TYK2 inhibitors for treatment of inflammatory bowel disease

Abstract

Compounds, compositions thereof, and methods of using the same in dosing regimens for inhibiting TYK2 and treating inflammatory conditions, including inflammatory bowel disease, including Crohn's disease or ulcerative colitis, are set forth.

Description

Technical Field

[0001] This invention relates to a method of administering a non-receptor tyrosine kinase 2 (TYK2) inhibitor (e.g., 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 in treating inflammatory conditions (e.g., inflammatory bowel disease, including Crohn's disease or ulcerative colitis). Background Technology

[0002] Protein kinases constitute a large family of structure-associated enzymes responsible for controlling various signal transduction processes within cells. Due to the conservation of their structure and catalytic function, protein kinases are believed to have evolved from a common ancestral gene. Almost all kinases contain similar catalytic domains of 250-300 amino acids. They can be classified into numerous families based on the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0003] Generally, protein kinases mediate intracellular signaling by facilitating the transfer of phosphoryl groups from nucleoside triphosphates to protein receptors involved in signaling pathways. These phosphorylation events act as molecular on / off switches, modulating or regulating the biological functions of target proteins. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), interleukin-12 (IL-12), interleukin-23 (IL-23), and tumor necrosis factor-α (TNF-α)), and growth factors (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to: cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis control, and cell cycle regulation.

[0004] Many diseases are associated with abnormal cellular responses triggered by events mediated by kinases. These diseases include (but are not limited to) autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurodegenerative diseases, some cancers, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases.

[0005] Tyrosine kinase 2 (TYK2) catalyzes the phosphorylation of STAT proteins downstream of various cytokine receptors, including type I interferon receptors and IL-12 and IL-23 receptors. TYK2-dependent receptor activation by its cytokine ligands leads to STAT-dependent transcription and activation of cellular functional responses specific to the receptors and cell types expressing them. The TYK2-regulated cytokine signaling pathway plays a crucial role in several immune-mediated diseases. Cytokine IL-12 is essential for the development of type 1 T helper cells (Th1), which produce interferon-γ, a major effector molecule in systemic autoimmune diseases such as systemic lupus erythematosus. Cytokine IL-23 is crucial for the expansion and survival of Th17 cells and innate lymphoid cells, both of which have been shown to play key pathogenic roles in autoimmunity. IL-23 stimulation drives Th17 cells to produce key pro-inflammatory cytokines, including IL-17A, IL-17F, and IL-22. All of these cytokines are important effector molecules in the pathogenesis of diseases such as inflammatory bowel diseases (including Crohn's disease or ulcerative colitis). Given TYK2's effects on the IL-23 / Th17 / Th22 axis, IL-12-mediated Th1 function, and type I interferon-driven regulation of various immune pathways and cell types, inhibition of TYK2 is expected to affect a variety of immune-mediated disorders.

[0006] Therefore, there is still a need to find TYK2 inhibitors that can be used as therapeutic agents. This disclosure addresses this need and offers other related advantages. Summary of the Invention

[0007] It has been found that certain TYK2 inhibitors are suitable for oral administration to patients for the treatment of inflammatory conditions (e.g., inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC)). Therefore, in one aspect, methods of treating IBD (including CD or UC) in patients of need may include administering to the patient a therapeutically effective amount of a TYK2 inhibitor (e.g., compound 1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Compound 1 has the following structure: 1 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.

[0009] In some implementation schemes, the patient may have IBD.

[0010] In some implementation schemes, patients may have moderate to severe active IBD.

[0011] In some implementations, for patients with CD, a reduction of greater than or equal to 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%) in the Simplified Endoscopic Score for Crohn's Disease (SES-CD) compared to baseline can be achieved in a centralized manner; or a reduction of about 50% to about 70%, about 70% to about 90%, or about 90% to about 100% in the SES-CD can be achieved.

[0012] In some implementation schemes, patients can achieve remission, including clinical remission and deep remission.

[0013] In some implementations, for patients with CD with isolated ileal disease, a score of less than or equal to 4 (e.g., about 4, about 3, about 2, about 1, or about 0) or a reduction of at least 2 points from baseline can be achieved by reading in a focused manner.

[0014] In some implementation schemes, the patient may have CD.

[0015] In some implementation schemes, patients may have moderate to severe active CD.

[0016] In some implementations, for patients with UC, a modified Mayo score (a scoring system for assessing ulcerative colitis activity) of less than or equal to 2 can be achieved, with a stool frequency sub-score of less than or equal to 1, a rectal bleeding sub-score of 0, and a central reading endoscopy score of less than or equal to 1 (a modified score of 1 to exclude fragility).

[0017] In some implementation schemes, the patient may have UC.

[0018] In some implementation schemes, patients may have moderate to severe active UC.

[0019] In some implementations, for patients with CD (including moderate to severe active CD), the method may achieve: a reduction in the simplified endoscopic score for Crohn's disease (SES-CD) of 50% or more (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%) from baseline, or a reduction in SES-CD of about 50% to about 70%, about 70% to about 90%, or about 90% to about 100%; or for isolated ileal disease, a reduction in the 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, read in a centralized manner.

[0020] In some embodiments, for patients with UC (including moderate to severe active UC), the method may achieve: a modified Mayo score (a scoring system for assessing ulcerative colitis activity) less than or equal to 2, wherein the stool frequency sub-score is less than or equal to 1, the rectal bleeding sub-score is 0, and the central reading endoscopy score is less than or equal to 1 (modified score 1 to exclude fragility). On the other hand, methods for inhibiting interferon-γ (IFNγ) production may include administering a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof or a combination thereof to a patient in need. In some embodiments, the method is associated with improvement in IBD (including CD or UC), such as those described above and elsewhere herein.

[0021] In some cases, the disclosed methods and uses of administering compound 1 to achieve certain pharmacokinetic parameters of this disclosure have certain advantages in the treatment of IBD (including CD or UC). For example, in some embodiments, the T of compound 1 in plasma 最大 It is reached within approximately 3 to 6 hours, or the t of compound 1 in the plasma. 1 / 2 It will be reached in approximately 17 to 37 hours.

[0022] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient in a dose of about 30 mg to up 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 a 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.

[0023] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is prepared to provide approximately 24 hours of IC50. 50 Coverage dosage application.

[0024] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is prepared to provide approximately 24 hours of IC50. 90 Coverage dosage application.

[0025] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in a single daily dose, a twice daily dose, or a multiple daily dose. In other embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for 2 weeks to 52 weeks or longer. 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 longer, for example, until the patient's IBD (including CD or UC) improves. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient 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., in humans).

[0026] In some implementations, prior to administration, the patient may have active moderate to severe ileal (terminal ileum), ileocolic, or colonic CD.

[0027] In some implementations, the patient's CDAI score can be between 220 and 450 (inclusive) prior to administration.

[0028] In some implementations, such as those determined by ileocolonoscopy prior to administration and defined by SES-CD greater than or equal to 6 (for isolated ileitis, SES-CD greater than or equal to 4), patients may present with CD-characteristic ulcers.

[0029] In some implementations, patients may have a recorded diagnosis of CD, including reports of the disease based on prior histological endoscopy, biopsy, and / or previous ileocolonoscopy.

[0030] In some implementation schemes, patients may have moderate to severe active UC prior to administration.

[0031] In some implementations, patients may have a modified Mayo score (a scoring system for assessing the activity of ulcerative colitis) of 5 to 9, with an endoscopic score greater than or equal to 2.

[0032] In some implementations, patients may have a recorded diagnosis of UC, including a histological endoscopy prior to administration, a biopsy report confirming the histological diagnosis, and / or a report recording the duration of the disease based on a previous colonoscopy, wherein the disease extends more than 15 cm from the anal margin.

[0033] In some implementation schemes, the following serum C levels can be achieved. 最大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. ng / mL, about 240 ng / mL to about 280 ng / mL, about 280 ng / mL to about 320 ng / mL, about 320 ng / mL to about 360 ng / mL, about 360 ng / mL to about 400 ng / mL, about 400 ng / mL to about 480 ng / mL, about 480 ng / mL to about 560 ng / mL, about 560 ng / mL to about 740 ng / mL, about 740 ng / mL to about 820 ng / mL, about 820 ng / mL to about 900 ng / mL, about 900 ng / mL to about 1000 ng / mL, about 1000 ng / mL to about 1200 ng / mL, about 1200 ng / mL to about 1400 ng / mL, about 1400 ng / mL to about 1600 ng / mL, about 1600 ng / mL to about 1800 ng / mL ng / mL, or approximately 1800 ng / mL to approximately 2000 ng / mL.

[0034] On the other hand, a method is provided for treating IBD (including CD or UC) in patients in need, the method comprising administering a therapeutically effective amount of compound 1 at a daily dose of about 30 mg to about 200 mg.

[0035] On the other hand, the use of compound 1 or a pharmaceutically acceptable salt thereof for the treatment of IBD (including CD or UC) is provided.

[0036] These and other aspects of this disclosure will become apparent upon reference to the following detailed description. Attached Figure Description

[0037] Figures 1A to 1BThis is a diagram illustrating the research designs in 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 metastasis.

[0038] Figures 2A to 2B It is a drawing ( Figure 2A TCT colitis model and ( Figure 2B A graph showing the colon weight to length ratio in an α-CD40 mAb colitis model. Significance in the graph was determined using ANOVA and Tukey's post-hoc test, and indicates: * 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; IC 50 50% inhibitory concentration; IC50 90 90% inhibition concentration; mAb, monoclonal antibody; ns, not significant; TCT, T cell metastasis.

[0039] Figures 3A to 3B It is a drawing ( Figure 3A TCT colitis model and ( Figure 3B A graph of the total histological score in an α-CD40 colitis model. Significance in the graph was determined using ANOVA and Tukey's post-hoc test, and indicates: * 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; IC 50 50% inhibitory concentration; IC50 90 90% inhibition concentration; mAb, monoclonal antibody; ns, not significant; TCT, T cell metastasis.

[0040] Figure 4 Transcriptomic heatmap and analysis of Th17 phenotype-related genes isolated from colon tissue in a TCT colitis model at the end of the treatment period. BID, twice daily; IC 50 50% inhibitory concentration; IC50 90 90% inhibition concentration; IL, interleukin; Th17, T helper cell 17. Detailed Implementation

[0041] TYK2 is a specific mediator of signal transduction via interleukin (IL-12, IL-23) and type I interferon (IFN) receptors, and is a validated therapeutic target in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC).

[0042] The compound 1 disclosed herein is an orally administered, allotropic, highly potent, and selective TYK2 inhibitor computationally designed to bind to the Janus homology 2 (JH2) domain of TYK2, but spatially isolated from the JH2 domains of Janus kinases (JAK) 1–3. Compound 1 is intended for the treatment of IBD (including CD or UC), psoriasis, psoriatic arthritis, and other inflammatory and autoimmune diseases. Furthermore, the selectivity and once-daily (QD) dosing of compound 1, with its potential to provide higher levels of TYK2 inhibition over a longer period, gives it a clinical and ultimately commercial advantage over other TYK2 inhibitors in development.

[0043] TYK2 is a member of the JAK kinase family, a class of intracellular signaling proteins that regulate chronic inflammation in inflammatory and autoimmune diseases. TYK2 plays a crucial role in the pathogenesis of IBD and other autoimmune diseases via signaling pathways downstream of IL-12, IL-23, and IFN α / β. Although JAK inhibition is effective in treating inflammatory and autoimmune diseases, and some JAK inhibitors have been approved for the treatment of UC, these inhibitors are associated with adverse events that may be related to JAK1–3 inhibition. JAK inhibition can also lead to off-target safety issues due to its modulation of numerous cytokine pathways. Therefore, although JAK inhibitors have become established oral treatments for many inflammatory and autoimmune diseases, their clinical efficacy is limited by the increased risk of infection and other side effects, leading to dose level restrictions and mandatory packaging warnings by the US Food and Drug Administration (FDA) as part of the labeling of these inhibitors. Due to the structural similarity between the catalytic (ortho- or JH1) sites targeted by drugs on the JAK catalytic domain, designing selective JAK inhibitors and dosing regimens that directly and specifically inhibit the function of the intended kinase is challenging. Based on human genetic data and a growing body of clinical evidence on the selectivity of allotropic TYK2 inhibitors, the sex-selective TYK2 inhibition method of this invention provides an optimal balance of achieving potent efficacy while potentially avoiding the safety issues associated with broader JAK inhibition for the treatment of a variety of inflammatory and autoimmune diseases.

[0044] In three Phase I studies, compound 1 was rapidly absorbed (median T). 最大 (3-6 hours), the increase in exposure is roughly proportional to the dose and the half-life (t) 1 / 2 The duration of exposure was 17–37 hours. Pharmacodynamics was tested using whole blood samples in cytokine-induced ex vivo assays. Treatment with compound 1 resulted in rapid inhibition of interferon-γ (IFNγ) production; increased exposure was associated with increased IFNγ inhibition. No serious adverse events (SAEs) or deaths were observed. Observed adverse events (AEs) included acneiform dermatitis, papules, aphthous ulcers, headache, and diarrhea. Laboratory abnormalities, including neutropenia, lymphopenia, elevated creatine phosphokinase levels, and elevated non-fasting triglycerides, occurred in more than one subject with a Common Adverse Event Evaluation Criteria (CTCAE) grade 2 or higher. Exploratory efficacy in patients with psoriasis demonstrated improvement at all tested doses (mean reductions in Psoriasis Area Severity Index (PASI) of 30%, 47%, and 48%, respectively, at 5 mg, 10 mg, and 30 mg; compared to 26% for placebo). The TYK2 inhibitors described herein are administered orally at the doses and schedules described herein.

[0045] In the following disclosure, certain specific details are set forth to provide a full understanding of the various embodiments. However, those skilled in the art will understand that the methods and uses described herein can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, throughout this specification and claims, the word “comprise” and its variations (e.g., “comprises” and “comprising”) shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”. Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0046] Throughout this specification, references to “one embodiment,” “some embodiments,” or “an embodiment” mean that a particular feature, structure, or characteristic set forth in connection with said embodiment is included in at least one embodiment. Therefore, the appearance of the phrases “in one embodiment,” “in some embodiments,” or “in an embodiment” throughout this specification does not necessarily refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in one or more embodiments in any suitable manner. Similarly, unless otherwise expressly indicated, the singular forms “a,” “an,” and “described” as used in this specification and the appended claims include a plural of indicators. It should also be noted that unless otherwise expressly indicated, the term “or” is generally used in its meaning, including “and / or.”

[0047] On the one hand, methods for treating patients with inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC), may include administering a therapeutically effective amount of compound 1 to the patient: 1 Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0049] In some implementations, daily application is continued for the following periods: 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 week to 2 weeks, approximately 2 weeks to 3 weeks, approximately 3 weeks to 4 weeks, approximately 4 weeks to 5 weeks, approximately 5 weeks to 6 weeks, approximately 6 weeks to 7 weeks, approximately 7 weeks to 8 weeks, approximately 8 weeks to 9 weeks, approximately 9 weeks to 10 weeks, approximately 10 weeks to 11 weeks, approximately 11 weeks to 12 weeks, approximately 12 weeks to 14 weeks, approximately... The duration of administration may vary from 14 to 16 weeks, from about 16 to 18 weeks, from about 18 to 21 weeks, from about 21 to 24 weeks, from about 24 to 27 weeks, from about 27 to 30 weeks, from about 30 to 33 weeks, from about 33 to 36 weeks, from about 36 to 39 weeks, from about 39 to 42 weeks, from about 42 to 45 weeks, from about 45 to 48 weeks, from about 48 to 51 weeks, from about 51 to 52 weeks, from about 1 year to 2 years, or from about 2 years to 3 years, from about 3 years to 4 years, or from about 4 years to 5 years. In other embodiments, daily application may continue for more than 5 years.

[0050] In some implementation schemes, the patient has IBD.

[0051] In some implementation schemes, the patient has moderate to severe active IBD.

[0052] In some implementations, application is long-term, or applied daily indefinitely.

[0053] In some implementations, for patients with CD, the method involves treating moderate to severe active CD.

[0054] In some implementations, for patients with CD, the average reduction in the Crohn's Disease Simplified Endoscopic Score (SES-CD) is approximately 50% or more.

[0055] In some implementations, for patients with CD, the average reduction in the Crohn's Disease Simplified Endoscopic Score (SES-CD) is approximately 70% or more.

[0056] In some implementations, for patients with CD, the average reduction in the Crohn's Disease Simplified Endoscopic Score (SES-CD) is approximately 90% or more.

[0057] In some implementations, the Crohn's Disease Simplified Endoscopic Score (SES-CD) is reduced by an average of approximately 100% in patients with CD.

[0058] In some implementations, the Crohn's Disease Simplified Endoscopic Score (SES-CD) is reduced by an average of approximately 50% to 70% for patients with CD.

[0059] In some implementations, the Crohn's Disease Simplified Endoscopic Score (SES-CD) is reduced by an average of approximately 70% to 90% for patients with CD.

[0060] In some implementations, the Crohn's Disease Simplified Endoscopic Score (SES-CD) is reduced by an average of approximately 90% to 100% for patients with CD.

[0061] In some implementations, for patients with Crohn's disease accompanied by isolated ileal disease, the simplified endoscopic score for Crohn's disease (SES-CD) read in a centralized manner is less than or equal to 4 (e.g., about 4, about 3, about 2, about 1, or about 0) or reduced by at least 2 points compared to baseline.

[0062] In some implementation schemes, the patient has CD.

[0063] In some implementation schemes, the patient has moderate to severe active CD.

[0064] In some implementations, for patients with UC, a modified Mayo score (a scoring system for assessing ulcerative colitis activity) of less than or equal to 2 is achieved, with a stool frequency sub-score of less than or equal to 1, a rectal bleeding sub-score of 0, and a central reading endoscopy score of less than or equal to 1 (a modified score of 1 is used to exclude fragility).

[0065] In some implementation schemes, the patient has UC.

[0066] In some implementation schemes, the patient has moderate to severe active UC.

[0067] In some implementations, for patients with CD (including moderate to severe active CD), the method achieves: a reduction of greater than or equal to 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%) in a centralized reading compared to baseline, or a reduction of about 50% to about 70%, about 70% to about 90%, or about 90% to about 100% in SES-CD; or for isolated ileal disease, a reduction of less than or equal to 4 (e.g., about 4, about 3, about 2, about 1, or about 0) or a reduction of at least 2 points compared to baseline in a centralized reading.

[0068] In some implementations, for patients with UC (including moderate to severe active UC), the method achieves a modified Mayo score (a scoring system for assessing the activity of ulcerative colitis) of less than or equal to 2, wherein the stool frequency sub-score is less than or equal to 1, the rectal bleeding sub-score is 0, and the central reading endoscopy score is less than or equal to 1 (modified score 1 to exclude fragility).

[0069] In some implementation schemes, the patient has inflammatory bowel disease (IBD).

[0070] In some implementations, IBD is moderate to severe activity.

[0071] In some implementation schemes, the patient has Crohn's disease (CD).

[0072] In some implementations, CD is moderate to severe active.

[0073] In some implementations, the method achieves an improvement in circulating cytokines and / or inflammatory biomarkers.

[0074] On one hand, methods for inhibiting the production of interferon-γ (IFNγ) in patients may include administering a therapeutically effective amount of compound 1 to the patient: 1 Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0076] In some implementations, the patient has inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC).

[0077] In some implementations, the T of compound 1 in the plasma 最大 It will arrive in approximately 3 to 6 hours.

[0078] In some implementations, the t of compound 1 in the plasma 1 / 2 It will be reached in approximately 17 to 37 hours.

[0079] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of up to about 200 mg.

[0080] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of about 30 mg to about 200 mg.

[0081] In some 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.

[0082] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is prepared to provide approximately 24 hours of IC50. 50 Coverage dosage application.

[0083] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is prepared to provide approximately 24 hours of IC50. 90 Coverage dosage application.

[0084] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in a single dose, such as a single dose within a day.

[0085] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in two doses, such as twice a day.

[0086] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in multiple doses.

[0087] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for two weeks.

[0088] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for 52 weeks.

[0089] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for 2 to 52 weeks.

[0090] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for 2 to 52 weeks, for example until the patient’s IBD (including CD or UC) improves.

[0091] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient daily for 1 to 5 years, for example until the patient’s IBD (including CD or UC) improves.

[0092] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient for a prolonged or indefinite period.

[0093] In some implementations, compound 1 is administered orally to the patient.

[0094] In some implementation schemes, the patient is a human.

[0095] In some implementation schemes, the following serum C levels are achieved. 最大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 about 240 ng / mL, about 240 ng / mL to about 280 ng / mL, about 280 ng / mL to about 320 ng / mL, about 320 ng / mL to about 360 ng / mL, about 360 ng / mL to about 400 ng / mL, about 400 ng / mL to about 480 ng / mL, about 480 ng / mL to about 560 ng / mL, about 560 ng / mL to about 740 ng / mL, about 740 ng / mL to about 820 ng / mL, about 820 ng / mL to about 900 ng / mL, about 900 ng / mL to about 1000 ng / mL, about 1000 ng / mL to about 1200 ng / mL, about 1200 ng / mL to about 1400 ng / mL, about 1400 ng / mL to about 1600 ng / mL, about 1600 From ng / mL to about 1800 ng / mL, or from about 1800 ng / mL to about 2000 ng / mL.

[0096] On the one hand, methods for treating patients with inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC), may include administering a therapeutically effective amount of compound 1: 1 The daily dose is approximately 30 mg to approximately 200 mg.

[0098] On the one hand, compound 1: 1 Or its pharmaceutically acceptable salts may be used to treat IBD, including CD or UC.

[0100] The compounds discussed herein include those outlined herein, and are further explained by the categories, subclasses, and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. For the purposes discussed herein, chemical elements are identified according to the periodic table (CAS edition, Handbook of Chemistry and Physics, 75th edition). Furthermore, the general principles of organic chemistry are expounded in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry,” 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0101] As used herein, the term “about” means within 20% of a given value. In some implementations, the term “about” means 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.

[0102] As used herein, the term "compound 1" refers to N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which has the following formula:

[0103] 1.

[0104] 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.

[0105] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic," "cycloaliphatic," or "cycloalkyl") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 3 aliphatic carbon atoms, and in other embodiments, the aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocyclic" or "cycloalkyl") means a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include (but are not limited to) substituted or unsubstituted straight-chain or branched alkyl, alkenyl, ynyl and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0106] As used herein, the term "bridging bicyclic" refers to any bicyclic system having at least one bridge, i.e., a carbocyclic or heterocyclic system, saturated or partially unsaturated. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or atoms or valence bonds connecting two bridgeheads, wherein a "bridgehead" is any skeletal atom in the ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridging bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridging bicyclic groups are well known in the art and include those groups set forth below, wherein each group is attached to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise specified, the bridging bicyclic group is optionally substituted with one or more substituents as set forth with respect to aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridging bicyclic group is optionally substituted. Exemplary bridging bicyclic groups include:

[0107]

[0108] The term "lower alkyl" refers to C 1-4 Straight-chain or branched alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0109] The term "lower haloalkyl" refers to a C-aryl group that has been substituted with one or more halogen atoms. 1-4 Straight-chain or branched alkyl groups.

[0110] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or a substituted nitrogen of a heterocycle, such as N (e.g., in 3,4-dihydro-2-) H -pyrrole group), NH (as in pyrroleyl group) or NR + (e.g., in N-substituted pyrroleyl groups).

[0111] As used in this article, the term "unsaturated" means that a portion has one or more unsaturated units.

[0112] As used in this article, the term "divalent C" 1-8 (or C) 1-6 "Saturated or unsaturated straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenyl, and ynylene chains as defined herein.

[0113] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2). n - where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below with respect to the substituted aliphatic group.

[0114] The term "alkenyl" refers to a divalent alkenyl group. A substituted alkenyl chain is a polymethylene group containing at least one double bond, wherein one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below with respect to the substituted aliphatic group.

[0115] The term "halogen" refers to F, Cl, Br, or I.

[0116] The term "aryl," used alone or as part of a larger body in "aralkyl," "aralkyloxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic system having a total of 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 some embodiments, "aryl" refers to an aromatic ring system, including (but not limited to) phenyl, biphenyl, naphthyl, anthracene, etc., which may have one or more substituents. As used herein, the scope of the term "aryl" also includes groups fused with an aromatic ring to one or more non-aromatic rings, such as dihydroindenyl, phthalimide, naphthylimide, phenanthridine, or tetrahydronaphthyl, etc.

[0117] The terms "heteroaryl" and "heteroary-" used alone or as a larger part in, for example, "heteroarylalkyl" or "heteroarylalkoxy" refer to having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ring atoms shared in a cyclic array. A group having electrons; and 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. Heteroaryl groups include (but are not limited to) thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridinyl, indazinyl, purine, naphridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups in which a heteroaryl ring is fused with one or more aryl, cycloaliphatic, or heterocyclic rings, wherein, unless otherwise specified, the linking group or linking point is located on or on one of the rings to which the heteroaryl ring is fused. Non-limiting examples include indole, isoindole, benzothiophene, benzofuran, dibenzofuran, indazole, benzimidazol, benzothiazolyl, quinolinyl, isoquinolinyl, terolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 H - Quinazinyl, carbazoyl, acridineyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroarylene," any of which includes an optionally substituted ring. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl group and the heteroaryl portion are optionally substituted independently.

[0118] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above, in addition to a carbon atom. When referring to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (e.g., in 3,4-dihydro-2-oxohydrogen ions). H -pyrrole group), NH (as in pyrroleyl group) or + NR (as in) N -In substituted pyrrolidinyl groups).

[0119] Heterocycles can be attached to their side groups at any heteroatom or carbon atom to obtain a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include (but are not limited to) tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, piperidinyl, pyrrololinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazine, dioxalyl, dioxazopentyl, diazapyrrolyl, oxazpyrrolyl, thioazpyrrolyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quininecycloyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclic ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indololinyl, 3 H -Indolyl, chromyl, phenanthridine, or tetrahydroquinolinyl. The heterocyclic group can be monocyclic or bicyclic. The term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl group and the heterocyclic group are optionally substituted independently.

[0120] As used herein, the term "partially unsaturated" refers to a ring moiety comprising at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but is not intended to include aryl or heteroaryl moiety as defined herein.

[0121] As illustrated herein, compounds may contain “optionally substituted” portions. Generally, the term “substituted”, regardless of whether it is preceded by the term “optionally,” means that one or more hydrogen atoms of the specified portion are replaced by suitable substituents. Unless otherwise indicated, the “optionally substituted” group may have suitable substituents at each substituted position of said group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated and illustrated herein are preferably those combinations that form stable or chemically viable compounds. As used herein, the term “stable” means that, for one or more purposes disclosed herein, the compound does not undergo substantial change when subjected to conditions that permit its generation, detection, and, in some embodiments, its recovery, purification, and use.

[0122] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; -(CH2) 0-4 R o ;-(CH2) 0-4 OR o ;-O(CH2) 0-4 R o -O-(CH2) 0-4C(O)OR o ;-(CH2) 0-4 CH(OR o )2;-(CH2) 0- 4SR o ;-(CH2) 0-4 Ph, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Replacement; -CH=CHPh, which can be replaced by R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl group, which can be R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0-4 N(R o )C(O)NR o 2; -N(R) o )C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2; -N(R) o )N(R o )C(O)OR o ;-N(R o )C(NR o )N(R o )2;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4OC(O)R o ;-OC(O)(CH2) 0-4 SR o ;-SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2; -C(S)NR o 2;-C(S)SR o ;-SC(S)SR o -(CH2) 0-4 OC(O)NR o 2; -C(O)N(OR) o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR) o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2; -N(R) o )S(O)2R o ;-N(OR) o )R o ;-C(NH)NR o 2; -P(O)2R o ;-P(O)R o 2; -OP(O)R o 2; -OP(O)(OR o )2;-SiR o 3; -(C 1-4 (linear or branched alkylene)ON(R) o )2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R) o )2, where each R o It can be replaced and independently of hydrogen and C as defined below. 1-6Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5- to 6-membered heteroaryl ring) or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, although defined above, two independently occurring R° together with their intermediate atom to form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0123] R o (or through two independently occurring R) o Suitable monovalent substituents on the ring formed together with its intermediate atom are independently halogens, -(CH2). 0-2 R ● -(halogenated R) ● -(CH2) 0-2 OH, -(CH2) 0-2 OR ● -(CH2) 0-2 CH(OR ● )2;-O(halogenated R ● -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- 2SH、-(CH2) 0-2 NH2、-(CH2) 0-2 NHR ● -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C 1-4 (straight-chain or branched alkylene)C(O)OR ● or -SSR ● , where each R ● It is either unsubstituted or, in the case of a preceding "halogen group," substituted with only one or more halogens, and independently selected from C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. R oSuitable divalent substituents on saturated carbon atoms include =O and =S.

[0124] Suitable divalent substituents on the saturated carbon atom of the "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-, where each independently occurring R * Selected from hydrogen, and C that can be substituted as defined below. 1-6 An aliphatic group or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents for the ortho-substituted carbon atom attached to the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independently occurring R * Selected from hydrogen, and C that can be substituted as defined below. 1-6 It is an aliphatic group or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0125] R * Suitable substituents on aliphatic groups include halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a preceding "halogen group," substituted by only one or more halogens, and independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0126] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R † -NR † 2. -C(O)R† -C(O)OR † -C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † )S(O)2R † ; where each R † Independently, hydrogen, and C that can be substituted as defined below. 1-6 Aliphatic group, unsubstituted -OPh, or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur, or, although defined above, two independently occurring R groups. † Together with its intermediate atom, it forms an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0127] R † Suitable substituents on the aliphatic group are independently halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a preceding "halogen group," substituted by only one or more halogens, and independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0128] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, anaphylaxis, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-p-ethylhexanoate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0129] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and nitrogen salts. + (C 1–4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, which are formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions.

[0130] Unless otherwise stated, the structures illustrated herein are also intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformations)) of said structures; for example, R and S configurations, Z and E double bond isomers, and Z and E conformational isomers for each asymmetry center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric (or conformations), are within the scope of the present invention. Unless otherwise stated, all tautomers of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures illustrated herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures having the structures of the present invention (including those using deuterium or tritium instead of hydrogen, or using...) 13 C or 14 Compounds that enrich carbon (instead of carbon) are within the scope of this invention. According to the invention, such compounds can be used as, for example, analytical tools, as probes in bioassays, or as therapeutic agents. In some embodiments, the warhead portion R of the provided compound... 1 It contains one or more deuterium atoms. In some embodiments, ring B of the provided compound may be substituted with one or more deuterium atoms.

[0131] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits TYK2 with measurable affinity. In some embodiments, the IC50 of the inhibitor is... 50 And / or the binding constant is less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0132] As 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 a combination thereof described herein and TYK2 protein kinase and an equivalent sample containing TYK2 protein kinase and not containing the compound or the combination thereof.

[0133] As used in this article, "C" 最大 "It is the maximum (or peak) serum concentration of the drug in a designated compartment or test area of ​​the body after the drug is administered and before the second dose is administered."

[0134] As used herein, “SDD” refers to a pharmaceutical formulation (e.g., a pharmaceutical formulation of compound 1 or a pharmaceutically acceptable salt thereof) that is a spray-dried formulation. The formulation may comprise the compounds of this disclosure and hydroxypropyl methylcellulose acetate succinate (HPMCAS). In one embodiment, HMPCAS is HPMCASS-M, where “M” indicates (acetyl content 7.0% to 11.0%, succinyl content 10% to 14%). The use of spray drying to produce powders from fluid raw materials is well known, with applications ranging from milk powders to bulk chemicals and pharmaceuticals. See U.S. Patent No. 4,187,617 and Mujumbar et al., 91 Drying, pp. 56-73 (1991). The use of spray drying to form solid amorphous dispersions of pharmaceuticals and concentrated polymers is also known. See European Patent Applications Nos. 0 901 786, 1 027 886, 1 027 887, and 1 027 888, and PCT Applications Nos. WO 00 / 168092 and WO 00 / 168055, each of which is hereby incorporated by reference. A typical spray drying apparatus includes a drying chamber, an atomizing device for atomizing and feeding a solvent-containing liquid into the drying chamber, a source of heated drying gas directed into the drying chamber, and a drying product collection device for separating the dried product from the cooled drying gas and vaporized solvent streams after it leaves the drying chamber. Examples of such apparatus include Niro Models PSD-1, PSD-2, and PSD-4 (Niro A / S, Soeborg, Denmark).

[0135] As used herein, the descriptive term "TPGS" or "Vitamin E TPGS" for pharmaceutical formulations of the disclosed compounds refers to a pharmaceutical formulation comprising (e.g., a pharmaceutical formulation of compound 1 or a pharmaceutically acceptable salt thereof) the following components: (a) an active compound; (b) one or more diluents (e.g., microcrystalline cellulose); (c) one or more solubilizers (e.g., D-α-tocopherol polyethylene glycol succinate [Vitamin E TPGS]); and (d) one or more binders (e.g., povidone). The formulation may be prepared using a granulation process (e.g., wet granulation). As used herein, "granulation" refers to a process that produces larger or smaller particles or granules of a substance or mixture of substances. Such processes may also remove fine particles and improve flowability within the formulation. Both wet granulation and / or dry granulation may be used. Dry granulation is achieved using only the particle assembly without any liquid on it. Compression is performed using a tableting machine to form large tablets, the weight of which varies due to the poor flowability of the formulation. The resulting clumps are then passed through a pellet mill to break them into granules, and then pressed again to obtain the final granular product.

[0136] 3. Exemplary compounds: According to one aspect, a method for treating inflammatory conditions (such as inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC)) in patients in need may include administering a therapeutically effective amount 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, double, or multiple (e.g., separate) dose.

[0137] U.S. Patent No. 11,046,698 describes certain therapeutically beneficial compounds, the entire contents of which are hereby incorporated by reference. Such compounds include compound 1. Compound 1 is designated I-908 in US 11,046,698, and its synthesis, properties, and use in the treatment of various diseases and conditions are described in detail in that patent. Numerous other TYK2 inhibitors are described in US 11,046,698, which can be used in the methods of this disclosure. Therefore, in some embodiments, the TYK2 inhibitor is one of those inhibitors described in US 11,046,698.

[0138] In some embodiments, the TYK2 inhibitor used in the disclosed method has Formula I:

[0139] I Or its pharmaceutically acceptable salt, wherein: R 3 -C(O)NH2; -C(O)NHR 3A ;-C(O)N(R 3A )2; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is separated by m R 5B replace; R 5 For hydrogen or -L 1 -R 5A ; R 6 For hydrogen, R A Or R B ; Or R 5 and R 6 Together with its intermediate atom, it forms a 4- to 7-membered partially unsaturated or heteroaryl ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 5A and n R C replace; R 7 Hydrogen, halogen, -NH2, -NHR 7Aor -NHC(O)R 7A ; Or R 6 and R 7 Together with its intermediate atom, it forms a 4- to 7-membered partially unsaturated or heteroaryl ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is surrounded by p R C replace; L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently -C(R) 5B )2-、-CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2- instead; R 3A and R 7A Each independently as R B And each was q R C replace; R 5A and each R 5B Each independently as R A Or R B And each is divided by r R C replace; Each R A Independently, it can be an oxo group, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R; Each R B Independently for C 1-6 Aliphatic group; phenyl group; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3- to 7-membered saturated or partially unsaturated carbocyclic ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R C Independently an oxo group, 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 a optionally substituted group selected from the following: C 1-6 Aliphatic group, phenyl group, 3- to 7-membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen, or a group selected from the following optionally substituted groups: C 1-6 Aliphatic group, phenyl group, 3- to 7-membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen atom together with their intermediate atom form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring, wherein the ring has 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the nitrogen atom. Each hydrogen atom bonded to carbon may optionally and independently be replaced by deuterium; and Each m, n, p, q, and r is independently 0, 1, 2, 3, or 4.

[0140] In some embodiments, the TYK2 inhibitor used in the disclosed method is compound 1a:

[0141] 1a Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0142] In some embodiments, the TYK2 inhibitor used in the disclosed method is compound 1: 1 Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0144] The compounds and compositions described herein are generally used to inhibit the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods described herein is TYK2.

[0145] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) protein kinase family. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins (including TYK2) are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by those receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons (such as IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitins)) and interleukins (such as IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncokinase M, ciliary neurotrophic factor, cardiac nutrient 1, cardiac nutrient-like cytokines, and LIF).Velasquez et al., "Aprotein 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 thetyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly ofStat1 and Stat3 complexes in human T cells and monocytes", J. Immunol. (1995) 155:1079; Bacon et al., "Interleukin 12 (IL-12) induces tyrosine phosphorylation of Jak2 and Tyk2: differential use of Janus family kinases by IL-2 and IL-12", J. Exp. Med. (1995) 181:399; Welham et al., “Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and insulin”, J. Biol. Chem. (1995) 270:12286; Parham et al., “A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R”, J. Immunol. (2002) 168:5699. Activated TYK2 then continues to phosphorylate other signal transduction proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0146] IL-23 activation of TYK2 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, as a downstream effector of IL-23, also plays a role in psoriasis, adhesive joint disease, and Behçet's disease. Cho et al., "Genomics and the multifactorial nature of human auto-immune disease", N. Engl. J. Med(2011) 365:1612-1623; Cortes et al., "Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-relatedloci", Nat. Genet. (2013) 45(7):730-738; Remmers et al., "Genome-wide associations study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease", Nat. Genet. (2010) 42:698-702.

[0147] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell proliferation (GCH) and excessive mucus secretion are mediated by IL-13-induced TYK2 activation, which in turn activates STAT6. (Zhang et al., “Docking protein Gab2 regulates mucin expression and gobletcell hyperplasia through TYK2 / STAT6 pathway”, FASEB J. (2012) 26:1-11.)

[0148] Reduced TYK2 activity can protect joints from collagen antibody-induced arthritis (a human model of rheumatoid arthritis). Mechanistically, reduced TYK2 activity decreases T... h 1 / T h 17. Production of related cytokines and matrix metalloproteinases, as well as other key markers of inflammation. Ishizaki et al., “Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in the mice”, Intl. Immunol. (2011) 23(9):575-582.

[0149] Compared to controls, TYK2 knockout mice showed complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) with no CD4 T cell infiltration in the spinal cord, indicating that TYK2 is crucial for pathogenic CD4-mediated disease development in MS. (Oyamada et al., “Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis”, J. Immunol. (2009) 183:7539-7546). This confirms previous studies linking 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 reduced neuronal demyelination and increased myelin regeneration, further demonstrating the role of TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0150] TYK2 is the only signal transduction messenger shared by both IL-12 and IL-23.

[0151] Studies on the co-associations and relationships between various type I IFN signaling genes and systemic lupus erythematosus (SLE, an autoimmune disease) have shown a strong and significant association between loss-of-function mutations in TYK2 and reduced SLE prevalence in families with affected members. (Sigurdsson et al., “Polymorphisms in the Tyrosine Kinase2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus”, Am. J. Hum. Genet. (2005) 76:528-537.) Genome-wide association studies of individuals with SLE relative to unaffected groups have shown a highly significant association 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.)

[0152] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice exhibit impaired cytotoxic T cell responses and accelerated tumor development. However, these effects are associated with effective suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for treating autoimmune diseases or transplant rejection. Although other JAK family members (such as JAK3) have similar roles in the immune system, TYK2 is considered a superior target due to its involvement in fewer and more closely related signaling pathways, resulting in fewer off-target effects. (Simma et al., “Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance”, Cancer Res. (2009) 69:203-211.)

[0153] However, contradicting the reduced tumor surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL's TYK2-STAT1-mediated signal transduction is highly dependent on IL-10 to maintain cancer cell survival by upregulating the anti-apoptotic protein BCL2. Knockdown of TYK2, rather than other JAK family members, reduced cell growth. TYK2-specific activating mutations that promote cancer cell survival include those in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, TYK2 kinase function has also been identified as essential for prolonging cancer cell survival, as TYK2 enzymes characterized by kinase-dead mutations (M978Y or M978F), in addition to activating mutations (E957D), lead to transformation failure. Sanda et al., "TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia", Cancer Disc. (2013) 3(5):564-577.

[0154] Therefore, selective inhibition of TYK2 has been considered a suitable target for patients with tumors addicted to IL-10 and / or BCL2, such as 70% of adult T-cell leukemia cases. Fontan et al., “Discovering What Makes STATSignaling TYK in T-ALL”, Cancer Disc. (2013) 3:494-496.

[0155] It has also been shown that TYK2-mediated STAT3 signaling mediates neuronal cell death induced by amyloid-β (Aβ) peptide. Decreased TYK2 phosphorylation of STAT3 after Aβ administration reduces neuronal cell death, and increased STAT3 phosphorylation has been observed in autopsy brains of Alzheimer's disease patients. Wan et al., “Tyk / STAT3 Signaling Mediatesβ-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease”, J. Neurosci. (2010) 30(20):6873-6881.

[0156] Inhibition of the JAK-STAT signaling pathway is also associated with hair growth and reversal of alopecia areata-related hair loss. 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.

[0157] Therefore, compounds that inhibit TYK2 activity are beneficial, especially those with superior selectivity to JAK2. Such compounds should deliver a pharmacological response that is advantageous for treating one or more of the disorders described herein, without the dose-limiting side effects associated with JAK1-3 inhibition.

[0158] Even though TYK2 inhibitors are known in the art, there remains a need for novel inhibitors with more potent or advantageous pharmaceutically relevant properties. For example, compounds with increased activity, selectivity superior to other JAK kinases (especially JAK2), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Therefore, in some embodiments, TYK2 inhibitors may exhibit superior selectivity compared to JAK2.

[0159] The activity of the compounds described herein as inhibitors of TYK2 or its mutants can be determined in vitro, in vivo, or in cell lines. In vitro assays include determinations of inhibition of phosphorylation activity and / or subsequent functional outcomes or ATPase activity of activated TYK2 or its mutants. Alternative in vitro assays quantify the ability of an inhibitor to bind TYK2. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex, and determining the amount of radiolabeled material bound. Alternatively, inhibitor binding can be determined by running a competition assay in which a novel inhibitor is incubated with TYK2 bound to a known radioligand. Representative in vitro and in vivo assays that can be used to determine TYK2 inhibitors include, for example, those set forth and disclosed in each reference incorporated herein by reference in its entirety. Detailed conditions for determining the compounds described herein as inhibitors of TYK2 or its mutants are set forth in the examples below and in US 11,046,698, incorporated herein by reference.

[0160] As used herein, the terms "treatment (treat and treating)" refer to reversing or alleviating a disease or condition or one or more symptoms thereof as described herein, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have been present. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., given a history of symptoms and / or given genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

[0161] The provided compounds are TYK2 inhibitors and are therefore suitable for treating one or more conditions associated with the activity of TYK2 or its mutants. Thus, in some embodiments, a method of treating a TYK2-mediated condition may include administering the compounds described herein or pharmaceutically acceptable combinations thereof to a patient in need.

[0162] As used herein, the term “TYK2-mediated” means any disease, ailment, or disorder in which TYK2 or its mutants are known to play a role. Therefore, another embodiment relates to treating or reducing the severity of one or more diseases in which TYK2 or its mutants are known to play a role. Such TYK2-mediated conditions include, but are not limited to, autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and transplant-related diseases.

[0163] In some embodiments, a method for treating one or more conditions, wherein the conditions are selected from autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and transplant-related diseases, the method may include administering a pharmaceutical composition to a patient in need, the pharmaceutical composition comprising an effective amount of a compound set forth herein or a pharmaceutically acceptable salt thereof.

[0164] In some implementations, the condition is an autoimmune disease. In some implementations, the condition 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).

[0165] In some implementations, the condition is an inflammatory condition. In some implementations, the inflammatory condition is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis (e.g., plaque psoriasis), psoriatic arthritis, hepatomegaly, IBD, CD, or UC.

[0166] In some implementations, methods of treating CD in patients in need may include administering a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof as described herein.

[0167] In some implementations, treatment of UC in patients in need may include administration of a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof as described herein.

[0168] In some implementations, methods of treating IBD in patients in need may include administering a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof as described herein.

[0169] In some implementations, the disease is a proliferative disease. In some implementations, the proliferative disease is a blood cancer. In some implementations, the proliferative disease is leukemia. In some implementations, the leukemia is T-cell leukemia. In some implementations, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some implementations, the proliferative disease is polycythemia vera, primary myelofibrosis, or thrombocytosis.

[0170] In some implementations, the condition is an endocrine disorder. In other implementations, the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

[0171] In some implementations, the condition is a neurological condition. In other implementations, the neurological condition is Alzheimer's disease.

[0172] In some embodiments, the proliferative disease 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, JH2 domain, or kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0173] In some implementations, the condition is related to transplantation. In some implementations, the transplant-related condition is transplant rejection or graft-versus-host disease.

[0174] In some implementations, the symptoms are associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some implementations, the symptoms are associated with type I interferon signaling. In some implementations, the symptoms are associated with IL-10 signaling. In some implementations, the symptoms are associated with IL-12 signaling. In some implementations, the symptoms are associated with IL-23 signaling.

[0175] The compounds described in this article can also be used to treat inflammatory or allergic skin conditions such as psoriasis (e.g., plaque psoriasis), contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, pemphigus parasiticus, acquired epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic skin conditions.

[0176] The compounds described herein can also be used to treat other diseases or conditions, such as those with inflammatory components, including eye diseases and conditions (e.g., ocular allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis), diseases affecting the nose (including allergic rhinitis), and inflammatory diseases involving autoimmune reactions or having autoimmune components or causes, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenic purpura), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, and Stevens-Johnson syndrome. Syndrome), idiopathic stomatitis diarrhea, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, nephropathy, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary cholecystitis, uveitis (anterior and posterior uveitis), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryptothermal protein-related periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome),Examples include idiopathic nephrotic syndrome or minimal change disease, chronic granulomatous disease, endometriosis, leptospirosis, glaucoma, retinal diseases, aging, headaches, pain, complex regional pain syndrome, cardiomegaly, muscle atrophy, catabolism, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, pigmentary disorders, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced asthma), acute lung injury, acute respiratory distress syndrome, eosinophilia, allergies, allergic reactions, sinusitis, eye allergies, silica-induced diseases, and COPD. (Damage, airway inflammation, bronchial hyperresponsiveness, reduced remodeling or disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation combined with systemic sclerosis, 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, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, purulent sweating Prostatitis, immunoglobulin 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, eustachian tube inflammation, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0177] In some implementation schemes, the 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), cryptothermal protein-associated periodic syndrome (CAPS), and osteoarthritis.

[0178] In some implementation schemes, inflammatory diseases that can be treated according to the methods described herein are T... h 1 or T h17-mediated diseases. In some implementations, T h 17. The mediated diseases are selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0179] In some implementations, the inflammatory diseases that can be treated according to the methods described herein are selected from Sjögren's syndrome, allergic conditions, osteoarthritis, eye diseases (e.g., ocular allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis) and diseases affecting the nose (e.g., allergic rhinitis).

[0180] Furthermore, the present invention can provide the use of compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, as defined herein, for the preparation of medicaments for the treatment of autoimmune diseases, inflammatory diseases or proliferative diseases or diseases generally related to transplantation.

[0181] Without being bound by any particular theory, it is believed that proximity of the inhibitor compound or its side chain portion to the water of interest facilitates the displacement or disruption of said water by the inhibitor compound or its side chain portion. In some embodiments, the water molecules displaced or disrupted by the inhibitor compound or its side chain portion are unstable water molecules.

[0182] In some embodiments, the method employs a complex comprising TYK2 and an inhibitor, wherein at least one unstable water of TYK2 is replaced or destroyed by the inhibitor. In some embodiments, at least two selected unstable water molecules are replaced or destroyed by the inhibitor.

[0183] 5. Pharmacokinetics / Pharmacodynamics In some embodiments, this disclosure provides a method of administering a TYK2 inhibitor (e.g., compound 1) to a patient in need, the method comprising administering to the patient a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof or a combination thereof, wherein certain pharmacokinetic parameters are achieved. In some embodiments, the disclosed method of administering compound 1 to achieve certain pharmacokinetic parameters of this disclosure and its use have advantages in treating diseases described herein, such as inflammatory conditions. Such diseases include inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC).

[0184] In some implementations, the T of TYK2 inhibitors (e.g., compound 1) in plasma 最大 It is reached within a maximum of approximately 10 hours, such as 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 time range generated by using two of the above times as endpoints. In some implementations, T最大 The timeframe is reached within approximately 1 to 10 hours, approximately 1 to 9 hours, approximately 2 to 10 hours, approximately 2 to 9 hours, approximately 3 to 10 hours, approximately 3 to 9 hours, approximately 4 to 10 hours, approximately 4 to 9 hours, approximately 5 to 10 hours, approximately 5 to 9 hours, approximately 6 to 10 hours, approximately 6 to 9 hours, approximately 7 to 10 hours, approximately 7 to 9 hours, approximately 8 to 10 hours, approximately 9 to 10 hours, or approximately 8 to 9 hours. In some embodiments, the T value of the TYK2 inhibitor (e.g., compound 1) in plasma is... 最大 It is achieved within approximately 3 hours at most. In some implementations, the T-cell concentration of TYK2 inhibitors (e.g., compound 1) in plasma is... 最大 It is achieved within approximately 4 hours at most. In some implementations, the T of compound 1 in the plasma... 最大 It is achieved within approximately 5 hours at most. In some implementations, the T-cell concentration of TYK2 inhibitors (e.g., compound 1) in plasma is... 最大 It will arrive in approximately 6 hours at most.

[0185] In some implementations, the T of TYK2 inhibitors (e.g., compound 1) in plasma 最大 The effect is achieved within approximately 1 to 4 hours, approximately 2 to 5 hours, approximately 3 to 6 hours, approximately 4 to 7 hours, approximately 5 to 8 hours, approximately 6 to 9 hours, or approximately 7 to 10 hours. In some embodiments, the T value of the TYK2 inhibitor (e.g., compound 1) in plasma is... 最大 It will arrive in approximately 3 to 6 hours.

[0186] In some implementations, the t of TYK2 inhibitors (e.g., compound 1) in plasma 1 / 2 This can be achieved within 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 time range generated by using two of the above times as endpoints. In some embodiments, the t of the TYK2 inhibitor (e.g., compound 1) in plasma... 1 / 2 It is achieved within approximately 17 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is...1 / 2 It is achieved within approximately 18 hours at most. In some implementations, the t of compound 1 in the plasma 1 / 2 It is achieved within approximately 19 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 20 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 21 hours at most. In some implementations, the t-value of a TYK2 inhibitor (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 22 hours at most. In some implementations, the t of compound 1 in the plasma 1 / 2 It is achieved within approximately 23 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 24 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 25 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 26 hours at most. In some implementations, the t of compound 1 in the plasma 1 / 2 It is achieved within approximately 27 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 28 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 29 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 30 hours at most. In some implementations, the t of compound 1 in the plasma 1 / 2 It is achieved within approximately 31 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 32 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 33 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 34 hours at most. In some implementations, the t of compound 1 in the plasma 1 / 2 It is achieved within approximately 35 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It is achieved within approximately 36 hours at most. In some implementations, the t-value of TYK2 inhibitors (e.g., compound 1) in plasma is... 1 / 2 It will arrive in approximately 37 hours at most.

[0187] In some implementations, the t of TYK2 inhibitors (e.g., compound 1) in plasma 1 / 2 The effect is achieved within approximately 10 to 30 hours, approximately 12 to 32 hours, approximately 14 to 34 hours, approximately 16 to 36 hours, approximately 18 to 38 hours, approximately 20 to 40 hours, or approximately 22 to 42 hours. In some embodiments, the t-value of the TYK2 inhibitor (e.g., compound 1) in plasma is... 1 / 2 It will arrive in approximately 17 to 37 hours.

[0188] In some embodiments, this disclosure provides a method of administering a TYK2 inhibitor (e.g., compound 1) to a patient in need, the method comprising administering to the patient a therapeutically effective amount of the TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein certain pharmacodynamic outcomes are achieved.

[0189] In some embodiments of the methods and uses disclosed herein, administration of a TYK2 inhibitor (e.g., compound 1) rapidly inhibits interferon-γ (IFNγ) production and increases exposure associated with increased IFNγ inhibition. In some embodiments, methods for inhibiting IFNγ production in a patient may include administering to the patient a TYK2 inhibitor (e.g., compound 1) described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0190] In some implementation schemes, the following serum C levels are achieved. 最大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 about 240 ng / mL, about 240 ng / mL to about 280 ng / mL, about 280 ng / mL to about 320 ng / mL, about 320 ng / mL to about 360 ng / mL, about 360 ng / mL to about 400 ng / mL, about 400 ng / mL to about 480 ng / mL, about 480 ng / mL to about 560 ng / mL, about 560 ng / mL to about 740 ng / mL, about 740 ng / mL to about 820 ng / mL, about 820 ng / mL to about 900 ng / mL, about 900 ng / mL to about 1000 ng / mL, about 1000 ng / mL to about 1200 ng / mL, about 1200 ng / mL to about 1400 ng / mL, about 1400 ng / mL to about 1600 ng / mL, about 1600 From approximately 1800 ng / mL to approximately 1800 ng / mL, or from approximately 1800 ng / mL to approximately 2000 ng / mL. In some embodiments, serum C levels are achieved at approximately 25 ng / mL to approximately 30 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 30 ng / mL to approximately 35 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 35 ng / mL to approximately 40 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 40 ng / mL to approximately 45 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 45 ng / mL to approximately 50 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 50 ng / mL to approximately 60 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 60 ng / mL to approximately 70 ng / mL.最大 In some implementations, serum C levels are achieved at approximately 70 ng / mL to approximately 80 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 80 ng / mL to approximately 90 ng / mL. 最大 In some implementations, serum C levels reach approximately 90 ng / mL to approximately 100 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 100 ng / mL to approximately 120 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 120 ng / mL to approximately 140 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 140 ng / mL to approximately 160 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 160 ng / mL to approximately 180 ng / mL. 最大 In some implementations, serum C levels reach approximately 180 ng / mL to approximately 200 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 200 ng / mL to approximately 240 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 240 ng / mL to approximately 280 ng / mL. 最大 In some implementations, serum C levels reach approximately 280 ng / mL to approximately 320 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 320 ng / mL to approximately 360 ng / mL. 最大 In some implementations, serum C levels reach approximately 360 ng / mL to approximately 400 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 400 ng / mL to approximately 480 ng / mL. 最大 In some implementations, serum C levels reach approximately 480 ng / mL to approximately 560 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 560 ng / mL to approximately 740 ng / mL. 最大 In some implementations, serum C levels reach approximately 740 ng / mL to approximately 820 ng / mL. 最大 In some implementations, serum C levels reach approximately 820 ng / mL to approximately 900 ng / mL. 最大 In some implementations, serum C levels reach approximately 900 ng / mL to approximately 1000 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 1000 ng / mL to approximately 1200 ng / mL.最大 In some implementations, serum C levels are achieved at approximately 1200 ng / mL to approximately 1400 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 1400 ng / mL to approximately 1600 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 1600 ng / mL to approximately 1800 ng / mL. 最大 In some implementations, serum C levels are achieved at approximately 1800 ng / mL to approximately 2000 ng / mL. 最大 .

[0191] 6. Dosage and Schedule In some embodiments, the methods and uses described herein are achieved by administering, for example, a therapeutically effective amount of a TYK2 inhibitor (e.g., compound 1) in a single, double, or multiple dose of up to 200 mg (e.g., orally), such as in the treatment of patients with inflammatory conditions (e.g., inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC)). In some embodiments, the TYK2 inhibitor is administered once, twice, three times, four times, five times, six times, seven times, or eight times daily. In some embodiments, the method includes administration of a single, two, or multiple doses (e.g., orally) in the range of about 30 to about 200 mg / dose, such as 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 of amounts generated by using two of the above amounts as endpoints. For example, oral doses may include TYK2 inhibitors (such as compound 1) or pharmaceutically acceptable salts thereof in dosage forms of 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.

[0192] In some embodiments, the method includes administration of a single, two, or multiple doses (e.g., orally) in the range of about 30 to about 200 mg / dose, such as 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 daily.

[0193] In some embodiments, the method includes administration (e.g., orally) of a single, two, or multiple doses ranging from the following: about 30 to about 200 mg daily, about 30 mg to about 35 mg, about 40 mg to about 45 mg, about 50 mg to about 60 mg, about 70 mg to about 80 mg, about 90 mg to about 100 mg, about 110 mg to about 120 mg, about 130 mg to about 140 mg, about 150 mg to about 160 mg, about 170 mg to about 180 mg, about 190 mg to about 200 mg, about 30 mg to about 50 mg, about 30 mg to about 75 mg, about 30 mg to about 100 mg, about 30 mg to about 150 mg, about 30 mg to about 200 mg, about 50 mg to about 75 mg, about 50 mg to about 100 mg, about 50 mg to about 150 mg, about 50 mg to about 200 mg, about 75 mg to about 100 mg, about 75 mg to about 150 mg daily. mg, about 75 mg to about 200 mg, about 100 mg to about 150 mg, about 100 mg to about 200 mg, or about 150 mg to about 200 mg. Any specific dosage amounts between the ranges in this paragraph should be considered. For example, for the statement “about 50 mg to about 60 mg,” this covers administration of about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, or about 10 mg. Any non-integer dosages between the ranges should also be considered; for example, for the range “about 50 mg to about 60 mg,” values ​​including about 50 mg, about 50.1 mg, about 50.2 mg, about 50.3 mg, about 50.4 mg, about 50.5 mg, about 50.6 mg, etc., should be considered.

[0194] In some embodiments, the method may include administration of a single, two, or multiple doses (e.g., orally), with the total dose intended to provide approximately 24 hours of IC (intracytoplasmic reticulum). 50 cover.

[0195] In some embodiments, the method may include administration of a single, two, or multiple doses (e.g., orally), with the total dose intended to provide approximately 24 hours of IC (intracytoplasmic reticulum). 90 cover.

[0196] As used herein, "24-hour coverage" means achieving or maintaining a desired plasma concentration of the compound over a 24-hour period, which produces the expected amount of the target protein effect. For example, "24-hour IC50 coverage" 50 "Coverage" refers to the use of a dose designed to increase the plasma concentration of the inhibitory compound to produce 50% inhibition of the target protein for 24 hours.

[0197] Any dose in the preceding period may be administered once, twice, three times, or four times a day. For example, a 50 mg dose may be administered as a 25 mg dose, followed by a second 25 mg dose after a certain period of time, to reach a total daily dose of 50 mg. As another example, a 50 mg dose may be administered throughout the day by administering 10 mg, followed by a second 10 mg after a certain period of time, a third 10 mg after a certain period of time, a fourth 10 mg after a certain period of time, and a fifth 10 mg after a certain period of time, to reach a total daily dose of 50 mg.

[0198] Therefore, in some embodiments, administering 30 mg of compound 1 comprises administering 15 mg, after a defined time period, and then administering a second 15 mg dose. In some embodiments, administering 50 mg of compound 1 comprises administering 25 mg, after a defined time period, and then administering a second 25 mg dose. In some embodiments, administering 75 mg of compound 1 comprises administering 37.5 mg, after a defined time period, and then administering a second 37.5 mg dose. In some embodiments, administering 100 mg of compound 1 comprises administering 50 mg, after a defined time period, and then administering a second 50 mg dose. In some embodiments, administering 150 mg of compound 1 comprises administering 75 mg, after a defined time period, and then administering a second 75 mg dose. In some embodiments, administering 200 mg of compound 1 comprises administering 100 mg, after a defined time period, and then administering a second 100 mg dose. The defined time period may be determined by a clinician and is influenced by individual patient metabolic considerations. In some implementations, the defined time period is about 2.5 hours to about 5 hours, about 5 hours to about 7.5 hours, about 7.5 hours to about 10 hours, about 10 hours to about 12.5 hours, about 12.5 hours to about 15 hours, about 15 hours to about 17.5 hours, about 17.5 hours to about 20 hours, about 20 hours to about 22.5 hours, or about 22.5 hours to about 24 hours.

[0199] In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 30 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 35 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 40 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 45 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 50 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 55 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 60 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 65 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 70 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 75 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 80 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 85 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 90 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of up to 95 mg (e.g., orally). In some embodiments, the TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of up to 100 mg (e.g., orally). In some embodiments, the TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of up to 150 mg (e.g., orally). In some embodiments, the TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of up to 200 mg (e.g., orally).In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient in a dose of about 30 mg to about 100 mg (e.g., 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 a patient in a dose of about 50 mg to about 150 mg (e.g., orally). In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is administered to a patient in a dose of about 75 mg to about 200 mg (e.g., orally).

[0200] In some implementations, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is used to provide an IC50 solution for approximately 24 hours. 50 Covered dose administration (e.g., orally).

[0201] In some implementations, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutically acceptable salt thereof is used to provide an IC50 solution for approximately 24 hours. 90 Covered dose administration (e.g., orally).

[0202] As provided by the preclinical data presented herein, TYK2 inhibitors (e.g., compound 1) or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof are administered to patients at a dosing schedule suitable for producing the desired disease remission and with minimal side effects. In some embodiments, TYK2 inhibitors (e.g., compound 1) or pharmaceutical compositions thereof are administered to patients daily (QD) for the following durations: 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 week to 2 weeks, approximately 2 weeks to 3 weeks, approximately 3 weeks to 4 weeks, approximately 4 weeks to 5 weeks, approximately 5 weeks to 6 weeks, approximately 6 weeks to 7 weeks, approximately 7 weeks to 8 weeks, approximately 8 weeks to 9 weeks, approximately 9 to 10 weeks, approximately 10 to 11 weeks, approximately 11 weeks to 1 week, and approximately 1 week to 1 week. 2 weeks, approximately 12 to 14 weeks, approximately 14 to 16 weeks, approximately 16 to 18 weeks, approximately 18 to 21 weeks, approximately 21 to 24 weeks, approximately 24 to 27 weeks, approximately 27 to 30 weeks, approximately 30 to 33 weeks, approximately 33 to 36 weeks, approximately 36 to 39 weeks, approximately 39 to 42 weeks, approximately 42 to 45 weeks, approximately 45 to 48 weeks, approximately 48 to 51 weeks, approximately 51 to 52 weeks, approximately 1 year to 2 years, approximately 2 years to 3 years, approximately 3 years to 4 years, or approximately 4 years to 5 years. In other embodiments, daily application continues for more than 5 years. In some implementations, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutical composition thereof is administered to the 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 implementations, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutical composition thereof is administered to the patient daily (QD) indefinitely.

[0203] 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 single daily dose of 2-200 mg for 2 weeks. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutical composition thereof is administered to a patient at multiple daily doses of 2-200 mg for 2 weeks. In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutical composition thereof is administered to a patient at a single daily dose, twice daily dose, or multiple daily dose of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, 75 mg, 100 mg, or 200 mg 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, 54 weeks, 57 weeks, 60 weeks, or indefinitely.

[0204] In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutical composition thereof is administered in a manner intended to provide approximately 24 hours of IC50. 50 The total dose covered is administered to patients as a single dose, twice daily, or multiple times daily 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, 54 weeks, 57 weeks, 60 weeks, or indefinitely.

[0205] In some embodiments, a TYK2 inhibitor (e.g., compound 1) or a pharmaceutical composition thereof is administered in a manner intended to provide approximately 24 hours of IC50. 90 The total dose covered is administered to patients as a single dose, twice daily, or multiple times daily 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, 54 weeks, 57 weeks, 60 weeks, or indefinitely.

[0206] 7. Formulations and Combinations Pharmaceutically acceptable compositions According to the methods described herein, compounds and compositions may be administered in any amount and via any route of administration effective for treating or alleviating the severity of any of the conditions disclosed herein. The exact amount required will vary from subject to subject, depending on the subject's species, age and general condition, severity of infection, specific agent, mode of administration, etc. The compounds described herein are preferably formulated in dosage units for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete unit of the agent suitable for the patient to be 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 reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the condition being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the time of administration, route of administration, and rate of excretion of the specific compound used; the duration of treatment; and similar factors well known in the medical field that are used in combination with or happen to be used with the specific compound used.

[0207] According to another embodiment, the composition may include the compound described herein or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator. The amount of the compound in the composition described herein is such that it effectively and measurably inhibits TYK2 protein kinase or its mutants in a biological sample or in a patient. In some embodiments, the amount of the compound in the composition described herein is such that it effectively and measurably inhibits TYK2 protein kinase or its mutants in a biological sample or in a patient. In some embodiments, the composition described herein is formulated for administration to a patient who requires the composition. In some embodiments, the composition described herein is formulated for oral administration to a patient.

[0208] As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0209] The term "pharmaceutically acceptable carrier, adjuvant, or mediator" refers to a non-toxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants, or mediators 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), buffering substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in glycerides, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0210] "Pharmaceutically acceptable derivatives" means any non-toxic salt, ester, ester salt or other derivative of the compound described herein that, when administered to a recipient, can directly or indirectly provide the compound described herein or its inhibitory metabolites or residues.

[0211] As used herein, the term "its inhibitory metabolites or residues" means that its metabolites or residues are also inhibitors of TYK2 protein kinase or its mutants.

[0212] The compositions described herein can be administered orally, parenterally, by inhalation spray, externally, rectally, intracerebrospinal, intraperitoneally, nasally, buccally, vaginally, or via an implantable cartridge. In some embodiments, the compounds described herein can be administered orally or parenterally at dose levels of about 0.01 mg / kg to about 50 mg / kg daily, and preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight, once or more daily to achieve the desired therapeutic effect. As used herein, the term "parentereal" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions described herein can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are often used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid are used to prepare injectable formulations.

[0213] Injectable formulations may be sterilized, for example, by filtration via a bacterial trapping filter or by incorporation of 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 prior to use.

[0214] To prolong the effects of the compounds described herein, it is generally desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. Therefore, the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of the parenteral form of the compound can be achieved by dissolving or suspending the compound in an oily medium. Injectable storage forms are prepared by forming microcapsule matrices of the compound in a biodegradable polymer (e.g., polylactic acid-polyglycolic acid). The rate of compound release can be controlled depending on the compound-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Storage injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0215] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol, or suppository wax), which is solid at ambient temperature but liquid at body temperature, and thus melts in the rectal or vaginal cavity and releases the active compound.

[0216] For this purpose, any mild, non-volatile oil, including synthetic mono- or diglycerides of glycerol, may be used. Fatty acids, such as oleic acid and its glycerol derivatives, can also be used to prepare injectable formulations, similar to pharmaceutically acceptable natural oils (e.g., olive oil or castor oil, especially in their polyoxyethylated form). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly 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 solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0217] The pharmaceutically acceptable compositions described herein can be administered orally in any orally acceptable dosage form, including (but not limited to) capsules, tablets, aqueous suspensions, or solutions. In the case of tablets intended for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, diluents include lactose and dry corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavoring agents, taste agents, or coloring agents may also be added if necessary.

[0218] Alternatively, the pharmaceutically acceptable compositions described herein may be administered in suppository form for rectal administration. These compositions can be prepared by mixing the agent with a suitable, non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0219] 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 calcium hydrogen phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicate; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) slowing agents, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; 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 contain a buffer. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field. They may optionally contain light-blocking agents and may also have a composition that optionally releases the active ingredient only or preferentially in a portion of the intestine in a delayed manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol.

[0220] The pharmaceutically acceptable compositions described herein can also be applied topically, particularly when the therapeutic target includes areas or organs that can be easily reached through topical application, including diseases of the eyes, skin, or lower intestine. Suitable topical formulations for each of these areas or organs are readily available.

[0221] External application to the lower intestine can be achieved using rectal suppositories (see above) or appropriate enema formulations. Transdermal patches may also be used.

[0222] For external application, the provided pharmaceutically acceptable compositions may be formulated in suitable ointments containing an active ingredient suspended or dissolved in one or more carriers. Other external dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. Carriers for the compounds described herein for external application include (but are not limited to) mineral oils, liquid paraffins, leucocele, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the provided pharmaceutically acceptable compositions may be formulated in suitable lotions or creams containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include (but are not limited to) mineral oils, sorbitan monostearate, polysorbate 60, cetyl wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water. If necessary, the active ingredient may be mixed with a pharmaceutically acceptable carrier and any desired preservative or buffer under aseptic conditions. Absorption enhancers can also be used to increase the flux of compounds across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel (e.g., in a transdermal patch for topical application).

[0223] For ophthalmic use, the provided pharmaceutically acceptable composition may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative (e.g., benzalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated in an ointment (e.g., paraffin oil).

[0224] The pharmaceutically acceptable compositions described herein can also be administered via nasal aerosol or inhalation. These compositions are prepared according to techniques well-known in the pharmaceutical formulation field and can be formulated into solutions in saline containing benzyl alcohol or other suitable preservatives, absorption enhancers (to improve bioavailability), fluorocarbons, and / or other conventional solubilizers or dispersants.

[0225] Most preferably, the pharmaceutically acceptable compositions described herein are formulated for oral administration. Such formulations may or may not be administered with 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.

[0226] The amount of compounds described herein that can be combined with carrier materials to produce compositions in a single dosage form will vary depending on the host being treated and the specific administration method. Preferably, the provided compositions are formulated such that an inhibitor can be administered to patients receiving these compositions at a dose of 0.01-100 mg / kg body weight / day.

[0227] Liquid dosage forms for oral administration may be used, including (but not limited to) pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, and mixtures thereof.

[0228] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, the attending physician's judgment, and the severity of the specific disease being treated. The amount of the compounds described herein in the composition will also depend on the specific compounds in the composition.

[0229] Depending on the specific disease or condition to be treated, other therapeutic agents typically used to treat said disease may be used in combination with the compounds and compositions set forth herein. As used herein, other therapeutic agents typically used to treat a specific disease or condition are referred to as “the disease or condition to be treated”.

[0230] In some embodiments, the provided combination or composition thereof is administered in combination with another therapeutic agent.

[0231] Examples of medications that can be combined, as described in this article, include (but are not limited to): for the treatment of 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, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; and agents used to treat multiple sclerosis (MS), such as beta-interferon (e.g., Avonex). ® and Rebif ® Copaxone ® And mitoxantrone; used to treat asthma, such as albuterol and Singulair. ® Medications used to treat schizophrenia, such as Zyprexa, Risperdal, Seroquel, and Haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 inhibitors, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, and mycophenolate mofetil. Drugs for treating cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; drugs for treating hepatitis, such as corticosteroids, cholestyramine, interferon, and antiviral agents; drugs for treating hematologic disorders, such as corticosteroids, antileukemic agents, and growth factors; drugs that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., metabolic destruction inhibitors) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir); and drugs for treating immunodeficiency disorders, such as gamma globulin.

[0232] In some implementations, the combination therapy or pharmaceutically acceptable composition described herein is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

[0233] These other agents may be administered separately from the provided combination therapy as part of a multiple-dose regimen. Alternatively, these agents may be part of a single dosage form, which is mixed with the compounds described herein in a single composition. If administered as part of a multiple-dose regimen, the two active agents may be delivered simultaneously, sequentially, or over a period of time, typically within five hours of each other.

[0234] As used herein, the terms “combination,” “in combination,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, the combinations described herein may be administered simultaneously or sequentially with another therapeutic agent in separate unit formulations or together in a single unit formulation.

[0235] The amount of other therapeutic agents present in the compositions described herein will not exceed the amount normally applied in a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of other therapeutic agents in the compositions disclosed herein will be in the range of about 50% to 100% of the amount normally present in a composition containing said agent as the sole active agent.

[0236] In one embodiment, the composition may include compound 1 and one or more other therapeutic agents. The therapeutic agent may be administered with compound 1, or may be administered before or after the administration of compound 1. Suitable therapeutic agents are further described in detail below. In some 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 therapeutic agent. In other 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 after the therapeutic agent.

[0237] In another embodiment, a method of treating inflammatory bowel disease (including Crohn's disease or ulcerative colitis) may include administering compound 1 and one or more other therapeutic agents to a patient in need. Such other therapeutic agents may be small molecule or recombinant biological agents and include, for example, clobetasol, methotrexate, Humira®, Stelara®, triamcinolone, ustekinumab, adalimumab, Cosentyx®, Remicade®, Taltz®, Skyrizi®, Tremfya®, etanercept, Ilumya®, and Avsol. a®, guselkumab, Inflectra®, ixekizumab, Renflexis®, risankizumab, secukinumab, tildrakizumab, fluocinonide, triamcinolone, Elocon®, calcipotriene, mometasone, Clobex®, Dovonex®, prednisone ednisone, desonide, hydrocortisone, Soriatane®, Taclonex®, Tazorac®, Acitretin®, Cyclosporine®, betamethasone, betamethasone / calcipotriol, halobetasol, Temovate®, Kenalog®, Kenalog-40®, Neoral®, Desoximetasone®, Fluocino nide-E®, Otrexup®, Trexall®, Coal Tar, Enstilar®, Fluocinolone, Tazarotene, Topicort®, Calcitriol, Cortizone-10®, Dexamethasone, Kenalog-10®, Locoid®, Methylprednisolone, Prednisolone, Rasuvo®, RediTrex®, Taclonex Scalp®, Tacrolimus, Triderm®, Vanos®, Vectical®, Acthar®, Ala-Cort®, Ala-Scalp®, Ala-ScalpHP®, aclometasone, ammonium lactate / halobetasol, Aquanil HC®, Aristocort A®, Aristocort R®, Aristospan®, Beta HC®, Bioelements Immediate Comfort®, Caldecort®, Cinolar®, Clinacort®, Cloderm®, Cordran®, Cordran Tape®, Cortizone-5®, Dermarest Plus Anti-Itch®, Dermovate®, Dermtex HC®, diflorasone, flurandrenolide, Gengraf®, Halog®, infliximab, Itch-X Lotion®, Locoid Lipocream®, NuCort®, Olux®, Olux-E®, Oxsoralen-Ultra®, Pandel®, Psoriasin®, Sarnol-HC®, Sernivo®, Synalar®, T exacort®, Trianex®, Tritocin®, U-Cort®, Abrilada®, amcinonide, Amjevita®, ammonium lactate / urea, Analpram-HC®, Analpram E®, Anthraforte®, anthralin, Anthrascalp®, Apexicon®, ApexiCon E®, Balnetar®, BetatarGel®, brodalumab, Bryhali®, Calcitrene®, Capex®, Carb-O-Lac5®, Carb-O-Lac HP®, Clovoveate®, Clocortolone, Clodan®, Coal Tar / Salicylic Acid / Sulfur, Coal Tar / Salicylic Acid, Cordran SP®, Cormax®, Cormax Scalp®, Corticotropin, Cutar®, Cyclocort®, Cyltezo®, Derma-Smoothe / FS®, Derma-Smoothe® / FS (Body Oil), Derma-Smoothe® / FS (Scalp), Dermatop®, Desonate®, DesOwen®, DHS Tar Shampoo®, Doak Tar®, Dritho-Scalp®, Drithoocreme®, Duobrii®, EltaTar®, Embeline®, Embeline E®, Epifoam®, Estar®, Fototar®, HP Acthar Gel®, Hadlima®, Halcinonide, Halobetasol / Tazarotene, Halonate®, HC Pram®, Hulio®, Hydrocortisone / Pramocaine, Hydroxyurea, Hyrimoz®, Impoyz®, Ionil T®, Ixifi®, Kalosar®, Kerasal Ultra 20®, LoKara®, Medotar®, Methoxasalen, MG217 Medicated Tar®, Neutrogena T® / Derm, Neutrogena T® / Gel, Nolix®, Novacort®, Oxipor VHC®, Pramosone®, Prednicarbate, Proctofoam HC®, RA Acne®, Resinol®, Resorcinol, Scytera®, Siliq®, Sorilux®, Synalar Ointment®, Tarsum®, Theraplex T®, Tovet®, Ultralytic®, Ultralytic 2®, Ultravate®, Verdeso®, Wynzora®, Yusimry®, Zithranol® and Zithranol-RR®.

[0238] In another embodiment, a method of treating an inflammatory disease, condition, or disorder may include administering compound 1 and one or more other therapeutic agents to a patient in need. Such other therapeutic agents may be small molecule or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), colchicine (Colcrys®), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), probenecid, allopurinol, and febuxostat. Uloric®, sulfasalazine (Azulfidine®), antimalarial drugs (such as hydroxychloroquine (Plaquenil® and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (such as sulganal®, myochrysine®, and auranofen (Ridaura®)), D-penicillamine (Depen® or Cuprinine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents (such as etanercept (Enbrel®), infliximab (Remicade®), and golimumab). (Simponi®), pegylated certolizumab pegol (Cimzia®) and adalimumab (Humira®), anti-IL-1 agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), canakinumab (Ilaris®), anti-Jak inhibitors (e.g., tofacitinib), antibodies (e.g., rituximab (Rituxan®), anti-T-cell agents (e.g., abatacept (Orencia®)), and anti-IL-6 agents (e.g., tocilizumab)Actemra®, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies (e.g., tanezumab), anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (e.g., cholestyramine), alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives (e.g., milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), anticholinergics or antispasmodics (e.g., dicyclomine). Inhaled corticosteroids include Bentyl®, Singulair®, β-2 agonists (e.g., salbutamol (Ventolin® HFA, Proventil® HFA), levosalbutamol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium bromide (Spiriva®), and inhaled corticosteroids (e.g., beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide). (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodiumIntal®, methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), IgE antibodies (e.g., omalizumab (Xolair®)), nucleoside reverse transcriptase inhibitors (e.g., zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine). Ingredients include: Zerit® and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors (e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®), and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors (e.g., tenofovir (Viread®), protease inhibitors (e.g., amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), and nelfinavir. Viracept®, Norvir®, Saquinavir (Fortovase® or Invirase®), and Tipranavir (Aptivus®), entry inhibitors (such as Enfuvirtide (Fuzeon®) and Maraviroc (Selzentry®)), integrase inhibitors (such as Raltegravir (Isentress®) and Doxorubicin), and other enzyme inhibitors.(a combination of Hydrodaunorubicin®, vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) with lenalidomide (Revlimid®), or any combination thereof.

[0239] In another embodiment, a method of treating rheumatoid arthritis may include administering compound 1 and one or more other therapeutic agents selected from the following to a patient in need: nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, lodine®, and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), sulfasalazine (Azulfidine®), antimalarial drugs (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., sulganal®, myochrysine®, and Ridaura®), D-penicillamine (Depen® or Cuprinine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), and nitrogen mustard phentermine. Acids (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents (such as etanercept (Enbrel®), indiximab (Remicade®), golimumab (Simponi®), pegylated cetuzumab (Cimzia®), and adalimumab (Humira®)), "anti-IL-1" agents (such as anaerobicin (Kineret®) and linalesip (Acalyst®)), antibodies (such as rituximab (Rituxan®)), "anti-T cell" agents (such as abatacept (Orencia®)), and "anti-IL-6" agents (such as tocilizumab (Actemra®)).

[0240] In some implementations, methods of treating osteoarthritis may include administering compound 1 and one or more other therapeutic agents selected from the following to a patient in need: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (such as aspirin, ibuprofen, naproxen, lodine®, and celecoxib), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies (such as tanizumab).

[0241] In some implementations, methods of treating cutaneous lupus erythematosus or systemic lupus erythematosus may include administering compound 1 and one or more other therapeutic agents selected from the following: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, lodine®, and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), antimalarial drugs (e.g., hydroxychloroquine (Plaquenil® and chloroquine (Aralen®)), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)).

[0242] In some implementations, methods of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease may include administering compound 1 and one or more other therapeutic agents selected from the following: mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal agents (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (e.g., cholestyramine), lotronex®, lumpyprostone (Amitiza®), laxatives (e.g., milk of magnesium, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), and anticholinergic or antispasmodic agents (e.g., betyl®), anti-TNF therapy, steroids, and antibiotics (e.g., Flagyl or ciprofloxacin)).

[0243] In some implementations, the method of treating asthma may include administering compound 1 and one or more other therapeutic agents selected from the following to a patient in need: Singulair®, β-2 agonists (e.g., salbutamol (Ventolin® HFA, Proventil® HFA), levosalbutamol (Xopenex®), isoproterenol (Alupent®), pibuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol sinemetone (Serevent®), and formoterol (Foradil®)), anticholinergic agents (e.g., ipratropium bromide (Atrovent®) and tiotropium bromide (Spiriva®)), and inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vance)). (e.g., ril®, triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolone (Aerobid®, Afviar®, Symbicort®, and Dulera®), sodium cromoglycate (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline) and IgE antibodies (e.g., omalizumab (Xolair®)).

[0244] In some implementations, methods of treating COPD may include administering compound 1 and one or more other therapeutic agents selected from the following to a patient in need: β-2 agonists (e.g., salbutamol (Ventolin® HFA, Proventil® HFA), levosalbutamol (Xopenex®), isoproterenol (Alupent®), pibuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol sinecurate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium bromide (Spiriva®)), methylxanthines (e.g., theophylline (Theo-Dur®, Theo... (lair®, Slo-bid®, Uniphyl®, Theo-24® and aminophylline), inhaled corticosteroids (such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar® and Vanceril®), triamcinolone (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolone (Aerobid®), Afviar®, Symbicort® and Dulera®).

[0245] In another embodiment, a method of treating hematologic malignancies may include administering compound 1 and one or more other therapeutic agents selected from the following: 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.

[0246] In another embodiment, a method of treating solid tumors may include administering compound 1 and one or more other therapeutic agents selected from the following: 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.

[0247] In another embodiment, the method of treating hematologic malignancy may include administering compound 1 and a Hedgehog (Hh) signaling pathway inhibitor to a patient in need. In some embodiments, the hematologic malignancy is DLBCL (Ramirez et al., “Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0248] In another embodiment, a method of treating diffuse large B-cell lymphoma (DLBCL) may include administering compound 1 and one or more other therapeutic agents selected from the following: rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, and combinations thereof to a patient in need.

[0249] In another embodiment, a method of treating multiple myeloma may include administering compound 1 and one or more other therapeutic agents selected from the following: bortezomib (Velcade®) and dexamethasone (Decadron®), hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and a combination of lenalidomide (Revlimid®) to a patient in need.

[0250] In another embodiment, a method of treating a disease or reducing its severity may include administering compound 1 and a BTK inhibitor to a patient in need, wherein the disease is selected from inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, neurolyme disease, Guillain-Barré syndrome. Syndrome, acute diffuse encephalomyelitis, Addison's disease, strabismus oculoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary cholecystitis, Reiter's syndrome, Takayasu's arteritisArteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia areata, Behçet's disease, chronic fatigue, autonomic nervous system disorders, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromuscular rigidity, scleroderma, vulvar pain, proliferative disorders, organ or tissue rejection, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, transfer Infusion, allergic reactions, allergies (e.g., allergies to plant pollen, latex, medications, food, insect toxins, animal hair, animal dander, dust mites, or cockroach calyxes), type I allergy, 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 Inflammation, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin 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, eustachian tube inflammation, 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, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom syndrome). Macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasma cell tumor, extranodal marginal zone B-cell lymphoma, nodular marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma.Lymphoma (leukemia or lymphomatoid granulomatosis), breast cancer, prostate cancer or mast cell cancer (e.g., mast cell tumor, mast cell leukemia, mast cell sarcoma, generalized mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including (but not limited to) rheumatoid arthritis), seronegative vertebral arthropathy (including adhesive spondylitis, psoriatic arthritis and Reiter's disease). Diseases including: Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases; thromboembolic diseases (e.g., myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass grafting, restenosis after aortocoronary artery bypass grafting, stroke, transient ischemic attack, peripheral artery occlusion, pulmonary embolism, deep vein thrombosis); inflammatory pelvic diseases, 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. Diseases, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyadenosis (also known as autoimmune polyadenosis syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolysis and thrombocytopenic state, goubacher syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, skin diseases. Cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative arthropathy, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0251] In another embodiment, a method of treating a disease or reducing its severity may include administering compound 1 and a PI3K inhibitor to a patient in need, wherein the disease is selected from cancer, neurodegenerative diseases, angiogenic diseases, viral diseases, autoimmune diseases, inflammatory diseases, hormone-related diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune disorders involving T cell activation, cardiovascular diseases, and CNS diseases.

[0252] In another embodiment, a method of treating a disease or reducing its severity may include administering compound 1 and a PI3K inhibitor to a patient in need, wherein the disease is selected from benign or malignant tumors, cancers or solid tumors of the brain, kidneys (e.g., renal cell carcinoma (RCC)), liver, adrenal glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, endometrium, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid, sarcoma, glioblastoma, neuroblastoma. Tumors, multiple myeloma, or gastrointestinal cancer (especially colon cancer or colorectal adenoma) or head and neck tumors, epidermal hyperplasia, psoriasis, benign prostatic hyperplasia, sarcoma formation, epithelial sarcoma formation, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also known as Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, including Cowden syndrome. Diseases of the PI3K / PKB pathway that are abnormally activated, including Lhermitte-Dudos syndrome, Bannayan-Zonana syndrome, or any type or cause of asthma (including both intrinsic (non-allergic) and non-intrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis-related asthma, exercise-induced asthma, occupational asthma, and post-bacterial infection-induced asthma), acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, airway or lung disease (COPD, COAD, or COLD) (including chronic bronchitis or associated dyspnea, emphysema), and exacerbations of airway hypersensitivity reactions with other drug therapies (especially other inhaled drug therapies), any type or cause of bronchitis (including (but not limited to) acute, arachidic, catarrhal, croupus, chronic, or tuberculous bronchitis), and any type or cause of pneumoconiosis (an inflammatory, usually occupational, lung disease).Both chronic and acute cases are often accompanied by airway obstruction and are caused by repeated inhalation of dust (including, for example, aluminosis, anthracite, asbestos, stone pneumoconiosis, hair pneumoconiosis, iron pneumoconiosis, silica pneumoconiosis, tobacco pneumoconiosis, and cotton pneumoconiosis), Loffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, and polyarteritis nodosa (including Chug-Straus syndrome). Eosinophilic granuloma and drug-induced eosinophilic-related conditions affecting the airways, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, leukoplakia, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, acquired epidermolysis bullosa, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting the nose (including allergic rhinitis) and those involving autoimmune reactions or having autoimmune components or causes. Inflammatory diseases, including autoimmune blood disorders (such as hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenic purpura), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic stomatitis diarrhea, autoimmune inflammatory bowel diseases (such as ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, and chronic... Allergic pneumonia, multiple sclerosis, primary cholecystitis, uveitis (anterior and posterior uveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, and glomerulonephritis (with and without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change disease), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, as well as neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.

[0253] In some embodiments, methods of treating a disease or reducing its severity may include administering compound 1 and a Bcl-2 inhibitor to a patient in need, wherein the disease is an inflammatory condition, an autoimmune condition, a proliferative condition, an endocrine condition, a neurological condition, or a transplant-related condition. In some embodiments, the condition is a proliferative condition, lupus, or lupus nephritis. In some embodiments, the proliferative condition is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematuria, or a solid tumor.

[0254] In some embodiments, methods of treating a disease or reducing its severity may include administering a TYK2 pseudokinase (JH2) domain-binding compound and a TYK2 kinase (JH1) domain-binding compound to a patient in need. In some embodiments, the disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a transplant-related disease. In some embodiments, the JH2-binding compound is compound 1. Other suitable JH2 domain-binding compounds include those set forth in WO2014074660A1, WO2014074661A1, and WO2015089143A1, the full text of each of which is incorporated herein by reference. Suitable JH1 domain-binding compounds include those set forth in WO2015131080A1, the full text of which is incorporated herein by reference.

[0255] According to one embodiment, a method for inhibiting protein kinase activity in a biological sample may include contacting the biological sample with a compound described herein or a composition containing the compound.

[0256] According to another embodiment, a method for inhibiting the activity of TYK2 or its mutants in a biological sample may include contacting the biological sample with a compound described herein or a composition containing the compound. In some embodiments, a method for irreversibly inhibiting the activity of TYK2 or its mutants in a biological sample may include contacting the biological sample with a compound described herein or a composition containing the compound.

[0257] In another embodiment, a method for selectively inhibiting TYK2 relative to one or more of JAK1, JAK2, and JAK3 is described. In some embodiments, the selectivity of the compounds described herein is more than twice that of JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds described herein is more than five times that of JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds described herein is more than ten times that of JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds described herein is more than 50 times that of JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds described herein is more than 100 times that of JAK1 / 2 / 3.

[0258] 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.

[0259] Inhibiting TYK2 (or its mutants) activity in biological samples can be used 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, biological sample storage, and bioassay.

[0260] 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 comprising the compound.

[0261] According to another embodiment, a method for inhibiting the activity of TYK2 or its mutants in a patient may include the step of administering to the patient a compound described herein or a composition comprising said compound. According to certain embodiments, a method for reversibly or irreversibly inhibiting the activity of one or more TYK2 or its mutants in a patient may include the step of administering to the patient a compound described herein or a composition comprising said compound. In other embodiments, a method for treating a TYK2- or mutant-mediated condition in a patient in need may include the step of administering to the patient a compound described herein or a pharmaceutically acceptable composition thereof. Such conditions are described in detail herein.

[0262] Depending on the specific ailment or disease to be treated, other therapeutic agents commonly used to treat said ailment may also be present in the compositions described herein. As used herein, other therapeutic agents commonly used to treat a particular ailment or disease are referred to as “the ailment or disease to be treated”.

[0263] The compounds described herein can also be advantageously used in combination with other therapeutic compounds. In some embodiments, these other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include (but are not limited to) aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-tumor antimetabolites; platinum compounds; compounds that target / reduce the activity of protein or lipid kinases and other anti-angiogenic compounds; compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isotypes; telomerase inhibitors; proteasome inhibitors; compounds used to treat hematologic malignancies; compounds that target, reduce, or inhibit Flt-3 activity; Hsp90 inhibitors, such as 17-AAG from Conforma Therapeutics. (17-Allylaminogeldanamycin (NSC330507), 17-DMAG (17-Dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010; Temozolomide (Temodal) ®); kinesin / spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and leucovorin. As used herein, the term "aromatase inhibitor" refers to compounds that inhibit estrogen production (e.g., the conversion of substrates androstenedione and testosterone into estrone and estradiol, respectively). The terms include (but are not limited to) steroids, especially atamestane, exemestane, and formestane, and particularly nonsteroidal drugs, especially aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testrolide, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is marketed under the brand name Aromasin™. Formestane is marketed under the brand name Lentaron™. Fadrozole is marketed under the brand name Afema™. Anastrozole is marketed under the brand name Arimidex™. Letrozole is marketed under the brand names Femara™ or Femar™. Aminoglutethimide is marketed under the brand name Orimeten™. The combinations described in this article may include chemotherapeutic agents that act as aromatase inhibitors, which are particularly useful for treating hormone receptor-positive tumors, such as breast tumors.

[0264] As used herein, the term "anti-estrogenic" refers to compounds that antagonize the effects 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 brand name Nolvadex™. Raloxifene hydrochloride is marketed under the brand name Evista™. Fulvestrant can be administered under the brand name Faslodex™. The combinations described herein may include chemotherapeutic agents as anti-estrogens, particularly for the treatment of estrogen receptor-positive tumors, such as breast tumors.

[0265] As used herein, the term "anti-androgen" refers to any substance capable of inhibiting the biological effects of androgens, and includes (but is not limited to) bicalutamide (Casodex™). As used herein, the term "goserelin agonist" includes (but is not limited to) abalexix, goserelin, and goserelin acetate. Goserelin may be administered under the brand name Zoladex™.

[0266] As used herein, the term "topoisomerase I inhibitor" includes (but is not limited to) topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecian and the macromolecular camptothecian conjugate PNU-166148. Irinotecan may be administered, for example, in its commercially available form (e.g., under the trademark Camptosar™). Topotecan is marketed under the trademark Hycamptin™.

[0267] As used herein, the term "topoisomerase II inhibitor" includes (but is not limited to) anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones such as mitoxantrone and losoxantrone; and podophillotoxine, etoposide, and teniposide. Etoposide is marketed under the brand name Etopophos™. Teniposide is marketed under the brand name VM 26-Bristol. Doxorubicin is marketed under the brand names Acriblastin™ or Adriamycin™. Epirubicin is marketed under the brand name Farmorubicin™. Idarubicin is marketed under the brand name Zavedos™. Mitoxantrone is marketed under the brand name Novantron.

[0268] The term "microtubule activator" refers to microtubule stabilizing, microtubule destabilizing compounds, and microtubule polymerization inhibitors, including (but not limited to) taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; colchicine and epothilone and their derivatives. Paclitaxel is marketed under the brand name Taxol™. Docetaxel is marketed under the brand name Taxotere™. Vinblastine sulfate is marketed under the brand name Vinblastin RP™. Vincristine sulfate is marketed under the brand name Farmistin™.

[0269] As used herein, the term "alkylating agent" includes (but is not limited to) cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the brand name Cyclostin™. Ifosfamide is marketed under the brand name Holoxan™.

[0270] The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylases and have antiproliferative activity. This includes (but is not limited to) succinyl aniline isohydroxamic acid (SAHA).

[0271] The term "anti-tumor antimetabolite" includes (but is not limited to) 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (such as 5-azacytidine and decitabine), methotrexate and edatrexate, and folic acid antagonists (such as pemetrexed). Capecitabine is marketed under the brand name Xeloda™. Gemcitabine is marketed under the brand name Gemzar™.

[0272] As used herein, the term "platinum compound" includes (but is not limited to) carboplatin, cisplatin, cisplatinum, and oxaliplatin. Carboplatin may be administered, for example, in its commercially available form (e.g., under the trademark Carboplat™). Oxaliplatin may be administered, for example, in its commercially available form (e.g., under the trademark Eloxatin™).

[0273] As used herein, the term "compounds that target / reduce the activity of protein or lipid kinases, or protein or lipid phosphatases; or other anti-angiogenic compounds" includes (but is not limited to) protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, reduce, or inhibit the activity of platelet-derived growth factor receptor (PDGFR), such as compounds that target, reduce, or inhibit the activity of PDGFR, especially compounds that inhibit PDGF receptors, such as N-phenyl-2-pyrimidinylamine derivatives, such as 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 insulin-like growth factor receptor I Compounds with IGF-IR activity, such as compounds that target, reduce, or inhibit IGF-IR activity, especially compounds that inhibit the kinase activity of IGF-I receptors or antibodies that target the extracellular domains of IGF-I receptors or their growth factors; d) compounds that target, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, reduce, or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce, or inhibit the activity of Ret receptor tyrosine kinases; g) compounds that target, reduce, or inhibit the activity of Kit / SCFR receptor tyrosine kinases, such as imatinib; h) compounds that target, reduce, or inhibit the activity of C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds that target, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds that inhibit c-Kit receptors, such as 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, such as compounds that target, reduce, or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidinylamine derivatives, such as imatinib or nilotinib. (AMN107); PD180970; AG957; NSC680410; PD173955 from Parke Davis; or dasatinib (BMS-354825);j) Compounds that target, reduce, or inhibit the activity of Raf family members, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK, and TEC family members and / or cyclin-dependent kinase family (CDK) members of protein kinase C (PKC) and serine / threonine kinases, including staurosporine derivatives such as midostaurin; other examples include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isoquinoline 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, such as imatinib mesylate (Gleevec™) or tyrosine phosphorylation inhibitors, such as tyrosine phosphorylation inhibitor A23 / RG-50810; AG 99; tyrosine phosphorylation inhibitor AG 213; tyrosine phosphorylation inhibitor AG 1748; tyrosine phosphorylation inhibitor AG 490; tyrosine phosphorylation inhibitor B44; tyrosine phosphorylation inhibitor B44 (+) enantiomers; tyrosine phosphorylation inhibitor AG 555; AG 494; tyrosine phosphorylation inhibitor AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adaphostin benzoate; NSC 680410, adaphostin); l) compounds that target, reduce or inhibit the activity of the epidermal growth factor family (EGFR1ErbB2, ErbB3, ErbB4 in homodimeric or heterodimeric form) and their mutants, such as compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, especially those that inhibit members of the EGF receptor tyrosine kinase family (e.g., EGF receptor, ErbB2, ErbB3 and ErbB4) or compounds, proteins or antibodies that bind to EGF or EGF-related ligands, CP 358774, ZD1839, ZM 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, such as compounds that target, reduce, or inhibit the activity of c-Met, especially compounds that inhibit the kinase activity of the c-Met receptor or targeting the extracellular domain of c-Met or antibodies binding to HGF; n) 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) PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds that target, reduce, or inhibit the kinase activity of PI3 kinase (PI3K), including (but not limited to) compounds. ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and q) compounds that target, reduce, or inhibit signal transduction effects of the hedgehog protein (Hh) or smooth receptor (SMO) pathway, including (but not limited to) cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[0274] As used herein, the term "PI3K inhibitor" includes (but is not limited to) compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, which includes (but is 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 that can be used in the methods described herein include (but are not limited to) ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupalixix, pictrelixix, PF-4691502, BYL-719, dartalixix, XL-147, XL-765, and adelalis.

[0275] As used herein, the term "BTK inhibitor" includes (but is not limited to) compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including (but not limited to) AVL-292 and ibrutinib.

[0276] As used herein, the term “SYK inhibitor” includes (but is not limited to) compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including (but not limited to) PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0277] As used herein, the term "Bcl-2 inhibitor" includes (but is not limited to) compounds with inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including (but not limited to) ABT-199, ABT-731, ABT-737, apogossypol, pan-Bcl-2 inhibitors of 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), obatoclax (and its analogues; see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (University of Michigan), and venetoclax. In some embodiments, Bcl-2 inhibitors are small molecule therapeutic agents. In some embodiments, Bcl-2 inhibitors are peptide mimics.

[0278] Other examples of BTK inhibitory compounds and diseases that can be treated by combination of such compounds with the compounds described herein can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0279] Other examples of SYK inhibitory compounds and diseases that can be treated by combination of such compounds with the compounds described herein can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

[0280] Other examples of PI3K inhibitory compounds and diseases that can be treated by combination of such compounds with the compounds described herein can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

[0281] Other examples of JAK inhibitory compounds and diseases that can be treated by combination of such compounds with the compounds described herein can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

[0282] Other anti-angiogenic compounds include those with an alternative mechanism of activity (e.g., unrelated to protein or lipid kinase inhibition), such as thalidomide (Thalomid™) and TNP-470.

[0283] Examples of proteasome inhibitors that can be used 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.

[0284] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases are, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives.

[0285] Compounds that induce cell differentiation include (but are not limited to) retinoic acid, α-, γ- or δ-tocopherol, or α-, γ- or δ-tocotrienol.

[0286] As used herein, the term cyclooxygenase inhibitors include (but are not limited to) Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroaniline)phenylacetic acid, lumiracoxib.

[0287] As used herein, the term "bisphosphonate" includes (but is not limited to) etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is marketed under the brand name Didronel™. Clodronic acid is marketed under the brand name Bonefos™. Tiludronic acid is marketed under the brand name Skelid™. Pamidronic acid is marketed under the brand name Aredia™. Alendronic acid is marketed under the brand name Fosamax™. Ibandronic acid is marketed under the brand name Bondranat™. Risedronic acid is marketed under the brand name Actonel™. Zoledronic acid is marketed under the brand name Zometa™. The term "mTOR inhibitor" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779, and ABT578.

[0288] As used herein, the term "heparinase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparan sulfate. This term includes (but is not limited to) PI-88. As used herein, the term "biological response modifier" refers to lymphokines or interferons.

[0289] As used herein, the term "inhibitor of Ras oncogenic isotypes (e.g., H-Ras, K-Ras, or N-Ras)" refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras; for example, "farnesyl transferase inhibitors," such as L-744832, DK8G557, or R115777 (Zarnestra™). As used herein, the term "telomerase inhibitor" refers to compounds that target, reduce, or inhibit telomerase activity. Compounds that target, reduce, or inhibit telomerase activity are particularly compounds that inhibit telomerase receptors, such as telomestatin.

[0290] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include (but are not limited to) benamide or its derivatives.

[0291] As used herein, the term "proteasome inhibitor" refers to a compound that targets, reduces, or inhibits proteasome activity. Compounds that target, reduce, or inhibit proteasome activity include (but are not limited to) bortezomib (Velcade™) and MLN341.

[0292] As used herein, the term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) includes (but is not limited to) collagen peptide mimics and non-peptide mimics inhibitors, tetracycline derivatives, such as the oxime peptide mimics inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996.

[0293] As used herein, the term "compounds for the treatment of hematologic malignancies" includes (but is not limited to) FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinosefuranylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds that target, reduce or inhibit anaplastic lymphoma kinase; and Bcl-2 inhibitors.

[0294] Compounds that target, reduce, or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R), especially compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, astrocytocin derivatives, SU11248, and MLN518.

[0295] As used herein, the term "HSP90 inhibitor" includes (but is not limited to) compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce, or inhibit HSP90 guest proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are particularly compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldmycin (17AAG, a geldmycin derivative); other geldmycin-related compounds; radicicol and HDAC inhibitors.

[0296] As used herein, the term "antiproliferative antibody" includes (but is not limited to) trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), and rituximab (Rituxan). ® ), PRO64553 (anti-CD40) and 2C4 antibody. Antibody refers to intact monoclonal antibody, polyclonal antibody, multispecific antibody formed by at least two intact antibodies, and antibody fragment, provided that the fragment exhibits the desired biological activity.

[0297] For the treatment of acute myeloid leukemia (AML), the compounds described herein can be used in combination with standard leukemia therapies, particularly those used to treat AML. Specifically, the compounds described herein can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs used to treat AML, such as donomycin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin, and PKC412. In some embodiments, treatment of AML associated with ITD and / or D835Y mutations may include the combined administration of the compounds described herein with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), astrocytocin derivatives (e.g., midotulin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitor is selected from quizartinib, midotulin, lestaurtinib, sorafenib, and sunitinib.

[0298] Other anti-leukemia compounds include, for example, Ara-C (a pyrimidine analog), a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogs of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC) inhibitors (such as sodium butyrate and salicylanilide hydroxamic acid (SAHA)) inhibit the activity of enzymes called histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A, and compounds disclosed in US 6,552,065, including (but not limited to) N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or pharmaceutically acceptable salts thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or pharmaceutically acceptable salts thereof, especially lactates. Somatostatin receptor antagonists, as used herein, refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Methods of tumor cell destruction refer to methods such as ionizing radiation. The term "ionizing radiation" as used above and below means ionizing radiation occurring in the form of electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha and beta particles). Ionizing radiation is provided in (but not limited to) radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, Principles and Practice of Oncology, eds. Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

[0299] This also includes EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate 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 resistance), and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0300] In particular, it also includes those compounds, proteins, or monoclonal antibodies against VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; o-aminobenzoic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibodies, angiozyme (RPI4610), and bevacizumab (Avastin™).

[0301] As used in this article, photodynamic therapy refers to the use of certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatments using compounds such as Visudyne™ and porfimer sodium.

[0302] As used in this article, vasopressor steroids refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epitope hydrocortisone, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone.

[0303] Implants containing corticosteroids refer to compounds such as fluocinolone acetonide and dexamethasone.

[0304] Other chemotherapeutic compounds include (but are not limited to) alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or various compounds or compounds with other or unknown mechanisms of action.

[0305] The compounds described herein can also be used as co-therapeutic compounds for combination with other active pharmaceutical ingredients (e.g., anti-inflammatory, bronchodilator, or antihistamine active pharmaceutical ingredients), particularly for the treatment of obstructive or inflammatory airway diseases (such as those mentioned above), for example, as therapeutic enhancers of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. The compounds described herein can be mixed with other active pharmaceutical ingredients in a fixed pharmaceutical composition, or they can be administered alone before, simultaneously with, or after other active pharmaceutical ingredients. Therefore, combinations of the compounds described herein with anti-inflammatory, bronchodilator, antihistamine, or antitussive active pharmaceutical ingredients, as described above, are possible in the same or different pharmaceutical compositions.

[0306] Suitable anti-inflammatory drugs include steroids, especially glucocorticoids, such as budesonide, beclomethasone 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, and SB 209247; LTD4 antagonists, such as montelukast and zafirlukast; and PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), and V-11294A. (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering- Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo; A2a agonists; A2b antagonists; and β-2 adrenergic receptor agonists, such as salbutamol, isoproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol and their pharmaceutically acceptable salts. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxitropium bromide, tiotropium bromide salts, and CHF 4226 (Chiesi) and glycopyrrolate.

[0307] Suitable antihistamine raw materials include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine, and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and tefenadine.

[0308] Other useful combinations of compounds described in this article with anti-inflammatory drugs include those combinations of: chemokine receptor (e.g., CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5) antagonists, particularly CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cycloheptene-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).

[0309] The structures of active compounds identified by their code name, generic name, or trade name can be obtained from the current version of the standard outline "The Merck Index" or from databases such as international patents (e.g., IMS World Publications).

[0310] The compounds described herein can also be used in combination with known treatment procedures, such as the administration of hormones or radiation. In some embodiments, the provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiotherapy.

[0311] 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 a fixed combination, or the compounds described herein may be administered alternately with one or more other therapeutic compounds or administered independently of each other, or a fixed combination may be administered in combination with one or more other therapeutic compounds. Furthermore, the compounds described herein may be administered, in particular, in combination with chemotherapy, radiotherapy, immunotherapy, light therapy, surgical intervention, or combinations of these therapies for cancer treatment. As described above, long-term therapy is also possible in the context of adjuvant therapy within other treatment strategies. Other possible treatments include therapies to maintain the patient's condition after tumor regression, or even, for example, chemopreventive therapy in patients at risk.

[0312] These other agents may be administered separately from the composition containing the compounds of the present invention as part of a multi-dosing regimen. Alternatively, these agents may be part of a single dosage form, which is mixed with the compounds described herein in a single composition. If administered as part of a multi-dosing regimen, the two active agents may be delivered simultaneously, sequentially, or over a period of time, typically within five hours of each other.

[0313] As used herein, the terms “combination,” “in combination,” 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 include the compounds described herein, other therapeutic agents, and pharmaceutically acceptable carriers, adjuvants, or mediators.

[0314] The amounts of both the compounds of the present invention and other therapeutic agents (in those compositions comprising other therapeutic agents as described above) that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the specific administration method. Preferably, the compositions described herein are formulated such that a dose of 0.01-100 mg / kg body weight / day of the compounds of the present invention can be administered.

[0315] In those compositions that include other therapeutic agents, the other therapeutic agents and the compounds set forth herein may act synergistically. Therefore, the amount of the other therapeutic agents in such compositions will be less than that required in a single therapy using only the aforementioned therapeutic agents. In such compositions, the other therapeutic agents can be administered at a dose of 0.01–1,000 μg / kg body weight / day.

[0316] The amount of other therapeutic agents present in the compositions described herein will not exceed the amount normally applied in a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of other therapeutic agents in the compositions disclosed herein will be in the range of about 50% to 100% of the amount normally present in a composition containing said agent as the sole active agent.

[0317] The compounds or pharmaceutical compositions thereof described herein may also be incorporated into compositions for coating implantable medical devices (e.g., prostheses, artificial valves, vascular grafts, stents, and catheters). For example, vascular stents have been used to overcome restenosis (restriction of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These unwanted effects can 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 represent another embodiment.

[0318] example As depicted in the examples below, in some exemplary embodiments, compounds are prepared according to the following general procedure. It should be understood that the following general methods and other methods known to those skilled in the art are applicable to all compounds and their respective subclasses and species as set forth herein. Other compounds set forth herein may be prepared by methods substantially similar to those set forth in the examples herein and by methods known to those skilled in the art. The TYK2 inhibitors set forth herein (e.g., compound 1) may be prepared by methods known to those skilled in the art, such as those set forth in US 11,046,698, the contents of which are incorporated herein by reference in their entirety.

[0319] Example 1: A Phase 2b study evaluating the efficacy and safety of oral compound 1 in subjects with moderate to severe active Crohn's disease.

[0320] Note: Expected total AUC generated by these dose levels 0-tau and C 最大 Within the observed preclinical exposure, the highest predicted AUC in this study, based on toxicokinetic data, was [data missing] when findings attributed to M6 metabolites (considered rat-specific). 0-tau Compared with the NOAEL maintained at 3.7-fold (AUC) and 7-fold (C) in the 26-week rat toxicity study, this was not observed. 最大 The difference was not statistically significant, and the NOAEL remained 8-fold (AUC) and 10-fold (C) higher than that observed in the 39-week monkey toxicity study. 最大 )gap.

[0321] Example 2: A phase 2, multicenter, randomized, placebo-controlled, double-blind induction study evaluating the efficacy and safety of oral compound 1 in subjects with moderate to severe active ulcerative colitis.

[0322] Notice The expected total AUC generated by these dose levels 0-tau and C 最大 Within the observed preclinical exposure, the highest predicted AUC in this study, based on toxicokinetic data, was [data missing] when findings attributed to M6 metabolites (considered rat-specific). 0-tau Compared with the NOAEL maintained at 3.7-fold (AUC) and 7-fold (C) in the 26-week rat toxicity study, this was not observed. 最大 The difference was not statistically significant, and the NOAEL remained 8-fold (AUC) and 10-fold (C) higher than that observed in the 39-week monkey toxicity study. 最大 )gap.

[0323] Example 3: A phase 1 randomized, double-blind, placebo-controlled, multiple-dose study of compound 1 in healthy volunteers (Study 104) summary Basic Principles: In a previous study (Study 101), healthy participants in two groups received either 20 mg or 35 mg of compound 1 daily for two weeks. Treatment was generally safe and well-tolerated, with no serious or severe adverse events reported. This study was designed to continue dose escalation in healthy participants to define a relatively wide dose range, thereby aiding in the selection of doses for future studies in patients with psoriasis and other autoimmune diseases. Nonclinical pharmacology, toxicology, and pharmacokinetics (PK) studies, as well as early clinical data, support multiple-dose studies of the proposed compound 1 in healthy participants.

[0324] Goals and End Points

[0325] Overall design This is a phase 1 randomized, double-blind, placebo-controlled, multiple-dose study of compound 1 in healthy participants.

[0326] The study cohort included healthy male participants aged 18 to 65 years and / or female participants who were not likely to have children. Two multiple-dose cohorts of eight healthy participants (cohort 1 and cohort 2) were established, with participants receiving either a daily dose of compound 1 (N=6) or placebo (N=2) for two weeks. Participants were admitted to the CRU on day -1. Participants remained restrained in the CRU until all scheduling procedures were completed on day 22, and were then discharged if medically appropriate. Safety laboratory tests, PK blood draws, PD blood draws, and adverse event assessments were performed according to the Schedule of Activities (SoA).

[0327] Group 2 was included after the PI and the client determined that Group 1 demonstrated sufficient safety and tolerability.

[0328] Patients were questioned about potential COVID-19 exposure / symptoms and tested for COVID-19 via PCR at the screening visit and Day-1, with samples sent to the central laboratory. Patients testing positive for PCR at screening or Day-1 were considered to have failed screening. Participants who developed symptoms consistent with COVID-19 infection after administration were tested via PCR and, if they had a positive result, withdrew from the study. This was recorded as an adverse event.

[0329] Public statement: This is a sequential interventional study with two groups, the commissioner, participants, and researchers, who are blinded in the study.

[0330] Number of participants: Approximately 16 participants were randomly assigned to the study intervention, and there were 16 evaluable participants (8 in each group).

[0331] Intervention group and duration: Sixteen participants are expected to receive either the active study drug or a placebo at the doses specified below.

[0332] Table 1: Groups and Dosage Levels

[0333] The screening period was approximately 28 days. Participants were confined to the CRU from day -1 to day 22. Treatment was administered daily for 14 days, and SFU visits were scheduled before discharge from the CRU on day 22. The total duration of study participation was approximately 50 days.

[0334] Dosage escalation stop rule After reviewing all relevant blinded safety / tolerance (e.g., adverse events, clinical laboratory tests, physical examinations, vital signs, and safety ECG) and PK data up to day 15 for at least six participants in group 1, the client and PI jointly decide to continue the next higher dose from group 1 to group 2. The client and PI jointly decide whether to continue the study as planned, whether to continue the study with additional safety evaluations, whether to continue the study at a dose different from that planned for group 2, or whether to discontinue dose escalation.

[0335] Dose escalation is terminated if at least two participants in the cohort meet any of the following criteria attributable to the investigational drug: • Drug-related SAEs.

[0336] • Experience drug-related Grade 3 or higher toxicity.

[0337] Dose escalation is terminated if, at a given dose level, even if only one participant meets the following criteria attributable to the study drug: 1. Evidence of drug-induced liver injury (DILI).

[0338] If a treatment-related SAE, ≥ grade 3 AE, and / or evidence indicating DILI is observed, a PK sample is collected and the client is notified. The PI may, at their discretion, unblind the treatment allocation for the relevant participant to determine if the event is related to compound 1 and whether the discontinuation criteria are met. Any unblinding of participant treatment is recorded.

[0339] Where applicable, provide the IRB with a written statement fully documenting the reasons for study termination. The study is monitored by the research team.

[0340] Dosage justification Compound 1 has been previously investigated in a first-in-human study (Study 101) in healthy volunteers at single-dose and two multiple-dose levels (SAD and MD). Single-dose administration between 5 mg and 200 mg daily and multiple-dose administration of 20 mg or 35 mg for 2 weeks were generally safe and well-tolerated. No serious or severe adverse events (AEs) or AEs leading to treatment discontinuation were observed. The most common adverse effect was a rash, acneiform dermatitis, observed in 7 of 17 subjects (41%) receiving a single dose of 100 mg or higher and in 8 of 12 subjects (67%) receiving multiple-dose administration. Although common, these events were mild in intensity and, even in the multiple-dose group, resolved within 1 to 2 weeks with limited or no intervention and without the need for treatment discontinuation.

[0341] In the single-dose group using the TPGS formulation, overall exposure to compound 1 increased approximately proportionally to the dose between 5 mg and 75 mg, and less proportionally to the dose between 100 mg and 200 mg. In summary, exposure to compound 1 as either TPGS or SDD formulations was similar after a single dose. Similar oral exposures were observed when compound 1 and SDD formulations were administered while the patient was eating or fasting.

[0342] In multiple-dose groups using TPGS formulations, moderate accumulation of compound 1 was observed at 20 mg and 35 mg daily dose levels. For both dosage regimens, C 最大 and AUC 0-tau The cumulative ratio of both was <3. At steady state, treatment with 20 mg resulted in approximately 207 ng / mL of C. 最大 and an AUC of approximately 3160 hr*ng / mL 最后 A daily dose of 35 mg was administered for 2 weeks, and the corresponding C was observed at steady state. 最大 and AUC 最后 The values ​​were approximately 325 ng / mL and 5839 hr*ng / mL. The AUC exposure level achieved with the higher dose of 35 mg tested was approximately 8 to 9 times lower than the NOAEL determined in 28-day repeated-dose toxicity studies in monkeys and rats, respectively.

[0343] This study investigated two additional multiple doses, namely 50 mg in group 1 and up to 100 mg in group 2, to expand the range of doses studied. SDD formulations were used in this study. Following administration of 50 mg and 100 mg doses (daily for 2 weeks), the inferred exposure levels were estimated to be approximately 7- and 8-fold lower (50 mg) and 3- and 4-fold lower (100 mg) lower, respectively, than the NOAELs determined in 28-day repeated-dose toxicity studies in monkeys and rats.

[0344] Non-clinical pharmacology, toxicology and pharmacokinetics (PK) studies, early clinical data, and modeling data at 50 mg and 100 mg doses support multiple dose studies of the proposed compound 1 in healthy participants, with 50 mg as the first dose tested.

[0345] Check-in Procedure (Day -1) On the morning of Day -1, all participants returned to the CRU. Inclusion and exclusion criteria were reviewed to ensure participants still met all inclusion criteria. A second PCR COVID-19 test was also performed, and samples were sent to the central laboratory. After the PCR test, participants remained in the isolation area until they received their results later that day. Participants who did not meet all inclusion criteria or met any of the exclusion criteria (including a positive COVID-19 test) on Day -1 were considered to have failed the screening.

[0346] Alternate participants who meet the inclusion criteria during screening are also returned to the CRU to complete Day-1 activities. If an alternate participant is not randomized because the target number of participants for each group has been met, they are still eligible for the next group. If an alternate participant is enrolled in the study the day after the initial Day-1 assessment, there is no need to repeat the Day-1 laboratory experiment.

[0347] Treatment period and monitoring period On the morning of Day 1, a pre-dosing evaluation was obtained. After review of all criteria, participants were randomized.

[0348] Participants received a single oral dose of compound 1 or placebo on the morning of Day 1 in a blinded manner, and then daily for a total of 14 days. Safety and tolerability were assessed during treatment via monitoring, including vital signs, clinical laboratory tests, 12-lead ECG, and adverse events (AEs). Blood samples for pharmacokinetic (PK) and PD assessments and urine samples for metabolite analysis were collected at the time points listed. Cardiac dynamics monitoring was also performed.

[0349] SFU Visit / Early Termination SFU visit was performed before discharge on day 22.

[0350] Safety and tolerability were assessed through monitoring, including vital signs, clinical laboratory tests, 12-lead ECG, and adverse events.

[0351] If the visit is terminated early, the procedures outlined in the SoA for the SFU visit should be performed. However, a blood sample is also collected for PK assessment. Following early termination of the visit, participants should return to the stated location for an SFU visit no more than 7 days after the last administration of the study drug.

[0352] Meal Schedule Meals and / or snacks may be provided on Day -1 as appropriate.

[0353] Participants were required to fast for at least 8 hours overnight before administration of the study drug, and then continue to fast for at least 4 hours only on day 1.

[0354] Fluid intake is restricted for 1 hour before and 1 hour after administration (except for water provided at the time of administration), but free fluid intake is permitted at all other times. Other fluids are permitted as part of a standard diet and / or snacks, but are restricted at all other times throughout the restriction period.

[0355] Constraint Duration Participants were required to remain in the CRU for 22 days.

[0356] Inclusion criteria Participants are eligible for inclusion in this study only if all of the following criteria apply: age 1. Participants must be between 18 and 65 years old (inclusive) when signing the informed consent form.

[0357] Participant type and disease characteristics 2. Participants were medically healthy volunteers who, as the PI considered them, had no clinically significant medical history, physical examination, laboratory findings, vital signs, or ECG at screening and Day-1. All laboratory results should generally be within the normal range specified by the CRU laboratory.

[0358] 3. Non-smokers (defined as individuals who have not used nicotine-containing products (including cigarettes and e-cigarettes) for at least 3 months prior to administration).

[0359] weight 4. At the time of screening and clinical admission, the body mass index (BMI) should be between 18-35 kg / m². 2 Within the range (including the endpoints).

[0360] gender 5. Men or women who are not likely to have children. Male participants and their female partners must use two methods of contraception: one considered highly effective as defined by the CTFG guidelines (CTFG 2014) (an annual failure rate of less than 1%), and the other a barrier method for intercourse during the study period. After the last dose, male participants and their partners should continue to use contraception and avoid donating sperm for 90 days. Female participants must have undergone sterilization or be postmenopausal (confirmed by an FSH test) at least 6 months prior to screening.

[0361] Informed Consent Form 6. Able to sign informed consent forms, which include compliance with the requirements and limitations set forth in the Informed Consent Form (ICF) and in this program.

[0362] Exclusion criteria Participants will be excluded from the study if any of the following criteria apply: medical illness 1. Any acute or chronic medical condition, including laboratory abnormalities (grade 1 or higher) or abnormal electrocardiogram (ECG) findings, or a mental illness that would prevent a participant from signing an informed consent form, place them at unacceptable risk if they participate in the study, or obscure the ability to interpret data from the study. Participants with evidence of mild active infection (e.g., upper respiratory tract, urinary tract, gastrointestinal) at screening may be brought back for rescreening after their symptoms have completely resolved and they have completed an appropriate course of treatment.

[0363] 2. Female participants who are likely to have children.

[0364] 3. Serologically positive for hepatitis B, hepatitis C, or human immunodeficiency virus (HBsAg, HCV Ab, or HIV Ab).

[0365] 4. A positive PCR test for COVID-19 at screening or Day-1 visit; or a suspected COVID-19 infection within 10 days of screening; or prior contact with another person diagnosed with or under investigation for COVID-19 within 10 days of screening. However, participants in Group 1 who tested positive for COVID-19 during screening may be rescreened in Group 2 after completing the appropriate isolation period as per CDC guidelines. Participants who, as the PI deems appropriate, have previously been infected with COVID-19 (based on clinical symptoms or laboratory tests) but have recovered symptomatically, tested negative for the COVID-19 antigen via PCR, and have no sequelae may also be screened for inclusion in the study.

[0366] 5. Participants with any surgical or medical condition that may affect the absorption, distribution, metabolism, or excretion of the study drug.

[0367] 6. Blood pressure less than 90 / 40 mmHg or greater than 140 / 90 mmHg at the time of screening.

[0368] 7. Heart rate below 40 bpm or above 99 bpm during screening.

[0369] 8. At the time of screening, the QTcF (Fridericia corrected) interval for men is >450 ms or for women is >470 ms, or there is a history of prolonged QT syndrome.

[0370] 9. Donate blood (including whole blood, platelets, or plasma) or suffer significant blood loss within 56 days prior to administration, or plan to donate blood within 30 days after the last administration of the study drug.

[0371] 10. Intolerance to oral medications.

[0372] 11. History of solid malignancy or hematologic malignancy within the past 5 years (including precancerous conditions such as myelodyplasia syndrome or lymphoproliferative disorders); excluding a history of surgically removed localized basal or squamous cell carcinoma of the skin with no evidence of recurrence, successfully treated ductal carcinoma in situ of the breast, and successfully treated cervical cancer in situ.

[0373] Previous / accompanying medications, supplements or procedures 12. Participants who have received any vaccine (including COVID-19) within 28 days of administration.

[0374] 13. Participants who have used a systemic prescription medication within 30 days of administration (or 5 half-lives of a concomitant therapy, whichever is longer), or who have used an over-the-counter medication, herbal remedy, vitamin supplement, or topical medication within 14 days of administration. The use of self-limiting medications (e.g., Tylenol) may be considered an exception if approved by the PI and the commissioner.

[0375] 14. Participants who plan to undergo elective medical procedures during the study.

[0376] 15. Participants who engage in recreational drug use or who test positive in drug screening tests during screening.

[0377] 16. Participants who tested positive for cotinine.

[0378] Previous / parallel clinical research experience 17. Within 30 days or 5 half-lives (whichever is longer) or, if the investigational drug is a biologic (e.g., an antibody), participants who have received the investigational drug or an approved drug in the study setting within 6 months of the administration of the investigational drug, or participants currently enrolled in an investigational study.

[0379] Diagnostic assessment 18. Participants who may have any other criteria (e.g., clinically significant screening blood test results) that, in the PI's view, may interfere with study implementation or outcomes.

[0380] Other exclusion criteria 19. Participants with any known allergies to any excipients contained in the study drug or placebo formulation.

[0381] 20. Randomize the alcohol consumption within 14 days.

[0382] Lifestyle considerations During participation in this study, dietary, medication use, and activity levels will be restricted, as outlined in the following sections.

[0383] Diet and dietary restrictions Participants were prohibited from consuming grapefruit or grapefruit juice for 14 days prior to administration, throughout the entire treatment period, and throughout the PK sample collection period.

[0384] Restrictions on caffeine, alcohol, tobacco, and cannabis The following foods and beverages are prohibited from consumption as instructed: Participants were prohibited from consuming products containing xanthine or caffeine for 48 hours prior to administration and throughout the PK sample collection period.

[0385] Participants must not consume alcohol or alcoholic products, or drink as described for the use of concomitant medications, for 14 days after administration. Cold medicines and other medications containing small amounts of alcohol are permitted if the PI deems it necessary.

[0386] Participants must not use tobacco or nicotine products (including smokeless tobacco, nicotine patches, or nicotine gum) while at the clinical unit and should avoid using such products during the study screening period.

[0387] Participants must not use recreational drugs, including cannabis products (in any form, including oral or sublingual), while in the clinical unit. Participants should also avoid using recreational drugs during the study screening period.

[0388] Activity From 48 hours prior to administration until the SFU visit, participants should limit their physical activity to a level sufficient for daily living activities (e.g., eating, bathing, dressing). Moderate or strenuous activities (e.g., pairs tennis, 3-5k running, marathon training / running, CrossFit training, or weightlifting) are not permitted during this period.

[0389] The research interventions applied

[0390] Security assessment The primary objective of this study was to assess the safety and tolerability of compound 1. Safety was determined by evaluating physical examination, vital signs, ECG, clinical laboratory parameters, and adverse events (AEs).

[0391] If deemed necessary, the PI will decide to implement additional safety measurements. Throughout the study, the Sponsor Medical Monitor may consult on any potential safety issues.

[0392] Physical examination Measure height (cm) and weight (kg).

[0393] The target physical examination includes at least an assessment of the cardiovascular, respiratory, gastrointestinal, musculoskeletal, and nervous systems. Height and weight are also measured and recorded (at screening only). BMI is calculated only at screening and clinical admission. Each participant is examined by a licensed physician or a qualified designated person. Physical examinations may be performed at various off-schedule time points if the PI deems it necessary.

[0394] Any abnormal findings during the screening period are recorded as medical history.

[0395] The principal investigator (PI) or designated personnel should pay attention to clinical signs associated with pre-existing conditions.

[0396] vital signs After resting for 5 minutes in a quiet and distraction-free environment (e.g., television, mobile phone), participants' vital signs were measured in a supine position. Vital signs were collected at least 10 minutes after rest, provided that the safety ECG was taken at the time point defined for cardiac dynamics ECG extraction. Signs included measurements of temperature (oral or tympanic), systolic and diastolic blood pressure, heart rate, and respiratory rate.

[0397] 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. The average of the three readings was used to determine participant eligibility at screening.

[0398] Measure vital signs on day -1. For blood pressure and heart rate, three readings should be taken and recorded. The average of the three readings should be used to confirm compliance.

[0399] On Day 1 and Day 2, vital signs should be obtained within 30 minutes before administration. Post-administration vital signs should be collected within 30 minutes of the designated time points in the activity schedule (i.e., 2, 4, 8, and 24 hours after administration).

[0400] Vital signs were also measured on the last day of study drug administration and at the SFU (see SoA). Blood pressure and heart rate should be taken three times and recorded.

[0401] The PI believes that additional measurements should be performed if necessary.

[0402] electrocardiogram For the purpose of the study, ECGs were classified as safety ECGs or cardiac dynamics ECGs and were performed.

[0403] Standard 12-lead ECG (Safety ECG) A 12-lead ECG was performed. Timing and recording techniques for all participants' ECGs were standardized. All safety ECGs were obtained and recorded in triplicate after administration of the study drug on Day 1.

[0404] Holter monitoring (cardiac dynamics ECG) The timing and recording techniques for ECGs of all participants involved in cardiac dynamics monitoring were standardized. Holter monitoring was performed on Day 1 and Day 14 to collect 12 consecutive leads of ECG data from 2 hours before administration to 24 hours after administration. During this period, ECG extractions were performed by a third-party vendor using data from the Holter monitor at defined time points typically paired with PK blood draws (except before administration; for pre-administration, cardiac dynamics monitoring required three independent pre-administration measurements at 60, 45, and 30 minutes before administration).

[0405] Clinical safety laboratory assessment As summarized above, clinical safety laboratory assessments were conducted.

[0406] The PI or a qualified person must review the laboratory report, document the review, and record any clinically relevant changes that occur during the study.

[0407] For values ​​deemed clinically significant during the study period, laboratory tests should be repeated until the values ​​return to the participant's baseline or the PI is no longer considered clinically significant.

[0408] If these values ​​do not return to normal / baseline within a reasonable timeframe for the PI assessment, the cause should be investigated and the client notified.

[0409] Any non-protocol-specified laboratory assessments that require changes to participant control or are deemed clinically significant (e.g., leading to adverse events) by the PI must also be documented in the CRF.

[0410] Drug-induced liver injury (DILI) Events that meet the definition of drug-induced liver injury (DILI): • In the presence of normal alkaline phosphatase (ALP), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3X ULN and total bilirubin (TBL) >2X ULN require immediate enhanced monitoring (minimum of all liver tests: ALT, AST, ALP, and TBL, and prothrombin time (PT) / INR) and evaluation of the cause of the abnormal liver test (FDA 2009).

[0411] • ALT or AST > 3xULN, with symptoms such as fatigue, nausea, vomiting, pain or tenderness in the right upper quadrant, fever, rash, and / or eosinophilia (>5%) (FDA 2009).

[0412] The medical supervisor should be contacted immediately. Additional medical control considerations (specific to the individual participant and potentially extending to a broader group) should be discussed during the evaluation process.

[0413] The following adverse events of particular concern need to be reported to the client immediately. The PI should inform the client within 24 hours of becoming aware of the following events.

[0414] •>Grade 2 cytopenia • Platelet count less than 75,000 / mm3 • WBC less than 3000 / mm3 • Neutrophils less than 1500 / mm3 • Lymphocytes less than 800 / mm3 • Heme levels less than 10 g / dL • Creatine phosphokinase (CPK) elevation > grade 3 [> 5X ULN] Pharmacokinetic Measurement Collect approximately 5 mL of blood sample for measuring the plasma concentrations of compound 1 and its metabolites.

[0415] Record the actual date and time (24-hour clock time) for each sample.

[0416] Samples were used to evaluate the pharmacokinetic (PK) of compound 1. Each sample was divided into two aliquots (one PK and one backup). Samples collected for plasma concentration analysis may also be used to evaluate safety aspects related to metabolite formation or issues that arose during or after the study.

[0417] Blood samples were collected for pharmacokinetic purposes as follows.

[0418] PK sampling

[0419] Urine samples were collected from all participants in group 2 on day 1 before administration and on day 14 as follows:

[0420] Pharmacodynamics As a measure of the pharmacodynamic response to treatment with compound 1, approximately 1 mL of whole blood was collected directly into the provided TruCulture (Myriad RBM) whole blood assay collection tube at selected time points. Collection was performed within a window of ± 30 minutes at the specified time points. These samples were incubated at 37°C (out-of-body temperature) for approximately 24 hours using a CRU, and the level of IFNγ in the cell supernatant in response to cytokine stimulation was quantified using an appropriate immunoassay.

[0421] Example 4: Treatment of IBD with Compound 1 Inflammatory bowel disease (IBD) represents one of the key potential differentiation opportunities for our sex-selective TYK2 inhibitor compound 1, in which we believe that the selectivity and PK and PD characteristics of compound 1 can achieve higher targeted TYK2 inhibition while maintaining favorable tolerability characteristics.

[0422] IBD is an inflammatory bowel disease caused by an immune response to environmental triggers. According to the Decision Resource Group, it is estimated that the two most common forms of IBD, ulcerative colitis and Crohn's disease, affect approximately 1.9 million U.S. adults. Ulcerative colitis and Crohn's disease are primarily distinguished by the parts of the gastrointestinal tract that are affected. Ulcerative colitis is characterized by inflammation of the large intestine or colon and rectum, while Crohn's disease encompasses inflammation of any part of the gastrointestinal tract, but most commonly affects the terminal small intestine or the junction of the small intestine and colon in the ileum. We estimate that approximately 980,000 adults in the U.S. and an equivalent number of adults in EU4 and UK are diagnosed with ulcerative colitis, and approximately 900,000 adults in the U.S. and EU4 plus UK are diagnosed with Crohn's disease.

[0423] Treatment for IBD is determined by a variety of factors, including disease severity, location of inflammation, previous response to treatment, side effects, and comorbidities. The most common oral treatment for ulcerative colitis is anti-inflammatory drugs containing 5-aminosalicylic acid (5-ASA). These drugs reduce inflammation in the intestinal wall and can reduce symptoms of ulcerative colitis and maintain remission, but are not as effective as in treating Crohn's disease. Corticosteroids and other oral immunomodulators can be used for short-term control of sudden relapses and to maintain remission in IBD patients who are unresponsive to other medications.

[0424] Injectable biologics are commonly used to treat moderate to severe ulcerative colitis and Crohn's disease. The most frequently prescribed biologics are anti-TNFα biologics (including AbbVie's Humira®, Johnson & Johnson's Remicade® and Simponi®, and UCB Pharma's Cimzia®). Newer biologic 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 Stelara®). Pfizer's oral JAK inhibitor Xeljanz® was approved in 2018 for the treatment of ulcerative colitis; however, commercialization has been limited due to the safety concerns mentioned above. BMS's Zeposia®, an oral S1P1R modulator, was approved in May 2021 for the treatment of moderate to severe ulcerative colitis.

[0425] In 2020, the IBD market across all severity levels in the United States was approximately $14 billion, and globally it was $25 billion. Global reported sales of ulcerative colitis treatments totaled an estimated $7.9 billion in 2020, while global annual sales of Crohn's disease treatments totaled an estimated $17.7 billion. Market research indicates significant growth potential for the IBD commercial market due to increasing disease incidence and the emergence of novel oral treatments. We believe the anticipated benefits of oral formulations will be supported by physician and patient support for oral administration over injectable biologics, high demand for new therapies with competing clinical features, and the potential for potent and well-tolerated oral formulations to expand overall treatment for the moderate to severe ulcerative colitis population.

[0426] TNF inhibitors currently dominate the ulcerative colitis treatment market, followed by other injectable biological therapies (anti-IL-12 / 23 antibodies and anti-integrin therapy) and oral 5-ASA therapy.

[0427] Example 5: Absorption, distribution, metabolism, excretion (ADME) and other properties of compound 1 The potency and selectivity of compound 1 were explored by screening 1 μmol concentrations of compound 1 for binding to a group of 631 kinases. Only one kinase was inhibited with >50% inhibition: PIP5K1C (54% inhibition). The various in vitro potency / selectivity results are summarized in the table below.

[0428]

[0429] Drug metabolism and pharmacokinetics (PK) studies of compound 1 were conducted in rodent (mice and rats) and non-rodent (dogs and monkeys) species, and systemic exposure of compound 1 after oral administration was evaluated in completed non-clinical safety studies.

[0430]

[0431] Preclinical Cl and Vss at 1 mpk IV dose *Hepatopac Low Turnover Rate Measurement **Predictions from Wajima allotropic growth and PBPK-gut model Compound 1 exhibited good cross-species absorption. The solubilities of FaSSIF / FeSSIF were 13 / 70 μg / mL (kinetic solubility 32 μM), respectively. Caco-2 P app (AB) is 15 x 10 -6 cm / sec, effluent ratio = 1. The likelihood of a DDI under clinically relevant exposure is low. CYP450 IC 50At 1A2, 2C9, and 2D6, the activity was >30 μM; at 2C19 and 3A4 (M), it was >8 μM; at 2 μM, it was 3A4 (T), with no time-dependent inhibition; low PXR activation (26% of the rifampicin control at 30 μM). We observed low overall metabolism; human in vitro metabolites were observed in hepatocytes of preclinical species (rat, cynomolgus monkey). Elimination was primarily via oxidative metabolism through multiple CYP450 enzymes, followed by conjugation.

[0432] Although numerous embodiments of the invention have been described, it will be apparent that modifications can be made to the basic embodiments to provide other embodiments utilizing the compounds and methods of the invention. Therefore, it should be understood that the scope of the invention will be defined by the appended claims rather than by the specific embodiments represented by way of example.

[0433] Example 6: Efficacy of oral tyrosine kinase 2 (TYK2) inhibitor compound 1 in two preclinical mouse models of colitis Tyrosine kinase 2 (TYK2), a member of the Jenas kinase (JAK) family, plays a crucial role in the pathogenesis of inflammatory bowel disease (IBD) and other autoimmune diseases via signaling pathways mediating downstream interleukin (IL)-12, IL-23, and interferon (IFN) α / β. Although some JAK inhibitors have been approved for the treatment of ulcerative colitis (UC), these inhibitors are associated with adverse events potentially related to JAK1-3 inhibition, leading to dose-limiting effects. Compound 1 is a highly potent and selective allotropic oral TYK2 inhibitor computationally engineered to bind to the Jenas homology 2 (JH2) domain of TYK2, but spatially isolated 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 programs have been approved by the Institutional Animal Care and Use Committee (IACUC).

[0434] Treatment In the adoptive TCT colitis model, CD4+ was introduced on day 0. + CD45RB hi T cells were transferred into severely combined immunodeficiency (SCID) mice, and then disease progression persisted for 48 days. Figure 1A In the α-CD40 model, T cells and B cells deficient in Rag2 were attacked with agonist α-CD40 mAb on day 0. - / -Mice, and then the disease progressed for 7 days ( Figure 1B ).

[0435] Mice were divided into four groups for each model (n=12-16 and n=10 in the TCT and α-CD40 mAb colitis models, respectively) to receive: the medium (negative control), orally, twice daily; and the drug, administered via IC50. 50 (Low) dose of compound 1, orally, twice daily (BID); with IC50 90 Compound 1, administered orally twice daily (BID); or α-IL-12 / 23p40 mAb (positive control), intraperitoneally once weekly (QW). In vivo doses were designed to achieve 24-hour coverage at the corresponding inhibitory concentrations and were modeled based on prior mouse pharmacokinetic data. At the end of the treatment period, colonic tissue from the TCT colitis model was obtained for RNA-seq processing, and transcriptomic profiling was analyzed using Reactome (reactome.org). Colonic weight:length ratio and total histological score were also assessed. Statistical significance of differences between groups was determined using analysis of variance (ANOVA) and Tukey's post-hoc test. All animal protocols were approved. Treatment regimens are summarized below: • Mice were divided into four groups for each model (n = 12–16 mice in the ICI model and n = 10 mice in the α-CD40 mAb colitis model) to receive: - Medium (negative control), orally, twice daily. - with IC 50 (Low) dose of compound 1, orally, twice daily. - with IC 90 (High) dose of compound 1, orally, twice daily; or - α-IL-12 / 23 p40 mAb (positive control), intraperitoneal, once a week.

[0436] • Treatment began on day 0 and ended on day 48 (TCT colitis model) and day 7 (a-CD40 mAb colitis model).

[0437] • At the end of the treatment period, assess the colon weight-to-length ratio and total histological score in both models.

[0438] Colonic tissue from a TCT colitis model was obtained for RNA-seq processing. Reactome (…) was used. https: / / reactome.org / Transcriptome profiling was performed.

[0439] In the TCT model, IC 50 and IC90 Compound 1 at the administered level significantly reduced colon weight relative to the carrier: length ratio (both). p <0.0001) ( Figures 2A to 2B (Table 1). In contrast, in the α-CD40 mAb colitis model, only in IC 90 Colon weight:length ratio significantly decreased at the administration level relative to the medium. p <0.01) ( Figures 2A to 2B (Table 1). In either model, at any dosage level, no significant difference was observed between compound 1 and the positive control. Additionally, in the TCT model, IC50... 50 and IC 90 At the administration level, the total histological score of compound 1 was significantly lower relative to the carrier (respectively...). p <0.01 and p <0.0001) ( Figures 3A to 3B (Table 1). In IC 90 At each dosing level, the reduction in total histological score was numerically greater, but there was no significant difference compared to the positive control at any dosing level. In contrast, in the α-CD40 mAb colitis model, only at IC50... 90 At the administration level, the total histological score was significantly lower relative to the vehicle. p <0.001). In IC 90 At the administration level, no significant difference was observed between compound 1 and the positive control.

[0440] In the TCT colitis model, compound 1 selectively downregulated genes associated with cytokine signaling, particularly those associated with the T helper cell 17 (Th17) phenotype, including those related to the IFN α / β pathway, the innate immune system, and interleukin signaling. Figure 4 ).

[0441] Compound 1 was effective in two preclinical mouse models of colitis, with IC50 showing a significant improvement. 90 It provides maximum efficacy in both models. Downregulation of expression of multiple genes involved in cytokine signaling pathways was observed. Results from this preclinical study support the potential role of potent and selective TYK2 inhibition in the treatment of IBD, with compound 1 showing promise of achieving IC50 in humans. 90 Coverage. For example, see 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.

[0442] Table 1. In TCT and α-CD40 mAb colitis models, the mediator, α-IL-12 / 23 p40, and IC50 levels were significantly different. 50 and IC 90 Mean differences in colon weight, length ratio, and total histological score of compound 1 at administration levels

[0443] Significance was determined using ANOVA and Tukey post-hoc test, and the following was indicated:* 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; IC 50 50% inhibitory concentration; IC50 90 90% inhibition concentration; mAb, monoclonal antibody; TCT, T cell transfer.

Claims

1. A method for treating inflammatory bowel disease, including Crohn's disease or ulcerative colitis, in patients in need, the method comprising administering to the patient a therapeutically effective amount of compound 1: 1 Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

2. The method of claim 1, wherein the daily application is performed for the following durations: 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 week to 2 weeks, approximately 2 weeks to 3 weeks, approximately 3 weeks to 4 weeks, approximately 4 weeks to 5 weeks, approximately 5 weeks to 6 weeks, approximately 6 weeks to 7 weeks, approximately 7 weeks to 8 weeks, approximately 8 weeks to 9 weeks, approximately 9 weeks to 10 weeks, approximately 10 weeks to 11 weeks, approximately 11 weeks to 12 weeks, approximately 12 weeks to 14 weeks. Weeks, approximately 14 to 16 weeks, approximately 16 to 18 weeks, approximately 18 to 21 weeks, approximately 21 to 24 weeks, approximately 24 to 27 weeks, approximately 27 to 30 weeks, approximately 30 to 33 weeks, approximately 33 to 36 weeks, approximately 36 to 39 weeks, approximately 39 to 42 weeks, approximately 42 to 45 weeks, approximately 45 to 48 weeks, approximately 48 to 51 weeks, approximately 51 to 52 weeks, approximately 1 year to 2 years, or approximately 2 years to 3 years, approximately 3 years to 4 years, approximately 4 years to 5 years, or more than 5 years.

3. The method of claim 1, wherein the daily application continues indefinitely.

4. The method of any one of claims 1-3, wherein for patients with Crohn's disease, the average reduction in the Crohn's Disease Simplified Endoscopic Score (SES-CD) is approximately 50% to 70%.

5. The method of any one of claims 1-3, wherein for patients with Crohn's disease, the average reduction in the Crohn's Disease Simplified Endoscopic Score (SES-CD) is approximately 70% to 90%.

6. The method of claim 4 or 5, wherein for patients with Crohn's disease, the average reduction in the Crohn's Disease Simplified Endoscopic Score (SES-CD) is approximately 90% to 100%.

7. The method of any one of claims 1-6, wherein for patients with Crohn's disease and isolated ileal disease, the Crohn's disease simplified endoscopic score (SES-CD) is less than or equal to 4 or reduced by at least 2 points from baseline, as read in a centralized manner.

8. The method of any one of claims 1-6, wherein for a patient with ulcerative colitis, a modified Mayo score (a scoring system for assessing the activity of ulcerative colitis) is less than or equal to 2, wherein the stool frequency sub-score is less than or equal to 1, the rectal bleeding sub-score is 0, and the central reading endoscopy score is less than or equal to 1 (modified score 1 to exclude fragility).

9. The method of any one of claims 1-8, wherein the patient suffers from inflammatory bowel disease.

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

11. The method of any one of claims 1-10, wherein the patient suffers from Crohn's disease.

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

13. The method of any one of claims 1-10, wherein the patient suffers from ulcerative colitis.

14. The method of claim 13, wherein the ulcerative colitis is moderate to severe active.

15. The method of claim 11, wherein for patients with Crohn's disease, including moderate to severe active Crohn's disease, the method achieves: a reduced Crohn's disease simplified endoscopic score (SES-CD) of 50% or more from baseline, or a reduction of about 50% to about 70%, about 70% to about 90%, or about 90% to about 100% in a centralized reading; or for isolated ileal disease, a reduced SES-CD of 4 or less or a reduction of at least 2 points from baseline in a centralized reading.

16. The method of claim 13, wherein for patients with ulcerative colitis, including moderate to severe active colitis, the method achieves: a modified Mayo score (a scoring system for assessing the activity of ulcerative colitis) less than or equal to 2, wherein the stool frequency sub-score is less than or equal to 1, the rectal bleeding sub-score is 0, and the central reading endoscopy score is less than or equal to 1 (modified score 1 to exclude fragility).

17. A method for inhibiting the production of interferon-γ (IFNγ) in a patient, the method comprising administering a therapeutically effective amount of compound 1 to a patient suffering from inflammatory bowel disease: 1 Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

18. The method of claim 17, wherein the patient suffers from Crohn's disease.

19. The method of claim 17, wherein the patient suffers from ulcerative colitis.

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

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

22. The method of claim 19, wherein the ulcerative colitis is moderate to severe active.

23. The method of any one of claims 1-22, wherein the T of compound 1 in the plasma 最大 It will arrive in approximately 3 to 6 hours.

24. The method of any one of claims 1-22, wherein the t of compound 1 in the plasma 1 / 2 It will be reached in approximately 17 to 37 hours.

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

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

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

30. The method of any one of claims 1-27, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in a dose that is taken multiple times daily.

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

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

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

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

35. The method of any one of claims 1-34, wherein the following serum C is achieved 最大 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 about 240 ng / mL, about 240 ng / mL to about 280 ng / mL, about 280 ng / mL to about 320 ng / mL, about 320 ng / mL to about 360 ng / mL, about 360 ng / mL to about 400 ng / mL, about 400 ng / mL to about 480 ng / mL, about 480 ng / mL to about 560 ng / mL, about 560 ng / mL to about 740 ng / mL, about 740 ng / mL to about 820 ng / mL, about 820 ng / mL to about 900 ng / mL, about 900 ng / mL to about 1000 ng / mL, about 1000 ng / mL to about 1200 ng / mL, about 1200 ng / mL to about 1400 ng / mL, about 1400 ng / mL to about 1600 ng / mL, about 1600 From ng / mL to about 1800 ng / mL, or from about 1800 ng / mL to about 2000 ng / mL.

36. A method for treating patients with moderate to severe active inflammatory bowel disease, including Crohn's disease or ulcerative colitis, the method comprising administering a therapeutically effective amount of compound 1: 1 The daily dose is approximately 30 mg to approximately 100 mg.

37. Compound 1: 1 Or its pharmaceutically acceptable salts for the treatment of inflammatory bowel diseases, including Crohn's disease or ulcerative colitis.

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