investigational or approved drug in a clinical trial setting or is currently enrolled in a clinical trial within 30 days or 5 half-lives (whichever is longer) of receiving the study drug, or within 6 months of receiving the study drug if the study drug is a biologic (e.g., antibody). Diagnostic evaluation 18.Participant with any other criteria (e.g., clinically significant screening blood test results) that, in the PI's opinion, may interfere with the conduct or outcome of the study. Other Exclusion Criteria 19. Participant with any known hypersensitivity to any of the excipients contained in the study drug or placebo preparation 20. Alcohol consumption within 14 days of randomization

[0378] Lifestyle Considerations Restrictions on diet, substance use, and activity levels were required during study participation, as outlined in the sections below.

[0379] Meals and dietary restrictions Participants are prohibited from consuming grapefruit or grapefruit juice for 14 days prior to dosing, throughout the entire treatment period, and throughout the PK sample collection period.

[0380] Limitations on caffeine, alcohol, tobacco, and cannabis As indicated, consumption of foods and beverages containing the following substances was prohibited:

[0381] Participants must not consume products containing xanthines or caffeine from 48 hours prior to dosing through the entire PK sampling period.

[0382] Participants must not consume alcohol or alcohol-containing products within 14 days of dosing or as described for concomitant medication use. Cold medicines and other medications containing small amounts of alcohol are permitted if deemed necessary by the PI.

[0383] Participants must not use tobacco or nicotine products (including smokeless tobacco, nicotine patches, or nicotine gum) while at the clinical site and must abstain from use of such products during the study screening period.

[0384] Participants must not use recreational drugs, including cannabis products (in any form, including oral or sublingual), while at the clinical site. Participants must also abstain from recreational drug use during the study screening period.

[0385] activity Participants must limit physical activity to a level sufficient to perform activities of daily living (e.g., eating, bathing, dressing) from 48 hours prior to dosing until the safety follow-up visit. No moderate or vigorous activity (e.g., doubles tennis, 3-5k running, marathon training / running, CrossFit training, or weightlifting) is permitted during this time. [Table 4]

[0386] Safety assessment The primary objective of this study was to evaluate the safety and tolerability of Compound 1. Safety was determined by evaluating physical examinations, vital signs, ECGs, clinical laboratory parameters, and AEs.

[0387] Additional safety measurements were performed at the discretion of the PI if deemed necessary. The Sponsor Medical Monitor was consulted throughout the study regarding any potential safety issues.

[0388] Physical Examination Results Height (in centimeters) and weight (in kilograms) were measured.

[0389] Physical examination findings included, at a minimum, evaluation of the circulatory, respiratory, gastrointestinal, musculoskeletal, and neurological systems. Height (at screening only) and weight were also measured and recorded. BMI was calculated at screening and clinic admission only. A licensed physician or qualified trustee examined each participant. Physical examinations may be performed at various unscheduled time points if deemed necessary by the PI.

[0390] Any abnormal findings during the screening period were recorded in the medical history.

[0391] The PI or eligible fiduciary must be alert for clinical signs related to pre-existing conditions.

[0392] Vital signs Vital signs were measured with participants in the supine position after 5 minutes of rest without distractions (e.g., television, cell phone). If the safety ECG coincided with the designated time point for drawing the hemodynamic ECG, vital signs were obtained after at least 10 minutes of rest. Vitals included measurements of temperature (oral or tympanic), systolic and diastolic blood pressure, heart rate, and respiratory rate.

[0393] Blood pressure and heart rate measurements were assessed with automated equipment. Manual techniques were used only when automated equipment was not available. Blood pressure and heart rate were read three times. Participants' eligibility at screening was determined using the average of the three readings.

[0394] Vital signs will be measured on day -1. Blood pressure and heart rate will have to be recorded with three readings taken. Eligibility will have to be confirmed using the average of the three readings.

[0395] On Days 1 and 2, vital signs must be obtained within 30 minutes pre-dose. Post-dose vital signs must be obtained within 30 minutes at the times specified on the Schedule of Activities (i.e., 2, 4, 8, and 24 hours after dosing).

[0396] Vitals will also be measured on the last day of study drug administration and at safety follow-up visits (see SoA). Blood pressure and heart rate should be recorded in triplicate readings.

[0397] If the PI deems it necessary, additional measurements must be performed.

[0398] electro-cardiogram At the time of study administration, ECGs were obtained and classified as safety ECGs or hemodynamic ECGs.

[0399] Standard 12-lead ECG (safety ECG) A 12-lead ECG was recorded. ECG timing and recording technique were standardized for all participants. All safety ECGs after study drug administration on Day 1 were obtained and recorded in triplicate.

[0400] Holter monitoring (cardiodynamic ECG) ECG timing and recording technique were standardized for all participants involved in hemodynamic monitoring. Continuous 12-lead ECG data was collected by Holter monitoring from 2 hours pre-dose to 24 hours post-dose on days 1 and 14. During this period, ECG extraction was performed by a third-party vendor using data from the Holter monitor at fixed time points (except pre-dose, where hemodynamic monitoring required three independent pre-dose measurements 60, 45, and 30 minutes prior to dosing) that were generally combined with PK blood sampling.

[0401] Laboratory evaluation of clinical safety Laboratory evaluation of clinical safety was performed as summarized above.

[0402] The PI or qualified individual must review the laboratory reports, document this review, and note any clinically meaningful changes that occur during the study.

[0403] Any clinical specimen test that results in a value considered to be clinically significantly abnormal during participation in the study must be repeated until the value returns to the participant's baseline or is no longer considered clinically significant to the PI.

[0404] If such values ​​do not return to normal / baseline within a time period deemed appropriate by the PI, the etiology should be investigated and the sponsor notified.

[0405] Non-protocol-defined laboratory evaluation results that require a change in participant management or that the PI considers to be clinically significant (eg, constitute an AE) must also be recorded on the CRF.

[0406] Drug-induced liver injury (DILI) Events that meet the definition of drug-induced liver injury (DILI): Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 times the ULN and total bilirubin (TBL) > 2 times the ULN in the presence of normal alkaline phosphatase (ALP) require prompt intensified monitoring (of all liver tests, at a minimum, ALT, AST, ALP, and TBL, and prothrombin time (PT) / INR) and evaluation for the cause of the liver test abnormalities (FDA 2009). ALT or AST >3x ULN, accompanied by fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and / or eosinophilia (>5%) (FDA 2009)

[0407] The medical monitor should be contacted promptly. Additional medical management considerations (for the given participant and possibly extended to the wider cohort) should be discussed while the evaluation is ongoing.

[0408] Adverse events of particular note listed below must be reported promptly to the Sponsor, and the PI must notify the Sponsor within 24 hours of becoming aware of any of the following events: Cytopenia > Grade 2 - Platelets less than 75,000 / mm3 - WBC less than 3000 / mm3 Neutrophil count less than 1500 / mm3 Lymphocyte count <800 / mm3 Hemoglobin less than 10g / dL Creatine phosphokinase (CPK) elevated >Grade 3 [>5x ULN]

[0409] Pharmacokinetic measurements Approximately 5 mL blood samples were collected for measurement of plasma concentrations of Compound 1 and its metabolites.

[0410] The actual date and time (24 hour clock) for each sample was recorded.

[0411] Samples were used to evaluate the PK of Compound 1. Each sample was split into two aliquots, one for PK and one for backup. Samples collected for plasma concentration analysis may be used to evaluate metabolite formation or safety aspects related to concerns raised during or after the study.

[0412] Pharmacokinetic blood samples were collected as follows. [Table 5]

[0413] Urine samples were collected from all Cohort 2 participants pre-dose on Day 1 and on Day 14 as follows: [Table 6]

[0414] Drug potency As a measure of the pharmacodynamic response to treatment with Compound 1, approximately 1 mL whole blood samples were collected directly from selected time points into provided TruCulture (Myriad RBM) whole blood assay collection tubes. Collection occurred within a time window of ±30 minutes from the designated time point. These samples were incubated ex-vivo in the CRU at 37° C. for approximately 24 hours, and appropriate immunoassays were used to quantitate the levels of IFNγ produced in response to stimulation with cytokines derived from the cell supernatants.

[0415] Example 4: Phase 2b Study in Subjects with Psoriasis Vulgaris The study was conducted according to Figure 1. Approximately 250 subjects will be randomized in the study (approximately 50 subjects / arm). The maximum study duration per subject will be approximately 20 weeks, including a screening period of up to 30 days, a treatment period of 12 weeks, and a safety follow-up period of 4 weeks. Compound 1 at doses of 2 mg, 5 mg, 15 mg, or 30 mg, or placebo will be administered orally once daily (QD) for 12 weeks. Compound 1 is available in capsules in strengths of 2 mg, 5 mg, and 15 mg. The corresponding placebo is equivalent to Compound 1 but does not contain the active ingredient. Subjects will be randomized in a 1:1:1:1:1:1 ratio. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0416] The main objectives are to: To evaluate the efficacy of Compound 1 administered orally at 2 mg, 5 mg, 15 mg, or 30 mg QD for 12 weeks in subjects with moderate to severe plaque psoriasis The secondary objectives are as follows: To evaluate the safety and tolerability of Compound 1 administered orally at 2 mg, 5 mg, 15 mg, or 30 mg QD for 12 weeks in subjects with moderate to severe plaque psoriasis To evaluate plasma concentrations of Compound 1 administered orally at 2 mg, 5 mg, 15 mg, or 30 mg QD in subjects with moderate to severe plaque psoriasis The exploratory goals are: To evaluate the effect of Compound 1 on joint pain in subjects with moderate to severe plaque psoriasis and concomitant psoriatic arthritis To evaluate the effects of Compound 1 on cytokines and other inflammatory biomarkers in the blood of subjects with moderate to severe plaque psoriasis

[0417] Evaluation items: Primary efficacy endpoints: Proportion of subjects achieving at least a 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI-75) at Week 12 Secondary Efficacy Endpoints: Percentage of subjects with a Physician's Global Assessment (PGA) of none (0) or almost none (1) at Week 12 Proportion of subjects achieving at least a 90% improvement from baseline in the Psoriasis Area and Severity Index (PASI-90) at Week 12 Percentage of subjects achieving a 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI-100) at Week 12 Change from baseline in Dermatology Life Quality Index (DLQI) at week 12 Exploratory efficacy endpoints: Percentage of subjects achieving at least a 50% improvement from baseline in the Psoriasis Area and Severity Index (PASI-50) at weeks 2, 4, 8, and 12 Percentage of subjects achieving PASI-75 at weeks 2, 4, and 8 Percentage of subjects achieving PASI-90 at weeks 2, 4, and 8 Percentage of subjects achieving PASI-100 at weeks 2, 4, and 8 Changes from baseline in Psoriasis Area and Severity Index (PASI) at weeks 2, 4, 8, and 12 Percentage change from baseline in PASI at weeks 2, 4, 8, and 12 Change from baseline in PGA at weeks 2, 4, 8, and 12 Percentage of subjects with a PGA of none (0) or almost none (1) at weeks 2, 4, and 8 Percentage of subjects who achieved a PGA decline of at least 2 grades from baseline at weeks 2, 4, 8, and 12 Changes from baseline in Body Surface Area (BSA) at weeks 2, 4, 8, and 12 Change from baseline in pruritus numerical rating scale (NRS) at weeks 2, 4, 8, and 12 The proportion of subjects with a baseline pruritus NRS score of 4 or greater who achieved a reduction in the pruritus NRS score of at least 4 points from baseline at weeks 2, 4, 8, and 12 Change from baseline in Dermatology Life Quality Index (DLQI) at weeks 4 and 8 Change from baseline in pain NRS at weeks 2, 4, 8, and 12 in subjects with concomitant psoriatic arthritis Secondary safety endpoints: Incidence of adverse events (AEs) Changes in vital signs, clinical laboratory parameters, and electrocardiogram (ECG) Secondary Pharmacokinetic (PK) Endpoints: 1. Measurement of Plasma Concentrations of Compound 1 in Actively Treated Subjects Exploratory pharmacodynamic (PD) endpoints: 2. Quantification of skin biomarkers (immune cell infiltration levels and mRNA expression levels) in lesional and non-lesional skin 3. Quantification of circulating cytokines and other inflammatory biomarkers

[0418] Study Design: This is a Phase 2b randomized, multicenter, double-blind, placebo-controlled, repeated-dose study designed to evaluate the efficacy, safety, and tolerability of Compound 1 in subjects with moderate to severe plaque psoriasis. The study will evaluate plasma concentrations of Compound 1 and explore immune responses to Compound 1 (in blood and skin) in subjects with moderate to severe plaque psoriasis. The study will randomize approximately 250 male and female subjects aged 18-70 years (inclusive) with moderate to severe plaque psoriasis. To be eligible for the study, subjects must have a history of plaque psoriasis for at least 6 months prior to the screening visit. In addition, subjects must have the following characteristics at screening and on day 1: PASI score of at least 12, PGA score of at least 3, and BSA associated with plaque psoriasis of at least 10%.

[0419] All subjects will read and sign an informed consent document (ICF) before undergoing any screening procedures. Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be included in the study. During the screening period from day -30 onwards to day -1, subjects will be randomized (day -7) to receive either compound 1 at one of four doses (2 mg, 5 mg, 15 mg, or 30 mg) or placebo on day 1. The goal is to randomize approximately 50 subjects per treatment group on day 1 (1:1:1:1:1 ratio). During the treatment period, compound 1 (2 mg, 5 mg, 15 mg, or 30 mg) or placebo will be administered orally QD for 12 weeks. The 12-week treatment period will be followed by a 4-week safety follow-up period. During scheduled study visits, subjects will visit the study site eight times: at screening, day 1, and at weeks 1, 2, 4, 8, 12 (end of treatment [EOT]), and 16 (end of study [EOS] / early withdrawal visit [ET]). Efficacy will be assessed in subjects with concomitant psoriatic arthritis using the PASI, PGA, BSA associated with psoriasis vulgaris, NRS for pruritus, and NRS for pain. Quality of life will be assessed using the DLQI. Safety will be assessed by collecting AEs, recording vital signs, performing physical examinations, and evaluating clinical laboratory and ECG results.

[0420] Blood samples are taken to measure plasma levels of Compound 1 as described below. Before administration and 1 hour (± 5 minutes) after administration on Day 1 - Before administration, 1 hour (± 5 minutes) after administration, and 4 hours (± 10 minutes) after administration in the fourth week Before Week 8 administration Any time during Week 12 (no study drug will be administered at this visit) Any time during the ET visit (if the ET visit is scheduled before the 12-week visit)

[0421] Urine samples may be collected on day 1 and at weeks 4, 12, and 16 to assess the effect of Compound 1 on exploratory biomarkers. Blood samples may be collected on day 1 and at weeks 4 and 12 to assess the effect of Compound 1 on circulating inflammatory biomarkers. In a subset of subjects who consent to the procedure, the effect of Compound 1 on skin biomarkers is assessed by collecting three or four random skin biopsies. Two 5mm punch biopsies (one from the lesion and one from adjacent non-lesional skin) are collected on day 1, and one 5mm punch biopsy is collected from the same lesioned skin (outside the scar from the previous biopsy and at least 1 cm away from the previous scar, even if the lesion has disappeared) at week 12. In addition, in subjects who consent to four skin biopsies, one 5mm punch biopsy is collected from the same lesioned skin (outside the scar from the previous biopsy and at least 1 cm away from the previous scar) at week 4. A photograph of the biopsy area is taken.

[0422] In a subset of subjects who consent to the procedure, the effect of Compound 1 on skin biomarkers will be evaluated by taking tape strips. Skin tape strips will be taken from lesional and adjacent non-lesional skin on day 1 and from the same lesional skin at week 12. Optional medical photographs of the whole body, front and back will be taken in a subset of consenting subjects at specific study sites to demonstrate the results of the study.

[0423] Inclusion / Exclusion Criteria: To be eligible to participate in this study, subjects must meet all of the following criteria at both Screening and Day 1 visits, or at only one of the given visits (Screening or Day 1), as described in the criteria. Male or female subjects aged 18-70 years (inclusive) at the time of consent Subjects must have a history of plaque psoriasis at least 6 months prior to the screening visit Subjects have had no significant psoriasis flares for at least 3 months prior to screening (information obtained from medical records, subject's physician, or directly from subject) Subjects have moderate to severe plaque psoriasis as defined by a PASI score of at least 12 and a PGA score of at least 3 at screening and day 1. Subjects have plaque psoriasis covering 10% of their total BSA at screening and day 1 Subjects must be candidates for phototherapy or systemic therapy Female subjects of childbearing potential who have engaged in any sexual intercourse that could result in conception: Subjects must agree to use highly effective methods of contraception from at least 4 weeks prior to Day 1 through at least 4 weeks after the last dose of study product. Highly effective methods of contraception include hormonal contraception (e.g., combination oral contraceptives, patch, vaginal ring, injection, or implant), intrauterine device or system, vasectomized partner(s) (indicated vasectomy was performed at least 4 months prior to screening), bilateral tubal ligation or bilateral tubal occlusion, or dual barrier contraception in conjunction with spermicide (e.g., male condom and cervical cap, male condom and diaphragm, and male condom and contraceptive sponge). Note: Subjects must have been taking hormonal contraception continuously for at least 4 weeks prior to Day 1. Note: The above listed contraceptive methods do not apply to subjects who have abstained for at least 4 weeks prior to Day 1 and intend to continue abstaining from penile-vaginal intercourse throughout the study. The reliability of abstinence must be evaluated with respect to the duration of the clinical trial and the subject's preferred and usual lifestyle. Intermittent abstinence (calendar, symptom-temperature, postovulatory) will not be permitted. Note: Female subjects of non-childbearing potential are defined as follows: -Women who have undergone sterilization surgery (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) - Female subjects who have ceased menstruation without alternative medical causes for at least 12 months prior to the screening visit and have a follicle-stimulating hormone (FSH) test result (reference range for confirmatory levels) confirming that pregnancy is not possible Female subjects of childbearing potential had a negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1. For male subjects who engage in any sexual intercourse that may result in conception, the subject must agree to use one of the highly effective methods of contraception listed in Inclusion Criteria 6 from Day 1 until at least 12 weeks after the last dose of study product. If the female partner of a male subject uses one of the hormonal contraceptive methods listed above, the female partner must use this method of contraception from at least 4 weeks prior to Day 1 until at least 12 weeks after the last dose of study product. NOTE: Male subjects must refrain from sperm donation from Day 1 until at least 12 weeks after the last dose of study product. Note: No restrictions are required for male subjects who have had a documented vasectomy at least 4 months prior to screening. If a vasectomy is not documented or occurred less than 4 months prior to screening, the male subject must follow the same contraception and sperm donation requirements as non-vasectomized subjects. Subjects' body mass index (BMI) is 18-38 kg / m 2 (BMI = weight [kg] / [height (m)]) 2 ), with a total weight of over 50 kg (110 lb). Subjects are willing to participate and able to provide informed consent. Note: Consent must be obtained prior to any study-related procedures. ·Subject must be willing and able to comply with all study procedures for the duration of the study.

[0424] Exclusion Criteria: Subjects meeting any of the following criteria at the screening and / or Day 1 visit, as applicable, will be excluded from participation in this study. 1. Subjects are females who are lactating, pregnant, or planning to become pregnant during the study. 2. Subjects have evidence of erythrodermic psoriasis, pustular psoriasis, predominantly guttate psoriasis, or drug-induced psoriasis. 3. Subject has a history of skin disease or has a skin condition that the Investigator believes would interfere with study evaluation. 4. Subject has an immune-mediated condition commonly associated with psoriasis, e.g., psoriatic arthritis, uveitis, inflammatory bowel disease, that requires systemic treatment (including corticosteroids, immunosuppressants, or biologics). NOTE: Subjects with immune-mediated conditions that do not require systemic treatment may be enrolled in the study. Specific therapies such as NSAIDs may be permitted but should be discussed with the medical monitor before determining the subject's eligibility. 5. Subject has any clinically significant medical condition, evidence of unstable clinical condition (e.g., cardiovascular, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic, or local active infection / infection), mental status, or abnormal vital signs / physical abnormalities / abnormal laboratory values / abnormal ECG that the Investigator believes would place the subject at undue risk or interfere with interpretation of study results. 6. Subject has had major surgery within 8 weeks prior to Day 1 or is scheduled to undergo major surgery during the study. 7. Subject has a history of Class III or Class IV congestive heart failure as defined by the New York Heart Association Criteria. 8. Subject has been hospitalized for asthma in the past 3 months, has ever required intubation for the treatment of asthma, currently requires oral corticosteroids for the treatment of asthma, or has required more than one short-term (≤2 weeks) course of oral corticosteroids for asthma within the 6 months prior to Day 1. 9. Subject has a history of cancer or lymphoproliferative disorder within 5 years prior to Day 1. Subjects who have been successfully treated for nonmetastatic cutaneous squamous cell or basal cell carcinoma and / or localized carcinoma in situ of the cervix will not be excluded. 10. Subject has a history of fever, inflammation, or systemic signs of illness suggestive of systemic or invasive infection within the 4 weeks prior to Day 1. 11. Subject has either an active bacterial, viral, fungal, mycobacterial, or other infection (including TB or atypical mycobacteriosis) requiring hospitalization or treatment with intravenous antibiotics within 12 weeks prior to Day 1 or treatment with oral antibiotics within 4 weeks prior to Day 1, or a major episode of infection. 12. Subject has a history of chronic or recurrent infections, including but not limited to, chronic kidney infections, chronic pulmonary infections, recurrent urinary tract infections, fungal infections (excluding superficial fungal infections of the nail bed), or infected skin wounds or ulcers. 13. Subject has a history of prosthetic joint infection or has received antibiotics for suspected prosthetic joint infection when the prosthesis has not been removed or replaced. 14. Subject has an active herpes infection within the 8 weeks prior to Day 1, including herpes simplex types 1 and 2, and varicella zoster (as documented by physical exam and / or medical history). 15. Subject has a history of known or suspected congenital or acquired immunodeficiency condition or condition that the Investigator believes may compromise the subject's immune status (e.g., splenectomy, history of primary immunodeficiency). 16. Subject has a positive result for antibodies to Hepatitis B surface antigen (HBsAg), Hepatitis B core antigen (anti-HBc), Hepatitis C virus (HCV), or Human Immunodeficiency Virus (HIV). 17. Subjects have clinical or laboratory evidence of active or latent tuberculosis (TB) infection at screening. Note: Subjects with a history of active or latent TB will not be enrolled in the study unless they can provide documentation of previous anti-TB treatment and completion of anti-TB treatment of appropriate duration and type according to current local country guidelines. Note: Subjects will be assessed for latent TB infection with the QuantiFERON-TB Gold (QFT) test at screening. Latent TB is defined as a positive QFT test or two consecutive indeterminate QFT tests at screening. 18.Subjects with any of the following laboratory values ​​at the screening visit: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥3 times the upper limit of normal (ULN) Hemoglobin level less than 11.0 g / dL (less than 110.0 g / L) White blood cell count 3.5×10 9 / L less than 3500 / mm 3 less than) Absolute neutrophil count 1.8×10 9 / L (less than 1800 / mm 3 less than) Absolute lymphocyte count is 1.0×10 9 / L (1000 / mm 3 less than) Platelet count is 100 x 10 9 / L (less than 100,000 / mm 3 less than) Total bilirubin >2x ULN 19.Subject has donated >50 mL of blood or plasma within 30 days of screening, or >500 mL of blood or plasma within 56 days of screening (during a clinical trial or while donating to a blood bank) 20. Subject has used any topical medication that may affect psoriasis (including corticosteroids, retinoids, vitamin D analogs [e.g., calcipotriol], JAK inhibitors, or tar) within the 2 weeks prior to Day 1. 21. Subject has used any systemic treatment that may be effective for psoriasis within the 4 weeks prior to Day 1, including oral, intravenous, intramuscular, or intralesional corticosteroids, oral retinoids, immunosuppressants / immunomodulators, methotrexate, cyclosporine, oral JAK inhibitors, or apremilast. Note: Intranasal and inhaled corticosteroids are allowed. Eye and ear drops containing corticosteroids are also allowed. 22. Subject has received any ultraviolet (UV)-B phototherapy (including tanning beds) or excimer laser within the 4 weeks prior to Day 1. 23. Subject has received treatment with psoralen and ultraviolet A (PUVA) within the 4 weeks prior to Day 1. 24. Subject has received any live attenuated vaccine within 4 weeks prior to Day 1 or is scheduled to receive a live attenuated vaccine during the study and up to 4 weeks after the last dose of the study product or 5 half-lives of the study product, whichever is longer. NOTE: Non-live attenuated vaccines against coronavirus disease 2019 (COVID-19) (e.g., RNA-based vaccines, adenovirus-based inactivated vaccines, protein-based vaccines) are permitted during the study. Study sites must follow local guidelines related to COVID-19. 25. Subject is currently using, or has been exposed to, a non-biologic investigational product or device within 4 weeks prior to Day 1. 26. Subject has received any marketed or investigational biologic agent within 12 weeks or 5 half-lives (whichever is longer) prior to Day 1 (except for those listed in Exclusion Criteria 27 and 28, which should be excluded for 6 months). 27. Subject was previously enrolled in any study with Compound 1. 28. Subject has a history of failure to respond to approved doses of any therapeutic agent targeting interleukin (IL)-12, IL-17, and / or IL-23 (e.g., ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, risankizumab) after at least 12 weeks of treatment and / or has received one of these therapeutic agents within 6 months prior to Day 1. 29. Subject has received rituximab or other immune cell depleting therapy within 6 months. 30. Subject is currently receiving treatment with a strong or moderate cytochrome P450 3A (CYP3A4) inhibitor (e.g., itraconazole) or has received a moderate or strong CYP3A4 inhibitor within 4 weeks prior to Day 1. 31. Subject is currently receiving treatment with terbinafine or has received terbinafine within the 4 weeks prior to Day 1. 32. Subject has consumed grapefruit within the week prior to Day 1. NOTE: Grapefruit consumption must be avoided throughout the treatment period and for at least 1 week after the last dose. 33. Subject has used a tanning booth or been overexposed to sunlight within the 4 weeks prior to Day 1, or does not intend to minimize exposure to natural and artificial sunlight during the study. Note: Use of sunscreen products and protective apparel is recommended when sun exposure cannot be avoided. 34. Subject has known or suspected allergy to Compound 1, or any component of the investigational product, or any other significant drug allergy (such as anaphylaxis or hepatotoxicity). 35. Subject has a known history of clinically significant abuse of drugs or alcohol in the past year prior to Day 1. 36. Only for subjects who consent to the collection of biopsy specimens: Subject has a history of allergic reactions or significant sensitivity to lidocaine or other local anesthetic agents. Subject has a history of hypertrophic scarring or keloid formation at the site of a scar or suture. Subjects have taken anticoagulants, e.g., heparin, low molecular weight (LMW) heparin, warfarin, or antiplatelet agents within the 2 weeks prior to Day 1 (except low dose aspirin up to 81 mg, which is permitted) or have a contraindication to skin biopsy. Nonsteroidal anti-inflammatory drugs are not considered antiplatelet agents and are permitted.

[0425] Categorical variables will be presented in tables as frequencies and percentages. Continuous variables will be summarized in tables and include numbers of subjects, mean, standard deviation (SD), median, lowest and highest values. Further details regarding the definition of efficacy and safety variables, analysis strategy, statistical rationale, and techniques for dealing with missing values ​​(if applicable) will be detailed in a separate Statistical Analysis Plan (SAP) that will be prepared prior to database lock and any analyses. Any deviation(s) from the SAP will be described and justified as appropriate in the final Clinical Study Report.

[0426] Unless otherwise specified in the SAP, all statistical tests are two-sided and performed at the 0.05 significance level. No alpha adjustments are made to account for multiple testing between treatment groups.

[0427] Efficacy analysis: The primary endpoint can be interpreted as a responder analysis, in which subjects are classified as responders if they achieve PASI-75 at week 12. Comparisons between groups for the primary endpoint will be performed using the Cochran-Mantel-Haenszel (CMH) method, and prior treatment with biologics will be included as a stratification factor. The primary efficacy analysis will be performed on the intent-to-treat (ITT) analysis set, while the per-protocol (PP) analysis set will be used as a sensitivity analysis.

[0428] Secondary endpoints of proportion of subjects will be analyzed on an intention-to-treat basis at each time point using the same approach as described for the primary efficacy analysis (CMH test). Continuous secondary endpoints of absolute change from baseline will be analyzed on the intention-to-treat analysis set only using a mixed-effects model for repeated measures (MMRM). The model includes treatment, visit, treatment x visit interaction, and prior biologic treatment (fixed effects), as well as baseline score (covariate).

[0429] Safety Analysis: All safety analyses will be performed using the Safety Analysis Set. No inferential statistics will be performed on safety variables. Adverse events and serious adverse events (SAEs) will be presented and tabulated according to the Medical Dictionary for Regulatory Affairs (MedDrA) classification by treatment group. AE description will include start date, end date (if resolved), severity and seriousness of the AE, causal relationship of the AE to the study article, actions taken with the study article, and outcome.

[0430] Reports of AEs will be summarized by the number of subjects in whom the event was reported, and by organ system class, preferred term, reported verbatim severity, seriousness, and investigator assessment of relationship to test article. For AE summaries by severity, count each subject only once within an organ system class or preferred term by using the AE with the highest intensity within each category in each analysis. For AE summaries by relationship to test article, count each subject only once within an organ system class or preferred term by using the AE with the highest reported relationship within each category. For AE summaries by relationship to test article and severity, count each subject only once within an organ system class or preferred term by using (1) the highest relationship reported, then (2) the highest intensity reported.

[0431] All information regarding AEs observed during the study will be listed by treatment group, subject, verbatim describing, organ system class, preferred term, start date, end date, strength, outcome, action taken with respect to the test article, and relationship to the test article. The occurrence of AEs will also be shown relative to the date of test article administration (in days). Serious adverse events will be tabulated by treatment group, relationship to test article, and reference date for occurrence of SAE relative to date of administration. Similar listings will be provided for SAEs and AEs that led to study discontinuation.

[0432] Vital signs, laboratory analyses, and ECG results will be tabulated by treatment group and visit using descriptive statistics. Observations at each visit and changes from baseline will be shown. For clinical laboratory results, tables showing changes into outlying normal ranges may be provided, and for vital signs, tables showing changes from normal to abnormal values ​​may be provided.

[0433] Concomitant medications will be coded according to the World Health Organization-Drug Dictionary (WHO-DD) and listed for each subject. A medication summary will also be tabulated.

[0434] Pharmacokinetic Analysis: Concentration data should be listed by subject and summarized descriptively by dose.

[0435] Pharmacodynamic Analysis: Analysis of urine, blood, and skin biomarker levels will be described in a separate analysis plan.

[0436] Other Analyses: A descriptive summary of subject disposition and baseline characteristics (including demographics and prior concomitant therapy) will be provided by treatment group. In addition, a list of subjects who discontinued the study will be provided along with reasons for discontinuation. Protocol deviations will be summarized by treatment and category.

[0437] Sample size considerations: Sample size determination is based on the quality of two independent response rate studies using two-sided testing at a significance level of alpha = 0.05 and 85% power. The formula used in the calculation is the same as that used in nQuery® (i.e., Fleiss's formula and normal approximation with continuity correction).

[0438] Assuming a 10% placebo response rate (proportion of subjects achieving PASI-75) at the end of week 12, the study will randomize a total of 250 subjects (50 per treatment group) to treatment groups receiving at least one dose of Compound 1, with a response rate of at least 40%, after adjusting for a 15% dropout rate. 50 subjects per treatment group will provide at least approximately 90% power to detect a difference in response rate in PASI-75 of at least 30% between any two treatment groups using a two-sample, one-sided Fisher's exact test with a significance level of 0.05.

[0439] Results: Baseline Characteristics: The demographic data of the study subjects and the baseline disease characteristics of the subjects are presented in the table below. [Table 8]

[0440] Results: The primary endpoint (PASI 75 response at week 12) was achieved with Compound 1 doses of 5 mg or higher. 68% of patients achieved PASI 75 at 15 mg QD and 67% achieved PASI 75 at 30 mg QD. Secondary endpoints were also achieved with Compound 1 doses of 5 mg or higher, with a greater proportion of patients achieving PASI 100 or PGA 0 at the highest dose of Compound 1, and 33% of patients achieved skin clearance at 30 mg QD. More detailed results of the primary endpoint (PASI 75 at week 12) in the modified Intent-to-Treat (mITT) analysis set are shown in the table below. Results are illustrated in Figure 13. A graph showing the percentage of patients achieving a PASI score of 75, 90, or 100 is shown in Figure 14. [Table 9]

[0441] Figure 15 shows the percentage of patients who achieved PGA0 / 1 at week 12. Both the percentage of PGA1 and PGA0 improved with increasing dose of Compound 1. The mean Dermatology Life Quality Index (DLQI) scores at baseline and 12 weeks for placebo and various dose levels of Compound 1 are shown in Figure 16A, and the change from baseline in DLQI at week 12 is shown in Figure 16B.

[0442] Safety results are summarized in the table below. [Table 10] [Table 11]

[0443] Figures 17A-17E show blood parameters and CPK data collected during the study. Data are mean ± standard deviation. Laboratory mean and change from baseline did not reveal any adverse trends in cell counts. CPK showed some variability at 15 mg and 30 mg with long error bars.

[0444] Figures 18A-18E show liver and renal parameters collected during the study. Data are mean ± standard deviation. Laboratory mean and changes from baseline did not reveal any adverse trends in liver enzymes, creatinine or eGFR.

[0445] Figures 19A-19E show lipid parameters collected during the study. Data are mean ± standard deviation. Laboratory mean and changes from baseline did not reveal adverse trends in cholesterol, HDL, or LDL. Triglycerides were minimally elevated.

[0446] Example 5: A Phase 2b Randomized, Multicenter, Double-Blind, Placebo-Controlled, Multiple-Dose Study to Evaluate the Efficacy, Safety, and Tolerability of Compound 1 in Subjects with Active Psoriatic Arthritis Test Site: Approximately 80 international trial sites across North America and Europe will participate in the study.

[0447] Number of subjects (planned): Approximately 260 subjects will be randomized in this study (approximately 65 subjects per arm).

[0448] Exam duration: The maximum study duration per subject is approximately 20 weeks, which includes up to a 30-day screening period, a 12-week treatment period, and a 4-week safety follow-up period.

[0449] Investigational product, dose, and method of administration: Compound 1 at doses of 5 mg, 15 mg, or 30 mg, or placebo, will be administered orally once daily (QD) for 12 weeks. Compound 1 is available in capsules in strengths of 5 mg and 15 mg. The corresponding placebo is equivalent to Compound 1 but does not contain the active ingredient.

[0450] Subjects will be randomized in a 1:1:1:1 ratio.

[0451] the goal: The main objectives are to: To evaluate the efficacy of Compound 1, administered orally at 5 mg, 15 mg, or 30 mg QD for 12 weeks, on rheumatic signs, symptoms, and function in subjects with active psoriatic arthritis (PsA).

[0452] The secondary objectives are as follows: To further evaluate the efficacy of Compound 1 administered orally at 5 mg, 15 mg, or 30 mg QD for 12 weeks in subjects with active PsA. To evaluate the safety and tolerability of Compound 1 administered orally at 5 mg, 15 mg, or 30 mg QD for 12 weeks in subjects with active PsA To evaluate plasma concentrations of Compound 1 administered orally at 5 mg, 15 mg, or 30 mg QD in subjects with active PsA

[0453] The exploratory goals are: To evaluate the effects of Compound 1 on cytokines and other inflammatory biomarkers in the blood of subjects with active PsA

[0454] Evaluation items: Primary efficacy endpoints: Percentage of subjects who achieved at least an American College of Rheumatology (ACR) 20 response at week 12

[0455] Secondary endpoints - Efficacy: Proportion of subjects achieving at least an ACR50 or ACR70 response at week 12 Change from baseline (Day 1) in tender joint counts at Week 12 Change from baseline (Day 1) in number of swollen joints at Week 12 Change from baseline (Day 1) in Patient Global Assessment of Psoriatic Arthritis at Week 12 Change from baseline (Day 1) in Patient Global Assessment of Psoriatic Arthritis Pain at Week 12 Change from baseline (Day 1) in Physician's Global Assessment of Psoriatic Arthritis at Week 12 Change from baseline (Day 1) in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores at Week 12 Change from baseline (Day 1) in dactylitis counts at Week 12 in subjects with dactylitis on Day 1 Change from baseline (Day 1) in Leed's Enthesitis Index at Week 12 in subjects with enthesitis on Day 1 Percentage of subjects with Minimal Disease Activity at Week 12 Change from baseline (Day 1) in Disease Activity Index for Psoriatic Arthritis at Week 12 The proportion of subjects who achieved a Psoriasis Area Severity Index (PASI) of -75 at Week 12 among subjects with psoriasis lesions of 3% or more of their Body Surface Area (BSA) on Day 1 Proportion of subjects with a static physician global assessment of 0 or 1 and at least a 2-point improvement from baseline at Week 12

[0456] Secondary endpoint - Safety: Incidence of adverse events (AEs), treatment-emergent AEs (TEAEs), treatment-emergent serious adverse events (TESAEs), and TESAEs leading to study drug discontinuation Assessment of clinically meaningful changes in vital signs, clinical laboratory parameters, proportion of subjects with clinically significant abnormal electrocardiograms (ECGs), and physical examination findings

[0457] Secondary endpoints - Pharmacokinetics: Measurement of plasma concentrations of Compound 1 in subjects administered 5 mg, 15 mg, or 30 mg of Compound 1

[0458] Exploratory endpoints: Quantification of circulating cytokines and other inflammatory biomarkers Change from baseline (Day 1) in the 36-Item Short Form Health Survey at Week 12 Change from baseline (Day 1) in Functional Assessment of Chronic Illness-Fatigue at Week 12 Changes from baseline (Day 1) in Disease Activity Score 28 and high-sensitivity C-reactive protein (hsCRP) at Week 12 Change from baseline (Day 1) in Psoriatic Disease Activity Score at Week 12 Change from baseline (Day 1) in Psoriatic Arthritis Response Criteria at Week 12 Percent change from baseline (Day 1) in PASI at Week 12 in subjects with ≥3% psoriatic BSA on Day 1 Change from baseline (Day 1) in BSA with psoriatic lesions at Week 12 in subjects who had ≥3% BSA with psoriatic lesions on Day 1 Change from baseline (Day 1) in Physician's Global Assessment of Psoriasis at Week 12

[0459] Study design This study is a Phase 2b, randomized, multicenter, double-blind, placebo-controlled, multiple-dose study designed to evaluate the efficacy, safety, and tolerability of Compound 1 in subjects with active PsA, including evaluating plasma concentrations of Compound 1 and exploring pharmacodynamic changes in blood levels of inflammatory cytokines in subjects with active PsA treated with Compound 1.

[0460] The study will randomize approximately 260 male and female subjects aged 18-70 years (inclusive) with active PsA. To be eligible for the study, subjects must have a history of a symptomatic PsA diagnosis for at least 6 months prior to the screening visit and must meet all of the inclusion criteria at screening and the baseline (Day 1) visit, including Classification Criteria for Psoriatic Arthritis (CASPAR) criteria plus 3 or more tender joints and 3 or more swollen joints, and active PsA despite prior treatment with a nonsteroidal anti-inflammatory drug (NSAID), conventional disease-modifying antirheumatic drug (DMARD), or one tumor necrosis factor inhibitor (TNFi).

[0461] All subjects will read and sign an informed consent document (ICF) before undergoing any screening procedures. Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be included in the study. During the screening period of up to 30 days, subjects will be randomized (day -7) to receive either Compound 1 in one of three doses (5 mg, 15 mg, or 30 mg) or placebo on day 1. The goal is to randomize approximately 65 subjects per treatment group (1:1:1:1 ratio). During the treatment period, Compound 1 (5 mg, 15 mg, or 30 mg) or placebo will be administered orally QD for 12 weeks. The 12-week treatment period will be followed by a 4-week safety follow-up period.

[0462] For scheduled study visits, subjects will visit the study site eight times: at Screening, Day 1, and at Weeks 1, 2, 4, 8, 12 (End of Treatment / Early Discontinuation Visit), and 16 (End of Study [EOS]).

[0463] Efficacy will be assessed using the composite index ACR20 (including tender joint count, swollen joint count, subject assessment of PsA pain visual analog scale [VAS], subject global assessment of PsA VAS, physician global assessment PsA VAS, HAQ-DI, and hsCRP), as well as the individual components. PASI, BSA, and physician global assessment will be used to measure efficacy against psoriasis in subjects with ≥3% BSA involved on Day 1.

[0464] Safety will be assessed by collecting AEs, recording vital signs, performing physical examinations, and evaluating clinical laboratory and ECG results.

[0465] Blood samples are taken to measure plasma concentrations of Compound 1.

[0466] Blood samples will also be taken to assess the effect of Compound 1 on circulating inflammatory biomarkers.

[0467] Day 1 (Visit 2), before administration and 1 hour (± 5 minutes) after administration

[0468] Week 4 (visit 5), pre-dose, 1 hour (± 5 minutes) post-dose, and 4 hours (± 10 minutes) post-dose

[0469] Week 8 (Visit 6), before administration

[0470] Week 12 (Visit 7), any time study drug administration is completed, or when ET is possible

[0471] Blood samples will also be taken on days 1, and weeks 4 and 12, or whenever possible at ET, to assess the effect of Compound 1 on circulating inflammatory biomarkers.

[0472] No interim analyses are planned for this study.

[0473] Inclusion Criteria: To be eligible to participate in this study, subjects must meet all of the following criteria at both Screening and Day 1 visits, or at only one of the given visits (Screening or Day 1), as described in the criteria. 1. Subjects are male or female subjects who are 18-70 years of age (inclusive) at the time of consent. 2. Subject has PsA based on CASPAR plus peripheral symptoms at the Screening visit as assessed by the Investigator. 3. Subject has symptoms of PsA for ≥6 months prior to screening as assessed by the investigator. 4. Subject has 3 or more tender joints and 3 or more swollen joints as assessed by the investigator at Screening and Day 1 visits. 5. Subject has at least one psoriasis vulgaris lesion ≥2 cm in diameter, or has nail changes characteristic of psoriasis, or has a documented history of psoriasis vulgaris. 6. As assessed by the investigator, the subject has active PsA despite having previously received standard doses of NSAIDs for ≥ 4 weeks, or conventional DMARDs (including methotrexate and sulfasalazine) for ≥ 3 months, or a TNFi for ≥ 3 months, OR the subject is intolerant to NSAIDs or DMARDs or TNFis. 7. If subject is receiving concomitant treatment for PsA, they must be taking a stable dose of the following for the duration of the study: a. Methotrexate (MTX): Subjects must have been on treatment for ≥ 3 months with a stable dose and stable route of administration (≤ 25 mg MTX per week) for ≥ 4 weeks prior to Day 1 and through Week 16 (EOS); subjects taking MTX should be taking folic acid supplementation according to local standard of care to minimize potential MTX-related toxicity. b. Sulfasalazine: Maximum dose 3 gm / day. Minimum duration of therapy 2 months, and stable dose for 4 weeks prior to Day 1. c. Other conventional DMARDs not listed may be considered on a case-by-case basis after consultation with the medical monitor. d. Oral Corticosteroids: Subjects must be on a stable dose, not exceeding the equivalent of 10 mg prednisone per day, for at least 2 weeks prior to Day 1. If the subject is not currently using oral corticosteroids, they must not have been on them for at least 2 weeks prior to Day 1. e. NSAIDs or paracetamol / acetaminophen as needed: Subjects must be on a stable dose for at least 2 weeks prior to Day 1. If not currently using an NSAID, they must not have been on one for at least 2 weeks prior to Day 1. 8. Female subjects of childbearing potential who have engaged in any sexual intercourse that could result in conception: Subjects must agree to use highly effective methods of contraception from screening until at least 4 weeks after the last dose of study drug. Highly effective methods of contraception include hormonal contraception (e.g., combination oral contraceptives, patch, vaginal ring, injection, or implant), intrauterine device or system, vasectomized partner(s) (indicated vasectomy occurred 4 months or more prior to screening), tubal ligation, or dual barrier contraception in conjunction with spermicide (e.g., male condom and cervical cap, male condom and diaphragm, and male condom and contraceptive sponge). Note: Subjects must have been taking hormonal contraception continuously for at least 4 weeks prior to Day 1. Note: The above listed contraceptive methods do not apply to subjects who have abstained for at least 4 weeks prior to Day 1 and intend to continue abstaining from penile-vaginal intercourse throughout the study. The reliability of abstinence must be evaluated with respect to the duration of the clinical trial and the subject's preferred and usual lifestyle. Intermittent abstinence (calendar, symptom-temperature, postovulatory) will not be permitted. Note: Female subjects of non-childbearing potential are defined as follows: a. Women who have undergone sterilization surgery (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) b. Female subjects who have ceased menstruation without alternative medical causes for at least 12 months prior to the screening visit and have a follicle-stimulating hormone test result (reference range for confirmatory level...

Claims

1. A pharmaceutical composition for treating psoriasis or psoriatic arthritis in patients, or for inhibiting interferon-gamma (IFNγ) production, comprising compound 1: 【Chemistry 1】 or containing a pharmaceutically acceptable salt thereof, A pharmaceutical composition in which compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient daily over a period of approximately 1 to 7 days, approximately 1 to 3 weeks, approximately 3 to 6 weeks, approximately 6 to 9 weeks, approximately 9 to 12 weeks, approximately 12 to 15 weeks, or approximately 15 to 18 weeks.

2. The pharmaceutical composition according to claim 1, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient in a dose of about 2 mg, about 5 mg, about 10 mg, about 15 mg, or about 30 mg.

3. The pharmaceutical composition according to claim 1, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient in a dose of about 5 mg to about 30 mg, or about 20 mg to about 100 mg, or about 100 mg to about 200 mg.

4. (a) an average reduction in the Psoriasis Area Severity Index (PASI) of about 50% to 75% or about 75% to 100% is achieved; (b) A physician's overall assessment (PGA) of 0 or 1 is achieved; (c) The Dermatology Life Quality Index (DLQI) score decreases by approximately 1 to 3 points, 3 to 6 points, 6 to 9 points, 9 to 12 points, 12 to 15 points, 15 to 18 points, 18 to 21 points, 21 to 24 points, 24 to 27 points, or 27 to 30 points; (d) The patient's body surface area (BSA) decreases by some percentage points between approximately 1 to 10 percent points, 10 to 20 percent points, 20 to 30 percent points, 30 to 40 percent points, 40 to 50 percent points, 50 to 60 percent points, 60 to 70 percent points, 70 to 80 percent points, 80 to 90 percent points, or 90 to 100 percent points; (e) A decrease of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on the Numerical Rating Scale for Pain is achieved; (f) A decrease of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on the Numerical Rating Scale for pruritus is achieved; (g) Inhibition rates of IL-12 / 18-induced IFNγ production are achieved between approximately 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100%; and / or (h) A serum C max of approximately 25 ng / ml to 50 ng / ml, approximately 50 ng / ml to 100 ng / ml, approximately 100 ng / ml to 125 ng / ml, approximately 125 ng / ml to 150 ng / ml, approximately 150 ng / ml to 175 ng / ml, approximately 175 ng / ml to 200 ng / ml, approximately 200 ng / ml to 225 ng / ml, approximately 225 ng / ml to 250 ng / ml, approximately 250 ng / ml to 275 ng / ml, or approximately 275 ng / ml to 300 ng / ml is achieved. The pharmaceutical composition according to claim 1.

5. A pharmaceutical composition according to any one of claims 1 to 4, wherein the patient has psoriasis vulgaris.

6. The pharmaceutical composition according to claim 5, wherein the psoriasis vulgaris is moderate to severe psoriasis vulgaris.

7. The pharmaceutical composition according to any one of claims 1 to 4, wherein the patient has psoriasis, and the psoriasis is moderate to severe.

8. A pharmaceutical composition according to any one of claims 1 to 4, wherein the patient has psoriatic arthritis, and the psoriatic arthritis is moderate to severe.

9. By administration, (a) At least the response of American College of Rhematology (ACR) 20 is realized; (b) In subjects with psoriatic lesions covering 3% or more of the body surface area (BSA) on day 1, improvement in the number of tender joints, number of swollen joints, overall assessment of psoriatic arthritis by the patient, overall assessment of pain from psoriatic arthritis by the patient, overall assessment of psoriatic arthritis by the physician, score on the Health Assessment Questionnaire-Disability Index (HAQ-DI), number of dactylitis, Leed's Enthesestis Index, Minimal Disease Activity, Disease Activity Index for Psoriatic Arthritis (DAPSA), or Psoriasis Area Severity was achieved at week 12. Achieving an Index (PASI) of 75, or at week 12, a physician-administered static global assessment of 0 or 1, with an improvement of at least 2 points from baseline; and / or (c) Improvement of circulating cytokines and / or inflammatory biomarkers, improvement of 36-Item Short Form Health Survey, improvement of Functional Assessment of Chronic Illness-Fatigue, improvement of Disease Activity Score 28 and high-sensitivity C-reactive protein (hsCRP), improvement of Psoriatic Disease Activity Score at 12 weeks of treatment, improvement of Psoriatic Arthritis Response Criteria at 12 weeks of treatment, Psoriasis Area Severity A mean reduction of 25% or more in the Index (PASI), or improvement in BSA with psoriatic lesions at week 12, or improvement in the physician's overall assessment of psoriasis at week 12 of treatment is achieved. The pharmaceutical composition according to claim 8.

10. T in plasma of compound 1 ｍａｘ However, this is achieved approximately 3 to 6 hours later, and / or in the plasma of compound 1. １／２ The pharmaceutical composition according to claim 1, which is achieved approximately 17 to 37 hours later.

11. The pharmaceutical composition according to claim 1, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient daily for 2 to 4 weeks.

12. The pharmaceutical composition according to claim 1, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient daily for four weeks.

13. The pharmaceutical composition according to claim 1, wherein the psoriasis does not include erythrodermic psoriasis, pustular psoriasis, mainly guttate psoriasis, or drug-induced psoriasis.

14. A pharmaceutical composition for treating moderate to severe psoriasis vulgaris, comprising compound 1: 【Transformation 3】 A pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in a daily dose of approximately 5 mg to approximately 30 mg.

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