TYK2 inhibitors for use in the treatment of inflammatory bowel disease

Abstract

This paper describes compounds, compositions, and methods of use of TYK2 inhibitors and inflammatory bowel diseases, including Crohn's disease or ulcerative colitis, in administration protocols.

Description

[Technical Field]

[0001] The present invention relates to a method for administering a non-receptor tyrosine kinase 2 (TYK2) inhibitor 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 for the treatment of inflammatory diseases (e.g., inflammatory bowel diseases, including Crohn's disease or ulcerative colitis). [Background technology]

[0002] Protein kinases constitute a large family of structurally related enzymes that regulate various intracellular signaling processes. Because their structure and catalytic function are conserved, protein kinases are thought to have evolved from a common ancestral gene. Almost all kinases contain a similar catalytic domain of 250-300 amino acids. Kinases can be classified into families based on the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0003] Generally, protein kinases mediate intracellular signaling by inducing phosphoryl transfer from nucleoside triphosphates to protein acceptors involved in the signaling pathway. These phosphorylation events act as on / off switches for molecules that can modulate or regulate the biological function of target proteins. These phosphorylation events are ultimately triggered in response to various extracellular and other stimuli. Examples of such stimuli include signals from environmental and chemical stresses (e.g., osmotic shock, heat shock, ultraviolet irradiation, 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 α (TNF-α)), and growth factors (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli may affect one or more cellular responses related to cell proliferation, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, regulation of protein synthesis, and regulation of the cell cycle.

[0004] Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events. These diseases include, but are 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 disorders.

[0005] Tyrosine kinase 2 (TYK2) catalyzes the phosphorylation of STAT proteins downstream of several cytokine receptors, including the type I interferon receptor and the receptors for IL-12 and IL-23. When TYK2-dependent receptors are activated by their cytokine ligands, STAT-dependent transcriptional and cellular functional responses specific to the receptor and the cell type in which they are expressed are activated. TYK2-regulated cytokine signaling pathways play crucial roles in several immune-mediated disorders. The cytokine IL-12 is essential for the development of type I T helper cells (Th1) that produce interferon-gamma, a major effector molecule in systemic autoimmune disorders such as systemic lupus erythematosus. The cytokine IL-23 is central to the proliferation and survival of Th17 cells and innate lymphoid cells, both of which have been shown to play important pathogenic roles in autoimmunity. IL-23 stimulation promotes the production of major pro-inflammatory cytokines by Th17 cells, including IL-17A, IL-17F, and IL-22, all of which are crucial effector molecules in the pathogenesis of conditions such as Crohn's disease or inflammatory bowel disease, including ulcerative colitis. Inhibition of TYK2 is expected to affect multiple immune-mediated disorders through its impact on the IL-23 / Th17 / Th22 axis, IL-12-mediated Th1 function, and the regulation of various immune pathways and immune cell types by type I interferons. Therefore, there remains a need to find TYK2 inhibitors that are useful as therapeutic agents. This disclosure satisfies this need and also provides other relevant advantages. [Overview of the project]

[0006] Certain TYK2 inhibitors have been found to be suitable for oral administration to patients for the treatment of inflammatory disorders (e.g., inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC)). Therefore, in one embodiment, a method for treating IBD, including CD or UC, in patients requiring treatment may include administering a therapeutically effective amount of a TYK2 inhibitor (e.g., compound 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the patient. Compound 1 has the following structure: [ka]

[0007] Compound 1 has the IUPAC name N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridine]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

[0008] In some embodiments, the patient may have IBD.

[0009] In some embodiments, patients may have moderate to severe IBD.

[0010] In some embodiments, for patients with Crohn's disease (CD), a reduction of 50% or more from centrally interpreted baseline in the simplified endoscopic score (SES-CD) can be achieved (e.g., approximately 50%, 60%, 70%, 80%, 90%, or 100%); or a reduction of approximately 50% to 70%, 70% to 90%, or 90% to 100% in SES-CD can be achieved.

[0011] In some embodiments, patients can achieve remission, including clinical remission and deep remission.

[0012] In some embodiments, in patients with cyclophosphamide (CD) who have isolated ileal disease, it is possible to achieve an SES-CD of 4 or less (e.g., about 4, about 3, about 2, about 1, or about 0), or a reduction of at least 2 points from baseline as determined by central radiology.

[0013] In some embodiments, the patient may have CD.

[0014] In some embodiments, patients may have moderate to severely active CD.

[0015] In some embodiments, UC patients can achieve a modified Mayo score (ulcerative colitis activity assessment scoring system) of 2 or less, a bowel movement frequency subscore of 1 or less, a rectal bleeding subscore of 0, and a central radiology endoscopy subscore of 1 or less (with a score of 1 modified to exclude vulnerability).

[0016] In some embodiments, the patient may have ulcerative colitis (UC).

[0017] In some embodiments, patients may have moderate to severely active ulcerative colitis (UC).

[0018] In some embodiments, for patients with Crohn's disease including moderately to severely active CD, the method can achieve: a reduction of 50% or more from baseline in the centrally read Crohn's disease simplified endoscopic score (SES-CD) (e.g., about 50%, 60%, 70%, 80%, 90%, or about 100%), or a reduction of about 50% to 70%, 70% to 90%, or 90% to 100% in the SES-CD; or, for isolated ileal disease, an SES-CD of 4 or less (e.g., about 4, 3, 2, 1, or about 0), or a reduction of at least 2 points from baseline in the centrally read.

[0019] In some embodiments, for UC patients, including those with moderate to severe UC, the method can achieve a modified Mayo score (ulcerative colitis activity scoring system) of 2 or less, a bowel movement frequency subscore of 1 or less, a rectal bleeding subscore of 0, and a central endoscopy subscore of 1 or less (with a score of 1 modified to exclude vulnerability). In another embodiment, a method to inhibit interferon-gamma (IFNγ) production may include administering a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, or a composition thereof, to patients in need. In some embodiments, the method is related to improvements in IBD, including CD or UC, for example, as described above and elsewhere in this specification.

[0020] In some cases, the disclosed methods and uses of administering compound 1 to achieve specific pharmacokinetic parameters of this disclosure have particular advantages in treating IBD, including CD or UC. For example, in some embodiments, the plasma Tmax of compound 1 is achieved in about 3 hours to about 6 hours, or the plasma Tmax of compound 1 is achieved in about 3 hours to about 6 hours. 1 / 2 This can be achieved in approximately 17 to 37 hours.

[0021] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in doses of about 30 mg to about 200 mg (e.g., about 35 mg to about 200 mg). In other embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in doses of about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg.

[0022] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is IC 50 It is administered in a dose intended to provide approximately 24 hours of coverage.

[0023] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is IC 90 It is administered in a dose intended to provide approximately 24 hours of coverage.

[0024] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in once-daily, twice-daily, or multiple-daily doses. In other embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for 2 to 52 weeks or more. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 2 weeks, at least 52 weeks, at least 2 years, at least 3 years, at least 4 years, at least 5 years or more, for example, until the IBD of the patient, including CD or UC, improves. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered long-term or indefinitely to treat the patient. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered orally to the patient (e.g., human).

[0025] In some embodiments, the patient may have moderate to severe ileal (terminal ileum), ileocolonic, or colonic comorbidity prior to administration.

[0026] In some embodiments, the patient may have a CDAI score between 220 and 450 (including 220 and 450) prior to administration.

[0027] In some embodiments, the patient may exhibit ulcer formation characteristic of CD, as determined by ileocolonoscopy prior to administration and defined by 6 or more SES-CDs (4 or more SES-CDs for isolated ileitis).

[0028] In some embodiments, the patient may have a documented diagnosis of CD prior to administration, including a report documenting the disease based on an endoscopy with tissue diagnosis, biopsy, and / or previous ileocolic endoscopy.

[0029] In some embodiments, the patient may have moderate to severe ulcerative colitis (UC) prior to administration.

[0030] In some embodiments, a patient may have a modified Mayo score of 5 to 9 points, along with two or more endoscopic subscores (a scoring system for assessing ulcerative colitis activity).

[0031] In some embodiments, the patient may have, prior to administration, a diagnostic record of UC including endoscopy and histology, a biopsy report confirming the histological diagnosis, and / or a report recording the duration of the disease based on past colonoscopies, with the disease extending more than 15 cm from the anal margin.

[0032] In some embodiments, the glycemic index ranges from approximately 25 ng / mL to approximately 30 ng / mL, approximately 30 ng / mL to approximately 35 ng / mL, approximately 35 ng / mL to approximately 40 ng / mL, approximately 40 ng / mL to approximately 45 ng / mL, approximately 45 ng / mL to approximately 50 ng / mL, approximately 50 ng / mL to approximately 60 ng / mL, approximately 60 ng / mL to approximately 70 ng / mL, approximately 70 ng / mL to approximately 80 ng / mL, approximately 80 ng / mL to approximately 90 ng / mL, approximately 90 ng / mL to approximately 100 ng / mL, approximately 100 ng / mL to approximately 120 ng / mL, approximately 120 ng / mL to approximately 140 ng / mL, approximately 140 ng / mL to approximately 160 ng / mL, approximately 160 ng / mL to approximately 180 ng / mL, approximately 180 ng / mL to approximately 200 ng / mL, approximately 200 ng / mL to approximately 240 ng / mL, and approximately 2 40ng / mL~about 280ng / mL, about 280ng / mL~about 320ng / mL, about 320ng / mL~about 360ng / mL, about 360ng / mL~about 400ng / mL, Approximately 400ng / mL to approximately 480ng / mL, approximately 480ng / mL to approximately 560ng / mL, approximately 560ng / mL to approximately 740ng / mL, approximately 740ng / mL to approximately 820ng / mL Serum C levels of approximately 820 ng / mL to 900 ng / mL, 900 ng / mL to 1000 ng / mL, 1000 ng / mL to 1200 ng / mL, 1200 ng / mL to 1400 ng / mL, 1400 ng / mL to 1600 ng / mL, 1600 ng / mL to 1800 ng / mL, or 1800 ng / mL to 2000 ng / mL max It is possible to achieve this.

[0033] In another embodiment, a method is provided for treating IBD, including CD or UC, in patients requiring treatment, comprising administering a therapeutically effective amount of compound 1 in a daily dose of about 30 mg to about 200 mg.

[0034] In another embodiment, the use of compound 1 or a pharmaceutically acceptable salt thereof in the treatment of IBD, including CD or UC, is provided.

[0035] The above-described and other embodiments of this disclosure will become apparent by referring to the following embodiments for carrying out the invention. [Brief explanation of the drawing]

[0036] [Figure 1] Figures 1A and 1B show the experimental designs for the TCT colitis model and the α-CD40 mAb colitis model. α-CD40, anti-CD40; mAb, monoclonal antibody; SCID, severe combined immunodeficiency; TCT, T cell transfer. [Figure 2A] Figures 2A and 2B are graphs showing the weight-to-length ratio of the colon in the TCT colitis model (Figure 2A) and the α-CD40 mAb colitis model (Figure 2B). In the figures, significance was determined using ANOVA along with Tukey's post-hoc test. The following are shown: *p<0.05; **p<0.01; ***p<0.001; ***p<0.0001. α-CD40, anti-CD40; α-IL-12 / 23 p40, anti-interleukin 12 and 23 p40; ANOVA, analysis of variance; BID, twice daily; QW, once weekly; IC50, 50% inhibitory concentration; IC90, 90% inhibitory concentration; mAb, monoclonal antibody; ns, not significant; TCT, T cell transfer. [Figure 2B] Same as above. [Figure 3A] Figures 3A and 3B are graphs showing the total histological scores in the TCT colitis model (Figure 3A) and the α-CD40 colitis model (Figure 3B). In the figures, significance was determined using ANOVA along with Tukey's post-hoc test. The following are shown: *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. α-CD40, anti-CD40; α-IL-12 / 23 p40, anti-interleukin 12 and 23 p40; ANOVA, analysis of variance; BID, twice daily; QW, once weekly; IC50, 50% inhibitory concentration; IC90, 90% inhibitory concentration; mAb, monoclonal antibody; ns, not significant; TCT, T cell transfer. [Figure 3B] Same as above. [Figure 4]Figure 4 shows a heatmap and analysis of the transcriptomics of Th17 phenotype-related genes in colon tissue isolated from a TCT colitis model at the end of the treatment period. BID, twice daily; IC50, 50% inhibitory concentration; IC90, 90% inhibitory concentration; IL, interleukin; Thr17, T-helper 17. [Modes for carrying out the invention]

[0037] Detailed description of a prescribed embodiment TYK2 is an essential mediator in interleukin (IL-12, IL-23) and type I interferon (IFN) receptor-mediated signaling and is a validated therapeutic target in inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC).

[0038] Compound 1 disclosed herein is an orally administered, allosteric, highly potent, and selective TYK2 inhibitor that binds to the Janus homology 2 (JH2) domain of TYK2 but is computationally designed to sterically occlude the JH2 domains of Janus kinase (JAK) 1-3. Compound 1 is used to treat IBD, including CD or UC, psoriasis, psoriatic arthritis, and other inflammatory and autoimmune diseases. Furthermore, the selectivity of Compound 1 and its potential to deliver even higher levels of TYK2 inhibition over longer periods with once-daily (QD) dosing may offer clinical and ultimately commercial advantages over other TYK2 inhibitors currently under development.

[0039] TYK2 is a member of the JAK family of kinases, a type of intracellular signaling protein, that modulates chronic inflammation in inflammatory and autoimmune diseases. TYK2 plays a crucial role in the pathogenesis of IBD and other autoimmune diseases through its mediation of downstream signaling pathways involving IL-12, IL-23, and IFNα / β. JAK inhibition can be effective in treating inflammatory and autoimmune diseases, and several JAK inhibitors have been approved for the treatment of UC; however, these are associated with adverse events likely related to JAK1-3 inhibition. JAK inhibition can also lead to off-target safety issues by modulating diverse cytokine pathways. Consequently, while JAK inhibitors are established as oral treatments for numerous inflammatory and autoimmune diseases, their clinical utility is limited by increased risk of infection and other side effects, resulting in dosage restrictions and boxed warnings mandated by the U.S. Food and Drug Administration (FDA) as part of their labels. Designing selective JAK inhibitors and administration protocols that directly and specifically inhibit the intended kinase function is challenging due to the structural similarities between catalytic sites (orthosteric or JH1 sites) for drug targeting within the JAK catalytic domain. Based on human genetic data and growing clinical evidence regarding the selectivity of allosteric TYK2 inhibitors, our present approach to selective allosteric inhibition of TYK2 offers an optimal balance for achieving potent efficacy while potentially avoiding the safety concerns associated with broad-spectrum JAK inhibition for the treatment of multiple inflammatory and autoimmune diseases.

[0040] Across three Phase I trials, compound 1 was absorbed rapidly (T max The median exposure time is 3-6 hours, and the increase in exposure is roughly proportional to the dose, with a half-life (t 1 / 2The incubation period was 17–37 hours. Pharmacokinetics were investigated by in vitro assays using whole blood samples and cytokine induction. Treatment with compound 1 accelerated inhibition of interferon-gamma (IFNγ) production, and increased exposure correlated with increased IFNγ inhibition. No serious adverse events (SAEs) or deaths were observed. Observed adverse events (AEs) included acneiform dermatitis, papular rash, aphthous ulcers, headache, and diarrhea. Laboratory abnormalities in more than one subject with a Common Terminology Criteria for Adverse Events (CTCAE) grade of 2 or higher included neutropenia, lymphopenia, elevated creatine phosphokinase levels, and elevated non-fasting triglycerides. Exploratory efficacy studies in psoriasis patients showed improvement at all doses tested (mean reductions in psoriasis area and severity index (PASI) were 30% with 5 mg, 47% with 10 mg, and 48% with 30 mg, compared to 26% with placebo). The TYK2 inhibitors described herein are provided orally in the doses and schedules described herein.

[0041] The following disclosure provides certain specific details to give a full understanding of the various embodiments. However, those skilled in the art will understand that the methods and uses described herein can be carried out even without these details. In other cases, well-known structures are not shown or described in detail so as not to unnecessarily complicate the description of the embodiments. Unless otherwise required by context, the word “comprise” and its variations, such as “comprises” and “comprising,” throughout the following specification and claims should be interpreted in an open and inclusive sense, i.e., “includes, but is not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute an interpretation of the scope and meaning of the claimed invention.

[0042] Throughout this specification, whenever the phrases “one embodiment,” “several embodiments,” or “a certain embodiment” are used, it means that a particular mechanism, structure, or feature described in relation to that embodiment is included in at least one embodiment. That is, whenever the phrases “one embodiment,” “several embodiments,” or “a certain embodiment” appear in various places throughout this specification, they do not necessarily all refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any preferred manner in one or more embodiments. Also, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple references unless the context clearly indicates otherwise. Note that the term “or” is generally used to mean “and / or” unless the context clearly indicates otherwise.

[0043] In one embodiment, a method for treating inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC), in patients requiring treatment, is a therapeutically effective amount of compound 1: [ka] This may include administering to a patient a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0044] In some embodiments, the administration period is approximately 1 to 2 days, 2 to 3 days, 3 to 4 days, 4 to 5 days, 5 to 6 days, 6 to 7 days, 1 to 2 weeks, 2 to 3 weeks, 3 to 4 weeks, 4 to 5 weeks, 5 to 6 weeks, 6 to 7 weeks, 7 to 8 weeks, 8 to 9 weeks, 9 to 10 weeks, 10 to 11 weeks, 11 to 12 weeks, 12 to 14 weeks, 14 to 16 weeks, and 16 weeks. The administration is performed daily for periods ranging from approximately 1 week to 18 weeks, 18 weeks to 21 weeks, 21 weeks to 24 weeks, 24 weeks to 27 weeks, 27 weeks to 30 weeks, 30 weeks to 33 weeks, 33 weeks to 36 weeks, 36 weeks to 39 weeks, 39 weeks to 42 weeks, 42 weeks to 45 weeks, 45 weeks to 48 weeks, 48 ​​weeks to 51 weeks, 51 weeks to 52 weeks, 1 year to 2 years, or 2 years to 3 years, 3 years to 4 years, or 4 years to 5 years. In other embodiments, administration is performed daily for a period longer than 5 years.

[0045] In some embodiments, the patient has IBD.

[0046] In some embodiments, the patient has moderate to severe IBD.

[0047] In some embodiments, the administration is long-term or performed daily over an indefinite period.

[0048] In some embodiments, for patients with CD, the method is intended for the treatment of moderate to severely active CD.

[0049] In some embodiments, an average reduction of more than 50% in the Crohn's Disease Simple Endoscopic Score (SES-CD) is achieved for patients with Crohn's disease (CD).

[0050] In some embodiments, an average reduction of over 70% in the Crohn's Disease Simple Endoscopic Score (SES-CD) is achieved for patients with Crohn's disease (CD).

[0051] In some embodiments, an average reduction of over 90% in the Crohn's Disease Simple Endoscopic Score (SES-CD) is achieved for patients with Crohn's disease (CD).

[0052] In some embodiments, an average reduction of approximately 100% in the Crohn's Disease Simple Endoscopic Score (SES-CD) is achieved for patients with Crohn's disease.

[0053] In some embodiments, an average reduction of approximately 50% to 70% in the Crohn's Disease Simple Endoscopic Score (SES-CD) is achieved for patients with Crohn's disease (CD).

[0054] In some embodiments, an average reduction of approximately 70% to 90% in the Crohn's Disease Simple Endoscopic Score (SES-CD) is achieved for patients with Crohn's disease.

[0055] In some embodiments, an average reduction of approximately 90% to 100% in the Crohn's Disease Simple Endoscopic Score (SES-CD) is achieved for patients with Crohn's disease.

[0056] In some embodiments, for Crohn's disease (CD) patients with isolated ileal disease, a simplified endoscopic score (SES-CD) of 4 or less (e.g., approximately 4, approximately 3, approximately 2, approximately 1, or approximately 0), or a reduction of at least 2 points from baseline as determined by central interpretation, is achieved.

[0057] In some embodiments, the patient has a CD.

[0058] In some embodiments, the patient has moderate to severely active CD.

[0059] In some embodiments, for UC patients, a modified Mayo score (a scoring system for assessing ulcerative colitis activity) of 2 or less is achieved, along with a bowel movement frequency subscore of 1 or less, a rectal bleeding subscore of 0, and a centrally read endoscopy subscore of 1 or less (a score of 1 is modified to exclude vulnerability).

[0060] In some embodiments, the patient has UC.

[0061] In some embodiments, the patient has moderate to severely active ulcerative colitis (UC).

[0062] In some embodiments, for patients with CD including moderately to severely active CD, the method is: a reduction of 50% or more from baseline in the centrally read Crohn's disease simplified endoscopic score (SES-CD) (e.g., about 50%, 60%, 70%, 80%, 90%, or about 100%), or a reduction of about 50% to 70%, 70% to 90%, or 90% to 100% in the SES-CD; or, for isolated ileal disease, an SES-CD of 4 or less (e.g., about 4, 3, 2, 1, or about 0), or a reduction of at least 2 points from baseline in the centrally read.

[0063] In some embodiments, for UC patients including those with moderate to severe UC, the method achieves a modified Mayo score of 2 or less (a scoring system for assessing ulcerative colitis activity), along with a bowel movement frequency subscore of 1 or less, a rectal bleeding subscore of 0, and a central endoscopy subscore of 1 or less (modified to 1 to exclude vulnerability).

[0064] In some embodiments, the patient has inflammatory bowel disease (IBD).

[0065] In some embodiments, IBD is moderately to severely active.

[0066] In some embodiments, the patient has Crohn's disease (CD).

[0067] In some embodiments, the CD is moderately to severely active.

[0068] In some embodiments, the method achieves improvement of circulating cytokines and / or inflammatory biomarkers.

[0069] In one embodiment, a method for inhibiting the production of interferon-gamma (IFNγ) in a patient is a therapeutically effective amount of compound 1:

Chemical Formula

[0070] In some embodiments, the patient has an inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC).

[0071] In some embodiments, the plasma T of Compound 1 max is achieved in about 3 hours to about 6 hours.

[0072] In some embodiments, the plasma t of Compound 1 1 / 2 is achieved in about 17 hours to about 37 hours.

[0073] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of up to about 200 mg.

[0074] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of about 30 mg to about 200 mg.

[0075] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient at a dose of about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg.

[0076] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose intended to provide about 24 hours of coverage at IC 50 .

[0077] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at IC 90It is administered in a dose intended to provide approximately 24 hours of coverage.

[0078] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient as a single dose, for example, once daily.

[0079] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in two doses, for example, twice a day.

[0080] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in multiple doses.

[0081] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for two weeks.

[0082] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for 52 weeks.

[0083] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for a period of 2 to 52 weeks.

[0084] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient daily for a period of 2 to 52 weeks, for example, until the patient's IBD, including CD or UC, improves.

[0085] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient daily for a period of 1 to 5 years, for example, until the patient's IBD, including CD or UC, improves.

[0086] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient for a long period or indefinitely.

[0087] In some embodiments, compound 1 is administered orally to the patient.

[0088] In some embodiments, the patient is human.

[0089] In some embodiments, the glycemic range is approximately 25 ng / mL to 30 ng / mL, approximately 30 ng / mL to 35 ng / mL, approximately 35 ng / mL to 40 ng / mL, approximately 40 ng / mL to 45 ng / mL, approximately 45 ng / mL to 50 ng / mL, approximately 50 ng / mL to 60 ng / mL, approximately 60 ng / mL to 70 ng / mL, approximately 70 ng / mL to 80 ng / mL, approximately 80 ng / mL to 90 ng / mL, approximately 90 ng / mL to 100 ng / mL, approximately 100 ng / mL to 120 ng / mL, approximately 120 ng / mL to 140 ng / mL, approximately 140 ng / mL to 160 ng / mL, approximately 160 ng / mL to 180 ng / mL, approximately 180 ng / mL to 200 ng / mL, approximately 200 ng / mL to 240 ng / mL, and approximately 24 0ng / mL~about 280ng / mL, about 280ng / mL~about 320ng / mL, about 320ng / mL~about 360ng / mL, about 360ng / mL~about 400ng / mL, about 4 00ng / mL ~ approx. 480ng / mL, approx. 480ng / mL ~ approx. 560ng / mL, approx. 560ng / mL ~ approx. 740ng / mL, approx. 740ng / mL ~ approx. 820ng / mL, approx. Serum C levels between 820 ng / mL and approximately 900 ng / mL, approximately 900 ng / mL and approximately 1000 ng / mL, approximately 1000 ng / mL and approximately 1200 ng / mL, approximately 1200 ng / mL and approximately 1400 ng / mL, approximately 1400 ng / mL and approximately 1600 ng / mL, approximately 1600 ng / mL and approximately 1800 ng / mL, or approximately 1800 ng / mL and approximately 2000 ng / mL. max This will be achieved.

[0090] In one embodiment, a method for treating inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC), in patients requiring treatment, is a therapeutically effective amount of compound 1: [ka]

[0091] This may include administering it at a daily dose of approximately 30 mg to 200 mg.

[0092] In one embodiment, compound 1: [ka]

[0093] Alternatively, a pharmaceutically acceptable salt thereof may be used to treat IBD, including CD or UC.

[0094] The compounds described herein include those generally described herein, and are further illustrated by the classes, subclasses, and chemical species disclosed herein. When used herein, unless otherwise specified, the following definitions shall apply. For the purposes described herein, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, and the entire contents of these are incorporated herein by reference.

[0095] 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.

[0096] As used herein, the term "compound 1" refers to N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridine]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide having the following formula: [ka] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is in an amorphous form. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is in a crystalline form.

[0097] As used herein, “aliphatic” or “aliphatic group” means a linear (i.e., unbranched) or branched hydrocarbon chain, substituted or unsubstituted, that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred herein as “carbocyclic,” “alicyclic,” or “cycloalkyl”) that is fully saturated or contains one or more unsaturated units but is not aromatic, and has one bond site to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another embodiment, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocyclic” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic and has one bond site to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0098] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system having at least one bridge, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic ring system. As defined by IUPAC, a “bridge” is an unbranched atomic chain, or an atom or valence bond, connecting two bridgeheads, where the “bridgehead” is any of the skeletal atoms (except hydrogen) of the ring system that are bonded to three or more skeletal atoms. In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those shown below, where each group is bonded to the remainder of its molecule by any of the replaceable carbon or nitrogen atoms. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, as defined for aliphatic groups. In addition to or instead of this, any of the replaceable nitrogen atoms of the bridged bicyclic group are optionally substituted. Examples of bridging biringular groups include the following: [ka]

[0099] The term "lower alkyl" refers to a linear or branched C 1-4 This refers to alkyl groups. Exemplary lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0100] The term "lower haloalkyl" refers to a linear or branched chain of carbon atoms substituted with one or more halogen atoms. 1-4 This refers to an alkyl group.

[0101] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen or; a substituteable nitrogen in a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR) + This means one or more of the following (including those found in N-substituted pyrrolidinyls).

[0102] As used herein, the term “unsaturated” means that a part has one or more unsaturated units.

[0103] When used herein, "divalent C, which is saturated or unsaturated and linear or branched" 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.

[0104] 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 1-6, 1-4, 1-3, 1-2, or 2-3. A substituted alkylene chain is a polymethylene group in which one or more hydrogen atoms of methylene are replaced by substituents. Suitable substituents include the groups listed below for substituted aliphatic groups.

[0105] 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 are replaced by substituents. Suitable substituents include the aliphatic groups listed below.

[0106] The term "halogen" refers to F, Cl, Br, or I.

[0107] When used alone or as part of a larger term, such as “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” the term “aryl” refers to a monocyclic or bicyclic ring system having a combined 5 to 14 ring members, wherein at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments, “aryl” refers to an aromatic ring system that may have one or more substituents, such as phenyl, biphenyl, naphthyl, anthrasyl, etc. When used herein, the term “aryl” also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthoimidyl, phenantridinyl, or tetrahydronaphthyl.

[0108] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger term, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; groups having 6, 10, or 14 π electrons shared in a cyclic arrangement; and groups having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. The terms "heteroaryl" and "hetero-" as used herein also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and unless otherwise specified, the radical or bond is located on the heteroaromatic ring or 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-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxadinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heterocyclic aromatic," any of which include rings in which the rings are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are optionally substituted independently.

[0109] As used herein, the terms “heterocyclic,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are interchangeable and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is either saturated or partially unsaturated and has one or more, preferably 1 to 4, heteroatoms as defined above, in addition to the carbon atom. The term “nitrogen,” when used in relation to the ring atoms of a heterocyclic ring, includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl).

[0110] A heterocyclic ring can be bonded to its pendant group by 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 “heterocyclic,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl. The heterocyclyl group may be monocyclic or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl moiety and the heterocyclyl moiety are independently and optionally substituted.

[0111] As used herein, the term “partially unsaturated” refers to a ring moiety containing at least one double or triple bond. The term “partially unsaturated” is intended to include rings having multiple unsaturated moies, but not to include aryl or heteroaryl moies as defined herein.

[0112] As described herein, compounds may include “optionally substituted” moieties. Generally, the term “substituted,” whether preceded by the term “optionally,” means that one or more hydrogens at a given site are replaced with preferred substituents. Unless otherwise indicated, an “optionally substituted” group may have preferred substituents at each of its substitutable positions, and where one or more positions in any given structure may be replaced with one or more substituents selected from a particular group, the substituents may be the same group or different groups at all positions. The substituent combinations assumed and described herein are preferably substituents that form stable compounds or chemically possible compounds. When used herein, “stable” means a compound that is substantially unchanged when subjected to conditions that enable their generation, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0113] Suitable monovalent substituents for the replaceable carbon atoms of the "arbitrarily substituted" group are, independently, halogens, (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(may be substituted with R°);-(CH2) 0-4 O(CH2) 0-1Ph (may be substituted with R°); -CH=CHPh (may be substituted with R°); -(CH2) 0-4 O(CH2) 0-1 -Pyridyl (may be 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) 0-4 N(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;-(C 1-4 Linear or branched alkylenes) ON(R°)2; or -(C 1-4 (Straight-chain or branched-chain alkylene)C(O)ON(R°)2, (each R° may be substituted as defined below and independently of hydrogen),C 1-6 Aliphatic,-CH2Ph, -O(CH2) 0-1 Ph,-CH2- (a 5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially saturated, or aryl ring having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, if there are two independent R° rings, an aryl monocyclic or bicyclic ring having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur in conjunction with the intervening atom(s), which may be substituted as defined below.

[0114] Suitable monovalent substituents for R° (or, if there are two independent R° atoms, the ring formed in conjunction with the intervening atom) are, independently, halogens, -(CH2) 0-2 R ● ,-(HaroR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 Ure ● ,-(CH2) 0-2 CH(OR ● )2, -O(HaroR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● ,-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● ,-(CH2) 0-2 SR ● ,-(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 C 1-4 alkylene)C(O)OR ● or -SSR ● , wherein each R ● is unsubstituted, or when preceded by "halo", substituted only with one or more halogens, and is independently selected from C 1-4 aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0115] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =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-, wherein when each R * is present independently, it is selected from hydrogen, an optionally substituted C as defined below 1-6 aliphatic group, or an unsubstituted 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bonded to adjacent substitutable carbons of an "optionally substituted" group include -O(CR * 2) 2-3 O-, wherein each independent occurrence of R * is independently selected from hydrogen, an optionally substituted C as defined below 1-6The group is selected from an aliphatic group, or an unsubstituted 5-6 membered saturated ring, a partially unsaturated ring, or an aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0116] R * Suitable substituents for the aliphatic group include halogens and -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2 or -NO2 are mentioned, in which case each R ● It is unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1-4 Aliphatic group, -CH2Ph, -O(CH2) 0-1 It is a saturated ring, a partially unsaturated ring, or an aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, with a pH of 5 to 6 members.

[0117] Suitable substituents for the substituted nitrogen of the "arbitrarily 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)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2 or -N(R † )S(O)2R † These are some examples, and in that case, each R † C may be independently substituted with hydrogen as defined below. 1-6An aliphatic group, an unsubstituted -OPh, or an unsubstituted 5-6 membered saturated ring, a partially unsaturated ring, or an aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or notwithstanding the above definition, R † If two of these atoms exist independently, they may unite with the intervening atom(s) to form an unsubstituted 3- to 12-membered monocyclic or bicyclic saturated ring, a partially unsaturated ring, or an aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0118] R † Suitable substituents for the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● It is 2 or -NO2, in which case each R ● It is unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1-4 Aliphatic group, -CH2Ph, -O(CH2) 0-1 It is a saturated ring, a partially unsaturated ring, or an aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, with a pH of 5 to 6 members.

[0119] As used herein, the term “pharmaceutically acceptable salt” refers to salts that, within the bounds of reasonable medical judgment, are suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmacochemically acceptable salts are well known in the art. For example, SMBerge et al., in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference), describe pharmaceutically acceptable salts in detail. Examples of pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic acids and inorganic bases, as well as organic acids and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanes. Examples include ruhonate, 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.

[0120] Suitable salts derived from bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0121] Unless otherwise specified, the structures shown herein are 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 chiral center, the Z and E double bond isomers, and the Z and E conformational isomers. Therefore, single stereochemical isomers of the compound, as well as enantiomers, diastereomers, and geometric (or conformational) mixtures, are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise stated, the structures shown herein also mean that the compounds differ only in the presence of one or more isotopically enriched atoms, for example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, including carbon substitution with 1C-enriched carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. In certain embodiments, the warhead portion R of the provided compound 1 It contains one or more deuterium atoms. In certain embodiments, ring B of the provided compound may be substituted with one or more deuterium atoms.

[0122] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits TYK2 with measurable affinity. In certain embodiments, the inhibitor is an IC50 with an IC50 of 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. 50 It has and / or coupling constants.

[0123] When used herein, the terms “measurable affinity” and “measurable inhibition” mean a measurable change in TYK2 protein kinase activity between a sample containing the compound or its composition and YK2 protein kinase described herein and a corresponding sample containing TYK2 protein kinase in the absence of the compound or its composition.

[0124] "C max When used herein, "highest (or peak) serum concentration" refers to the highest serum concentration of the drug achieved in a given area of ​​the body or test site after the first administration of the drug and before the second administration.

[0125] When used herein, “SDD” refers to a spray-dried pharmaceutical formulation (e.g., a formulation of Compound 1 or a pharmaceutically acceptable salt thereof). The formulation may contain the compounds of this disclosure and hypromellose acetate succinate (HPMCAS). In one embodiment, HMPCAS is HPMCAS-M, where “M” represents (acetyl content 7.0% to 11.0%, succinoyl content 10% to 14%). The use of spray drying to produce powders from fluid feedstocks is well known, with applications ranging from powdered milk to bulk chemicals and pharmaceuticals. See U.S. Patent 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. 0901786, 1027886, 1027887, and 1027888, and PCT Applications WO00 / 168092 and WO00 / 168055 (each incorporated herein by reference). A typical spray drying apparatus includes a drying chamber, atomizing means for atomizing a solvent-containing liquid supplied to the drying chamber, a source for supplying heated drying gas to be introduced into the drying chamber, and drying product recovery means for separating the drying product from the cooled drying gas and vaporized solvent stream after discharge from the drying chamber. Examples of such apparatuses include the Niro Model PSD-1, PSD-2, and PSD-4 (Niro A / S, Soeborg, Denmark).

[0126] When used herein, “TPGS” or “Vitamin E TPGS” as descriptors for pharmaceutical formulations of the compounds disclosed herein refers to a pharmaceutical formulation (e.g., a pharmaceutical formulation of Compound 1 or a pharmaceutically acceptable salt thereof) comprising the following components: (a) the 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). As used herein, “granulation” refers to a process of producing larger or smaller granules or particles of a substance or mixture of substances. This process may also remove fine granules and improve the fluidity within the formulation. Both wet granulation and / or dry granulation may be used. Dry granulation is achieved using only a combination of granules, without the need to use a liquid thereon. Slugging involves using a tablet press to form large tablets with varying weights due to the low fluidity of the formulation. Next, the slag is passed through a granulator to crush it into granules, which are then compressed again to produce the final granulated product.

[0127] 3. Exemplary compounds: According to one embodiment, a method for treating an inflammatory disorder (e.g., inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC)) in a patient requiring treatment may include administering a therapeutically effective dose of a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering up to 200 mg of a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof in a single dose, a double dose, or a multiple dose (e.g., a divided dose).

[0128] U.S. Patent No. 11,046,698, which is incorporated herein by reference in its entirety, describes certain therapeutically beneficial compounds. Such compounds include Compound 1, which is designated I-908 in U.S. Patent No. 11,046,698, and its synthesis, characterization, and use in treating various diseases and disorders are described in detail therein. Numerous other TYK2 inhibitors are described in U.S. Patent No. 11,046,698, and those inhibitors may be used in the manner of this disclosure. Thus, in some embodiments, the TYK2 inhibitor is one of those described in U.S. Patent No. 11,046,698.

[0129] In certain embodiments, the TYK2 inhibitor used in the disclosed method is the following formula I: [ka] It is a substance or a pharmaceutically acceptable salt thereof, in the formula, R 3 -C(O)NH2, -C(O)NHR 3A ,-C(O)N(R 3A )2, or a monocyclic heteroaryl ring of 5-6 members having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is an example of R 5B Replaced by; R 5 is hydrogen or -L 1 -R 5A and; R 6 is hydrogen, R A Or R B is; or R 5 and R 6 It, together with the intervening atom, forms a 4- to 7-membered partially unsaturated ring or a heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is R 5A及 R in n example C Replaced by; R 7 Hydrogen, halogen, -NH2, -NHR 7AOr -NHC(O)R 7A is; or R 6 and R 7 It, together with the intervening atom, forms a 4- to 7-membered partially unsaturated ring, or independently a heteroaryl ring having 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the ring is the R of example p. C Replaced by; L 1 This is a divalent C that is covalent, or a saturated or unsaturated straight or branched chain. 1-4 A hydrocarbon chain in which one or two methylene units of the chain are arbitrarily and independently -C(R 5B )2-, -CH(R 5B Substituted by -, -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 Each is independent of R B And each of them is R of q example. C Replaced by; R 5A and each R 5B Each is independent of R A or R B And each of them has r R C It is replaced by, R A Each of these examples is 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; R B Each of these examples is independent, C 1-6Aliphatic group; phenyl; monocyclic heteroaryl rings of 5-6 members having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; bicyclic heteroaryl rings of 8-10 members having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; saturated or partially unsaturated carbocyclic rings of 3-7 members; saturated or partially unsaturated monocyclic or heterocyclic rings of 3-7 members having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or saturated or partially unsaturated bicyclic or heterocyclic rings of 7-12 members having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R C Each of these examples is independent of 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 C 1-6 An optionally substituted group selected from an aliphatic group, a phenyl group, a saturated or partially unsaturated heterocyclic ring of 3 to 7 members having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a heteroaryl ring of 5 to 6 members having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently either hydrogen or C 1-6 An optionally substituted group selected from an aliphatic group, a phenyl group, a saturated or partially unsaturated heterocyclic ring of 3 to 7 members having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a heteroaryl ring of 5 to 6 members having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Two R groups on the same nitrogen atom, together with the intervening atom, independently form saturated or partially unsaturated heteroaryl rings of 4-7 membered rings, each containing 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur in addition to its nitrogen; Each hydrogen atom bonded to a carbon atom can be optionally and independently substituted with deuterium; The examples of m, n, p, q, and r are independently 0, 1, 2, 3, or 4.

[0130] In some embodiments, the TYK2 inhibitor used in the disclosed method is compound 1a: [ka] or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0131] In some embodiments, the TYK2 inhibitor used in the disclosed method is compound 1. [ka] or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0132] 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.

[0133] 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, JAK3, and JAK2. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors in response to 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 cytokines, 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. Subsequently, activated TYK2 phosphorylates further signaling proteins, such as STAT family members including STAT1, STAT2, STAT4, and STAT6. .

[0134] IL-23-mediated TYK2 activation is associated with 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 is also involved in psoriasis, ankylosing spondylitis, and Behçet's disease as a downstream effector of IL-23. 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.

[0135] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucosal 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.

[0136] Decreased TYK2 activity protects joints from arthritis (a model of human rheumatoid arthritis) induced by collagen antibodies. The mechanism is that decreased TYK2 activity leads to T h 1 / T h It reduced the production of 17 related cytokines, as well as matrix metalloproteinases and other important inflammatory markers. 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.

[0137] TYK2 knockout mice exhibited complete resistance to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) compared to controls, with no CD4 T cell infiltration in the spinal cord. This suggests that TYK2 is essential for the development of pathogenic CD4-mediated disease 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 TYK2 expression 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 lead to decreased neuronal demyelination and increased remyelination, which further suggests a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0138] TYK2 is the only signaling messenger common to both IL-12 and IL-23.

[0139] Studies of the linkage and association of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder) have shown a strong and significant correlation between loss-of-function mutations in TYK2 and reduced SLE prevalence in families with affected individuals. 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 between individuals in the SLE cohort and individuals in the 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.

[0140] TYK2 has been shown to play a crucial role in maintaining tumor surveillance, and TYK2 knockout mice have shown defects in cytotoxic T cell responses and accelerated tumor development. However, these effects are associated with the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for treating autoimmune disorders or transplant rejection. Other JAK family members, such as JAK3, also play similar roles in the immune system, but TYK2 is involved in more or less closely related signaling pathways and has fewer off-target effects than other members, suggesting it to be a superior target. Simma et al. “Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance,” Cancer Res. (2009) 69:203-211.

[0141] However, contrary to the decreased 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, to maintain cancer cell survival through the upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2, rather than 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), the JH2 domain (V731I), and the kinase domain (E957D and R1027H). However, since TYK2 enzymes characterized by kinase-dead mutations (M978Y or M978F) in addition to the activating mutation (E957D) could not be transformed, it was also identified that kinase function of TYK2 is necessary to increase cancer cell survival. Sanda et al. “TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia,” Cancer Disc. (2013)3(5):564-577.

[0142] In other words, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10-dependent and / or BCL2-dependent tumors, e.g., 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.

[0143] TYK2-mediated STAT3 signaling has also been shown to mediate amyloid-beta (Aβ) peptide-induced neuronal cell death. Following Aβ administration, decreased STAT3 phosphorylation by TYK2 resulted in reduced neuronal cell death, and increased STAT3 phosphorylation 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.

[0144] Inhibition of the JAK-STAT signaling pathway is also involved in hair growth and the 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.

[0145] Therefore, compounds that inhibit TYK2 activity, particularly those exhibiting selectivity compared to JAK2, are beneficial. Such compounds should produce pharmacological responses that favorably treat one or more of the conditions described herein without the side effects associated with JAK1-3 inhibition that impose limitations on dosage levels.

[0146] Although TYK2 inhibitors are known in the art, there is a continuing need to provide novel inhibitors with more effective or advantageous pharmaceutically important properties. For example, compounds with improved activity, selectivity over other JAK kinases (particularly JAK2) and ADMET, and properties (absorption, distribution, metabolism, excretion, and / or toxicity). In other words, in some embodiments, inhibitors of TYK2 can exhibit selectivity over JAK2.

[0147] The activity of the compounds or their variants described herein as TYK2 inhibitors may be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays to determine the inhibition of either the phosphorylation activity and / or subsequent functional consequences, or the ATPase activity, of activated TYK2 or its variants. Alternative in vitro assays quantify the ability of inhibitors to bind to TYK2. Inhibitor binding can be measured by radiolabeling the inhibitor before binding, isolating the inhibitor / TYK2 complex, and determining the amount of radiolabeled binding. Alternatively, inhibitor binding may be determined by performing competitive experiments 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, the assays described and disclosed in each of the literatures into which they are incorporated by reference. Detailed conditions for assaying the compounds or their variants described herein as TYK2 inhibitors are set out in the following examples and in US11,046,698 (incorporated herein by reference).

[0148] As used herein, the terms “treatment,” “to treat,” and “to treat” mean reversing, alleviating, delaying the onset of, or inhibiting the progression of one or more of the diseases or disorders or their symptoms as described herein. In some embodiments, treatment may be performed after the onset of one or more symptoms. In other embodiments, treatment may be administered when there are no symptoms. For example, treatment may be performed on a highly susceptible individual before the onset of symptoms (for example, taking into account a history of the symptoms and / or genetic or other susceptibility factors). Treatment may also be continued after the disappearance of symptoms, for example, to prevent or delay recurrence.

[0149] The compounds provided are inhibitors of TYK2 and are therefore useful for treating one or more disorders associated with the activity of TYK2 or its variants. Accordingly, in certain embodiments, a method for treating a TYK2-mediated disorder may include administering a compound described herein or a pharmaceutically acceptable composition thereof to a patient in need of treatment.

[0150] As used herein, the terms “TYK2-mediated” disorders, diseases and / or conditions mean any disease or other adverse condition in which TYK2 or its variants are known to play a role. Therefore, another embodiment relates to treating or mitigating the severity of one or more diseases in which TYK2 or its variants are known to be involved. Such disorders mediated by TYK2 include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-related disorders.

[0151] In some embodiments, the method is for treating one or more disorders, the disorders being selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-related disorders, and the method may include administering to a patient in need of treatment a pharmaceutical composition comprising an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the disorder is an autoimmune disorder. In some embodiments, the disorder is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis (e.g., plaque psoriasis), Behçet's disease, POEMS syndrome, inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC).

[0153] In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis (e.g., psoriasis vulgaris), psoriatic arthritis, hepatomegaly, IBD, CD, or UC.

[0154] In some embodiments, a method of treating CD in patients requiring treatment may include administering a TYK2 inhibitor described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, a method for treating UC in patients requiring treatment may include administering a TYK2 inhibitor described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, a method for treating IBD in patients requiring treatment may include administering a TYK2 inhibitor described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof.

[0157] 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, essential myelofibrosis, or thrombocytosis.

[0158] 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.

[0159] In some embodiments, the disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[0160] 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 in 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.

[0161] In some embodiments, the disorder is related to transplantation. In some embodiments, the transplantation-related disorder is transplant rejection or graft-versus-host disease.

[0162] In some embodiments, the impairment is related to the signaling of type I interferon, IL-10, IL-12, or IL-23. In some embodiments, the impairment is related to the signaling of type I interferon. In some embodiments, the impairment is related to the signaling of IL-10. In some embodiments, the impairment is related to the signaling of IL-12. In some embodiments, the impairment is related to the signaling of IL-23.

[0163] The compounds described herein are also useful in treating inflammatory or allergic conditions of the skin, such as psoriasis (e.g., psoriasis vulgaris), 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, acquired epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0164] The compounds described herein are for the treatment of other diseases or conditions having inflammatory components, such as eye diseases and conditions such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal keratoconjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having autoimmune components or etiologies, such as autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, erythrocytic anemia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, and multiple inflammatory diseases. Chondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriasis Juvenile arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis, glaucoma, retinal disease, 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, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic syndromes Fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergy, silica-induced disease, COPD (injury, airway inflammation, bronchial hypersensitivity, remodeling, or reduction of disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, systemic sclerosis with myositis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis,Atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, panentotitis, epicondylitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulinia It may also be used to treat A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0165] In some embodiments, inflammatory diseases that can be treated according to the methods described herein are 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.

[0166] In some embodiments, inflammatory diseases that can be treated according to the methods described herein are T h 1 or T h 17 is a disease in which 17 is involved. In some embodiments, T h Diseases involving 17 are selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0167] In some embodiments, inflammatory diseases that can be treated according to the methods described herein are selected from Sjögren's syndrome, allergic disorders, osteoarthritis, ocular conditions such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca and vernal keratoconjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[0168] Furthermore, the present invention can provide the use of a compound as defined in the present invention, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for the preparation of a medicament for treating autoimmune disorders, inflammatory disorders or proliferative disorders, or disorders commonly occurring in connection with transplantation.

[0169] While not wishing to be bound by any particular theory, it is believed that when the inhibitory compound or the pendant moiety of the inhibitory compound is in proximity to the target water, the displacement or disruption of that water by the inhibitory compound or the pendant moiety of the inhibitory compound is facilitated. In some embodiments, the water molecule displaced or disrupted by the inhibitory compound or the pendant moiety of the inhibitory compound is a labile water molecule.

[0170] In certain embodiments, the method utilizes a complex comprising TYK2 and an inhibitor, wherein at least one of the labile waters of TYK2 is displaced or disrupted by the inhibitor. In some embodiments, at least two selected labile waters are displaced or disrupted by the inhibitor.

[0171] 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 of treatment, comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a composition thereof, to achieve specific pharmacokinetic parameters. In some embodiments, the disclosed methods and uses of administering Compound 1 to achieve the specific pharmacokinetic parameters of the present disclosure have the benefit of treating the diseases described herein, such as inflammatory disorders. Such diseases include inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC).

[0172] In some embodiments, the plasma T maxThis is achieved in a maximum of approximately 10 hours, for example, approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, 6 hours, approximately 7 hours, approximately 8 hours, approximately 9 hours, or approximately 10 hours, or any of the time ranges created by using two of the above times as endpoint values. In some embodiments, T max This is achieved in approximately 1 to 10 hours, 1 to 9 hours, 2 to 10 hours, 2 to 9 hours, 3 to 10 hours, 3 to 9 hours, 4 to 10 hours, 4 to 9 hours, 5 to 10 hours, 5 to 9 hours, 6 to 10 hours, 6 to 9 hours, 7 to 10 hours, 7 to 9 hours, 8 to 10 hours, 9 to 10 hours, or 8 to 9 hours. In some embodiments, plasma T of a TYK2 inhibitor (e.g., compound 1) max This is achieved in approximately 3 hours. In some embodiments, plasma T1 is obtained by introducing a TYK2 inhibitor (e.g., compound 1). max This is achieved in approximately 4 hours. In some embodiments, the plasma T of compound 1 is observed. max This is achieved in approximately 5 hours. In some embodiments, plasma T1 is obtained by introducing a TYK2 inhibitor (e.g., compound 1). max This can be achieved in approximately 6 hours.

[0173] In some embodiments, a TYK2 inhibitor (e.g., compound 1) is used in plasma T max This is achieved in approximately 1 to 4 hours, 2 to 5 hours, 3 to 6 hours, 4 to 7 hours, 5 to 8 hours, 6 to 9 hours, or 7 to 10 hours. In some embodiments, plasma T1 of a TYK2 inhibitor (e.g., compound 1) max This can be achieved in approximately 3 to 6 hours.

[0174] In some embodiments, a TYK2 inhibitor (e.g., compound 1) is administered to plasma t 1 / 2This is achieved in a maximum of approximately 50 hours, for example, approximately 10 hours, approximately 11 hours, approximately 12 hours, approximately 13 hours, approximately 14 hours, approximately 15 hours, 16 hours, approximately 17 hours, approximately 18 hours, approximately 19 hours, approximately 20 hours, approximately 21 hours, approximately 22 hours, approximately 23 hours, approximately 24 hours, approximately 25 hours, 26 hours, approximately 27 hours, approximately 28 hours, approximately 29 hours, approximately 30 hours, approximately 31 hours, approximately 32 hours, approximately 33 hours, approximately 34 hours, approximately 35 hours, 36 hours, approximately 37 hours, approximately 38 hours, approximately 39 hours, approximately 40 hours, approximately 41 hours, approximately 42 hours, approximately 43 hours, approximately 44 hours, approximately 45 hours, 46 hours, approximately 47 hours, approximately 48 hours, approximately 49 hours, or approximately 50 hours, or any of the time ranges created by using two of the above times as endpoint values. In some embodiments, a TYK2 inhibitor (e.g., compound 1) is administered to plasma t 1 / 2 This is achieved in approximately 17 hours. In some embodiments, the plasma t 1 / 2 This is achieved in approximately 18 hours. In some embodiments, the plasma of compound 1 is t 1 / 2 This is achieved in approximately 19 hours. In some embodiments, the plasma t of a TYK2 inhibitor (e.g., compound 1) 1 / 2 This is achieved in approximately 20 hours. In some embodiments, the plasma t 1 / 2 This is achieved in approximately 21 hours. In some embodiments, the plasma t 1 / 2 This is achieved in approximately 22 hours. In some embodiments, the plasma of compound 1 is t 1 / 2 This is achieved in approximately 23 hours. In some embodiments, the plasma t 1 / 2 This is achieved in approximately 24 hours. In some embodiments, the plasma t 1 / 2 This is achieved in approximately 25 hours. In some embodiments, the plasma t 1 / 2 This is achieved in approximately 26 hours. In some embodiments, the plasma of compound 1 is t 1 / 2 This is achieved in approximately 27 hours. In some embodiments, the plasma t 1 / 2This is achieved in approximately 28 hours. In some embodiments, the plasma t 1 / 2 This is achieved in approximately 29 hours. In some embodiments, the plasma t of a TYK2 inhibitor (e.g., compound 1) 1 / 2 This is achieved in approximately 30 hours. In some embodiments, compound 1 is expressed in plasma t 1 / 2 This is achieved in approximately 31 hours. In some embodiments, the plasma t of a TYK2 inhibitor (e.g., compound 1) 1 / 2 This can be achieved in up to approximately 32 hours. In some embodiments, the plasma t of a TYK2 inhibitor (e.g., compound 1) 1 / 2 This is achieved in approximately 33 hours. In some embodiments, the plasma t 1 / 2 This is achieved in approximately 34 hours. In some embodiments, compound 1 is present in plasma t 1 / 2 This is achieved in approximately 35 hours. In some embodiments, the plasma t 1 / 2 This is achieved in approximately 36 hours. In some embodiments, the plasma t 1 / 2 This can be achieved in approximately 37 hours.

[0175] In some embodiments, a TYK2 inhibitor (e.g., compound 1) is administered to plasma t 1 / 2 This is achieved in approximately 10-30 hours, 12-32 hours, 14-34 hours, 16-36 hours, 18-38 hours, 20-40 hours, or 22-42 hours. In some embodiments, the plasma t of a TYK2 inhibitor (e.g., compound 1) is 1 / 2 This can be achieved in approximately 17 to 37 hours.

[0176] In some embodiments, the present disclosure provides a method for administering a TYK2 inhibitor (e.g., compound 1) to a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of the TYK2 inhibitor (e.g., compound 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, thereby achieving a specific pharmacokinetic outcome.

[0177] In some embodiments of the methods and uses disclosed herein, administration of a TYK2 inhibitor (e.g., compound 1) results in rapid inhibition of interferon-gamma (IFNγ) production and increased exposure correlated with increased inhibition of IFNγ. In some embodiments, a method for inhibiting IFNγ production in a patient may include administering to the patient a TYK2 inhibitor (e.g., compound 1) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0178] In some embodiments, the glycemic range is approximately 25 ng / mL to 30 ng / mL, approximately 30 ng / mL to 35 ng / mL, approximately 35 ng / mL to 40 ng / mL, approximately 40 ng / mL to 45 ng / mL, approximately 45 ng / mL to 50 ng / mL, approximately 50 ng / mL to 60 ng / mL, approximately 60 ng / mL to 70 ng / mL, approximately 70 ng / mL to 80 ng / mL, approximately 80 ng / mL to 90 ng / mL, approximately 90 ng / mL to 100 ng / mL, approximately 100 ng / mL to 120 ng / mL, approximately 120 ng / mL to 140 ng / mL, approximately 140 ng / mL to 160 ng / mL, approximately 160 ng / mL to 180 ng / mL, approximately 180 ng / mL to 200 ng / mL, approximately 200 ng / mL to 240 ng / mL, and approximately 24 0ng / mL~about 280ng / mL, about 280ng / mL~about 320ng / mL, about 320ng / mL~about 360ng / mL, about 360ng / mL~about 400ng / mL, about 4 00ng / mL ~ approx. 480ng / mL, approx. 480ng / mL ~ approx. 560ng / mL, approx. 560ng / mL ~ approx. 740ng / mL, approx. 740ng / mL ~ approx. 820ng / mL, approx. Serum C levels between 820 ng / mL and approximately 900 ng / mL, approximately 900 ng / mL and approximately 1000 ng / mL, approximately 1000 ng / mL and approximately 1200 ng / mL, approximately 1200 ng / mL and approximately 1400 ng / mL, approximately 1400 ng / mL and approximately 1600 ng / mL, approximately 1600 ng / mL and approximately 1800 ng / mL, or approximately 1800 ng / mL and approximately 2000 ng / mL. max This is achieved. In some embodiments, serum C between approximately 25 ng / mL and approximately 30 ng / mL is achieved. max This is achieved. In some embodiments, serum C between approximately 30 ng / mL and approximately 35 ng / mL is achieved.max This is achieved. In some embodiments, serum C between approximately 35 ng / mL and approximately 40 ng / mL is achieved. max This is achieved. In some embodiments, serum C between approximately 40 ng / mL and approximately 45 ng / mL is achieved. max This is achieved. In some embodiments, serum C between approximately 45 ng / mL and approximately 50 ng / mL is achieved. max This is achieved. In some embodiments, serum C between approximately 50 ng / mL and approximately 60 ng / mL is achieved. max This is achieved. In some embodiments, serum C between approximately 60 ng / mL and approximately 70 ng / mL is achieved. max This is achieved. In some embodiments, serum C between approximately 70 ng / mL and approximately 80 ng / mL is achieved. max This is achieved. In some embodiments, serum C between approximately 80 ng / mL and approximately 90 ng / mL is achieved. max This is achieved. In some embodiments, serum C between approximately 90 ng / mL and approximately 100 ng / mL max This is achieved. In some embodiments, serum C between approximately 100 ng / mL and approximately 120 ng / mL max This is achieved. In some embodiments, serum C between approximately 120 ng / mL and approximately 140 ng / mL is obtained. max This is achieved. In some embodiments, serum C between approximately 140 ng / mL and approximately 160 ng / mL is obtained. max This is achieved. In some embodiments, serum C between approximately 160 ng / mL and approximately 180 ng / mL max This is achieved. In some embodiments, serum C between approximately 180 ng / mL and approximately 200 ng / mL max This is achieved. In some embodiments, serum C between approximately 200 ng / mL and approximately 240 ng / mL max This is achieved. In some embodiments, serum C between approximately 240 ng / mL and approximately 280 ng / mL max This is achieved. In some embodiments, serum C between approximately 280 ng / mL and approximately 320 ng / mL. max This is achieved. In some embodiments, serum C between approximately 320 ng / mL and approximately 360 ng / mL. maxThis is achieved. In some embodiments, serum C between approximately 360 ng / mL and approximately 400 ng / mL max This is achieved. In some embodiments, serum C between approximately 400 ng / mL and approximately 480 ng / mL max This is achieved. In some embodiments, serum C between approximately 480 ng / mL and approximately 560 ng / mL. max This is achieved. In some embodiments, serum C between approximately 560 ng / mL and approximately 740 ng / mL. max This is achieved. In some embodiments, serum C between approximately 740 ng / mL and approximately 820 ng / mL. max This is achieved. In some embodiments, serum C between approximately 820 ng / mL and approximately 900 ng / mL max This is achieved. In some embodiments, serum C between approximately 900 ng / mL and approximately 1000 ng / mL max This is achieved. In some embodiments, serum C between approximately 1000 ng / mL and approximately 1200 ng / mL max This is achieved. In some embodiments, serum C between approximately 1200 ng / mL and approximately 1400 ng / mL max This is achieved. In some embodiments, serum C between approximately 1400 ng / mL and approximately 1600 ng / mL max This is achieved. In some embodiments, serum C between approximately 1600 ng / mL and approximately 1800 ng / mL max This is achieved. In some embodiments, serum C between approximately 1800 ng / mL and approximately 2000 ng / mL max This will be achieved.

[0179] 6. Medication and Schedule In some embodiments, the methods and uses described herein, for example, in the treatment of inflammatory disorders (including Crohn's disease (CD) or inflammatory bowel disease (IBD), including ulcerative colitis (UC)) in patients requiring treatment, are achieved by administering a therapeutically effective dose of a TYK2 inhibitor (e.g., compound 1) in a single, double, or multiple dose (e.g., orally), for example, up to 200 mg. In some embodiments, the TYK2 inhibitor is administered once, twice, three, four, five, six, seven, or eight times daily. In some embodiments, the method involves administering (e.g., orally) a single dose, a double dose, or a multi-dose amount ranging from about 30 to about 200 mg / dose, for example, about 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or about 200 mg, or any range created with the two aforementioned amounts as endpoints. For example, oral doses may include 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg / dosage form of a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the method includes administering (e.g., orally) in single, double, or multiple doses in the range of approximately 30 to approximately 200 mg / dose per day, for example, approximately 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.

[0181] In some embodiments, the method involves doses of approximately 30 mg to 200 mg per day, approximately 30 mg to 35 mg, approximately 40 mg to 45 mg, approximately 50 mg to 60 mg, approximately 70 mg to 80 mg, approximately 90 mg to 100 mg, approximately 110 mg to 120 mg, approximately 130 mg to 140 mg, approximately 150 mg to 160 mg, approximately 170 mg to 180 mg, approximately 190 mg to 200 mg, approximately 30 mg to 50 mg, approximately 30 mg to 75 mg, and approximately 30 mg to 100 mg. This includes administering (e.g., orally) in single, double, or multiple doses in the range of approximately 30 mg to 150 mg, 30 mg to 200 mg, 50 mg to 75 mg, 50 mg to 100 mg, 50 mg to 150 mg, 50 mg to 200 mg, 75 mg to 100 mg, 75 mg to 150 mg, 75 mg to 200 mg, 100 mg to 150 mg, 100 mg to 200 mg, or 150 mg to 200 mg. Any specific doses between each range in this paragraph are also envisioned. For example, the description "approximately 50mg to approximately 60mg" includes doses of approximately 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, or 10mg. It is also assumed that non-integer doses within the range are included; for example, the range "approximately 50mg to approximately 60mg" includes values ​​such as approximately 50mg, 50.1mg, 50.2mg, 50.3mg, 50.4mg, 50.5mg, and 50.6mg.

[0182] In some embodiments, the method is IC 50 The overall dose intended to provide approximately 24 hours of coverage may include single, double, or multiple doses (e.g., orally).

[0183] In some embodiments, the method is IC 90 The overall dose intended to provide approximately 24 hours of coverage may include single, double, or multiple doses (e.g., orally).

[0184] As used herein, “24-hour coverage” means reaching or maintaining the desired plasma concentration of the compound that produces the intended amount of target protein effect over a 24-hour period. For example, “IC 50 "24-hour coverage" means using a dosage intended to increase the plasma concentration of the inhibitor compound, causing 50% inhibition of the target protein over 24 hours.

[0185] Any of the dosages mentioned in the previous paragraph may be administered as one, two, three, or four doses per day. For example, a 50 mg dose may be achieved by administering a 25 mg dose, followed by a second 25 mg dose after a certain period of time has elapsed, to reach a total of 50 mg throughout the day. To give another example, a 50 mg dose can be administered in one day by administering 10 mg, waiting a while, then a second 10 mg, waiting a while, a third 10 mg, waiting a while, a fourth 10 mg, waiting a while, and then a fifth 10 mg, to reach a total of 50 mg throughout the day.

[0186] Thus, in some embodiments, the administration of 30 mg of compound 1 includes administering 15 mg, allowing a specified period of time, and then administering a second dose of 15 mg. In some embodiments, the administration of 50 mg of compound 1 includes administering 25 mg, allowing a specified period of time, and then administering a second dose of 25 mg. In some embodiments, the administration of 75 mg of compound 1 includes administering 37.5 mg, allowing a specified period of time, and then administering a second dose of 37.5 mg. In some embodiments, the administration of 100 mg of compound 1 includes administering 50 mg, allowing a specified period of time, and then administering a second dose of 50 mg. In some embodiments, the administration of 150 mg of compound 1 includes administering 75 mg, allowing a specified period of time, and then administering a second dose of 75 mg. In some embodiments, the administration of 200 mg of compound 1 includes administering 100 mg, allowing a specified period of time, and then administering a second dose of 100 mg. The prescribed elapsed time may be determined by the clinician and will be taken into consideration the metabolism of each individual patient. In some embodiments, the prescribed elapsed time is approximately 2.5 hours to 5 hours, 5 hours to 7.5 hours, 7.5 hours to 10 hours, 10 hours to 12.5 hours, 12.5 hours to 15 hours, 15 hours to 17.5 hours, 17.5 hours to 20 hours, 20 hours to 22.5 hours, or 22.5 hours to 24 hours.

[0187] In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 30 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 35 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 40 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 45 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 50 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 55 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 60 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 65 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 70 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 75 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 80 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 85 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 90 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 95 mg.In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 100 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 150 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses up to 200 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses ranging from about 30 mg to about 100 mg, for example, about 30 mg, about 50 mg, about 75 mg, or about 100 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses ranging from about 50 mg to about 150 mg. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient (e.g., orally) in doses of about 75 mg to about 200 mg.

[0188] In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is IC 50 It is administered (e.g., orally) in a dose intended to provide approximately 24 hours of coverage.

[0189] In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is IC 90 It is administered (e.g., orally) in a dose intended to provide approximately 24 hours of coverage.

[0190] As provided in consideration of the preclinical data described herein, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered to the patient in a dosing schedule suitable for achieving the desired disease regression with minimal side effects. In some embodiments, the TYK2 inhibitor (e.g., compound 1) or a pharmaceutical composition thereof is administered over approximately 1 to 2 days, approximately 2 to 3 days, approximately 3 to 4 days, approximately 4 to 5 days, approximately 5 to 6 days, approximately 6 to 7 days, approximately 1 to 2 weeks, approximately 2 to 3 weeks, approximately 3 to 4 weeks, approximately 4 to 5 weeks, approximately 5 to 6 weeks, approximately 6 to 7 weeks, approximately 7 to 8 weeks, approximately 8 to 9 weeks, approximately 9 to 10 weeks, approximately 10 to 11 weeks, approximately 11 to 12 weeks, approximately 12 to 14 weeks, approximately 14 weeks The drug is administered to patients daily (QD) for periods of approximately 16 weeks, 16 to 18 weeks, 18 to 21 weeks, 21 to 24 weeks, 24 to 27 weeks, 27 to 30 weeks, 30 to 33 weeks, 33 to 36 weeks, 36 to 39 weeks, 39 to 42 weeks, 42 to 45 weeks, 45 to 48 weeks, 48 ​​to 51 weeks, 51 to 52 weeks, 1 to 2 years, 2 to 3 years, 3 to 4 years, or 4 to 5 years. In other embodiments, administration is daily for longer than 5 years. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or its pharmaceutical composition is administered to a patient daily (QD) for 2 weeks, 4 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 ​​weeks, 51 weeks, 52 weeks, 1 year, 2 years, 3 years, 4 years, 5 years, or longer. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or its pharmaceutical composition is administered to a patient daily (QD) for an indefinite period.

[0191] In some embodiments, a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered to a patient at a dose of 2 to 200 mg once daily for 2 weeks. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or the pharmaceutical composition thereof is administered to a patient at a dose of 2 to 200 mg multiple times a day for 2 weeks. In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or the pharmaceutical composition thereof is administered to the patient at a once-daily dose, twice-daily dose, or multiple-times-daily dose of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, 75 mg, 100 mg, or 200 mg over a period of 2 weeks, 4 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, or an indefinite period of time.

[0192] In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or the pharmaceutical composition thereof is administered in a single dose, twice-daily dose, or multiple-times-daily dose over a period of 2 weeks, 4 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, or an indefinite period of time, IC 50 is administered to the patient as a total dose intended to provide approximately 24 hours of coverage at.

[0193] In some embodiments, the TYK2 inhibitor (e.g., Compound 1) or the pharmaceutical composition thereof is administered in a single dose, twice-daily dose, or multiple-times-daily dose over a period of 2 weeks, 4 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 weeks, 51 weeks, 54 weeks, 57 weeks, 60 weeks, or an indefinite period of time, IC 90 is administered to the patient as a total dose intended to provide approximately 24 hours of coverage at.

[0194] 7. Formulations and Combinations Pharmaceutically acceptable compositions Compounds and compositions prepared according to the methods described herein may be administered in any amount and via any route of administration that is effective in treating or reducing the severity of any of the disorders disclosed herein. The exact required amount will vary from subject to subject, depending on the subject's race, age and general condition, the severity of the infection, the specific drug, and the method of administration. The compounds described herein are preferably formulated in dosage units for ease of administration and uniformity of dosage. The term "dosage unit" as used herein refers to a physically distinct drug unit appropriate for the patient being treated. However, it should be understood that the total daily dose of the compounds and compositions described herein will be determined by the attending physician within the bounds of reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and its severity, the activity of the specific compound used, the specific composition used, the patient's age, weight, general health, sex and diet, the timing of administration, route of administration, and excretion rate of the specific compound used, the duration of treatment, any drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field.

[0195] In another embodiment, the composition may include a compound described herein or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition described herein is such that it is effective in inhibiting TYK2 protein kinase or its variants to a measurable degree in a biological sample or patient. In certain embodiments, the amount of the compound in the composition described herein is such that it is effective in inhibiting TYK2 protein kinase or its variants to a measurable degree in a biological sample or patient. In certain embodiments, the composition described herein is formulated for administration to a patient requiring such a composition. In some embodiments, the composition described herein is formulated for oral administration to a patient.

[0196] When used herein, the term “patient” means an animal, preferably a mammal, most preferably a human.

[0197] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound formulated with it. Examples of 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, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin tallow.

[0198] "Pharmacologically acceptable derivatives" means any non-toxic salt, ester, ester salt or other derivative of any compound described herein that, when administered to a subject, can directly or indirectly deliver the compound described herein, or its inhibitory metabolites or residues thereof.

[0199] As used herein, the term “inhibitory metabolite or residue thereof” means that the metabolite or residue thereof is also an inhibitor of TYK2 protein kinase or a variant thereof.

[0200] The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, intracisionally, intraperitoneally, nasally, orally, vaginally, or via an implanted reservoir. In certain embodiments, the compounds described herein may be administered orally or parenterally once or more daily at a dose level of about 0.01 mg / kg to about 50 mg / kg per body weight of the subject per day, preferably about 1 mg / kg to about 25 mg / kg, to produce the desired therapeutic effect. The term “parenteral,” as used herein, includes techniques of injection or infusion into the subcutaneous, intravenous, intramuscular, intra-articular, intra-sacral, intrasternal, intrathecal, intrahepatic, intrafocal, and intracranial regions. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injection forms of the compositions described herein may be aqueous suspensions or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixatives have conventionally been employed as solvents or suspension media. For this purpose, any less irritating fixative, including synthetic monoglycerides or diglycerides, may be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0201] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0202] To extend the effects of the compounds described herein, it is often desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material having insufficient water solubility. Thus, the absorption rate of a compound depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, the absorption delay of parenterally administered compound forms is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot formulations are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The release rate of the compound can be controlled depending on the ratio of the compound to the polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Injectable depot formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0203] The compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds described herein with a suitable non-irritating excipient or carrier, such as cocoa butter or polyethylene glycol, or suppository waxes that are solid at ambient temperature but liquid at body temperature, and therefore dissolve in the rectum or vaginal cavity to release the active compound.

[0204] For this purpose, any mildly irritating fixed oil may be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, and similarly, naturally pharmaceutically acceptable oils such as olive oil or castor oil are useful, especially in their polyoxyethylated versions. Solutions or suspensions of these oils may also include diluents or dispersants of long-chain alcohols, such as carboxymethylcellulose, or similar dispersants widely used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers, or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, may also be used for formulation purposes.

[0205] The pharmaceutically acceptable compositions described herein may be administered orally in any acceptable oral dosage form, which may include, but is not limited to, capsules, tablets, aqueous suspensions, or solutions. For tablets intended for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Specific sweeteners, flavorings, flavorings, or colorings may also be added, if desired.

[0206] Alternatively, the pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal administration. These suppositories can be prepared by mixing a drug with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such substances include cocoa butter, beeswax, and polyethylene glycol.

[0207] Examples of 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, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents 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 starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. Similar solid compositions may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules may be prepared using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical field. They may optionally contain opacifying agents and may be composed to release the active ingredient(s) only in a specific part of the intestinal tract, or preferentially in a specific part, in an optionally delayed manner. Examples of usable inclusion compositions include polymers and waxes. Similar solid compositions may also be used as fillers in soft and hard gelatin capsules using excipients, such as lactose or lactose and high molecular weight polyethylene glycol.

[0208] The pharmaceutically acceptable compositions described herein may be administered topically, particularly when the therapeutic target includes areas or organs that are easily accessible by topical application, including diseases of the eyes, skin, or lower intestines. Suitable topical formulations are readily prepared for each of these areas or organs.

[0209] Topical application to the lower intestinal tract can be performed using rectal suppositories (see above) or appropriate enema formulations. Topical transdermal patches may also be used.

[0210] The pharmaceutically acceptable compositions provided may be formulated for topical application as suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. 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 waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester waxes, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, with any required preservative or buffer. Absorption enhancers can also be used to increase the amount of compound that penetrates the skin. The rate can be controlled either by providing a rate-controlling membrane (for example, in a transdermal patch applied topically) or by dispersing the compound in a polymer matrix or gel.

[0211] The pharmaceutically acceptable composition provided can be formulated for ophthalmic use as an atomizing suspension in isotonic pH-adjusted sterile saline, or preferably as a solution in isotonic pH-adjusted sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, the pharmaceutically acceptable composition can be formulated for ophthalmic use as an ointment such as petrolatum.

[0212] The pharmaceutically 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 pharmaceutical field and prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons and / or other conventional solubilizers or dispersants.

[0213] Most preferably, the pharmaceutically acceptable compositions described herein are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, the pharmaceutically acceptable compositions described herein are administered with food.

[0214] The amount of compounds described herein that may be combined with a carrier material to produce a single-dosage-form composition may vary depending on the host being treated and the specific method of administration. Preferably, the compositions provided should be formulated to administer an inhibitor in a dose of 0.01 to 100 mg / kg body weight / day to a patient receiving these compositions.

[0215] Liquid dosage forms for oral administration may be used, and such dosage forms include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain, in addition to, inert diluents widely 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, as well as mixtures thereof.

[0216] It should be understood that the specific dosage and treatment regimen for any particular patient will depend on various factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, excretion rate, drug combinations, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound described herein in a composition will also depend on the specific compound in that composition.

[0217] Depending on the specific 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. When used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as “suitable for the disease or condition being treated.”

[0218] In certain embodiments, the provided combination or composition is administered in combination with another therapeutic agent.

[0219] Examples of combinations of drugs described herein and those that may be combined in further ways include, but are not limited to, drugs used to treat Alzheimer's disease such as Aricept® and Excelon®; drugs used to treat HIV such as ritonavir; drugs used to treat Parkinson's disease such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexefenzil, and amantadine; drugs used to treat multiple sclerosis (MS) such as beta-interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; drugs used to treat asthma such as albuterol and Singulair®; drugs used to treat schizophrenia such as Zyprexa, Risperdal, Seroquel, and haloperidol; corticosteroids, TNF blockers, IL-1 Anti-inflammatory agents such as RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressant agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents; beta-blockers, ACE inhibitors, diuretics, nitrates, calcium Examples include drugs for treating cardiovascular diseases such as muchannel blockers and statins; drugs for treating liver diseases such as corticosteroids, cholestyramine, interferons, and antivirals; drugs for treating hematological disorders such as corticosteroids, antileukemia agents, and growth factors; drugs that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozol and ritonavir); and drugs for treating immunodeficiency disorders such as gamma globulin.

[0220] In certain embodiments, the combination therapies described herein, or any pharmaceutically acceptable compositions thereof, are administered in combination with monoclonal antibodies or siRNA therapeutics.

[0221] These additional agents may be administered separately from the combination therapy provided as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form mixed integrally with the compounds described herein as a single composition. When administered as part of a multi-dose regimen, these two activators may be administered simultaneously, sequentially, or within a period of time from one to the other, typically within 5 hours from the other.

[0222] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combinations described herein may be administered simultaneously or sequentially with other therapeutic agents, in separate unit dosage forms or together in a single unit dosage form.

[0223] The amount of additional therapeutic agents present in the compositions described herein will not exceed the amount that would normally be administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agents in the compositions of this disclosure will be in the range of about 50% to 100% of the amount that would normally be present in a composition containing that agent as the sole therapeutic active agent.

[0224] In one embodiment, the composition may include compound 1 and one or more additional therapeutic agents. These therapeutic agents may be administered together with compound 1, or before or after the administration of compound 1. Preferred therapeutic agents are described in further detail below. In certain embodiments, compound 1 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 before the administration of the therapeutic agent. In other embodiments, compound 1 may be administered 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.

[0225] In another embodiment, a method for treating inflammatory bowel disease, including Crohn's disease or ulcerative colitis, may include administering compound 1 and one or more additional therapeutic agents to a patient in need of treatment. Such additional therapeutic agents may be small molecule or recombinant biopharmaceuticals, for example, clobetasol, methotrexate, Humira®, Stellara®, 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®, Ta clonex(registered trademark), Tazorac(registered trademark), Acitretin(registered trademark), Cyclosporine(registered trademark), Betamethasone, Betamethasone / Calcipotriene, Halobetasol, Temovate(registered trademark), Kenalog(registered trademark), Kenalog-40(registered trademark), Neoral(registered trademark), Desoximetasone(registered trademark), Fluocinonide-E(registered trademark), Otrexup(registered trademark), Trexall(registered trademark), Coal Tar, Enstilar(registered trademark), Fluocinolone, Tazarotene, Topicrt(registered trademark), Calcitriol, Cortizone-10(registered trademark), Dexamethasone, Kenalog-10(registered trademark), Locid(registered trademark), Methylprednisolone, Prednisolone, Rasuvo(registered trademark), RediTrex(registered trademark), Taclonex Scalp (registered trademark), Tacrolimus, Triderm (registered trademark), Vanos (registered trademark), Vectical (registered trademark), Achar (registered trademark), Ala-Cort (registered trademark), Ala-Scalp (registered trademark), Ala-ScalpHP (registered trademark), Alclomethasone, Ammonium lactate / Halobetasol, Aquanil HC (registered trademark), Aristocort A (registered trademark), Aristocort R (registered trademark), Aristospan (registered trademark), Beta HC (registered trademark), Bioelements Immediate Comfort (registered trademark), Caldecort (registered trademark), Cinolar (registered trademark), Clincort (registered trademark), Cloderm (registered trademark), Cordran (registered trademark), Coorran Tape (registered trademark), Cortizone-5 (registered trademark), Dermaest Plus Anti-Itch (registered trademark), Dermovate (registered trademark), Dermtex HC (registered trademark), Diflorazone, Flulandalenolide, Gengraf (registered trademark), Halog (registered trademark), Infliximab, ITch-X Lotion (registered trademark), Locoid Lipocream(registered trademark), NuCort(registered trademark), Olux(registered trademark), Olux-E(registered trademark), Oxsoralen-Ultra(registered trademark), Pandel(registered trademark), Psoriasin(registered trademark), Sarnol-HC(registered trademark), Sernivo(registered trademark), Synalar(registered trademark), Texaccort(registered trademark), Trianex(registered trademark), Tritocin(registered trademark), U-Cort(registered trademark), Abrillada(registered trademark), Amcinonide, Amjevita(registered trademark), Ammonium lactate / urea, Analpram-HC(registered trademark), Analpram E(registered trademark), Anthraforte(registered trademark), Anthraline, Anthrascalp(registered trademark), Apexicon(registered trademark), ApexiCon E(registered trademark), Balnetar(registered trademark), Betatar Gel (registered trademark), Brodalumab, Bryhali (registered trademark), Calcitrene (registered trademark), Capex (registered trademark), Carb-O-Lac5 (registered trademark), Carb-O-Lac HP (registered trademark), Clobevate (registered trademark), Collocortolone, Clodan (registered trademark), Coal tar / Salicylic acid / Sulfur, Coal tar / Salicylic acid, Cordran SP (registered trademark), Cormax (registered trademark), CormaxScalp (registered trademark), Corticotropin, Cutar (registered trademark), Cyclocort (registered trademark), Cytezo (registered trademark), Derma-Smoothe / FS (registered trademark), Derma-Smoothe (registered trademark) / FS (body oil), Derma-Smoothe (registered trademark) / FS (Scalp), Dermatop (registered trademark), Desonate (registered trademark), DesOwen (registered trademark), DHS Tar Shapoo (registered trademark), Doak Taret (registered trademark), Dritho-Scalp (registered trademark), Drithocreme (registered trademark), Diobrii (registered trademark), Elta Tar (registered trademark), Embeline (registered trademark), Embeline E (registered trademark), Epifoam (registered trademark), Estar (registered trademark), Fototar (registered trademark), HP Acthar Gel (registered trademark), Hadima (registered trademark), Halcinonide, Halobetasol / Tazarotene, Halonate (registered trademark), HC Pram(registered trademark), Hurio(registered trademark), Hydrocortisone / Pramoxin, Hydroxyurea, Hyrimoz(registered trademark), Ipoyz(registered trademark), Ionil T(registered trademark), Ixfi(registered trademark), Kalosar(registered trademark), Kerasal Ultra 20(registered trademark), LoKara(registered trademark), Medotar(registered trademark), Mesoxsalen, MG217 Medicated Tar(registered trademark), Neutrogena T(registered trademark) / Derm, Neutrogena T(registered trademark) / Gel, Nolix(registered trademark), Novacort(registered trademark), Oxipor VHC(registered trademark), Pramosone(registered trademark), Prednicarbart, Proctofoam HC(registered trademark), RA Acne(registered trademark), Resorcinol(registered trademark), Scytera(registered trademark), Silq(registered trademark), Soriux(registered trademark), Synal Ointment(registered trademark), Tarsum(registered trademark), Theraplex T(registered trademark), Tovet(registered trademark), Ultralytic(registered trademark), UltralyticExamples include 2 (registered trademark), Ultravate (registered trademark), Verdeso (registered trademark), Wynzora (registered trademark), Yusimry (registered trademark), Zithranol (registered trademark), and Zithranol-RR (registered trademark).

[0226] In another embodiment, a method for treating an inflammatory disease, disorder, or condition may include administering compound 1 and one or more additional therapeutic agents to a patient in need. Such additional therapeutic agents may be small molecules or recombinant biopharmaceuticals, and may include, 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, and hydrocortisone, probenecid, allopurinol, febuxostat (Ulori c(registered trademark), sulfasalazine (Azufidin(registered trademark)), antimalarial agents such as hydroxychloroquine (Prakunil(registered trademark)) and chloroquine (Aralen(registered trademark)), methotrexate (Rheumatrex(registered trademark)), gold thioglucose (Solganal(registered trademark)), gold thiomalate (Myochrysine(registered trademark)) and gold salts such as auranofin (Ridaura(registered trademark)), D-penicillamine (Depen(registered trademark) or Cupr imin(registered trademark)), azathioprine (Imuran(registered trademark)), cyclophosphamide (Cytoxan(registered trademark)), chlorambucil (Leukran(registered trademark)), cyclosporine (Sandimmune(registered trademark)), leflunomide (Arava(registered trademark)), and, for example, etanercept (Enbrel(registered trademark)), infliximab (Remicade(registered trademark)), golimumab (Simponi(registered trademark)), certolizumab pegol (Cimzia(registered trademark)) and Anti-TNF agents such as adalimumab (Humira®), anti-IL-1 agents such as anakinra (Kineret®) and lilonacept (Arcalyst®), anti-Jak inhibitors such as canakinumab (Ilaris®) and tofacitinib, antibodies such as rituximab (Rituxan®), and anti-T cell agents such as abatacept (Orencia®), for example, tocilizumab (Actemra®)."Anti-IL-6" agents such as diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Cumadin®), antidiarrheal agents such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, allosetron (Lotronex®), and lubiprostone (Amitiza®), for example, Mik of Laxatives such as Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senkot®; anticholinergics or anticonvulsants such as dicyclomine (Bentyl®), Singulair®; beta-2 steroids such as albuterol (Ventolin® HFA, Proventil® HFA), revalbuterol (Xopenex®), metaprotenol (Alupent®), pyrbuterol acetate (Maxair®), terbutaline sulfate (Brethir®), salmeterol xinafoate (Servent®), and formoterol (Foradil®); Anticholinergic agents such as agonists, ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunizolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines, for example, theophylline (Theo-Dur®),IgE antibodies such as Theolair®, Slo-bid®, Uniphyl®, Theo-24®, and aminophylline, omalizumab (Xolair®), zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtri Nucleoside reverse transcriptase inhibitors such as va(registered trademark), lamivudine (Epivir(registered trademark)), lamivudine / zidovudine (Combivir(registered trademark)), staudin (Zerit(registered trademark)), and zalcitabine (Hivid(registered trademark)); non-nucleoside reverse transcriptase inhibitors such as delavirudine (Rescriptor(registered trademark)), efabrents (Sustiva(registered trademark)), nevirapine (Virmune(registered trademark)), and etravirine (Intelence(registered trademark)); tenofovir Nucleotide reverse transcriptase inhibitors such as (Viread®), amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezita®), hosanprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), Saki Entry inhibitors such as Navir (Fortovase® or Invirase®), tipranavir (Aptivus®), enfuvirtide (Fuzeon®), and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®),This includes integrase inhibitors such as dexamethasone (Decadron®) used in combination with lenalidomide (Revlimid®), or any combination(s) of these.

[0227] In another embodiment, a method for treating rheumatoid arthritis involves providing a patient in need of treatment with compound 1 and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, and hydrocortisone, antimalarial drugs such as sulfasalazine (Azulfidine®), hydroxychloroquine (Plaquenil®), and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold thioglucose (Solg Gold salts such as anal(registered trademark), gold thiomalate (Myocrysine(registered trademark)), and auranofin (Ridaura(registered trademark)), D-penicillamine (Depen(registered trademark)) or Cuprimin(registered trademark)), azathioprine (Imuran(registered trademark)), cyclophosphamide (Cytoxan(registered trademark)), chlorambucil (Leukran(registered trademark)), cyclosporine (Sandimmune(registered trademark)), leflunomide (Arava(registered trademark)), and "anti-TNF" agents, such as etanercept (Enbrel(registered trademark)), infliximab (Remicade(registered trademark)), and golimumab (Simpon). i) may include administering one or more additional therapeutic agents selected from certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and lilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), and "anti-IL-6" agents such as tocilizumab (Actemra®).

[0228] In some embodiments, a method for treating osteoarthritis may include administering to a patient in need of treatment compound 1 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.

[0229] In some embodiments, a method for treating cutaneous lupus erythematosus or systemic lupus erythematosus may include administering to a patient in need of treatment compound 1 and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib; corticosteroids such as prednisone, prednisolone, methylprednisolone, and hydrocortisone; antimalarial drugs such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®); cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0230] In some embodiments, a method for treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease may include administering to a patient in need of treatment compound 1 and one or more therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), for example diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), and lubiprostone (Amitza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, coror®, and Senocot®, as well as anticholinergics or anticonvulsants such as dicyclomine (Bentyl®), anti-TNF therapy, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0231] In some embodiments, a method for treating asthma involves providing a patient in need of treatment with compound 1 and beta-2 agonists such as Singulair®, for example, albuterol (Ventolin®) HFA, Proventil® HFA), revalbuterol (Xopenex®), metaprotenol (Alupent®), pyrbuterol acetate (Maxair®), terbutaline sulfate (Brethare®), salmeterol xinafoate (Servent®), and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®), Qvar®, and Vanceril®. This may include administering one or more therapeutic agents selected from liamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunizolid (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®), Theolair®, Slo-bid®, Uniphyl®, Theo-24®, and aminophyllines, and IgE antibodies such as omalizumab (Xolair®).

[0232] In some embodiments, a method for treating COPD involves providing a patient in need of treatment with compound 1 and a beta-2 agonist such as albuterol (Ventolin® HFA, Proventil®, revalbuterol (Xopenex®), metaproterenol (Alupent®), pyrbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), or an anti-inflammatory drug such as ipratropium bromide (Atrovent®) or tiotropium (Spiriva®). This may include administering cholinergic agents such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and methylxanthine derivatives such as aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), and one or more therapeutic agents selected from triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®.

[0233] In another embodiment, a method for treating hematological malignancies may include administering compound 1 and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, Hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof to a patient in need of treatment.

[0234] In another embodiment, a method for treating a solid tumor may include administering to a patient in need of treatment compound 1 and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0235] In another embodiment, a method for treating a hematological malignancy may include administering compound 1 and a hedgehog (Hh) signaling pathway inhibitor to a patient in need of treatment. 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 on July 17 and incorporated herein in its entirety by reference.

[0236] In another embodiment, a method for treating diffuse large B-cell lymphoma (DLBCL) may include administering to a patient in need of treatment compound 1 and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, and combinations thereof.

[0237] In another embodiment, a method for treating multiple myeloma may include administering to a patient in need of treatment compound 1 and one or more additional therapeutic agents selected from bortezomib (Velcade®) and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0238] In another embodiment, a method for treating a disease or reducing its severity may include administering compound 1 and a BTK inhibitor to a patient in need, where the disease is 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 mellitus, myasthenia gravis, Hashimoto's thyroiditis, Audrey's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme nerve Borreliosis, Guillain-Barré syndrome, acute disseminated meningitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture 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 generalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerulonephropathy, endometriosis, interstitial cystitis, uterine palsy Smallpox, bullous pemphigoid, neuromyotonia, scleroderma, chronic vulvodynia, hyperproliferative disorder, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, food, insect toxins, animal hair, animal scales, house dust mites or cockroach pods), type 1 hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, Bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, panentotitis, epicondylitis, epididymitis, fasciitis, connective tissue inflammation, 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, tendinitis, 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 lymphoblastic leukemia, pre-B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasmacytoma), non-Hodgkin lymphoma, Hodgkin lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B Large cell lymphoma, mantle cell lymphoma, mediastinal (thymic) primary large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer or mast cell cancer (e.g., mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of bone and joint (but not limited to, rheumatoid arthritis, seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behçet's disease, Sjögren's syndrome, systemic sclerosis, Osteoporosis, bone cancer, bone metastasis, thromboembolic disorders (e.g., myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass, restenosis after coronary artery bypass, cerebral infarction, transient ischemia, peripheral artery 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, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjögren's disease Tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and autoimmune thrombocytopenic conditions, Goodpasture syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes mellitus, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis,The following conditions are selected: juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, osteoarthritis, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0239] In another embodiment, a method for treating a disease or reducing its severity may include administering compound 1 and a PI3K inhibitor to a patient in need thereof, the disease being selected from cancer, neurodegenerative disorders, angiogenesis disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related disorders, organ transplant-related conditions, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, cell death-related conditions, thrombin-induced platelet aggregation, chronic myeloid leukemia (CmL), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune conditions with T-cell activation, cardiovascular disorders and CNS disorders.

[0240] In another embodiment, a method for treating or reducing the severity of a disease may include administering compound 1 and a PI3K inhibitor to a patient in need thereof, wherein the disease is a benign or malignant tumor, carcinoma or solid tumor, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, particularly colon cancer or colorectal adenoma, tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, abdomen, stomach, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, urogenital tract, esophagus, larynx, skin, bone or thyroid gland, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, particularly colon cancer or colorectal adenoma, tumor of the head and neck, Diseases including epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasms, epithelial plasma neoplasms, adenomas, adenocarcinomas, keratosacral cell tumors, epidermal carcinomas, large cell carcinomas, non-small cell lung cancers, lymphomas (including, for example, non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also known as Hodgkin or Hodgkin's disease)), breast cancer, follicular adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminomas, melanoma, or leukemia, Cowden syndrome, Lhermitt-Dacros disease and Nonnayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is abnormally activated, or any type or source of asthma (endogenous (non-allergic) asthma) Both and exogenous (allergic) asthma, including mild asthma, moderate asthma, severe asthma, bronchitis 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 airway disease or chronic obstructive pulmonary disease (COPD, COAD or COLD) (including chronic bronchitis or dyspnea associated with chronic bronchitis, emphysema, and exacerbations of airway hyperresponsiveness resulting from other drug therapies, particularly other inhaled drug therapies), bronchitis of any type or origin (acute, arachnoid). This includes, but is not limited to, sinusoidal, catarrhal, croup, chronic or narrow-type bronchitis, pneumoconiosis of any type or source (whether chronic or acute, often accompanied by airway obstruction, and caused by repeated inhalation of dust, generally occupational diseases, including aluminum pneumonitis, anthrax, asbestosis, lithiasis, tyrosis, iron disease, silicosis, tobacco poisoning and comostomosis), Loeffler syndrome, eosinophilic, pneumonia, parasitic (especially metazoan) invasion (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, herpetiform dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, acquired epidermolysis bullosa, conjunctivitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, rhinitis Diseases affecting the immune system (including allergic rhinitis), inflammatory diseases involving autoimmune reactions or those with autoimmune elements or etiologies (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) The following conditions are selected: 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 keratoconjunctivitis), interstitial pulmonary fibrosis, psoriatic arthritis, glomerulonephritis (regardless of whether it is complicated with nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.

[0241] In some embodiments, a method for treating a disease or reducing its severity may include administering compound 1 and a Bcl-2 inhibitor to a patient in need thereof, 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.

[0242] In some embodiments, a method for treating a disease or reducing its severity may include administering a TYK2 pseudokinase (JH2) domain-conjugated compound and a TYK2 kinase (JH1) domain-conjugated compound to a patient in need. 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-conjugated compound is compound 1. Other suitable JH2 domain-conjugated compounds include those described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, each of which is incorporated herein by reference in whole. Suitable JH1 domain-conjugated compounds include those described in WO2015131080A1, which is incorporated herein by reference in whole.

[0243] According to one embodiment, a method for inhibiting protein kinase activity in a biological sample may include the step of contacting the biological sample with a compound described herein, or a composition containing such compound.

[0244] According to another embodiment, a method for inhibiting the activity of TYK2 or its variants in a biological sample may include contacting the biological sample with a compound described herein or a composition containing said compound. In a particular embodiment, a method for irreversibly inhibiting the activity of TYK2 or its variants in a biological sample may include contacting the biological sample with a compound described herein or a composition containing said compound.

[0245] Another embodiment describes a method for selectively inhibiting TYK2 more selectively than one or more of JAK1, JAK2, and JAK3. In some embodiments, the compounds described herein are more than twice as selective as JAK1 / 2 / 3. In some embodiments, the compounds described herein are more than five times as selective as JAK1 / 2 / 3. In some embodiments, the compounds described herein are more than ten times as selective as JAK1 / 2 / 3. In some embodiments, the compounds described herein are more than fifty times as selective as JAK1 / 2 / 3. In some embodiments, the compounds described herein are more than one hundred times as selective as JAK1 / 2 / 3.

[0246] As used herein, the term “biological sample” includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears or other bodily fluids, or extracts thereof.

[0247] Inhibition of TYK2 (or its variants) activity in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological specimens, and bioassays.

[0248] In another embodiment, a method for inhibiting protein kinase activity in a patient may include administering to the patient a compound described herein, or a composition containing such compound.

[0249] According to another embodiment, a method for inhibiting the activity of TYK2 or its variants in a patient may include administering to the patient a compound described herein or a composition containing said compound. According to a particular embodiment, a method for reversibly or irreversibly inhibiting one or more of the activity of TYK2 or its variants in a patient may include administering to the patient a compound described herein or a composition containing said compound. In another embodiment, a method for treating a disorder mediated by TYK2 or its variants in a patient requiring treatment may include administering to the patient a compound described herein or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0250] Depending on the specific condition or disease being treated, additional therapeutic agents that are typically administered to treat that condition may also be present in the compositions described herein. When used herein, additional therapeutic agents that are typically administered to treat a particular disease or condition are known as “suitable for the disease or condition being treated.”

[0251] The compounds described herein may be used in combination with other therapeutic compounds to yield benefits. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule activating compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and further anti-angiogenic compounds; compounds that target, reduce, or inhibit protein or lipid phosphatase activity; gonadrelin agonists; anti-androgens; methionine aminopeptidase inhibitors; Matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, reduce, or inhibit Flt-3 activity; Hsp90 inhibitors, e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Examples of such compounds include, but are not limited to, Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, e.g., SB715992 or SB743921 (GlaxoSmithKline); or pentamidine / chlorpromazine (CombinatoRx); MEK inhibitors, e.g., ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer); and leucovorin. As used herein, the term “aromatase inhibitor” refers 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, particularly atamestane, exemestane, and formestan, as well as nonsteroids, particularly aminoglutethimide, logrethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, volozol, fadrozol, anastrozole, and letrozole. Exemestane is marketed under the trade name Aromasin®. Formestan is marketed under the trade name Lentaron®. Fadrozol is marketed under the trade name Afema®. Anastrozole is marketed under the trade name Arimidex®. Letrozole is marketed under the trade names Femara® or Femar®. Aminoglutethimide is marketed under the trade name Orimeten®. The combinations described herein may include chemotherapeutic agents that are aromatase inhibitors, which are particularly useful for the treatment of hormone receptor-positive tumors, such as tumors of the breast.

[0252] The term “anti-estrogen” as used herein refers to compounds that antagonize and inhibit 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 marketed under the trade name Nolvadex®. Raloxifene hydrochloride is marketed under the trade name Evista®. Fulvestrant may be administered under the trade name Faslodex®. The combinations described herein may include chemotherapeutic agents that are anti-estrogen, which are particularly useful in the treatment of estrogen receptor-positive tumors, such as tumors of the breast.

[0253] As used herein, the term “antiandrogenic agent” refers to any substance that can inhibit the biological effects of androgenic hormones, including but not limited to bicalutamide (Casodex®). As used herein, the term “gonadrelin agonist” includes, but is not limited to, abalerix, goserelin, and goserelin acetate. Goserelin, traded under the name Zoladex®, may be administered.

[0254] The term "topoisomerase I inhibitor," as used herein, includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin, and the high molecular weight camptothecin conjugate PNU-166148. For example, irinotecan may be administered in the form marketed under the trade name Camptosar®. Topotecan is marketed under the trade name Hycamptin®.

[0255] The term "topoisomerase II inhibitor," 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 losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is marketed under the trade name Etopophos®. Teniposide is marketed under the trade name VM 26-Bristol. Doxorubicin is marketed under the trade names Acriblastin® or Adriamycin®. Epirubicin is marketed under the trade name Farmorubicin®. Idarubicin is marketed under the trade name Zavedos®. Mitoxantrone is marketed under the trade name Novantron.

[0256] The term "microtubule activators" refers to microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubule polymerization inhibitors, and includes, but is not limited to, taxanes, e.g., paclitaxel and docetaxel; vinca alkaloids, e.g., vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides, colchicine, and epothirone, and their derivatives. Paclitaxel is marketed under the trade name Taxol®. Docetaxel is marketed under the trade name Taxotere®. Vinblastine sulfate is marketed under the trade name Vinblastin RP®. Vincristine sulfate is marketed under the trade name Farmistin®.

[0257] The term "alkylating agent," as used herein, includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin®. Ifosfamide is marketed under the trade name Holoxan®.

[0258] The terms "histone deacetylase inhibitor" or "HDAC inhibitor" refer to compounds that inhibit histone deacetylase and also possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0259] The term "antitemoid antimetabolites" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylation compounds such as 5-azacitidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda®. Gemcitabine is marketed under the trade name Gemzar®.

[0260] The term "platin compound," as used herein, includes, but is not limited to, carboplatin, cisplatin, cisplatin, and oxaliplatin. Carboplatin can be administered in forms such as those marketed under the trade name Carboplat®. Oxaliplatin can be administered in forms such as those marketed under the trade name Eloxatin®.

[0261] As used herein, the term “compounds that target / reduce protein or lipid kinase activity, or protein or lipid phosphatase activity, or further anti-angiogenic compounds” includes, for example, inhibitors of protein tyrosine kinase and / or serine and / or threonine kinase or lipid kinases, e.g., a) compounds that target, reduce, or inhibit the activity of platelet-derived growth factor receptor (PDGFR), e.g., compounds that target, reduce, or inhibit PDGFR activity, in particular compounds that inhibit PDGF receptor, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce, or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, reduce, or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), e.g., compounds that target, reduce, or inhibit IGF-IR activity. d) Compounds that reduce or inhibit the activity of the IGF-I receptor, in particular compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor; e) Compounds that target, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; f) Compounds that target, reduce, or inhibit the activity of the AxI receptor tyrosine kinase family; g) Compounds that target, reduce, or inhibit the activity of the Ret receptor tyrosine kinase; h) Compounds that target, reduce, or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, e.g., imatinib; h) Compounds that target, reduce, or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, e.g., compounds that target, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, e.g., imatinib;i) Compounds that target, reduce, or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g., BCR-Abl kinase), and mutants, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN107); PD180970; AG957; NSC Compounds that target, reduce, or inhibit the activity of members of the serine / threonine kinase protein kinase C (PKC) and Raf family, members of the MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and TEC family, and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives such as midostaurin; further examples of compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; illmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521;LY333531 / LY379196;Isochinoline compounds;FTI;PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor);k)Compounds that target, reduce, or inhibit the activity of protein tyrosine kinase inhibitors, for example, imatinib mesylate (Gleevec®) or tilphostin A23 / RG-50810;AG99;tilphostin AG 213;tilphostin AG 1748;tilphostin AG 490;tilphostin B44;tilphostin B44(+) enantiomer;tilphostin AG 555;AG 494;tilphostin AG 556, AG957 and adaphostine (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantyl benzoate;1) Compounds that target, reduce, or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGF1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their variants, such as compounds that target, reduce, or inhibit the activity of the epidermal growth factor receptor family, in particular, compounds that inhibit members of the EGF receptor tyrosine kinase family such as the EGF receptor, ErbB2, ErbB3, and ErbB4, or EGF or EGF-related ligands, CP 358774, ZD 1839, ZM Compounds, proteins, or antibodies that bind to 105180; trastuzumab (Herceptin®), cetuximab (Erbitux®), Iressa, Tarceva, OSI-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, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, reduce, or inhibit the activity of the c-Met receptor, e.g., compounds that target, reduce, or inhibit the activity of c-Met, in particular compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) PRT-062070, SB Compounds that target, reduce, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to -1578, baricitinib, pacritinib, momerotinib, 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, pictrelisib, PF-4691502, BYL-719, dactricib, XL-147, XL-765, and idelalisib;Furthermore, q) includes, but is not limited to, compounds that target, reduce, or inhibit the signaling effects of the Hedgehog protein (Hh) or Smoothund receptor (SMO) pathway, including, cyclopamine, bismodegib, itraconazole, erythmodegib, and IPI-926 (salidegib).

[0262] As used herein, the term “PI3K inhibitor” includes, but is not limited to, compounds having inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family, including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, 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, pictrelisib, PF-4691502, BYL-719, dactricib, XL-147, XL-765, and idelalisib.

[0263] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds having inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0264] As used herein, the term “SYK inhibitor” includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including, but is not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and hostamatinib.

[0265] As used herein, the term “Bcl-2 inhibitor” includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but is not limited to, ABT-199, ABT-731, ABT-737, apogosipol, the pan-Bcl-2 inhibitor Ascenta, curcumin (and its analogues), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogues; see WO2008118802), navitoclax (and its analogues, see US7390799), NH-1 (Shenayng Pharmaceutical University), ovatoclax (and its analogues, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments, Bcl-2 inhibitors are small molecule therapeutics. In some embodiments, Bcl-2 inhibitors are peptide mimes.

[0266] Further examples of BTK inhibitory compounds, and the conditions treatable by such compounds in combination with the compounds described herein, can be found in WO2008039218 and WO2011090760, which are incorporated herein by reference in their entirety.

[0267] Further examples of SYK inhibitory compounds, and the conditions treatable by such compounds in combination with the compounds described herein, can be found in WO2003063794, WO2005007623, and WO2006078846, all of which are incorporated herein by reference.

[0268] Further examples of PI3K inhibitory 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, all of which are incorporated herein by reference.

[0269] JAK inhibitors and conditions treatable by such compounds in combination with the compounds described herein can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, which are incorporated herein by reference.

[0270] Further angiogenesis inhibitory compounds include those with alternative mechanisms of activity, such as those not related to the inhibition of protein kinases or lipid kinases, such as thalidomide (Thalomid®) and TNP-470.

[0271] 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.

[0272] Compounds that target, reduce, or inhibit the activity of protein phosphatases or lipid phosphatases include, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives.

[0273] 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.

[0274] The term cyclooxygenase inhibitor, as used herein, includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid and its derivatives, such as celecoxib (Celebrex®), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as lumiracoxib, which is 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid.

[0275] The term "bisphosphonate," as used herein, includes, but is not limited to, etidronic acid, clodronic acid, dydronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is marketed under the trade name Didronel®. Clodronic acid is marketed under the trade name Bonefos®. Dydronic acid is marketed under the trade name Skelid®. Pamidronic acid is marketed under the trade name Aredia®. Alendronic acid is marketed under the trade name Fosamax®. Ibandronic acid is marketed under the trade name Bondranat®. Risedronic acid is marketed under the trade name Actonel®. Zoledronic acid is marketed under the trade name Zometa®. The term "mTOR inhibitor" refers to compounds that inhibit the mammalian target (mTOR) of rapamycin and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican®), CCI-779, and ABT578.

[0276] The term "heparanase inhibitor," as used herein, refers to a compound that targets, reduces, or inhibits the degradation of heparin sulfate. This term includes, but is not limited to, PI-88. The term "biological response modifier," as used herein, refers to a lymphokine or interferon.

[0277] The term “inhibitor of oncogenic isoforms of Ras,” such as H-Ras, K-Ras, or N-Ras, as used herein, refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras, e.g., “farnesyltransferase inhibitors,” e.g., L-744832, DK8G557, or R115777 (Zarnestra®). The term “telomerase inhibitor,” as used herein, refers to compounds that target, reduce, or inhibit the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are, in particular, compounds that inhibit the telomerase receptor, e.g., telomestatin.

[0278] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Examples of compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamides or their derivatives.

[0279] As used herein, the term "proteasome inhibitor" refers to a compound that targets, reduces, or inhibits the activity of the proteasome. Examples of compounds that target, reduce, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade®) and mLN341.

[0280] The term “matrix metalloproteinase inhibitor” or “(“MMP” inhibitor)” as used herein includes, but is not limited to, inhibitors that are collagen peptide mimes and non-peptide mimes, tetracycline derivatives, such as the peptide mime of hydroxamate inhibitor bacistat and its orally administered and in vivo-available analogues maristat (BB-2516), prinostat (AG3340), metastat (NSC683551), BMS-279251, BAY12-9566, TAA211, MMI270B, or AAJ996.

[0281] The term "compounds used in the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, interferons, 1-β-D-arabinofrancilcytosine (ara-c), and busulfan, which are compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R), ALK inhibitors, which are compounds that target, reduce, or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[0282] Compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are, in particular, compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248, and mLN518.

[0283] The term "HSP90 inhibitor," as used herein, includes, but is not limited to, compounds that target, reduce, or inhibit the endogenous ATPase activity of HSP90, or compounds that degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce, or inhibit the endogenous ATPase activity of HSP90 include, 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.

[0284] 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. An antibody means an intact monoclonal antibody, a polyclonal antibody, a multispecific antibody formed from at least two intact antibodies, and an antibody fragment insofar as it exhibits the desired biological activity.

[0285] 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 therapies used to treat 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, a method for treating AML associated with ITD and / or D835Y mutations may 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 restaurtinib), 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, tozacertib, and sunitinib.

[0286] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analog that is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are 6-mercaptopurine (6-MP), a purine analog of hypoxanthine, and fludarabine phosphate. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxanoate (SAHA), inhibit the activity of the enzyme known as histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A, and compounds disclosed in US6,552,065, which include, but are not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indole-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salts, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indole-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salts, particularly lactates. When used herein, somatostatin receptor antagonists 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" as used above and below means ionizing radiation that occurs either as electromagnetic waves (such as X-rays and gamma rays) or as particles (such as alpha and beta particles). Ionizing radiation is supplied in radiotherapy and is known in the art, but is not limited to the following: Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th See Edition, Vol. 1, pp. 248-275 (1993).

[0287] This also includes EDG conjugates and ribonucleotide reductase inhibitors. As used herein, the term “EDG conjugate” refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term “ribonucleotide reductase inhibitor” 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 pentostatins. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0288] Certain compounds included in these categories are also 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salts, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin®; Endostatin®; Anthranilamide; ZD4190; ZD6474; SU5416; SU6668; Bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g., rhuMAb and RHUFab; VEGF aptamers, e.g., Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, angiozymes (RPI 4610) and proteins such as bevacizumab (Avastin®), or monoclonal antibodies of VEGF.

[0289] As used herein, photodynamic therapy refers to therapies that treat or prevent cancer using certain chemical substances known as photosensitizing compounds. Examples of photodynamic therapy include treatment with compounds such as Visudyne® and porfimer sodium.

[0290] As used herein, anti-angiogenic steroids refer to compounds that block or inhibit angiogenesis, such as anecoltab, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone.

[0291] Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

[0292] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds and antagonists, biological response modifiers, preferably lymphokines or interferons, antisense oligonucleotides or oligonucleotide derivatives, shRNA or siRNA, or miscellaneous compounds, or other or unknown compounds with a mechanism of action.

[0293] The compounds described herein are particularly useful as combination therapeutic compounds used in combination with other drug substances, such as anti-inflammatory, bronchodilating, or antihistamine drug substances, in the treatment of obstructive or inflammatory airway diseases, for example, as enhancers of the therapeutic activity of such drugs, or as a means of reducing the required dose or potential side effects of such drugs. The compounds described herein may be mixed with other drug substances in a certain pharmaceutical composition, or administered before, simultaneously with, or separately after other drug substances. Accordingly, combinations of the compounds described herein and anti-inflammatory, bronchodilating, antihistamine, or antitussive drug substances, the compounds described herein, and the drug substances may be present in the same pharmaceutical composition or in different pharmaceutical compositions.

[0294] Suitable anti-inflammatory drugs include steroids, particularly glucocorticosteroids such as budesonide, beclametasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate; nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; siromiramilast (Ariflo® GlaxoSmithKline), roflumiramilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), and allophylline (Almirall). Examples include PDE4 inhibitors such as 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 Kogyo); A2a agonists; A2b antagonists; and β-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and in particular formoterol, as well as pharmaceutically acceptable salts thereof. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxytropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolates.

[0295] Appropriate antihistamines include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine, fexofenadine hydrochloride, acribastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and terfenadine.

[0296] Other useful combinations of the compounds described herein with anti-inflammatory agents include antagonists of chemokine receptors, e.g., CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, and CXCR5, particularly CCR-5 antagonists, e.g., Schering-Plough antagonists SC-351125, SCH-55700, and SCH-D, as well as Takeda antagonists, e.g., N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]aminophenyl]phenyl]methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0297] The structures of active compounds, identified by code number, generic name, or trade name, may be obtained from the current edition of the standard abstract "The Merck Index" or from databases such as Patents International (e.g., IMS World Publications).

[0298] The compounds described herein may also be used in combination with known therapeutic processes, such as hormone administration or radiation therapy. In certain embodiments, the compounds provided are used as radiosensitizers, particularly for the treatment of tumors that are less sensitive to radiotherapy.

[0299] The compounds described herein may be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may take the form of fixed combinations, alternating administration of the compounds described herein with one or more other therapeutic compounds, or administration of each independently, or combination administration of the fixed combination with one or more other therapeutic compounds. The compounds described herein may be administered in combination with or in addition to chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof, particularly for the treatment of tumors. Long-term therapy is also possible, as with other therapeutic strategies as described above, such as adjuvant therapy. Other possible therapies are those to maintain the patient's condition after tumor regression, or even after chemoprevention therapy, for example, in patients at risk.

[0300] These additional agents may be administered separately from the composition containing the compounds of the present invention as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form mixed with the compounds described herein in a single composition. When administered as part of a multi-dose regimen, these two activators may be supplied simultaneously, sequentially, or within a period of time from one to the other, typically within 5 hours from the other.

[0301] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents. For example, the compounds described herein may be administered simultaneously or sequentially with another therapeutic agent, in separate unit dosage forms or together in a single unit dosage form. Thus, a single unit dosage form may contain the compounds described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0302] The amounts of the compound of the present invention and any additional therapeutic agent (in the composition containing the additional therapeutic agent as described above), which may be combined with a carrier material to produce a single dosage form, will vary depending on the host being treated and the specific method of administration. Preferably, the compositions described herein should be formulated so that the compound of the present invention can be administered at a dose of 0.01 to 100 mg / kg body weight / day.

[0303] In compositions containing additional therapeutic agents, the additional therapeutic agent and the compounds described herein may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than the amount required for monotherapy using only that therapeutic agent. In such compositions, the additional therapeutic agent can be administered at a dose of 0.01 to 1,000 μg / kg body weight / day.

[0304] The amount of additional therapeutic agents present in the compositions described herein will not exceed the amount typically administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agents in the compositions disclosed herein will be in the range of about 50% to 100% of the amount typically present in a composition containing that agent as the sole therapeutic active agent.

[0305] The compounds or pharmaceutical compositions described herein may be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Vascular stents are used, for example, to relieve restenosis (narrowing of the vascular wall after injury). However, patients using stents or other implantable devices are at risk of blood clot formation or platelet activation. These undesirable effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. Implantable devices coated with the compounds described herein are another embodiment. [Examples]

[0306] As shown in the following examples, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. It will be understood that the following general method, and other methods known to those skilled in the art, are applicable to all compounds, as well as to each of the subclasses and species of these compounds, as described herein. Additional compounds described herein may be prepared by methods substantially similar to those described in the examples, and by 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 (whose contents are incorporated herein in their entirety by reference). Example 1: Phase 2b study to evaluate the efficacy and safety of oral compound 1 in patients with moderate to severely active Crohn's disease. [Table 1] Example 2: Phase 2 multicenter randomized placebo-controlled double-blind induction study to evaluate the efficacy and safety of oral compound 1 in patients with moderate to severe ulcerative colitis. [Table 2]

[0307] Example 3: Phase 1 randomized, double-blind, placebo-controlled, multi-dose study of compound 1 in healthy volunteers (Study 104) overview Rationale: In a previous study (Study 101), two cohorts of healthy participants were administered compound 1 at doses of 20 mg or 35 mg daily for two weeks. The treatment was generally safe, well-tolerated, and no serious or severe adverse events were reported. The study of the present invention was designed to define a relatively broad dose range and to continue dose escalation in healthy participants to help select doses in future studies in patients with psoriasis and other autoimmune diseases. Nonclinical pharmacological, toxicological, and pharmacokinetic (PK) studies, as well as historical clinical data, support the proposal for multi-dose studies of compound 1 in healthy participants. Goals and evaluation items [Table 3]

[0308] overall design This was a phase 1 randomized, double-blind, placebo-controlled, multi-dose trial of compound 1 in healthy participants.

[0309] The study population consisted of healthy male participants aged 18–65 years and / or female participants not of pregnancy potential. There were two multi-dose cohorts (Cohort 1 and Cohort 2), each consisting of eight healthy participants who received either compound 1 (N=6) or placebo (N=2) at a daily dose for two weeks. Participants were admitted to the CRU on day 1. Participants remained in the CRU until day 22, after which they were discharged if medically appropriate, until all scheduled procedures were completed. Safety tests, blood draws for PK, blood draws for PD, and adverse event assessments were performed according to the Schedule of Activities (SoA).

[0310] Cohort 2 was not enrolled until the PI and sponsor determined that the safety and tolerability of Cohort 1 had been adequately demonstrated.

[0311] Patients were questioned about their potential exposure to COVID-19 and / or symptoms of COVID-19. PCR testing for COVID-19 was performed at the screening visit and on day 1-1, and samples were sent to the central laboratory. Patients who tested positive for COVID-19 at screening or on day 1-1 were considered ineligible for screening. Participants who developed symptoms consistent with COVID-19 infection after administration underwent PCR testing, and were excluded from the study if the result was positive. This was recorded as an adverse event. Disclosure Statement: This is a sequential intervention trial involving two cohorts, blinded to the sponsor, participants, and principal investigator. Number of participants:

[0312] There were approximately 16 participants who were randomly assigned to test the intervention, and 16 evaluable participants (8 per cohort).

[0313] Intervention group and duration: The 16 participants will receive either the investigational drug or a placebo in the doses specified below. [Table 4]

[0314] The screening period was approximately 28 days. Participants were confined to the CRU from day 1 to day 22. Treatment was administered once daily for 14 days, and a safety follow-up visit was scheduled for day 22, prior to discharge from the CRU. The total duration of participation in the study was approximately 50 days.

[0315] Rules for discontinuing dose escalation For at least six participants in Cohort 1, the decision to move from Cohort 1 to Cohort 2 and to the next higher dose was made jointly by the sponsor and PI, based on all reasonable blinded safety / tolerability data up to day 15 (e.g., AEs, clinical laboratory results, physical examination results, vital signs, and safety ECGs), as well as consideration of PK data. In addition, the sponsor and PI determined whether to continue the trial as planned, continue the trial with additional safety assessments, continue the trial with a different dose than the dose planned for Cohort 2, or discontinue dose escalation.

[0316] Dose escalation was stopped if at least two participants in the cohort met any of the following criteria related to the study drug. • There are drug-related SAEs. • Drug-related toxicity of grade 3 or higher has been observed.

[0317] If even one participant met the following criteria related to the study drug at a given dose level, the dose escalation was stopped.

[0318] 1. There is evidence of drug-induced liver injury (DILI). If evidence suggesting a treatment-related SAE, grade 3 or higher AE, and / or DILI was observed, the PK sample was collected and notified by the sponsor. At the discretion of the PI, the allocation of the corresponding participant to treatment may be unblinded to determine whether the event is related to compound 1 and whether the discontinuation criteria are met. Any unblinding of participant treatment was documented.

[0319] Where applicable, the IRB was provided with a written explanation of the reasons for terminating the trial. This trial was monitored by the trial team.

[0320] Rationale for dosage Compound 1 had previously been investigated in a human trial (Study 101) involving healthy volunteers at both single-dose and two multi-dose levels (SAD and MD). Single doses of 5 mg to 200 mg daily for two weeks, and repeated doses of 20 mg or 35 mg, were generally safe and well-tolerated. No serious or severe adverse events, nor any AEs leading to treatment discontinuation, were observed. The most common adverse event was skin rash, i.e., acneiform dermatitis, occurring in 7 out of 17 subjects (41%) receiving a single dose of 100 mg or more, and in 8 out of 12 subjects (67%) receiving repeated doses. Although these events were frequent, they were all mild and resolved within 1-2 weeks with limited or no intervention, even in the multi-dose groups, without requiring treatment discontinuation.

[0321] In the single-dose cohort using the TPGS formulation, overall exposure to compound 1 increased roughly proportionally with the dose at 5 mg–75 mg, and below a dose-proportional level at 100 mg–200 mg. Overall, exposure levels were similar after a single dose of compound 1 as either the TPGS or SDD formulation. Similar oral exposure levels were observed whether compound 1 using the SDD formulation was administered in a well-fed or fasted state.

[0322] In the multi-dose cohort using the TPGS formulation, moderate accumulation of compound 1 was observed at daily dose levels of 20 mg and 35 mg, and in all dose-dosing plans, C max and AUC 0-tau The accumulation rate was less than 3 across both. In the steady state, treatment with 20 mg resulted in C max This is approximately 207 ng / mL, and the AUC last This was approximately 3160hr*ng / mL. When 35mg was administered daily for 2 weeks, the corresponding C observed at steady state was max The value is approximately 325 ng / mL, AUC lastThe value was 5839 hr*ng / mL. The AUC exposure level achieved at the higher dose investigated, namely 35 mg, was approximately 1 / 8 to 1 / 9 of the NOAEL determined in 28-day repeated-dose toxicity studies in monkeys and rats, respectively.

[0323] In this study, two additional multi-dose regimens, namely 50 mg in Cohort 1 and up to 100 mg in Cohort 2, were investigated to expand the range of the study dose. The SDD formulation was used in this study. The predicted exposure levels after daily administration of 50 mg and 100 mg for two weeks are predicted to be approximately 1 / 7–1 / 8 (50 mg) and approximately 1 / 3–1 / 4 (100 mg), respectively, of the NOAELs obtained in 28-day repeated-dose toxicity studies in monkeys and rats.

[0324] Nonclinical pharmacological, toxicological, and pharmacokinetic (PK) studies, historical clinical data, and modeling data for 50 mg and 100 mg doses support the proposal for a multi-dose study of compound 1 using 50 mg as the initial dose in healthy participants. Check-in procedure (Day 1)

[0325] -On the morning of day 1, all participants returned to the CRU. Inclusion and exclusion criteria were reviewed to ensure that participants continued to meet all entry criteria. A second COVID-19 PCR test was also administered, and the samples were sent to the central laboratory. After the PCR test, participants remained in the isolation area until the test results became available later that day. -Participants who did not meet all inclusion criteria or who met any of the exclusion criteria (including a positive COVID-19 test) on day 1 were considered ineligible for screening.

[0326] Other participants who met the entry criteria during screening also returned to the CRU and completed the -1 day activities. Even if these other participants were not randomly assigned due to meeting the participant target per cohort, they were still eligible for subsequent cohorts. If these other participants were enrolled in the trial the day after the initial -1 day assessment, they did not need to repeat the -1 day examination.

[0327] Treatment and monitoring period On the morning of the first day, pre-administration evaluation results were obtained. Once all criteria had been reviewed, participants were randomly assigned.

[0328] Participants received either compound 1 or placebo as a single oral dose on the morning of day 1, followed by daily doses for a total of 14 days. Safety and tolerability were assessed throughout the treatment period through monitoring, including vital signs, clinical laboratory tests, lead 12 ECG, and adverse events (AEs). Blood samples for PK and PD assessment, and urine samples for metabolite profiling, were collected at the listed time points. Hemodynamic monitoring was also performed.

[0329] Safety follow-up examination / Early discontinuation On the 22nd day, a follow-up examination was conducted to monitor the patient's safety before discharge.

[0330] Safety and tolerability were evaluated through monitoring, including vital signs, clinical laboratory tests, 12-lead ECG, and adverse events.

[0331] In the event of early discontinuation, the safety follow-up examination must be conducted according to the procedures outlined in the Statement of Action (SoA). However, blood samples for PK evaluation were also collected. Following the visit for early discontinuation, the participant must revisit the facility within 7 days of the last dose of the study drug for a safety follow-up examination.

[0332] Meal schedule -On the first day, meals and / or snacks were provided as needed.

[0333] Participants were required to fast for at least 8 hours overnight before receiving the study drug, and then continue fasting for at least 4 hours on the first day only.

[0334] Water (except for water provided with administration) was restricted from one hour before to one hour after administration, but was free to consume at all other times. Other fluids were permitted as part of a standard meal and / or snack, but were restricted at all other times throughout the entire period of restraint.

[0335] Duration of detention The participants were detained at the CRU for 22 days.

[0336] Inclusion Criteria Participants were only considered eligible to take the exam if they met all of the following criteria. age 1. Participants must be between 18 and 65 years of age (including both ages) at the time of signing the informed consent form. Participant types and disease characteristics 2. Participants are medically healthy volunteers who, at screening and on day 1, the PI (Primary Inspector) considers to have no clinically significant medical history, physical examination findings, specimen profile, vital signs, or ECG. All specimen test results should generally be within the normal range defined by the CRU (Clinical Research Unit) laboratory. 3. Non-smokers (defined as individuals who have not used nicotine-containing products, including tobacco and e-cigarettes, for at least three months prior to administration) body weight 4. At screening and clinic admission, body mass index (BMI) is between 18 and 35 kg / m². 2 (Including both numbers) sex 5. Men or women who are not capable of becoming pregnant. Male participants and their female partners must use two methods of contraception during the study: one considered highly effective (less than 1% failure rate per year) as defined in the CTFG guidelines (CTFG2014), and the other, the barrier method, when engaging in sexual intercourse. After the last dose, male participants and their partners must continue using contraception for 90 days and refrain from sperm donation. Female participants must be either surgically infertile or menopausal (confirmed by FSH testing) at least 6 months prior to screening. Informed consent 6. You may submit a signed informed consent document (ICF) and the requirements and limitations listed in this protocol.

[0337] Exclusion criteria Participants were excluded from the study if they met any of the following criteria. Medical condition 1. Participants with evidence of a mild, active infection (e.g., upper respiratory tract, urinary tract, gastrointestinal tract) at the time of screening for any acute or chronic medical condition (including abnormal laboratory values ​​(grade 1 or greater), abnormal electrocardiogram (ECG) results, or psychosis that would prevent a participant from signing an informed consent document, or that would cause a participant to be classified as an unacceptably high-risk individual if they participated in the study, or that would impair their ability to interpret data derived from the study) may be re-screened after their symptoms have completely resolved and they have completed an appropriate course of treatment. 2. Female participants who may be pregnant 3. Positive serological test for hepatitis B, hepatitis C, or human immunodeficiency virus (HBsAg positive, HCV Ab positive, or HIV Ab positive) 4. At the time of screening or on day -1, the individual has tested positive for COVID-19 via PCR, or within 10 days of the screening visit, has been suspected of having COVID-19, or has been diagnosed with COVID-19 or has had prior contact with another person under investigation for COVID-19 within 10 days of the screening. However, in Cohort 1, individuals who test positive for COVID-19 during screening may be re-screened for Cohort 2 after completing an appropriate quarantine period in accordance with CDC guidelines. Individuals who have previously been infected with COVID-19 (based on clinical symptoms or clinical specimen testing), have recovered from symptoms, are negative for COVID-19 antigen by PCR, and have no sequelae may be screened for study enrollment if the PI deems it appropriate. 5. Participants with any surgical condition or medical condition that may affect the absorption, distribution, metabolism, or excretion of the study drug. 6. Blood pressure is less than 90 / 40 mmHg or greater than 140 / 90 mmHg at the time of screening. 7. Heart rate is less than 40 bpm or greater than 99 bpm at the time of screening. 8. The QTcF (Fridericia-corrected) interval is >450 msec for men and >470 msec for women at the time of screening, or there is a history of long QT syndrome. 9. You have received a blood transfusion (including whole blood, platelets, or plasma) or significant blood loss within 56 days prior to administration, or you are scheduled to receive a blood transfusion within 30 days of your last administration of the study drug. 10. Unable to tolerate oral administration 11. A history of solid or hematological malignancies (including premalignant conditions, such as myelodysplastic syndrome or lymphoproliferative disorders) within the past five years (excluding a history of focal basal cell carcinoma or squamous cell carcinoma of the skin that has been surgically removed and for which there is no evidence of recurrence, successfully treated ductal carcinoma in situ, and successfully treated carcinoma in situ). Previously used / concurrently used medications, supplements, or treatments 12. Participants who received any vaccine, including COVID-19, within 28 days of administration. 13. Participants who have used a systemic prescription drug within 30 days of administration (or within 5 half-lives of the concomitant therapy drug, whichever is longer), or who have used an over-the-counter drug, herbal medicine, vitamin supplement, or topical medication within 14 days of administration. Self-limiting use of a drug (e.g., Tylenol) may be considered an exception if approved by the PI and sponsor. 14. Participants who are scheduled to receive selective medical treatment during the trial. 15. Participants who, at the time of screening, are involved in recreational drug use or have tested positive for drug screening. 16. Participants who test positive for cotinine Past / contemporary clinical trial experience 17. Participants who have received the investigational drug or an approved drug in a clinical trial environment within 30 days of administration of the investigational drug or within 5 half-lives (whichever is longer), or, if the investigational drug is a biologic (e.g., an antibody), within 6 months of administration of the investigational drug, or who are currently enrolled in the clinical trial. Diagnostic evaluation 18. Participants who, in the opinion of the PI, have any of the other criteria (such as clinically significant screening blood test results) that could interfere with the conduct or outcome of the study. Other exclusion criteria 19. Participants with a known hypersensitivity to any of the excipients in the study drug or placebo formulation. 20. Alcohol consumption within 14 days of randomization

[0338] Lifestyle considerations As outlined in the sections below, participants were required to restrict their diet, substance use, and activity levels during the study.

[0339] Diet and dietary restrictions Participants are prohibited from consuming grapefruit or grapefruit juice for 14 days prior to medication administration, throughout the entire treatment period, and throughout the entire period of PK sample collection.

[0340] Restrictions on caffeine, alcohol, tobacco, and cannabis As indicated, the consumption of foods and beverages containing the following substances is prohibited.

[0341] Participants must not ingest any products containing xanthine or caffeine from 48 hours prior to administration through the entire period of PK sample collection.

[0342] Participants must not consume alcohol or alcohol-containing products within 14 days of administration, or as described regarding concomitant medication use. Cold medicines and other medications containing small amounts of alcohol are permitted if deemed necessary.

[0343] Participants must not use tobacco or nicotine products (including smokeless tobacco, nicotine patches, or nicotine gum) while at the clinical site, and must refrain from using such products during the trial screening period.

[0344] Participants must not use recreational drugs, including cannabis products (in any form, including oral or sublingual), while at the clinical site. Participants must also refrain from using recreational drugs during the trial screening period.

[0345] activity Participants must limit their physical activity to a level sufficient for daily living activities (e.g., eating, bathing, dressing) from 48 hours before administration until the safety follow-up appointment. During this time, moderate or vigorous activities (e.g., doubles tennis, 3-5km running, marathon training / running, CrossFit training, or weightlifting) are not permitted. [Table 5]

[0346] Safety evaluation The primary objective of this study was to evaluate the safety and tolerability of compound 1. Safety was assessed by evaluating physical examination, vital signs, ECG, clinical laboratory parameters, and adverse events (AEs).

[0347] Additional safety measurements were performed at the discretion of the PI where deemed necessary. The Sponsor Medical Monitor was available to discuss any potential safety issues throughout the trial.

[0348] Physical examination results Height (in centimeters) and weight (in kilograms) were measured.

[0349] The physical examination results included assessments of at least the circulatory, respiratory, gastrointestinal, musculoskeletal, and nervous systems. Height (only at screening) and weight were also measured and recorded. BMI was calculated only at screening and upon admission to the clinic. Each participant was examined by a qualified physician or qualified contractor. Physical examinations may be performed at various unscheduled points in time if the PI deemed it necessary.

[0350] All abnormal findings during the screening period were recorded as part of the patient's medical history.

[0351] PIs or qualified contractors must pay attention to clinical signs related to pre-existing conditions.

[0352] Vital signs In participants in a supine position, vital signs were measured after 5 minutes of rest in an environment free from distractions (e.g., television, mobile phone). If the safety ECG coincided with the time specified for the extraction of the hemodynamic ECG, vital signs were taken after at least 10 minutes of rest. Vital signs included measured values ​​of temperature (oral or tympanic), systolic and diastolic blood pressure, heart rate, and respiratory rate.

[0353] Blood pressure and heart rate measurements were assessed using automated equipment. Manual techniques were used only when automated equipment was unavailable. Three readings were taken for both blood pressure and heart rate. Participant eligibility at screening was determined using the average of the three readings.

[0354] Vital signs were measured on day 1. Blood pressure and heart rate must be recorded with three readings. Eligibility must be confirmed using the average of the three readings.

[0355] On days 1 and 2, vital signs must be taken within 30 minutes prior to administration. Post-administration vital signs must be taken within 30 minutes of the times specified in the Schedule of Activities (i.e., 2 hours, 4 hours, 8 hours, and 24 hours after administration).

[0356] In addition, vital signs were measured on the last day of administration of the study drug and during safety follow-up (see SoA). Blood pressure and heart rate must be recorded with three readings.

[0357] If PI is deemed necessary, additional measurements must be performed.

[0358] electro-cardiogram During the trial, ECGs were obtained by classifying them as either safety ECGs or hemodynamic ECGs. Standard 12-lead ECG (safety ECG)

[0359] 12-lead ECGs were recorded. The timing and recording techniques of the ECGs were standardized for all participants. All safety ECGs after administration of the study drug on day 1 were obtained and recorded using the triplicate method.

[0360] Holter monitoring (circulatory dynamics ECG) The timing and recording techniques of ECG were standardized for all participants involved in hemodynamic monitoring. Holter monitoring was performed on days 1 and 14 from 2 hours before administration to 24 hours after administration to collect continuous 12-lead ECG data. During this period, ECG extraction was performed by a third-party vendor using data from the Holter monitor at certain time points (except for the pre-administration period, when three independent pre-administration measurements were required for hemodynamic monitoring: 60 minutes, 45 minutes, and 30 minutes before administration) that were generally combined with blood sampling for PK.

[0361] Laboratory evaluation of clinical safety As summarized above, we conducted a laboratory evaluation of clinical safety.

[0362] The PI or qualified person must review the laboratory report, document this review, and record any clinically significant changes that occurred during the trial.

[0363] Clinical laboratory tests that produce values ​​considered clinically significant 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.

[0364] If the above values ​​do not return to normal / baseline levels within the period deemed appropriate for a PI, the etiology must be investigated and the sponsor notified.

[0365] Laboratory evaluation results not specified in the protocol that require changes in participant management or that the PI considers clinically significant (e.g., resulting in an AE) must also be recorded in the CRF.

[0366] Drug-induced liver injury (DILI) Events that meet the definition of drug-induced liver injury (DILI): • In the presence of normal alkaline phosphatase (ALP), if alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is more than 3 times the ULN, and total bilirubin (TBL) is more than 2 times the ULN, prompt intensified monitoring of all liver tests (at least ALT, AST, ALP, and TBL, as well as prothrombin time (PT) / INR) and an assessment of the cause of the liver test abnormalities are required (FDA 2009). • ALT or AST levels greater than 3 times the ULN level, accompanied by fatigue, nausea, vomiting, pain or tenderness in the right upper abdomen, fever, rash, and / or eosinophilia (greater than 5%) (FDA 2009)

[0367] The medical monitor must be contacted immediately. During the evaluation, additional medical management considerations (for designated participants, and potentially extending to a broader cohort) must be considered.

[0368] The following particularly noteworthy adverse events must be reported to the sponsor immediately, and the PI must notify the sponsor within 24 hours of becoming aware of the event. • Blood cell count exceeding Grade 2 • Platelet count is less than 75,000 / mm³ • WBC count is less than 3000 / mm • Neutrophil count is less than 1500 / mm³ • Lymphocyte count less than 800 / mm3 • Hemoglobin level less than 10 g / dL • Creatine phosphokinase (CPK) levels increased to over Grade 3 [more than 5 times higher than ULN].

[0369] Pharmacokinetic measurements Approximately 5 mL of blood sample was collected to measure the plasma concentrations of compound 1 and its metabolites.

[0370] The actual date and time (in 24-hour format) for each sample was recorded.

[0371] The pharmacokinetics (PK) of compound 1 were evaluated using the samples. Each sample was divided into two aliquots (one for PK and one for backup). Samples taken for plasma concentration analysis may be used to evaluate the formation of metabolites or safety aspects related to concerns that arose during or after the test.

[0372] Blood samples for pharmacokinetic analysis were collected as follows: [Table 6]

[0373] Urine samples were collected from all participants in Cohort 2 before administration on day 1 and on day 14, as described below. [Table 7]

[0374] Pharmacokinetics As a measure of the pharmacokinetic response to treatment with compound 1, approximately 1 mL of whole blood sample was collected directly from a designated time point into a provided TruCulture (Myriad RBM) whole blood assay tube. Collection was performed within a time frame of ±30 minutes from the designated time point. These samples were incubated in vitro at 37°C for approximately 24 hours in CRU, and the level of IFNγ produced in response to stimulation by cytokines derived from the cell supernatant was quantified using an appropriate immunoassay.

[0375] Example 4: Treatment of IBD with Compound 1 Inflammatory bowel disease (IBD) represents one of the key potential differentiation opportunities for Compound 1, our selective TYK2 allosteric inhibitor. We believe that the selectivity, PK profile, and PD profile of Compound 1 may further enhance its targeted inhibitory effect on TYK2 while maintaining a favorable tolerability profile.

[0376] IBD is inflammation of the gastrointestinal tract caused by an immune response to environmental stimuli. According to the Decision Resources Group, the two most common forms of IBD, ulcerative colitis and Crohn's disease, are estimated to affect approximately 1.9 million adults in the United States. Ulcerative colitis and Crohn's disease are primarily distinguished by the affected part of the gastrointestinal tract. Ulcerative colitis is characterized by inflammation of the large intestine or colon and rectum, while Crohn's disease involves inflammation of any part of the gastrointestinal tract, but most commonly affects the terminal part of the small intestine or ileum connected to the colon. The inventors believe that approximately 980,000 adults in the United States and a similar number of adults in the four EU countries and the United Kingdom are diagnosed with ulcerative colitis, and approximately 900,000 adults in the United States, the four EU countries, and the United Kingdom are diagnosed with Crohn's disease.

[0377] The approach to treating IBD is determined by several factors, including disease severity, location of inflammation, past response to treatment, side effects, and comorbidities. The most common oral medications for ulcerative colitis are anti-inflammatory agents, including 5-aminosalicylic acid (5-ASA). These drugs reduce inflammation of the intestinal wall and may alleviate symptoms and maintain remission in ulcerative colitis, but they are less effective in treating Crohn's disease. Corticosteroids and other oral immunomodulators may be used for short-term control of exacerbations and maintenance of remission in IBD patients who have not responded to other medications.

[0378] Injectable biologics are generally available for the treatment of moderate to severe ulcerative colitis and Crohn's disease. The most commonly prescribed biologics are anti-TNFα biologics (including AbbVie's Humira®, Johnson & Johnson's Remicade® and Simponi®, and UCB Pharma's Cimzia®). Newer biological treatment options include anti-integrin therapy for ulcerative colitis (Takeda's Entyvio®) and anti-IL-12 / IL-23 antibodies for Crohn's disease (e.g., Johnson & Johnson's Stellara®). Pfizer's oral JAK inhibitor, Xeljanz®, was approved in 2018 for the treatment of ulcerative colitis, but its market availability is limited due to the safety concerns mentioned above. Zeposia®, a registered trademark of BMS, is an S1P1R oral modulator that was approved in May 2021 for the treatment of moderate to severe ulcerative colitis.

[0379] In 2020, the market for IBD at all levels of severity was approximately $14 billion in the United States and $25 billion globally. Global reported sales of ulcerative colitis treatments totaled an estimated $7.9 billion in 2020, and global annual sales of Crohn's disease treatments totaled an estimated $17.7 billion in 2020. Market research suggests that the IBD market has significant growth potential, driven by rising disease prevalence and the emergence of novel oral medications. The inventors believe that the growth potential of oral formulations is supported by physician and patient preference for oral administration over injectable biotherapy agents, a high demand for new therapies with competitive clinical profiles, and the potential for potent and well-tolerated oral formulations to expand the overall treatment population for moderate to severe ulcerative colitis.

[0380] Currently, TNF inhibitors dominate the market for the treatment of ulcerative colitis, followed closely by other injectable biological therapies (anti-IL-12 / 23 antibodies and anti-integrin therapies) and oral 5-ASA therapies.

[0381] Example 5: Absorption, distribution, metabolism, excretion (ADME), and other properties of Compound 1 The potency and selectivity of compound 1 were investigated by screening its binding to a panel of 631 kinases at a concentration of 1 micromolar. Only one kinase was inhibited with an inhibition rate of over 50% (PIP5K1C (inhibition rate 54%)). Various results for potency / selectivity in vitro are summarized in the table below. [Table 8]

[0382] Drug metabolism and pharmacokinetic (PK) studies were conducted with compound 1 in rodent (mice and rats) and non-rodent (dogs and monkeys) species, and systemic exposure to compound 1 after oral administration was evaluated in completed non-clinical safety studies. [Table 9]

[0383] Compound 1 showed good absorption across species. FaSSIF solubility was 13 μg / mL, and FeSSIF solubility was 70 μg / mL (dynamic solubility 32 μM). Caco-2 P app (AB) is 15 × 10 -6 The effusion rate was cm / second, and the effusion ratio was 1. The likelihood of drug interactions in DDI was low at clinically significant exposure levels. CYP450 IC 50 The levels were over 30 μM for 1A2, 2C9, and 2D6, over 8 μM for 2C19 and 3A4(M), and 2 μM for 3A4(T). PXR activation was low (26% of the control rifampicin at 30 μM), indicating low overall metabolism, and the inventors observed low overall metabolism. Human metabolites were observed in vitro in hepatocytes of preclinical species (rats and cynomolgus monkeys). Elimination was primarily via oxidative metabolism by multiple CYP450 enzymes followed by conjugation.

[0384] While many embodiments of the present invention have been described, it is clear that the basic embodiments of the present invention can be modified to provide other embodiments utilizing the compounds and methods of the present invention. Therefore, it will be understood that the scope of the present invention should be defined by the appended claims, rather than by the specific embodiments shown as examples.

[0385] Example 6: Efficacy of oral tyrosine kinase 2 (TYK2) inhibitor compound 1 in two preclinical mouse models of colitis. Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and plays a crucial role in the pathogenesis of inflammatory bowel disease (IBD) and other autoimmune diseases through its mediation of downstream signaling pathways for interleukin (IL)-12, IL-23, and interferon (IFN) α / β. While several JAK inhibitors are approved for the treatment of ulcerative colitis (UC), they are associated with adverse events likely related to JAK1-3 inhibition, resulting in limited dose levels. Compound 1 is a highly potent and selective allosteric oral TYK2 inhibitor computer-designed to bind to the Janus homology 2 (JH2) domain of TYK2, but is designed to be sterically shielded from the JH2 domains of JAK1-3. This study evaluated the efficacy of compound 1 in two IL-23-dependent preclinical mouse models of colitis induced by (i) adoptive T cell transfer (TCT) and (ii) anti-CD40 monoclonal antibody (α-CD40 mAb). All animal protocols were approved by the Animal Care Committee (IACUC).

[0386] Processing method In the adopted TCT colitis model, CD4 + CD45RB hi T cells were transferred into severe combined immunodeficiency (SCID) mice on day 0, and disease progression was followed for 48 days (Figure 1A). In the α-CD40 model, Rag2 cells lacking T cells and B cells were used. - / -Mice were administered the agonist α-CD40 mAb on day 0, and disease progression was tracked for 7 days (Figure 1B). Mice were divided into four groups per model (TCT and α-CD40 mAb colitis models, with n=12-16 and n=10 per group, respectively), and the mice were given a vehicle (negative control) orally twice daily; IC 50 Compound 1 (low) taken orally twice daily (BID); IC 90 Compound 1 (high) was administered orally twice daily (BID); or α-IL-12 / 23 p40mAb (positive control) was administered intraperitoneally once weekly (QW). In vivo doses were modeled based on previous mouse pharmacokinetic data, intended to achieve 24-hour coverage at inhibitory concentrations. At the end of the treatment period, colon tissue from the TCT colitis model was obtained for RNA-seq analysis, and transcriptome profiles were analyzed using Reactome (reactome.org). Colon weight:length ratio and total histological score were also evaluated. Statistical significance of differences between groups was determined using analysis of variance (ANOVA) along with Tukey's post-hoc test. All animal protocols were approved. The treatment methods are summarized below. The mice were divided into four groups for each model (ICI colitis model and a-CD40 mAb colitis model, with n=12-16 and n=10 respectively), and the mice were given - Vehicle (negative control) taken orally twice a day -I C 50 (Low) Compound 1 is taken orally twice a day. -I C 90 (High) Compound 1 is administered orally twice a day; or -α-IL-12 / 23 p40mAb (positive control) was administered intraperitoneally once a week. The treatment began on day 0 and ended on day 48 (TCT colitis model) and day 7 (a-CD40mAb colitis model). At the end of the treatment period, the weight-to-length ratio of the colon and the total histological score were evaluated in both models. Colon tissue derived from a TCT colitis model was obtained for RNA-seq analysis. Transcriptomics profile analysis was performed using Reactome. https: / / reactome.org / ) was used.

[0387] In the TCT model, IC 50 and IC 90 At both dosage levels, compound 1 significantly reduced the colon weight:length ratio compared to the vehicle (both p<0.0001) (Figures 2A-2B; Table 1). In contrast, in the α-CD40mAb colitis model, IC 90 Only at the medication level was the colon weight:length ratio significantly reduced compared to the vehicle (p<0.01) (Figure 2A-2B; Table 1). No significant difference was observed between compound 1 and the positive control at any medication level in any model. Furthermore, in the TCT model, the total histological score was higher in IC 50 and IC 90 Compound 1 significantly reduced the score compared to the vehicle at both dosage levels (p<0.01 and p<0.0001, respectively) (Figures 3A-3B; Table 1). There was no significant difference in the reduction of the total histology score compared to the positive control at either dosage level, however, IC 90 The values ​​were higher at the medication level. In contrast, in the α-CD40mAb colitis model, IC 90 Only at the medication level was the total histological score significantly lower compared to the vehicle (p<0.001). IC was observed between compound 1 and the positive control. 90 No significant differences were observed at the medication level.

[0388] In the TCT colitis model, compound 1 selectively downregulated genes related to cytokine signaling, particularly those associated with the helper T17 (Th17) cell phenotype, including those related to the IFNα / β pathway, the innate immune system, and interleukin signaling, compared to the vehicle (Figure 4). Compound 1 was effective in two preclinical mouse models of colitis. IC90 It yielded maximum efficacy in both models. Downregulation was observed in the expression of multiple genes involved in cytokine signaling pathways. These preclinical results support the potential role of potent and selective TYK2 inhibition in IBD treatment, and compound 1 was IC12 in humans. 90This coverage is expected to be achieved. See, for example, Leit S et al. J.Med.Chem. 2023;66:10473-96, Herrera-deGuise C et al. Front Med. (Lausanne), 2023;10:1089099, and Gangolli EA et al. STAT, 2022;1:5. [Table 10]

Claims

1. A method for treating inflammatory bowel disease, including Crohn's disease or ulcerative colitis, in patients requiring treatment, comprising: a therapeutically effective amount of compound 1: 【Chemistry 1】 The method comprising administering a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

2. The aforementioned administration lasts for approximately 1 to 2 days, 2 to 3 days, 3 to 4 days, 4 to 5 days, 5 to 6 days, 6 to 7 days, 1 to 2 weeks, 2 to 3 weeks, 3 to 4 weeks, 4 to 5 weeks, 5 to 6 weeks, 6 to 7 weeks, 7 to 8 weeks, 8 to 9 weeks, 9 to 10 weeks, 10 to 11 weeks, 11 to 12 weeks, 12 to 14 weeks, 14 to 16 weeks, 16 to 18 weeks, and 18 to 21 weeks. The method according to claim 1, performed daily for a week, a period of approximately 21 to 24 weeks, 24 to 27 weeks, 27 to 30 weeks, 30 to 33 weeks, 33 to 36 weeks, 36 to 39 weeks, 39 to 42 weeks, 42 to 45 weeks, 45 to 48 weeks, 48 ​​to 51 weeks, 51 to 52 weeks, 1 to 2 years, or 2 to 3 years, 3 to 4 years, 4 to 5 years, or a period exceeding 5 years.

3. The method according to claim 1, wherein the administration is performed daily over an indefinite period.

4. The method according to any one of claims 1 to 3, wherein an average reduction of approximately 50% to 70% in the Crohn's disease simplified endoscopic score (SES-CD) is achieved in patients with Crohn's disease.

5. The method according to any one of claims 1 to 3, wherein an average reduction of approximately 70% to 90% in the Crohn's disease simplified endoscopic score (SES-CD) is achieved in patients with Crohn's disease.

6. The method according to claim 4 or 5, wherein an average reduction of approximately 90% to 100% in the Crohn's disease simplified endoscopic score (SES-CD) is achieved in patients with Crohn's disease.

7. The method according to any one of claims 1 to 6, wherein a Crohn's disease patient with isolated ileal disease achieves a Crohn's disease simplified endoscopic score (SES-CD) of 4 or less, or a reduction of at least 2 points from baseline as determined by central interpretation.

8. The method according to any one of claims 1 to 6, wherein, in a patient with ulcerative colitis, the modified Mayo score (a scoring system for evaluating the activity of ulcerative colitis) is 2 or less, the bowel movement frequency subscore is 1 or less, the rectal bleeding subscore is 0, and the central endoscopy subscore is 1 or less (a score of 1 is modified to exclude vulnerability).

9. The method according to any one of claims 1 to 8, wherein the patient has inflammatory bowel disease.

10. The method according to claim 9, wherein the inflammatory bowel disease is moderate to severely active.

11. The method according to any one of claims 1 to 10, wherein the patient has Crohn's disease.

12. The method according to claim 11, wherein the Crohn's disease is moderate to severely active.

13. The method according to any one of claims 1 to 10, wherein the patient has ulcerative colitis.

14. The method according to claim 13, wherein the ulcerative colitis is moderate to severely active.

15. The method according to claim 11, wherein, for patients with Crohn's disease, including moderately to severely active Crohn's disease, the method achieves: a reduction of 50% or more from baseline in the centrally interpreted simplified endoscopic score for Crohn's disease (SES-CD), or a reduction of approximately 50% to approximately 70%, approximately 70% to approximately 90%, or approximately 90% to approximately 100% of the SES-CD; or, for isolated ileal disease, an SES-CD of 4 or less, or a reduction of at least 2 points from baseline as centrally interpreted.

16. The method according to claim 13, wherein, for patients with ulcerative colitis including moderate to severely active colitis, the method achieves: a modified Mayo score of 2 or less (a scoring system for assessing the activity of ulcerative colitis) and a bowel movement frequency subscore of 1 or less, a rectal bleeding subscore of 0, and a central endoscopy subscore of 1 or less (with the score modified to 1 to exclude vulnerability).

17. A method for inhibiting the production of interferon-gamma (IFNγ) in a patient, comprising: a therapeutically effective dose of compound 1 in a patient with inflammatory bowel disease. 【Chemistry 2】 The method comprising administering a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

18. The method according to claim 17, wherein the patient has Crohn's disease.

19. The method according to claim 17, wherein the patient has ulcerative colitis.

20. The method according to claim 17, wherein the inflammatory bowel disease is moderate to severely active.

21. The method according to claim 18, wherein the Crohn's disease is moderate to severely active.

22. The method according to claim 19, wherein the ulcerative colitis is moderate to severely active.

23. The method according to any one of claims 1 to 22, wherein the plasma Tmax of compound 1 is achieved in about 3 hours to about 6 hours.

24. Compound 1 in plasma t １／２ The method according to any one of claims 1 to 22, wherein the result is achieved in approximately 17 to 37 hours.

25. The method according to any one of claims 1 to 24, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of up to about 200 mg.

26. The method according to any one of claims 1 to 24, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in a dose of about 30 mg to about 100 mg.

27. The method according to any one of claims 1 to 24, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in doses of about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg.

28. The method according to any one of claims 1 to 27, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in a once-daily dose.

29. The method according to any one of claims 1 to 27, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in a dose twice daily.

30. The method according to any one of claims 1 to 27, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in multiple daily doses.

31. The method according to any one of claims 1 to 30, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for 12 weeks.

32. The method according to any one of claims 1 to 30, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for 60 weeks.

33. The method according to any one of claims 1 to 32, wherein compound 1 is administered orally to the patient.

34. The method according to any one of claims 1 to 33, wherein the patient is a human being.

35. About 25 ng / mL to about 30 ng / mL, about 30 ng / mL to about 35 ng / mL, about 35 ng / mL to about 40 ng / mL, about 40 ng / mL to about 45 ng / mL, about 45 ng / mL to about 50ng / mL, about 50ng / mL to about 60ng / mL, about 60ng / mL to about 70ng / mL, about 70ng / mL to about 80ng / mL, about 80ng / mL to about 9 0ng / mL, about 90ng / mL to about 100ng / mL, about 100ng / mL to about 120ng / mL, about 120ng / mL to about 140ng / mL, about 140ng / mL to about 160ng / mL, about 160ng / mL to about 180ng / mL, about 180ng / mL to about 200ng / mL, about 200ng / mL to about 240ng / mL, about 240ng / mL ~about 280ng / mL, about 280ng / mL to about 320ng / mL, about 320ng / mL to about 360ng / mL, about 360ng / mL to about 400ng / mL, about 400ng / mL to about 480ng / mL, about 480ng / mL to about 560ng / mL, about 560ng / mL to about 740ng / mL, about 740ng / mL to about 820ng / mL, about 820 Serum C levels between ng / mL and approximately 900 ng / mL, approximately 900 ng / mL and approximately 1000 ng / mL, approximately 1000 ng / mL and approximately 1200 ng / mL, approximately 1200 ng / mL and approximately 1400 ng / mL, approximately 1400 ng / mL and approximately 1600 ng / mL, approximately 1600 ng / mL and approximately 1800 ng / mL, or approximately 1800 ng / mL and approximately 2000 ng / mL ｍａｘ The method according to any one of claims 1 to 34, wherein the objective is achieved.

36. A method for treating moderate to severe inflammatory bowel disease, including Crohn's disease or ulcerative colitis, in patients requiring treatment, comprising a therapeutically effective amount of compound 1: 【Transformation 3】 The method comprising administering the substance in a daily dose of approximately 30 mg to approximately 100 mg.

37. Compound 1: 【Chemistry 4】 The use of pharmaceutically acceptable salts thereof in the treatment of inflammatory bowel diseases, including Crohn's disease or ulcerative colitis.

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