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WO2025062372A1 - Inhibiteurs de tyk2 destinés à être utilisés dans le traitement d'une maladie inflammatoire de l'intestin - Google Patents

Inhibiteurs de tyk2 destinés à être utilisés dans le traitement d'une maladie inflammatoire de l'intestin Download PDF

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Publication number
WO2025062372A1
WO2025062372A1 PCT/IB2024/059183 IB2024059183W WO2025062372A1 WO 2025062372 A1 WO2025062372 A1 WO 2025062372A1 IB 2024059183 W IB2024059183 W IB 2024059183W WO 2025062372 A1 WO2025062372 A1 WO 2025062372A1
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weeks
compound
disease
patient
hours
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Namita Singh
Carole Elizabeth HARBISON
Chandra DURAIRAJ
Van Anh NGUYEN
Graham Alastair Richard HEAP
Guliang Xia
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the present invention relates to methods of administering a non-receptor tyrosine kinase 2 (TYK2) inhibitor, such as N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2- oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 1), and uses thereof for treating inflammatory disorders (e.g., inflammatory bowel disease including Crohn’s disease or ulcerative colitis).
  • inflammatory disorders e.g., inflammatory bowel disease including Crohn’s disease or ulcerative colitis.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
  • protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli.
  • 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 ⁇ (TNF- ⁇ )), and growth factors (e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)).
  • 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 ⁇ (TNF- ⁇ )
  • growth factors e.g.
  • An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.
  • diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, some cancers, cardiovascular diseases, allergies and asthma, Alzheimer’s disease, and hormone-related diseases.
  • Tyrosine kinase 2 catalyzes the phosphorylation of STAT proteins downstream of a number of cytokine receptors, including the Type I interferon receptor and the IL-12 and IL-23 receptors.
  • the activation of TYK2-dependent receptors by their cytokine ligands results in the activation of STAT-dependent transcription and cellular functional responses specific for the receptors and cell types on which they are expressed.
  • the cytokine signaling pathways regulated by TYK2 play key roles in several immune-mediated disorders.
  • the cytokine IL-12 is essential for the development of Type 1 T-helper cells (Th1) which produce interferon-gamma, a major effector molecule in systemic autoimmune disorders such as systemic lupus erythematosus.
  • Th1 Type 1 T-helper cells
  • the cytokine IL-23 is central 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 the production of key proinflammatory cytokines by Th17 cells, including IL-17A, IL-17F, and IL-22, all of which are effector molecules important for pathogenesis of conditions such as inflammatory bowel disease, including Crohn’s disease or ulcerative colitis.
  • TYK2 inhibitors are suitable for oral administration to a patient for treating an inflammatory disorder (e.g., inflammatory bowel disease (IBD), including Crohn’s disease (CD) or ulcerative colitis (UC).
  • IBD inflammatory bowel disease
  • CD Crohn’s disease
  • UC ulcerative colitis
  • a method of treating IBD, including CD or UC, to a patient in need thereof can include administering to a patient a therapeutically effective amount of a TYK2 inhibitor (e.g., Compound 1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a TYK2 inhibitor e.g., Compound 1
  • Compound 1 has the following structure: 2 57406284.1 [0007]
  • Compound 1 has the IUPAC name N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3- carboxamide.
  • the patient can have IBD. [0009] In some embodiments, the patient can have moderately to severely active IBD. [0010] In some embodiments, for patients with CD, a decrease in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of greater than or equal to 50% (e.g., about 50%, about 60%, about 70% about 80%, about 90%, or about 100%) from baseline, read centrally, can be achieved; or a decrease in SES-CD of about 50% to about 70%, about 70% to about 90%, or about 90% to about 100%, can be achieved. [0011] In some embodiments, the patient can reach remission, including clinical remission and deep remission.
  • SES-CD Simple Endoscopic Score for Crohn’s Disease
  • an SES-CD of less than or equal 4 e.g., about 4, about 3, about 2, about 1, or about 0
  • at least a 2-point reduction from baseline read centrally
  • the patient can have CD.
  • the patient can have moderately to severely active CD.
  • a modified Mayo Score Scoring System for Assessment of Ulcerative Colitis Activity
  • stool frequency subscore of less than or equal to 1
  • rectal bleeding subscore of 0,
  • central read endoscopic subscore of less than or equal to 1
  • core of 1 modified to exclude friability can be achieved.
  • the patient can have UC.
  • the patient can have moderately to severely active UC.
  • the method can achieve: a decrease in Simple Endoscopic Score for Crohn’s 3 57406284.1 Disease (SES-CD) of greater than or equal to 50% (e.g., about 50%, about 60%, about 70% about 80%, about 90%, or about 100%) from baseline, read centrally, or a decrease in SES- CD of about 50% to about 70%, about 70% to about 90%, or about 90% to about 100%; or an SES-CD less than or equal to 4 (e.g., about 4, about 3, about 2, about 1, or about 0) or at least a 2-point reduction from baseline, read centrally, for isolated ileal disease.
  • SES-CD Simple Endoscopic Score for Crohn’s 3 57406284.1 Disease
  • the method can achieve: a modified Mayo Score (Scoring System for Assessment of Ulcerative Colitis Activity) of less than or equal to 2 with stool frequency subscore of less than or equal to 1, rectal bleeding subscore of 0, and central read endoscopic subscore of less than or equal to 1 (score of 1 modified to exclude friability).
  • a method of inhibiting interferon gamma (IFN ⁇ ) production can include administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a composition thereof.
  • the method is associated with improvements in IBD, including CD or UC, such as those described above and elsewhere herein.
  • the disclosed methods and uses of administering Compound 1 achieving certain pharmacokinetic parameters of the disclosure has certain advantages in treating IBD, including CD or UC.
  • a Tmax of Compound 1 in plasma is achieved in about 3 hours to about 6 hours or a t 1/2 of Compound 1 in plasma is achieved in about 17 hours to about 37 hours.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 mg to up to about 200 mg (e.g., from about 35 mg to about 200 mg) to the patient.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg to the patient. [0022] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose intended to provide approximately 24-hour coverage at IC50. [0023] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose intended to provide approximately 24-hour coverage at IC90.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient as a single daily dose, twice daily doses, or in multiple daily doses. In other embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is 4 57406284.1 administered to the patient daily for between 2 weeks and 52 weeks or longer. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 2 weeks, for at least 52 weeks, for at least 2 years, for at least 3 years, for at least 4 years, for 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 chronically or indefinitely to treat the patient.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally to the patient (e.g., a human).
  • the patient can have active moderate to severe ileal (terminal ileum), ileocolonic, or colonic CD prior to administration.
  • the patient can have a CDAI score between 220 and 450 (including 220 and 450) prior to administration.
  • the patient can present with ulcerations characteristic to CD as determined by ileocolonoscopy and defined by the SES-CD greater than or equal to 6 (SES- CD greater than or equal to 4 for isolated ileitis) prior to administration.
  • the patient can have a documented diagnosis of CD including endoscopy with histology, biopsy, and/or a report documenting disease based upon prior ileocolonoscopy, prior to administration.
  • the patient can have moderately to severely active UC prior to administration.
  • the patient can have a modified Mayo Score (Scoring System for Assessment of Ulcerative Colitis Activity) of 5 to 9 points with an endoscopic subscore of greater than or equal to 2.
  • the patient can have a documented diagnosis of UC including endoscopy with histology, a biopsy report confirming histological diagnosis, and/or a report documenting disease duration based on prior colonoscopy, with disease extending greater than 15 cm from the anal verge, prior to administration.
  • a serum Cmax between about 25 ng/mL to about 30 ng/mL, about 30 ng/mL to about 35 ng/mL, about 35 ng/mL to about 40 ng/mL, about 40 ng/mL to about 45 ng/mL, about 45 ng/mL to about 50 ng/mL, about 50 ng/mL to about 60ng/mL, about 60 ng/mL to about 70 ng/mL, about 70 ng/mL to about 80 ng/mL, about 80 ng/mL to about 90 ng/mL, about 90 ng/mL to about 100 ng/mL, about 100 ng/mL to about 120 ng/mL, about 120 ng/mL to about 140 ng/mL, about 140 ng/mL to about 160 ng/mL, about 160 ng/mL to about 180 ng/mL, about 180 ng/mL to about 200 ng/mL, about
  • FIGS. 1A-1B are graphics depicting the study design in the TCT colitis model and the ⁇ -CD40 mAb colitis model.
  • FIGS.2A-2B are graphs depicting colon weight:length ratios in the (FIG.2A) TCT colitis model and (FIG. 2B) ⁇ -CD40 mAb colitis model.
  • significance was determined using ANOVA with Tukey’s post hoc test and denotes: *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; ****p ⁇ 0.0001.
  • FIGS.3A-3B are graphs depicting total histology scores in the (FIG.3A) TCT colitis model and the (FIG. 3B) ⁇ -CD40 colitis model.
  • TYK2 is an obligate mediator of signaling via interleukin (IL-12, IL-23, and the 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).
  • IBD interleukin
  • CD Crohn’s disease
  • UC ulcerative colitis
  • Compound 1 disclosed herein is an oral, allosteric, highly potent, and selective TYK2 inhibitor computationally designed to bind to the Janus homology 2 (JH2) domain of TYK2 but to be sterically occluded from the JH2 domains of Janus kinase (JAK) 1-3.
  • Compound 1 is used for the treatment of IBD, including CD or UC, psoriasis, psoriatic arthritis, and other inflammatory and autoimmune diseases.
  • Compound 1’s selectivity and potential to provide higher levels of TYK2 inhibition for a longer period with once-daily (QD) dosing may confer clinical and ultimately commercial advantages over other TYK2 inhibitors in development.
  • TYK2 is a member of the JAK family of kinases, 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 the mediation of signaling pathways downstream of IL-12, IL-23, and IFN ⁇ / ⁇ .
  • JAK inhibition can be effective in treating inflammatory and autoimmune diseases and some JAK inhibitors have been approved for the treatment of UC, they are associated with adverse events likely related to JAK1-3 inhibition. JAK inhibition can also produce off-target safety issues by modulating a broad variety of cytokine pathways.
  • JAK inhibitors have become established oral treatments for numerous inflammatory and autoimmune diseases, their clinical utility is constrained by elevated risk of infections and other side effects that have resulted in dose level limitations and U.S. Food and Drug Administration (FDA)-mandated boxed warnings as part of their labeling.
  • FDA Food and Drug Administration
  • IFN ⁇ interferon gamma
  • CCAE Common Terminology Criteria for Adverse Events
  • a method of treating inflammatory bowel disease (IBD), including Crohn’s disease (CD) or ulcerative colitis (UC), in a patient in need thereof can include administering to a patient a therapeutically effective amount of Compound 1: or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • IBD inflammatory bowel disease
  • CD Crohn’s disease
  • UC ulcerative colitis
  • the administration is daily for a period between about 1 day to about 2 days, about 2 days to about 3 days, about 3 days to about 4 days, about 4 days to about 5 days, about 5 days to about 6 days, about 6 days to about 7 days, about 1 week to about 2 weeks, about 2 weeks to about 3 weeks, about 3 weeks to about 4 weeks, about 4 weeks to about 5 weeks, about 5 weeks to about 6 weeks, about 6 weeks to about 7 weeks, about 7 weeks to about 8 weeks, about 8 weeks to about 9 weeks, about 9 weeks to about 10 weeks, about 10 weeks to about 11 weeks, about 11 weeks to about 12 weeks, about 12 weeks to about 14 weeks, about 14 weeks to about 16 weeks, about 16 weeks to about 18 weeks, about 18 weeks to about 21 weeks, about 21 weeks to about 24 weeks, about 24 weeks to about 27 weeks, about 27 weeks to about 30 weeks, about 30 weeks to about 33 weeks, about 33 weeks to about 36 weeks, about 36 weeks to about 39 weeks, about 39 weeks to about 42 weeks, about 42 weeks to about 45 weeks, about 45 weeks to about
  • the administration is daily for longer than 5 years.
  • the patient has IBD.
  • the patient has moderately to severely active IBD.
  • the administration is chronic, or daily for an indefinite period. 9 57406284.1
  • the method is directed to the treatment of moderately to severely active CD.
  • a mean decrease in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of about 50% or greater is achieved.
  • a mean decrease in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of about 70% or greater is achieved.
  • a mean decrease in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of about 90% or greater is achieved.
  • a mean decrease in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of about 100% is achieved.
  • a mean decrease in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of about 50% to 70% is achieved.
  • a mean decrease in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of about 70% to 90% is achieved.
  • a mean decrease in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of about 90% to 100% is achieved.
  • a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of less than or equal to 4 (e.g., about 4, about 3, about 2, about 1, or about 0) or at least a 2-point reduction from baseline, read centrally, is achieved.
  • the patient has CD.
  • the patient has moderately to severely active CD.
  • a modified Mayo Score Scoring System for Assessment of Ulcerative Colitis Activity
  • stool frequency subscore of less than or equal to 1
  • rectal bleeding subscore of 0,
  • central read endoscopic subscore of less than or equal to 1 (score of 1 modified to exclude friability)
  • the patient has UC.
  • the patient has moderately to severely active UC.
  • the method achieves: a decrease in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of greater than or equal to 50% (e.g., about 50%, about 60%, about 70% about 80%, about 90%, or about 100%) from baseline, read centrally, or a decrease in SES-CD of about 50% to about 70%, about 70% to about 90%, or about 90% to about 100%; or an SES- 10 57406284.1 CD less than or equal to 4 (e.g., about 4, about 3, about 2, about 1, or about 0) or at least a 2- point reduction from baseline, read centrally, for isolated ileal disease.
  • SES-CD Simple Endoscopic Score for Crohn’s Disease
  • the method achieves: a modified Mayo Score (Scoring System for Assessment of Ulcerative Colitis Activity) of less than or equal to 2 with stool frequency subscore of less than or equal to 1, rectal bleeding subscore of 0, and central read endoscopic subscore of less than or equal to 1 (score of 1 modified to exclude friability).
  • the patient has inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the IBD is moderately to severely active.
  • the patient has Crohn’s disease (CD).
  • CD is moderately to severely active.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered at a dose of up to about 200 mg to the patient.
  • 11 57406284.1 In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of from about 30 mg to about 200 mg to the patient.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg to the patient.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered at a dose intended to provide approximately 24-hour coverage at IC50.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered at a dose intended to provide approximately 24-hour coverage at IC90.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient as a single dose, for example, a single dose in one day.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient as two doses, for example, two doses in one day.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient in multiple doses.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient daily for 2 weeks.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient daily for 52 weeks.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient daily for between 2 weeks and 52 weeks. [0087] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient daily for between 2 weeks and 52 weeks, for example, until the patient’s IBD, including CD or UC, improves. [0088] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient daily for between 1 and 5 years, for example, until the patient’s IBD, including CD or UC, improves. [0089] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered chronically or indefinitely to the patient.
  • Compound 1 is administered orally to the patient.
  • the patient is a human. 12 57406284.1
  • a serum C max between about 25 ng/mL to about 30 ng/mL, about 30 ng/mL to about 35 ng/mL, about 35 ng/mL to about 40 ng/mL, about 40 ng/mL to about 45 ng/mL, about 45 ng/mL to about 50 ng/mL, about 50 ng/mL to about 60ng/mL, about 60 ng/mL to about 70 ng/mL, about 70 ng/mL to about 80 ng/mL, about 80 ng/mL to about 90 ng/mL, about 90 ng/mL to about 100 ng/mL, about 100 ng/mL to about 120 ng/mL, about 120 ng/mL to about 140 ng/mL, about 140 ng/mL, about 140 ng/mL
  • a method of treating inflammatory bowel disease (IBD), including Crohn’s disease (CD) or ulcerative colitis (UC), in a patient in need thereof can include administering a therapeutically effective amount of Compound 1: [0094] at a daily dose of mg.
  • Compound 1: 13 57406284.1 [0096] or a pharmaceutically acceptable salt thereof can be used in the treatment of IBD, including CD or UC.
  • Compounds described herein include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
  • the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.
  • Compound 1 refers to N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide having the formula:
  • acceptable salt thereof is in amorphous form.
  • Compound 1 or a pharmaceutically acceptable salt thereof is in crystalline form.
  • aliphatic or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the 14 57406284.1 molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups.
  • any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bridged bicyclics include: NH 15 57406284.1 O HN O O O NH NH NH NH NH NH NH NH NH
  • Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • the term “lower haloalkyl” refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • bivalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
  • a heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle 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 moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to 17 57406284.1 four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N– substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono– or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds may contain “optionally substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned and described herein are preferably those that result in the formation of stable or chemically feasible compounds.
  • Suitable monovalent substituents on R ⁇ are independently halogen, —(CH2)0–2R ⁇ , –(haloR ⁇ ), –(CH2)0–2OH, –(CH2)0–2OR ⁇ , –(CH2)0– 2 CH(OR ⁇ ) 2 ; -O(haloR ⁇ ), –CN, –N 3 , –(CH 2 ) 0–2 C(O)R ⁇ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0– 2C(O)OR ⁇ , –(CH2)0–2SR ⁇ , –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR ⁇ , –(CH2)0–2NR ⁇ 2, – NO 2 ,
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2–3 O–, wherein each independent occurrence of R * is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5– to 6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2, –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH2C(O)R ⁇ , -S(O) 2 R ⁇ , wherein each R ⁇ is as defined below, unsubstituted –OPh, or an unsubstituted 5– to 6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3– to 12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, –R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or -NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5– to 6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • a warhead moiety, R 1 of a provided compound comprises one or more deuterium atoms.
  • Ring B of a provided compound may be substituted with one or more deuterium atoms.
  • an inhibitor is defined as a compound that binds to and /or inhibits TYK2 with measurable affinity.
  • an inhibitor has an IC50 and/or binding constant of less than about 50 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change in a TYK2 protein kinase activity between a sample comprising a compound described herein, or composition thereof, and a TYK2 protein kinase, and an equivalent sample comprising an TYK2 protein kinase, in the absence of said compound, or composition thereof.
  • Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose.
  • SDD refers to a pharmaceutical formulation (e.g., of Compound 1 or a pharmaceutically acceptable salt thereof) which is a spray dried formulation.
  • the formulation may comprise a compound of the disclosure and hypromellose acetate succinate (HPMCAS).
  • HPMCAS hypromellose acetate succinate
  • the HMPCAS is HPMCAS-M, wherein the “M” indicates (acetyl content 7.0% to 11.0%, succinoyl content 10% to 14%).
  • spray-drying to 22 57406284.1 produce powders from fluid feed stocks is well known, with applications ranging from powdered milk to bulk chemicals and pharmaceuticals. See U.S. Pat. No.
  • a typical spray-drying apparatus comprises a drying chamber, atomizing means for atomizing a solvent-containing liquid feed into the drying chamber, a source of heated drying gas directed into the drying chamber and dried product collection means for separating the dried product from the cooled drying gas and vaporized solvent stream following its exit from the drying chamber.
  • Examples of such apparatus include Niro Models PSD-1, PSD-2 and PSD- 4 (Niro A/S, Soeborg, Denmark).
  • TPGS or “Vitamin E TPGS” as a descriptor for a pharmaceutical formulation for a compound of the disclosure, as used herein, refers to a pharmaceutical formulation (e.g., of Compound 1 or a pharmaceutically acceptable salt thereof) which includes the components of (a) the active compound; (b) one or more diluents (e.g., microcrystalline cellulose); (c) one or more solubilizers (e.g., D- ⁇ -tocopherol polyethylene glycol succinate [Vitamin E TPGS]); and (d) one or more binders (e.g., povidone).
  • the formulation may be prepared using granulation processes (e.g., wet granuation).
  • “Granulation,” as used herein, refers to a process to produce larger or smaller granules or particles of a substance or mixture of substances. The process also may remove fine granules and improve flowability within the formulation. Both wet granulation and/or dry granulation may be employed. Dry granulation is achieved using only a combination of granules without the need for any liquid thereon. Slugging uses a tablet press to form large tablets that vary in weight due to the poor flowability of the formulation. The slugs created are then put through a granulator to be broken down into granules and then compressed once again for a final granulated product. 3.
  • a method for treating inflammatory disorders can include administering a therapeutically effective amount of a TYK2 inhibitor (e.g., Compound 1), or a pharmaceutically acceptable salt thereof.
  • a TYK2 inhibitor e.g., Compound 1
  • the method comprises administering up to 200 mg of a TYK2 inhibitor (e.g., 23 57406284.1 Compound 1), or a pharmaceutically acceptable salt thereof, in single, two, or multiple (e.g., divided) doses.
  • TYK2 inhibitor is one of those described in US 11,046,698.
  • a TYK2 inhibitor for use in a disclosed method is of formula I: or a pharmaceutically acceptable salt
  • R 3 is –C(O)NH2; –C(O)NHR 3A ; -C(O)N(R 3A )2; or a 5 ⁇ to 6 ⁇ membered monocyclic heteroaryl ring having 1 ⁇ 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with m instances of R 5B ;
  • R 5 is hydrogen, or -L 1 -R 5A ;
  • R 6 is hydrogen, R A , or R B ; or R 5 and R 6 are taken together with their intervening atoms to form a 4 ⁇ to 7 ⁇ membered partially unsaturated, or heteroaryl ring having 0 ⁇ 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted by R 5A and n instances of R C ;
  • R 7 is hydrogen, halogen, -NH2, –NHR 7
  • the TYK2 inhibitor for use in a disclosed method is Compound 1a: or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the TYK2 inhibitor for use in a disclosed method is Compound 1: or a pharmaceutically composition thereof.
  • Compounds and compositions described herein are generally useful for the inhibition of kinase activity of one or more enzymes.
  • the kinase inhibited by the compounds and methods described herein is TYK2.
  • TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases.
  • JAK proteins are integral to cytokine signaling.
  • TYK2 associates 26 57406284.1 with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding.
  • Cytokines implicated in TYK2 activation include interferons (e.g. IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , and IFN- ⁇ (also known as limitin), and interleukins (e.g.
  • Velasquez et al. “A protein kinase in the interferon ⁇ / ⁇ signaling pathway,” Cell (1992) 70:313; Stahl et al., “Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 ⁇ receptor components,” Science (1994) 263:92; Finbloom et al., “IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes,” J. Immunol.
  • TYK2 activation by IL-23 has been linked to inflammatory bowel disease (IBD), Crohn’s disease, and ulcerative colitis.
  • TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis.
  • COPD chronic obstructive pulmonary disease
  • GCH Goblet cell hyperplasia
  • mucous hypersecretion is mediated by IL-13-induced activation of TYK2, which in turn activates STAT6.
  • TYK2 knockout mice showed complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)), with no infiltration of CD4 T cells in the spinal cord, as compared to controls, suggesting that TYK2 is essential to pathogenic CD4-mediated disease development in MS.
  • EAE experimental autoimmune encephalomyelitis
  • MS multiple sclerosis
  • TYK2 is the sole signaling messenger common to both IL-12 and IL-23.
  • TYK2 has been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response and accelerated tumor development. However, these effects were linked to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or transplant rejection.
  • NK natural killer
  • JAK2 has been suggested as a superior target because of its involvement in fewer and more closely related 28 57406284.1 signaling pathways, leading to 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.
  • T-ALL T-cell acute lymphoblastic leukemia
  • TYK2 T-cell acute lymphoblastic leukemia
  • STAT1-mediated signal transduction to maintain cancer cell survival through upregulation of anti-apoptotic protein BCL2.
  • Knockdown of TYK2, but not other JAK family members reduced cell growth.
  • Specific activating mutations to TYK2 that promote cancer cell survival include those to the FERM domain (G36D, S47N, and R425H), the JH2 domain (V731I), and the kinase domain (E957D and R1027H).
  • TYK2 enzymes featuring kinase-dead mutations M978Y or M978F
  • E957D activating mutation
  • selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and/or BCL2-addicted tumors, such as 70% of adult T-cell leukemia cases. Fontan et al.
  • TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid- ⁇ (A ⁇ ) peptide. Decreased TYK2 phosphorylation of STAT3 following A ⁇ administration lead to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer’s patients. Wan et al. “Tyk/STAT3 Signaling Mediates ⁇ -Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer’s Disease,” J. Neurosci. (2010) 30(20):6873-6881.
  • Such compounds should deliver a pharmacological response that favorably treats one or more of the conditions described herein without the side-effects associated with the inhibition of JAK1-3, that result in dose level limitations. 29 57406284.1 [0149]
  • TYK2 inhibitors are known in the art, there is a continuing need to provide novel inhibitors having more effective or advantageous pharmaceutically relevant properties. For example, compounds with increased activity, selectivity over other JAK kinases (especially JAK2), and ADMET (absorption, distribution, metabolism, excretion, and/or toxicity) properties.
  • inhibitors of TYK2 can show selectivity over JAK2.
  • the activity of a compound described herein as an inhibitor of TYK2, or a mutant thereof may be assayed in vitro, in vivo, or in a cell line.
  • In vitro assays include assays that determine inhibition of either the phosphorylation activity and/or the subsequent functional consequences, or ATPase activity of activated TYK2, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to TYK2. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/TYK2 complex and determining the amount of radiolabel bound.
  • inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with TYK2 bound to known radioligands.
  • Representative in vitro and in vivo assays useful in assaying a TYK2 inhibitor include those described and disclosed in, e.g., each of which is herein incorporated by reference in its entirety. Detailed conditions for assaying a compound described herein as an inhibitor of TYK2, or a mutant thereof, are set forth in the Examples below and in US 11,046,698, which is hereby incorporated by reference.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • a method for treating a TYK2-mediated disorder can include the step of administering to a patient in need thereof a compound described herein, or pharmaceutically acceptable composition thereof.
  • TYK2-mediated disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which TYK2 or a mutant 30 57406284.1 thereof is known to play a role. Accordingly, another embodiment relates to treating or lessening the severity of one or more diseases in which TYK2, or a mutant thereof, is known to play a role.
  • Such TYK2-mediated disorders include but are not limited to autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders and disorders associated with transplantation.
  • a method for treating one or more disorders, wherein the disorders are selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and disorders associated with transplantation said method can include administering to a patient in need thereof, a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the disorder is an autoimmune disorder.
  • the disorder is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis (e.g., plaque psoriasis), Behçet’s disease, POEMS syndrome, inflammatory bowel disease (IBD), Crohn’s disease (CD), and ulcerative colitis (UC).
  • the disorder is an inflammatory disorder.
  • the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis (e.g., plaque psoriasis), psoriatic arthritis, hepatomegaly, IBD, CD, or UC.
  • a method of treating CD in a patient in need thereof can include administering a TYK2 inhibitor (e.g., Compound 1) described herein, or a pharmaceutically acceptable salt thereof.
  • a method of treating UC in a patient in need thereof can include administering a TYK2 inhibitor (e.g., Compound 1) described herein, or a pharmaceutically acceptable salt thereof.
  • a method of treating IBD in a patient in need thereof can include administering a TYK2 inhibitor (e.g., Compound 1) described herein, or a pharmaceutically acceptable salt thereof.
  • the disorder is a proliferative disorder.
  • the proliferative disorder is a hematological cancer.
  • the proliferative disorder is a leukemia.
  • the leukemia is a T-cell leukemia.
  • the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL).
  • the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocytosis.
  • the disorder is an endocrine disorder.
  • the endocrine disorder is polycystic ovary syndrome, Crouzon’s syndrome, or type 1 diabetes.
  • the disorder is a neurological disorder.
  • the neurological disorder is Alzheimer’s disease.
  • the proliferative disorder is associated with one or more activating mutations in TYK2.
  • the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.
  • the disorder is associated with transplantation. In some embodiments the disorder associated with transplantation is transplant rejection, or graft versus host disease. [0165] In some embodiments the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments the disorder is associated with type I interferon signaling. In some embodiments the disorder is associated with IL-10 signaling.
  • the disorder is associated with IL-12 signaling. In some embodiments the disorder is associated with IL-23 signaling.
  • Compounds described herein are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis (e.g., plaque psoriasis), contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.
  • Compounds described herein may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g.
  • hemolytic anemia aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia
  • cutaneous lupus erythematosus systemic lupus erythematosus, 32 57406284.1 rheumatoid arthritis, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn’s disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Grave’s disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis
  • the inflammatory disease which can be treated according to the methods described herein is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic juvenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis.
  • the inflammatory disease which can be treated according to the methods described herein is a Th1- or Th17-mediated disease.
  • the T h 17 mediated disease is selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis).
  • the inflammatory disease which can be treated according to the methods described herein is selected from Sjogren’s syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.
  • the invention can provide the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof for the preparation of a medicament for the treatment of an autoimmune disorder, an inflammatory disorder, or a proliferative disorder, or a disorder commonly occurring in connection with transplantation.
  • a compound according to the definitions herein or a pharmaceutically acceptable salt, or a hydrate or solvate thereof for the preparation of a medicament for the treatment of an autoimmune disorder, an inflammatory disorder, or a proliferative disorder, or a disorder commonly occurring in connection with transplantation.
  • proximity of an inhibitor compound, or pendant moiety of an inhibitor compound, to the water of interest facilitates displacement or disruption of that water by the inhibitor compound, or pendant moiety of an inhibitor compound.
  • a water molecule displaced or disrupted by an inhibitor compound, or pendant moiety of an inhibitor compound is an unstable water molecule.
  • the method employs a complex comprising TYK2 and an inhibitor, wherein at least one unstable water of TYK2 is displaced or disrupted by the inhibitor. In some embodiments, at least two unstable waters selected are displaced or disrupted by the inhibitor. 5.
  • Pharmacokinetics/Pharmacodynamics the present disclosure provides a method of administering a TYK2 inhibitor (e.g., Compound 1) to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound 1, or a pharmaceutically 34 57406284.1 acceptable salt thereof, or composition thereof, wherein certain pharmacokinetic parameters are achieved.
  • a T max of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 10 hours, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours, or any range of time created by using two of the aforementioned times as endpoints.
  • a T max is achieved in about 1 to about 10 hours, about 1 to about 9 hours, about 2 to about 10 hours, about 2 to about 9 hours, about 3 to about 10 hours, about 3 to about 9 hours, about 4 to about 10 hours, about 4 to about 9 hours, about 5 to about 10 hours, about 5 to about 9 hours, about 6 to about 10 hours, about 6 to about 9 hours, about 7 to about 10 hours, about 7 to about 9 hours, about 8 to about 10 hours, about 9 to about 10 hours, or about 8 to about 9 hours.
  • a Tmax of a TYK2 inhibitor e.g., Compound 1 in plasma is achieved in up to about 3 hours.
  • a Tmax of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 4 hours. In some embodiments, a T max of Compound 1 in plasma is achieved in up to about 5 hours. In some embodiments, a Tmax of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 6 hours.
  • a Tmax of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved from about 1 hour to about 4 hours, from about 2 hours to about 5 hours, from about 3 hours to about 6 hours, from about 4 hours to about 7 hours, from about 5 hours to about 8 hours, from about 6 hours to about 9 hours, or from about 7 hours to about 10 hours.
  • a Tmax of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved from about 3 hours to about 6 hours.
  • a t1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 50 hours, for example, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 25 hours, 26 hours, about 27 hours, about 28 hours, about 29 hours, about 30 hour, about 31 hour, about 32 hours, about 33 hours, about 34 hours, about 35 hours, 36 hours, about 37 hours, about 38 hours, about 39 hours, about 40 hour, about 41 hour, about 42 hours, about 43 hours, about 44 hours, about 45 hours, 46 hours, about 47 hours, about 48 hours, about 49 hours, or about 50 hours, or any range of time created by using two of the aforementioned times as 35 57406284.1 endpoints.
  • a TYK2 inhibitor e.g., Compound 1
  • a t 1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 17 hours. In some embodiments, a t1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 18 hours. In some embodiments, a t 1/2 of Compound 1 in plasma is achieved in up to about 19 hours. In some embodiments, a t1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 20 hours. In some embodiments, a t 1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 21 hours.
  • a t1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 22 hours. In some embodiments, a t 1/2 of Compound 1 in plasma is achieved in up to about 23 hours. In some embodiments, a t1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 24 hours. In some embodiments, a t 1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 25 hours. In some embodiments, a t 1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 26 hours.
  • a t1/2 of Compound 1 in plasma is achieved in up to about 27 hours.
  • a t 1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 28 hours.
  • a t1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 29 hours.
  • a t1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 30 hours.
  • a t1/2 of Compound 1 in plasma is achieved in up to about 31 hours.
  • a t 1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 32 hours. In some embodiments, a t1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 33 hours. In some embodiments, a t 1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 34 hours. In some embodiments, a t1/2 of Compound 1 in plasma is achieved in up to about 35 hours. In some embodiments, a t 1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 36 hours.
  • a t 1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved in up to about 37 hours.
  • a t1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved from about 10 hours to 30 hours, from about 12 hours to 32 hours, from about 14 hours to 34 hours, from about 16 hours to 36 hours, from about 18 hours to 38 hours, from about 20 hours to 40 hours, or from about 22 hours to 42 hours.
  • a t 1/2 of a TYK2 inhibitor (e.g., Compound 1) in plasma is achieved from about 17 hours to 37 hours.
  • the present disclosure provides a method of administering a TYK2 inhibitor (e.g., Compound 1) to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a TYK2 inhibitor (e.g., Compound 1), or a 36 57406284.1 pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, wherein certain pharmacodynamic results are achieved.
  • a TYK2 inhibitor e.g., Compound 1
  • the administration of a TYK2 inhibitor leads to rapid inhibition of interferon gamma (IFN ⁇ ) production and increasing exposure correlated with the increased inhibition of IFN ⁇ .
  • a method of inhibiting IFN ⁇ production in a patient can include administering to the patient a TYK2 inhibitor (e.g., Compound 1) described herein, or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof.
  • a serum C max between about 25 ng/ml to about 30 ng/mL, about 30 ng/mL to about 35 ng/mL, about 35 ng/mL to about 40 ng/mL, about 40 ng/mL to about 45 ng/mL, about 45 ng/mL to about 50 ng/mL, about 50 ng/mL to about 60ng/mL, about 60 ng/mL to about 70 ng/mL, about 70 ng/mL to about 80 ng/mL, about 80 ng/mL to about 90 ng/mL, about 90 ng/mL to about 100 ng/mL, about 100 ng/mL to about 120 ng/mL, about 120 ng/
  • a serum C max between about 25 ng/ml to about 30 ng/mL is achieved. In some embodiments, a serum Cmax between about 30 ng/mL to about 35 ng/mL is achieved. In some embodiments, a serum C max between about 35 ng/mL to about 40 ng/mL is achieved. In some embodiments, a serum Cmax between about 40 ng/mL to about 45 ng/mL is achieved. In some embodiments, a serum C max between about 45 ng/mL to about 50 ng/mL is achieved. In some embodiments, a serum Cmax between about 50 ng/mL to about 60ng/mL is achieved.
  • a serum C max between about 60 ng/mL to about 70 ng/mL is achieved. In some embodiments, a serum Cmax between about 70 ng/mL to about 80 ng/mL is achieved. In some embodiments, a serum Cmax between about 80 ng/mL to about 90 ng/mL is achieved. In some embodiments, a serum C max between about 90 ng/mL to about 100 ng/mL is achieved. In some embodiments, a serum Cmax between about 100 ng/mL to about 120 ng/mL is achieved. In some embodiments, a serum C max between 37 57406284.1 about 120 ng/mL to about 140 ng/mL is achieved.
  • a serum C max between about 140 ng/mL to about 160 ng/mL is achieved. In some embodiments, a serum Cmax between about 160 ng/mL to about 180 ng/mL is achieved. In some embodiments, a serum C max between about 180 ng/mL to about 200 ng/mL is achieved. In some embodiments, a serum Cmax between about 200 ng/mL to about 240 ng/mL is achieved. In some embodiments, a serum Cmax between about 240 ng/mL to about 280 ng/mL is achieved. In some embodiments, a serum C max between about 280 ng/mL to about 320 ng/mL is achieved.
  • a serum Cmax between about 320 ng/mL to about 360 ng/mL is achieved. In some embodiments, a serum C max between about 360 ng/mL to about 400 ng/mL is achieved. In some embodiments, a serum Cmax between about 400 ng/mL to about 480 ng/mL is achieved. In some embodiments, a serum C max between about 480 ng/mL to about 560 ng/mL is achieved. In some embodiments, a serum Cmax between about 560 ng/mL to about 740 ng/mL is achieved. In some embodiments, a serum C max between about 740 ng/mL to about 820 ng/mL is achieved.
  • a serum Cmax between about 820 ng/mL to about 900 ng/mL is achieved. In some embodiments, a serum C max between about 900 ng/mL to about 1000 ng/mL is achieved. In some embodiments, a serum Cmax between about 1000 ng/mL to about 1200 ng/mL is achieved. In some embodiments, a serum C max between about 1200 ng/mL to about 1400 ng/mL is achieved. In some embodiments, a serum Cmax between about 1400 ng/mL to about 1600 ng/mL is achieved. In some embodiments, a serum C max between about 1600 ng/mL to about 1800 ng/mL is achieved.
  • an oral dosage can include 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg/dosage form of a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof.
  • a TYK2 inhibitor e.g., Compound 1 or a pharmaceutically acceptable salt thereof.
  • the method comprises administering (e.g., orally), in a single, two, or multiple doses ranging from about 30 to about 200 mg/dosage, 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.
  • administering e.g., orally
  • a single, two, or multiple doses ranging from about 30 to about 200 mg/dosage, 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,
  • the method comprises administering (e.g., orally), in a single, two, or multiple doses ranging from about 30 to about 200 mg, 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, 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 daily.
  • administering e.g., orally
  • any specific dosage amount in between each of the ranges of this paragraph is contemplated.
  • this encompasses 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 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., are contemplated.
  • the method can include administering (e.g., orally), in a single, two, or multiple doses at an overall dose intended to provide approximately 24-hour coverage at IC50.
  • the method can include administering (e.g., orally), in a single, two, or multiple doses at an overall dose intended to provide approximately 24-hour coverage at IC 90 .
  • 39 57406284.1 “24-hour coverage” as used herein means reaching or sustaining a desired plasma concentration of a compound that results in an intended amount of target protein effect over a 24-hour period.
  • “24-hour coverage at IC 50 ” means to use a dosage intended to raise plasma concentrations of an inhibitory compound to cause 50% inhibition of a target protein for 24 hours.
  • Any dosage of the preceding paragraph may be administered as one, two, three, or four doses during a single day.
  • the 50 mg dose may be administered as a 25 mg dose administration followed by a second 25 mg dose administration after an elapsed period of time, to arrive at the 50 mg dose.
  • the 50 mg dose can be administered during a single day by administering 10 mg, allowing time to elapse, administering a second 10 mg, allowing time to elapse, administering a third 10 mg, and allowing time to elapse, administering a fourth 10 mg, and allowing time to elapse, and administering a fifth 10 mg to result in 50 mg total administered throughout the day.
  • administration of 30 mg of Compound 1 comprises administration of 15 mg, allowing a defined period of time to elapse and administering a second dose of 15 mg.
  • administration of 50 mg of Compound 1 comprises administration of 25 mg, allowing a defined period of time to elapse and administering a second dose of 25 mg.
  • administration of 75 mg of Compound 1 comprises administration of 37.5 mg, allowing a defined period of time to elapse and administering a second dose of 37.5 mg.
  • administration of 100 mg of Compound 1 comprises administration of 50 mg, allowing a defined period of time to elapse and administering a second dose of 50 mg.
  • administration of 150 mg of Compound 1 comprises administration of 75 mg, allowing a defined period of time to elapse and administering a second dose of 75 mg.
  • administration of 200 mg of Compound 1 comprises administration of 100 mg, allowing a defined period of time to elapse and administering a second dose of 100 mg. The defined period of time may be determined by the clinician and subject to individual patient metabolic considerations.
  • the defined period of time is between about 2.5 hr to about 5 hr, about 5 hr to about 7.5 hr, about 7.5 hr to about 10 hr, about 10 hr to about 12.5 hr, about 12.5 hr to about 15 hr, about 15 hr to about 17.5 hr, about 17.5 hr to about 20 hr, about 20 hr to about 22.5 hr, or about 22.5 hr to about 24 hr.
  • a TYK2 inhibitor e.g., Compound 1 or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 30 mg to the patient.
  • a TYK2 inhibitor e.g., Compound 1 or a pharmaceutically acceptable 40 57406284.1 salt thereof is administered (e.g., orally) at a dose of up to 35 mg to the patient.
  • a TYK2 inhibitor e.g., Compound 1 or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 40 mg to the patient.
  • a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 45 mg to the patient.
  • a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 50 mg to the patient. In some embodiments, a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 55 mg to the patient. In some embodiments, a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 60 mg to the patient.
  • a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 65 mg to the patient. In some embodiments, a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 70 mg to the patient. In some embodiments, a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 75 mg to the patient.
  • a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 80 mg to the patient. In some embodiments, a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 85 mg to the patient. In some embodiments, a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 90 mg to the patient.
  • a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 95 mg to the patient. In some embodiments, a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 100 mg to the patient. In some embodiments, a TYK2 inhibitor (e.g., Compound 1) or a pharmaceutically acceptable salt thereof is administered (e.g., orally) at a dose of up to 150 mg to the patient.
  • 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 dosing schedule appropriate to give the desired disease regression with minimum side effects.
  • a TYK2 inhibitor e.g., Compound 1 or pharmaceutical composition thereof is administered to a patient daily (QD) for a period between about 1 day to about 2 days, about 2 days to about 3 days, about 3 days to about 4 days, about 4 days to about 5 days, about 5 days to about 6 days, about 6 days to about 7 days, about 1 week to about 2 weeks, about 2 weeks to about 3 weeks, about 3 weeks to about 4 weeks, about 4 weeks to about 5 weeks, about 5 weeks to about 6 weeks, about 6 weeks to about 7 weeks, about 7 weeks to about 8 weeks, about 8 weeks to about 9 weeks, about 9 weeks to 10 weeks, about 10 weeks to about 11 weeks, about 11 weeks to about 12 weeks, about 12 weeks to about 14 weeks, about 14 weeks to about 16 weeks, about 16 weeks to about 18 weeks, about 18 weeks to about 21 weeks, about 21 weeks to about 24 weeks, about 24 weeks to about 27 weeks, about 27 weeks to about 30 weeks, about 30 weeks to about 33 weeks, about 33 weeks to about 36 weeks, about 36 weeks to about 39 weeks
  • a TYK2 inhibitor e.g., Compound 1 or pharmaceutical composition thereof is administered to a patient daily (QD) for 2 weeks, 4 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 weeks, 51 weeks, 52 weeks, 1 year, 2 years, 3 years, 4 years, 5 years, or longer.
  • a TYK2 inhibitor (e.g., Compound 1) or pharmaceutical composition thereof is administered to a patient daily (QD) indefinitely.
  • a TYK2 inhibitor e.g., Compound 1 or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof is administered to a patient at a single daily dose of 2-200 mg for 2 weeks.
  • a TYK2 inhibitor e.g., Compound 1 or pharmaceutical composition thereof is administered to a patient at multiple daily doses of 2-200 mg for 2 weeks.
  • a TYK2 inhibitor e.g., Compound 1
  • a TYK2 inhibitor e.g., Compound 1
  • pharmaceutical composition thereof is administered to a patient at a single dose, two daily doses, or multiple daily doses at an overall dose intended to provide approximately 24-hour coverage at IC50 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.
  • a TYK2 inhibitor e.g., Compound 1
  • a pharmaceutical composition thereof is administered to a patient at a single dose, two daily doses, or multiple daily doses at an overall dose intended to provide approximately 24-hour coverage at IC 90 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. 7.
  • Pharmaceutically acceptable compositions [0197]
  • the compounds and compositions, according to the method described herein, may be administered using any amount and any route of administration effective for treating or lessening the severity of any disorder disclosed herein.
  • unit dosage form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions described herein will be decided by the attending physician within the scope of sound medical judgment.
  • compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxy
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound described herein that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound described herein or an inhibitory active metabolite or residue thereof.
  • inhibitory active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of a TYK2 protein kinase, or a mutant thereof.
  • compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, intracisternally, intraperitoneally, nasally, buccally, vaginally or via an implanted reservoir.
  • the compounds described herein may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • the active ingredient is combined with emulsifying and suspending agents.
  • certain sweetening, perfuming, flavoring or coloring agents may also be added.
  • pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by 46 57406284.1 mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • Pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
  • compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel (e.g.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • Pharmaceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • pharmaceutically acceptable compositions described herein are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions described herein are administered with food.
  • compositions described herein that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host 48 57406284.1 treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • Liquid dosage forms for oral administration may be used and include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • combination therapies described herein, or a pharmaceutically acceptable composition thereof are administered in combination with a monoclonal antibody or an siRNA therapeutic.
  • Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with a compound described herein in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a combination described herein may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the amount of additional therapeutic agent present in the compositions described herein will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • a composition can include Compound 1 and one or more additional therapeutic agents.
  • the therapeutic agent may be administered together with Compound 1, or may be administered prior to or following administration of Compound 1. 50 57406284.1 Suitable therapeutic agents are described in further detail below.
  • a 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.
  • 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 following the therapeutic agent.
  • a method of treating inflammatory bowel disease can include administering to a patient in need thereof Compound 1 and one or more additional therapeutic agents.
  • additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, clobetasol, methotrexate, Humira®, Stelara®, triamcinolone, ustekinumab, adalimumab, Cosentyx®, Remicade®, Taltz®, Skyrizi®, Tremfya®, etanercept, Ilumya®, Avsola®, guselkumab, Inflectra®, ixekizumab , Renflexis®, risankizumab, secukinumab, tildrakizumab, fluocinonide, triamcinolone, Elocon®, calcipotriene, mometasone, Clobex
  • a method of treating an inflammatory disease, disorder or condition can include administering to a patient in need thereof Compound 1 and one or more additional therapeutic agents.
  • additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti- inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheum
  • NSAIDS non
  • a method of treating rheumatoid arthritis can include administering to a patient in need thereof Compound 1 and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or
  • NSAIDS non-
  • a method of treating osteoarthritis can include administering to a patient in need thereof Compound 1 and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • a method of treating cutaneous lupus erythematosus or systemic lupus erythematosus can include administering to a patient in need thereof Compound 1 and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine® or Liquae
  • NSAIDS non-ster
  • a method of treating COPD can include administering to a patient in need thereof Compound 1 and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, be
  • beta-2 agonists such
  • a method of treating a solid tumor can include administering to a patient in need thereof Compound 1 and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.
  • additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and
  • a method of treating a hematological malignancy can include administering to a patient in need thereof Compound 1 and a Hedgehog (Hh) signaling pathway inhibitor.
  • the hematological malignancy is DLBCL (Ramirez et al “Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).
  • a method of treating diffuse large B-cell lymphoma can include administering to a patient in need thereof Compound 1 and one or more 55 57406284.1 additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.
  • additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.
  • a method of treating multiple myeloma can include administering to a patient in need thereof Compound 1 and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
  • additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
  • a method of treating or lessening the severity of a disease can include administering to a patient in need thereof Compound 1 and a BTK inhibitor, 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, Sjogren’s syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison’s disease, opsoclonus-myoclonus syndrome, anky
  • a method of treating or lessening the severity of a disease can include administering to a patient in need thereof Compound 1 and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of
  • ulcerative colitis and Crohn's disease endocrine ophthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
  • idiopathic nephrotic syndrome or minimal change nephropathy including idiopathic nephrotic syndrome or minimal change nephropathy, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.
  • the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin’s disease, small-cell lung cancer, non-small-cell lung cancer, myelodysplastic syndrome, lymphoma, a hematological neoplasm, or solid tumor.
  • a method of treating or lessening the severity of a disease can include administering to a patient in need thereof a TYK2 pseudokinase (JH2) domain binding compound and a TYK2 kinase (JH1) domain binding compound.
  • the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
  • the JH2 binding compound is Compound 1.
  • suitable JH2 domain binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1, the entirety of each of which is incorporated herein by reference.
  • Suitable JH1 domain binding compounds include those described in WO2015131080A1, the entirety of which is incorporated herein by reference.
  • a method of inhibiting protein kinase activity in a biological sample can include the step of contacting said biological sample with a compound described herein, or a composition comprising said compound.
  • a method of inhibiting TYK2, or a mutant thereof, activity in a biological sample can include the step of contacting said biological sample with a compound described herein, or a composition comprising said compound.
  • a method of irreversibly inhibiting TYK2, or a mutant thereof, activity in a biological sample can include the step of contacting said biological sample with a compound described herein, or a composition comprising said compound.
  • a method of selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3 is described.
  • a compound described herein is more than 2-fold selective over JAK1/2/3.
  • a compound described herein is more than 5-fold selective over JAK1/2/3.
  • a compound described herein is more than 10-fold selective over JAK1/2/3.
  • a compound described herein is more than 50-fold selective over JAK1/2/3.
  • a compound described herein is more than 100-fold selective over JAK1/2/3.
  • a method of inhibiting protein kinase activity in a patient can include the step of administering to said patient a compound described herein, or a composition comprising said compound.
  • a method of inhibiting activity of TYK2, or a mutant thereof, in a patient can include the step of administering to said patient a compound described herein, or a composition comprising said compound.
  • a method of reversibly or irreversibly inhibiting one or more of TYK2, or a mutant thereof, activity in a patient can include the step of administering to said patient a compound described herein, or a composition comprising said compound.
  • a method for treating a disorder mediated by TYK2, or a mutant thereof, in a patient in need thereof can include the step of administering to said patient a compound described herein or pharmaceutically acceptable composition thereof.
  • additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions described herein.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as “appropriate for the disease, or condition, being treated.”
  • a compound described herein may also be used to advantage in combination with other therapeutic compounds.
  • the other therapeutic compounds are antiproliferative compounds.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; 61 57406284.1 protea
  • aromatase inhibitor as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane is marketed under the trade name AromasinTM.
  • Formestane is marketed under the trade name LentaronTM.
  • Tamoxifen is marketed under the trade name NolvadexTM.
  • Raloxifene hydrochloride is marketed under the trade name EvistaTM.
  • Fulvestrant can be administered under the trade name FaslodexTM.
  • a combination described herein can include a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CasodexTM).
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name ZoladexTM.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CaelyxTM), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide is marketed under the trade name EtopophosTM.
  • Teniposide is marketed under the trade name VM 26-Bristol
  • Doxorubicin is marketed under the trade name Acriblastin TM or AdriamycinTM.
  • Paclitaxel is marketed under the trade name TaxolTM.
  • Docetaxel is marketed under the trade name TaxotereTM.
  • Vinblastine sulfate is marketed under the trade name Vinblastin R.PTM.
  • Vincristine sulfate is marketed under the trade name FarmistinTM.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
  • Cyclophosphamide is marketed under the trade name CyclostinTM. Ifosfamide is marketed under the trade name HoloxanTM.
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • Gemcitabine is marketed under the trade name GemzarTM.
  • the term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in 63 57406284.1 the form as it is marketed, e.g. under the trademark CarboplatTM.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark EloxatinTM.
  • the term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds” as used herein 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 targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (I
  • BCR-Abl kinase and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2- pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK and TEC family, and/or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further
  • PI3K inhibitors useful in the methods described herein include but are not limited 65 57406284.1 to 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.
  • the term “BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.
  • SYK inhibitor includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.
  • Bcl-2 inhibitor includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ.
  • the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic.
  • BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds described herein can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.
  • SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds described herein can be found in WO2003063794, WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference.
  • PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds described herein can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.
  • JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds described herein can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.
  • Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (ThalomidTM) and TNP-470.
  • proteasome inhibitors useful for use in combination with compounds described herein include, but are not limited to bortezomib, disulfiram, epigallocatechin-3- gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g.
  • inhibitors of phosphatase 1, phosphatase 2A, or CDC25 such as okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, ⁇ - ⁇ - or ⁇ - tocopherol or ⁇ - ⁇ - or ⁇ -tocotrienol.
  • cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CelebrexTM), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • Cox-2 inhibitors such as celecoxib (CelebrexTM), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • Zoledronic acid is marketed under the trade name ZometaTM.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (CerticanTM), CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88.
  • biological response modifier as used herein refers to a lymphokine or interferons.
  • inhibitor of Ras oncogenic isoforms such as H-Ras, K-Ras, or N-Ras
  • inhibitor of Ras oncogenic isoforms refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a “farnesyl transferase inhibitor” such as L-744832, DK8G557 or R115777 (ZarnestraTM).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or 67 57406284.1 inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VelcadeTM) and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1- ⁇ -D-arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HerceptinTM), Trastuzumab-DM1, erbitux, bevacizumab (AvastinTM), rituximab 68 57406284.1 (Rituxan ® ), PRO64553 (anti-CD40) and 2C4 Antibody.
  • trastuzumab HerceptinTM
  • Trastuzumab-DM1 erbitux
  • bevacizumab AvastinTM
  • rituximab 68 57406284.1 Renuxan ®
  • PRO64553 anti-CD40
  • AML acute myeloid leukemia
  • compounds described herein can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds described herein can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • a method of treating AML associated with an ITD and/or D835Y mutation can include administering a compound described herein together with a one or more FLT3 inhibitors.
  • the FLT3 inhibitors are selected from quizartinib (AC220), a staurosporine derivative (e.g. midostaurin 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.
  • AC220 quizartinib
  • a staurosporine derivative e.g. midostaurin or lestaurtinib
  • sorafenib e.g. midostaurin or lestaurtinib
  • tandutinib e.g. midostaurin or lestaurtinib
  • LY-2401401 e.
  • the FLT3 inhibitors are selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.
  • Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 ' -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
  • HDAC histone deacetylase
  • SAHA suberoylanilide hydroxamic acid
  • 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-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl) ⁇ 2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
  • Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • ionizing radiation means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See 69 57406284.1 Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol.1, pp.
  • EDG binders refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6- mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1 ,3-dione derivatives.
  • VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; AngiostatinTM; EndostatinTM; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610)
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as VisudyneTM and porfimer sodium.
  • Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11- ⁇ -epihydrocotisol, cortexolone, 17 ⁇ -hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.
  • Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • the compounds described herein are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of 70 57406284.1 therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • a compound described herein may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists such LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden),V-11294A
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.
  • chemokine receptors 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, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH- 55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4- methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N- dimethyl-2H-pyran-4- aminium chloride (TAK-770).
  • TAK-770 antagonists such as N-[[4-[[[[6,7-dihydro-2-(4- methylphenyl)-5H-benzo-cyclohepten-8-yl]
  • a compound described herein may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation.
  • a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • the compounds described herein, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • Vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • Implantable devices coated with a compound described herein are another embodiment.
  • EXEMPLIFICATION As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Additional compounds described herein may be prepared by methods substantially similar to those described herein in the Examples and methods known to one skilled in the art.
  • the TYK2 inhibitors (e.g., Compound 1) described herein can be prepared by methods known to one of ordinary skill in the art, for example, as described in US 11,046,698, the contents of which are incorporated herein by reference in their entireties.
  • Objectives and Endpoints Objectives: Endpoints: Primary Objective: Primary Endpoint: To evaluate the efficacy of Compound 130 Endoscopic response at Week 12, assessed as proportion of mg, 50 mg and 75 mg orally administered QD, subjects achieving decrease in Simple Endoscopic Score for compared to placebo, in achieving endoscopic Crohn's Disease (SES-CD) ⁇ 50% from baseline (or for response at Week 12 in subjects with subjects with isolated ileal disease, SES-CD ⁇ 4 or at least a moderately to severely active CD. 2-point reduction from baseline) read centrally.
  • the highest AUC0-tau projected in this study maintains 3.7-fold (AUC) and 7-fold (Cmax) margins to the observed NOAEL in the 26-week rat toxicity study when findings attributed to the M6 metabolite, considered to be rat- specific, are excluded, and 8-fold (AUC) and 10-fold (C max ) margins to the NOAEL in the 39- week monkey toxicity study.
  • Example 3 A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study of Compound 1 in Healthy Volunteers (Study 104) Synopsis [0310] Rationale: In a previous study (Study 101), two cohorts of healthy participants received Compound 1 at the dose of 20 mg or 35 mg daily for 2 weeks. Treatment was generally safe and well tolerated, without serious or severe adverse events reported. The present study was designed to continue dose escalation in healthy participants in order to define a relatively broad dose range to help select doses for future studies in patients with psoriasis and other autoimmune diseases.
  • Dose escalation was terminated if at least 2 participants in a cohort meet any of the following criteria attributable to study drug: ⁇ Have a drug-related SAE. ⁇ Experience a drug-related grade 3 or higher toxicity. [0320] Dose escalation was terminated if even 1 participant at a given dose level meets the following criterion attributable to study drug: 1. Has evidence of drug-induced liver injury (DILI).
  • DILI drug-induced liver injury
  • Single doses between 5 mg and 200 mg and multiple doses of 20 mg or 35 mg daily for 2 weeks were generally safe and well tolerated. There were no serious or severe AEs, nor AEs that led to discontinuation of treatment. The most common adverse effect was a form of skin rash, acneiform dermatitis, seen in 7 of 17 (41%) of subjects receiving single doses of 100 mg or higher and 8 of 12 (67%) of subjects receiving multiple doses. While common, these events were all mild in intensity and, even in the multiple dose groups, resolved within 1 to 2 weeks with limited or no intervention and without requiring discontinuation of treatment.
  • the projected exposure levels following administration of 50 mg and 100 mg doses given daily for 2 weeks are projected to be approximately 7- and 8-fold lower (50 mg) and 3- and 4-fold lower (100 mg) than the NOAELs determined in 28-day repeat-dose toxicity studies in monkeys and rats, respectively.
  • the nonclinical pharmacology, toxicology, and pharmacokinetic (PK) studies, early clinical data, as well as the modeling data for the 50 mg and 100 mg dose support the proposed multiple dose study of Compound 1 in healthy participants, with 50 mg as the first dose being tested.
  • Check-In Procedures (Day -1) [0328] On the morning of Day -1, all participants returned to the CRU. Inclusion and exclusion criteria were reviewed to ensure participants continue to meet all entry criteria.
  • a second PCR COVID-19 test were also performed, and samples sent to a central laboratory. After the PCR test has been performed, participants remained in an isolated area until the test results are received later that day. Participants who do not meet all the inclusion criteria or meet any of the exclusion criteria on Day -1 (including a positive COVID-19 test) were considered Screen Failures. [0329] Alternates who meet entry criteria at screening also returned to the CRU to complete Day -1 activities. If the alternates were not randomized because the target number of participants per cohort had been met, they were still eligible for the following cohort. Day -1 labs did not need to be repeated if the alternates are enrolled in the study the day following their initial Day -1 assessment.
  • Treatment and Monitoring Period [0330] On the morning of Day 1, pre-dose evaluations were obtained. Upon completing review of all criteria, the participant was randomized. [0331] Participants received a single oral dose of Compound 1 or placebo in a blinded manner on the morning of Day 1 and then daily for a total of 14 days. Safety and tolerability 79 57406284.1 were assessed during the treatment period through monitoring, including of vital signs, clinical laboratory tests, 12-lead ECGs, and AEs. Blood samples for PK and PD assessments and urine samples for metabolite profiling were collected at the timepoints as listed. Cardiodynamic monitoring was also conducted. SFU Visit/Early Termination [0332] The SFU visit was performed on Day 22 prior to discharge.
  • Any acute or chronic medical condition including the presence of laboratory abnormalities (greater than Grade 1) or electrocardiogram (ECG) examination abnormalities, or psychiatric illness, that would prevent the participant from signing the Informed Consent form, place the participant at an unacceptable risk if he/she were to participate in the study, or confound the ability to interpret data from the study.
  • Participants with evidence of mild active infection e.g., upper respiratory, urinary, gastrointestinal
  • Participants with evidence of mild active infection e.g., upper respiratory, urinary, gastrointestinal
  • Female participants of childbearing potential 3. Positive serology for hepatitis B, hepatitis C, or human immunodeficiency virus (HBsAg, HCV Ab, or HIV Ab positive).
  • Clinical Safety Laboratory assessments were made as summarized above. [0365] The PI or qualified must review the laboratory report, document this review, and record any clinically relevant changes occurring during the study. [0366] Laboratory tests with values considered clinically significantly abnormal during participation in the study should be repeated until the values return to the participant’s baseline or are no longer considered clinically significant by the PI. [0367] If such values do not return to normal/baseline within a period of time judged reasonable by the PI, the etiology should be investigated, and the Sponsor notified. [0368] Non-protocol specified laboratory assessments requiring a change in participant management or considered clinically significant by the PI (e.g., resulting in an AE) must also be recorded in the CRF.
  • ⁇ ALT or AST>3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) (FDA 2009).
  • the Medical Monitor should be contacted immediately. Additional medical management considerations (for the specific participant and possibly extending to the broader cohort) while the evaluation is ongoing should be discussed.
  • the following adverse events of special interest require expedited reporting to Sponsor, the PI should inform the Sponsor within 24 hours of learning of the following events.
  • PK Sampling Timepoint Allowable Windows Pre-dosing Day 1, 8 and 14 ⁇ 30mins 0.5 hour post-dose (Day 1 and 14) ⁇ 5mins 1 hour post-dose (Day 1 and 14) ⁇ 5mins 87 57406284.1 2 hours post-dose (Day 1 and 14) ⁇ 5mins 3 hours post-dose (Day 1 and 14) ⁇ 10mins 4 hours post-dose (Day 1 and 14) ⁇ 30mins 6 hours post-dose (Day 1 and 14) ⁇ 60mins 8 hours post-dose (Day 1 and 14) ⁇ 60mins 12 hours post-dose (Day 1 and 14) ⁇ 60mins 24 hours (Day 2 and 15) post-dose ⁇ 60mins 48 hours post-dose (Day 3 and 16) ⁇ 120mins 72 hours post-dose (Day 4 and 17)
  • Ulcerative colitis and Crohn’s disease are distinguished primarily by the affected portion of the gastrointestinal tract. Ulcerative colitis is characterized by inflammation of the large intestine or colon and the rectum, while Crohn’s disease encompasses inflammation of any part of the gastrointestinal tract, but most often impacts the end of the small intestine or the ileum where it joins the colon.
  • Ulcerative colitis is characterized by inflammation of the large intestine or colon and the rectum
  • Crohn’s disease encompasses inflammation of any part of the gastrointestinal tract, but most often impacts the end of the small intestine or the ileum where it joins the colon.
  • the approach to IBD treatment is determined by multiple factors, including disease severity, location of inflammation, previous response to treatment, side effects and co- morbidities.
  • the most common oral treatments for ulcerative colitis are anti-inflammatories that contain 5-aminosalicylic acid (5-ASA). These drugs decrease inflammation at the intestinal wall and may reduce symptoms and maintain remission in ulcerative colitis but are not as effective in treating Crohn’s disease.
  • Corticosteroids and other oral immunomodulators may be used for short-term control of flare-ups and to maintain remission in IBD patients who have not responded to other medications.
  • Injectable biologics generally are reserved for treatment of moderate-to-severe ulcerative colitis and Crohn’s disease.
  • the most commonly prescribed biologics are anti-TNF ⁇ biologics (including AbbVie’s Humira®, Johnson & Johnson’s Remicade® and Simponi®, and UCB Pharma’s Cimzia®).
  • Newer biologic treatment options include anti-integrin therapies for ulcerative colitis (Takeda’s Entyvio®) and anti-IL-12/IL-23 antibodies (e.g., Johnson & Johnson’s Stelara®) for Crohn’s disease.
  • Pfizer oral JAK inhibitor, Xeljanz®, was approved for treatment of ulcerative colitis in 2018; however commercial uptake has been limited due to the aforementioned safety concerns.
  • BMS Zeposia®, an S1P1R oral modulator, was approved for treatment of moderate-to-severe ulcerative colitis in May 2021. 89 57406284.1 [0382]
  • the IBD market for all levels of severity was approximately $14 billion in the U.S. and $25 billion globally.
  • Global reported sales of treatments for ulcerative colitis totaled an estimated $7.9 billion in 2020, while global annual sales of treatments for Crohn’s disease totaled an estimated $17.7 billion in 2020.
  • TNF inhibitor sales currently dominate the ulcerative colitis treatment market, closely followed by sales of other injectable biologic therapies (anti-IL-12/23 antibodies and anti-integrin therapies), and oral 5-ASA therapies.
  • Example 5 Absorption, Distribution, Metabolism, Excretion (ADME) and Other Properties of Compound 1 [0384] The potency and selectivity for Compound 1 were explored by screening Compound 1 at a 1 micromolar concentration for binding against a panel of 631 kinases. Only one kinase was inhibited with >50% inhibition: PIP5K1C (54% inhibition). Various in vitro potency/selectivity results are summarized in the table below.
  • the FaSSIF / FeSSIF Solubilities were 13 / 70 ⁇ g/mL, respectively (kinetic solubility 32 ⁇ M).
  • DDI perpetrator potential was low at clinically relevant 91 57406284.1 exposures.
  • CYP450 IC 50 s >30 ⁇ M at 1A2, 2C9, 2D6, >8 ⁇ M at 2C19 and 3A4 (M), 2 uM 3A4 (T), no time-dependent inhibition; low PXR activation (26% of rifampicin control at 30 ⁇ M).
  • Tyrosine kinase 2 (TYK2), a member of the Janus kinase (JAK) family, plays a crucial role in the pathogenesis of inflammatory bowel disease (IBD) and other autoimmune diseases via the mediation of signaling pathways downstream of interleukin (IL)-12, IL-23, and interferon (IFN) ⁇ / ⁇ .
  • IBD inflammatory bowel disease
  • IFN interferon
  • JAK inhibitors have been approved for the treatment of ulcerative colitis (UC), they are associated with adverse events likely to be associated with JAK1-3 inhibition, resulting in dose level limitations.
  • Compound 1 is a highly potent and selective, allosteric, oral TYK2 inhibitor computationally designed to bind to the Janus homology 2 (JH2) domain of TYK2 but to be sterically occluded from the JH2 domains of JAK1-3.
  • JH2 Janus homology 2
  • CD4 + CD45RB hi T cells were transferred to severe combined immunodeficient (SCID) mice at Day 0 and disease progression followed for 48 days (FIG. 1A).
  • SCID severe combined immunodeficient
  • ⁇ -CD40 model T- and B-cell-deficient Rag2 -/- mice were challenged with agonistic ⁇ -CD40 mAb at Day 0, and disease progression followed for 7 days (FIG. 1B).
  • In vivo doses were intended to achieve 24-hour coverage at the respective inhibitory concentration and were modelled based on previous mouse pharmacokinetic data.
  • colonic tissue from the TCT colitis model was obtained for RNA-seq processing and transcriptomic profiles analysed using Reactome (reactome.org). Colon weight:length rations and total histology scores were also assessed. The tatistical significance of differences between groups was determined using analysis of variance (ANOVA) with Tukey’s post hoc test. All animal protocols were approved.
  • ANOVA analysis of variance
  • ⁇ Treatment started on Day 0 and ended on Day 48 (TCT colitis model) and Day 7 (a- CD40 mAb colitis model).
  • Compound 1 selectively downregulated genes associated with cytokine signalling relative to vehicle, in particular those associated with T- helper 17 (Th17) cell phenotypes, including those related to the IFN ⁇ / ⁇ pathway, the innate immune system, and interleukin signaling (FIG.4).
  • Compound 1 was efficacious in two preclinical mouse models of colitis, with IC 90 providing maximal efficacy in both models. Downregulation was observed in the expression of multiple genes involved in cytokine signaling pathways.

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Abstract

L'invention concerne des composés, des compositions de ceux-ci et des méthodes d'utilisation de ceux-ci dans des protocoles de dosage pour l'inhibition de TYK2, et le traitement de troubles inflammatoires comprenant une maladie intestinale inflammatoire, y compris la maladie de Crohn ou la rectocolite hémorragique.
PCT/IB2024/059183 2023-09-21 2024-09-20 Inhibiteurs de tyk2 destinés à être utilisés dans le traitement d'une maladie inflammatoire de l'intestin Pending WO2025062372A1 (fr)

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