Crystal form of TYK2 inhibitor and application thereof

Abstract

The present disclosure relates, in part, to crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1, 2, 4-triazol-3-yl) phenyl) amino)-5-(propionyl-3, 3, 3-d3) pyridin-2-yl) cyclopropanecarboxamide hydrochloride and pharmaceutical compositions thereof.

Description

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 341,528, filed on May 13, 2022, and U.S. Provisional Patent Application No. 63 / 405,577, filed on September 12, 2022; the entire contents of which are incorporated herein by reference. Background Art

[0002] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. TYK2 activation is associated with diseases and disorders such as, for example, autoimmune disorders, inflammatory disorders, proliferative disorders (e.g., cancer), endocrine disorders, and neurological disorders. For example, TYK2 activation is associated with inflammatory bowel disease (IBD), Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis. TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Therefore, compounds that inhibit TYK2 activity are beneficial, particularly those that are selective for JAK2. These compounds should provide a pharmacological response that advantageously treats one or more of the conditions described herein without the side effects associated with JAK2 inhibition.

[0003] Polymorphism is the ability of a substance to crystallize in more than one lattice arrangement. Crystallinity or polymorphism can affect many aspects of the solid-state properties of a drug substance. Crystalline substances can be very different from amorphous forms, and different crystal modifications of a substance can differ greatly from each other in many aspects, including solubility, dissolution rate, and / or bioavailability. In general, it is difficult to predict whether a given compound will form any crystalline solid-state forms. It is even more difficult to predict the physical properties of these crystalline solid-state forms. Therefore, for certain formulations and / or production processes, a crystalline form of a therapeutic agent can be advantageous. Summary of the invention

[0004] The present disclosure relates, at least in part, to crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride.

[0005] For example, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 9.7 2θ degrees, for example, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 9.7, 20.8 and 22.9 The invention relates to a powder having characteristic peaks at 2θ degrees of about 9.3, 9.7, 19.6, 20.3, 20.8 and 22.9, for example, characterized in that the powder X-ray diffraction pattern has characteristic peaks at 2θ degrees of about 8.3, 9.3, 9.7, 13.6, 17.2, 17.6, 19.6, 20.3, 20.8, 21.3, 22.9 and 27.4.

[0006] N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide is, for example, a modulator of tyrosine kinase 2 (TYK2) (eg, an inhibitor of TYK2), and is represented by the following formula:

[0007]

[0008] Further contemplated herein is a pharmaceutical composition comprising a disclosed crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride and a pharmaceutically acceptable excipient, for example, a composition formulated for oral administration. Further contemplated herein is a drug substance comprising at least a detectable amount of a disclosed crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride. For example, disclosed herein is a drug substance comprising a substantially pure crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride.

[0009] Also provided herein is a method of treating a TYK2-mediated disorder in a patient in need thereof, the method comprising administering to the patient an effective amount of the disclosed crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride.

[0010] For example, provided herein is a method of treating one or more of the following in a patient in need thereof: Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis, the method comprising administering to the patient an effective amount of a disclosed crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 Depicted is the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (Form 1).

[0012] Figure 2 The differential scanning calorimetry (DSC) curve of Form 1 is depicted.

[0013] Figure 3 Thermogravimetric analysis (TGA) curve of Form 1 is depicted.

[0014] Figure 4 The dynamic vapor sorption (DVS) curve of Form 1 is plotted.

[0015] Figure 5 Depicted is the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (Form 2).

[0016] Figure 6 The differential scanning calorimetry (DSC) curve of Form 2 is depicted.

[0017] Figure 7 Thermogravimetric analysis (TGA) curve of Form 2 is depicted.

[0018] Figure 8Depicted is the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (Form 3).

[0019] Fig. 9 Depicted is the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (Form 5).

[0020] Fig.10 The differential scanning calorimetry (DSC) curve of Form 5 is depicted.

[0021] Fig.11 Thermogravimetric analysis (TGA) curve of Form 5 is depicted.

[0022] Fig.12 Depicted is the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (Form 6).

[0023] Fig.13 The differential scanning calorimetry (DSC) curve of Form 6 is depicted.

[0024] Fig.14 Thermogravimetric analysis (TGA) curve of Form 6 is depicted. DETAILED DESCRIPTION

[0025] The features and other details of the present disclosure will now be described in more detail. Before further describing the present disclosure, certain terms used in this specification, examples, and the appended claims are collected herein. These definitions should be interpreted in light of the remainder of the present disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those of ordinary skill in the art.

[0026] definition

[0027] The term "crystalline form" refers to a crystal form or modification that can be characterized by analytical methods such as X-ray powder diffraction (XRPD) and / or differential scanning calorimetry (DSC). The crystalline compounds disclosed herein may exist in solvated forms with solvents such as water, ethanol, etc., as well as in unsolvated forms. Unless otherwise indicated or inferred, the disclosed crystalline compounds include both solvated and unsolvated forms.

[0028] "Treatment" encompasses any effect resulting in an improvement in the condition, disease, disorder, etc., such as lessening or reducing, regulating or eliminating.

[0029] Unless otherwise indicated, the term "disorder" refers to the terms "disease," "condition," or "illness" and are used interchangeably.

[0030] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet the sterility, pyrogenicity and general safety and purity standards required by the FDA's Bureau of Biologics Standards.

[0031] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, etc. that are compatible with drug administration. The use of these media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplementary, additional or enhanced therapeutic functions.

[0032] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein formulated with one or more pharmaceutically acceptable excipients.

[0033] "Individual", "patient" or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and preferably humans. The compounds of the present disclosure can be administered to mammals (such as humans), but can also be administered to other mammals, such as animals in need of veterinary treatment, for example, livestock (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammals treated in the methods of the present disclosure are expected to be mammals in need of, for example, treatment of cancer or blood diseases. "Modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0034] In this specification, the term "effective amount" or "therapeutically effective amount" means the amount of the subject compound that will cause a biological or medical response in a tissue, system or animal (e.g., mammal or human) that is sought by a researcher, veterinarian, hospital physician or other physician. The compounds of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventive effect.

[0035] As used herein, the term "pharmaceutically acceptable salt" refers to salts of basic groups that may be present in the compounds used in the composition. The compounds contained in the present composition are basic in nature and are capable of forming a variety of salts with a variety of inorganic and organic acids.

[0036] Unless otherwise indicated, the term "and / or" means "and" or "or" in this disclosure.

[0037] As used herein, the terms "a", "an" and "an" are intended to include one or more unless otherwise specified. For example, the term "agent" encompasses a single agent and a combination of two or more agents.

[0038] When the term "about" is used before a quantitative value, unless otherwise specifically stated, the disclosure also includes the specific quantitative value itself. As used herein, unless otherwise indicated or inferred, the term "about" refers to a ±10% variation from the nominal value. In the context of a peak at 2θ degrees, the term "about" means that there is an uncertainty in the measured value of 2θ (expressed in 2θ) of ±0.2. In general, a DSC thermogram may have a variation within the range of ±2°C. Therefore, temperature values ​​are understood to be values ​​contained within the range of approximately ±2°C.

[0039] In general, unless otherwise indicated, provided herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride that is substantially free of any other crystalline form. As used herein, "substantially free" or "substantially free of any other crystalline form" means that the disclosed crystalline form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, or about 1% or less of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride as determined, for example, by XRPD. any other crystalline form of cyclopropanecarboxamide hydrochloride, or any other crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride with less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1%, as determined by, for example, XRPD. Thus, the disclosed crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride described herein as being substantially free of any other crystalline form may be understood as containing greater than 80% (w / w), greater than 90% (w / w), greater than 95% (w / w), greater than 98% (w / w) or greater than 99% (w / w) of this crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride. Thus, in some embodiments, the disclosed crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride may contain 1% to 20% (w / w), 5% to 20% (w / w), or 5% to 10% (w / w) of one or more other crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride.

[0040] Crystal form

[0041] The present disclosure relates, at least in part, to crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride. Also disclosed are crystalline hydrates, anhydrates, hemihydrates, solvates, tautomers, and co-crystals of any crystalline form described herein.

[0042] For example, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (referred to herein as "Form 1"), characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 9.7 degrees 2θ.

[0043] In one embodiment, Form 1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 8.3 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 9.3 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 9.7 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 13.6 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 14.8 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 15.5 2θ degrees. , characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 17.2 degrees 2θ, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 17.6 degrees 2θ, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 19.6 degrees 2θ, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 20.3 degrees 2θ, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 20.8 degrees 2θ, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 21.3 degrees 2θ, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 22.9 degrees 2θ, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 27.4 degrees 2θ, and / or characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 30.5 degrees 2θ. In another embodiment, Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 9.7, 20.8, and 22.9. In another embodiment, Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 9.3, 9.7, 19.6, 20.3, 20.8, and 22.9. In yet another embodiment, Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 8.3, 9.3, 9.7, 17.6, 19.6, 20.3, 20.8, 21.3, and 22.9. In another embodiment, Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 8.3, 9.3, 9.7, 13.6, 17.2, 17.6, 19.6, 20.3, 20.8, 21.3, 22.9, and 27.4. In another embodiment, Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 8.3, 9.3, 9.7, 13.6, 14.8, 15.5, 17.2, 17.6, 19.6, 20.3, 20.8, 21.3, 22.9, 27.4, and 30.5. For example, a contemplated form has Figure 1The powder X-ray diffraction pattern shown is: In one embodiment, the powder X-ray diffraction pattern of the crystalline form is obtained using Cu Ka radiation.

[0044] The contemplated crystalline Form 1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride can be characterized by a differential scanning calorimetry (DSC) curve showing a characteristic endotherm with an onset of about 237° C. and a peak of about 243° C. (enthalpy 179.57 J / g). For example, Form 1 can be characterized by Figure 2 The differential scanning calorimetry curves are shown.

[0045] The contemplated crystalline Form 1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride can be characterized by a thermogravimetric analysis (TGA) curve showing a mass loss of about 0.67 wt.% between about 22°C and about 160°C. For example, Form 1 can be characterized by Figure 3 In some embodiments, Form 1 can be characterized as having an irregular crystalline morphology as observed by polarized light microscopy.

[0046] In some embodiments, Form 1 can be characterized by a dynamic vapor sorption (DVS) curve that exhibits a reversible total mass change of about 0.2 wt.% between about 0% to about 80% relative humidity (RH) at 25°C. In other embodiments, Form 1 can be characterized by a dynamic vapor sorption (DVS) curve that exhibits a reversible total mass change of about 0.3 wt.% between about 0% to about 90% relative humidity (RH) at 25°C. In certain embodiments, the contemplated Form 1 is an anhydrous crystalline form. For example, Form 1 can be characterized by Figure 4 The dynamic vapor adsorption is shown to be characterized.

[0047] In another embodiment, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 9.7 2θ degrees (referred to herein as "Form 2").

[0048] In one embodiment, Form 2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride is characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 7.7 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 9.9 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 11.5 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 15.2 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 15.2 2θ degrees. The invention relates to a crystalline Form 2 having a characteristic peak at about 15.5 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 17.6 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 19.9 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 22.2 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 23.4 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 25.9 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 27.8 2θ degrees, and / or characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 31.4 2θ degrees. In one embodiment, Form 2 is characterized in that the powder X-ray diffraction pattern has at least one or more characteristic peaks at about 7.7, 11.5 and 25.9 2θ degrees. In another embodiment, Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 7.7, 9.9, 11.5, 19.9, 25.9, and 27.8. In yet another embodiment, Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 7.7, 9.9, 11.5, 15.2, 15.5, 19.9, 22.2, 25.9, and 27.8. In another embodiment, Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 7.7, 9.9, 11.5, 15.2, 15.5, 17.6, 19.9, 22.2, 23.4, 25.9, 27.8, and 31.4. For example, the contemplated forms have Figure 5 The powder X-ray diffraction pattern shown is: In one embodiment, the powder X-ray diffraction pattern of the crystalline form is obtained using Cu Ka radiation.

[0049] The contemplated crystalline Form 2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride can be characterized by a differential scanning calorimetry (DSC) curve showing a characteristic endotherm with an onset of about 226° C. and a peak of about 237° C. (enthalpy 197.35 J / g). For example, Form 2 can be characterized by Figure 6 The differential scanning calorimetry curves are shown.

[0050] The contemplated Form 2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride can be characterized by a thermogravimetric analysis (TGA) curve showing a mass loss of about 0.76 wt.% between about 22°C and about 160°C. For example, Form 2 can be characterized by Figure 7 Thermogravimetric analysis curves shown are characterized. In certain embodiments, the contemplated Form 2 is an anhydrous form. In some embodiments, Form 2 can be characterized as having a needle-like crystalline morphology observed by polarized light microscopy.

[0051] In another embodiment, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 8.9 degrees 2θ (referred to herein as "Form 3").

[0052] In one embodiment, Form 3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 5.6 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 6.6 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 8.9 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 10.9 2θ degrees, and a powder X-ray diffraction pattern having a characteristic peak at about 10.9 2θ degrees. The invention relates to a crystalline Form 3 having a characteristic peak at about 13.1 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 13.8 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 16.7 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 17.8 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 19.7 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 23.6 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 30.2 2θ degrees, and / or characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 34.6 2θ degrees. In one embodiment, Form 3 is characterized in that the powder X-ray diffraction pattern has at least one or more characteristic peaks at about 8.9, 13.1 and 23.6 2θ degrees. In another embodiment, Form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 5.6, 8.9, 10.9, 13.1, 13.8, and 23.6. In yet another embodiment, Form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 5.6, 6.6, 8.9, 10.9, 13.1, 13.8, 17.8, 23.6, and 30. In another embodiment, Form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 5.6, 6.6, 8.9, 10.9, 13.1, 13.8, 16.7, 17.8, 19.7, 23.6, 30.2, and 34.6. For example, the considered form has Figure 8 The powder X-ray diffraction pattern shown is: In one embodiment, the powder X-ray diffraction pattern of the crystalline form is obtained using Cu Ka radiation.

[0053] In another embodiment, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 23.0 degrees 2θ (referred to herein as "Form 5").

[0054] In one embodiment, Form 5 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 6.8 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 10.5 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 11.3 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 13.6 2θ degrees, and a powder X-ray diffraction pattern having a characteristic peak at about 14.6 2θ degrees. The invention relates to a crystalline Form 5 having a characteristic peak at about 16.7 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 17.6 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 19.8 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 21.0 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 23.0 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 23.4 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 27.0 2θ degrees, and / or characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 27.4 2θ degrees. In one embodiment, Form 5 is characterized in that the powder X-ray diffraction pattern has at least one or more characteristic peaks at about 6.8, 23.0 and 27.0 2θ degrees. In another embodiment, Form 5 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 6.8, 10.5, 19.8, 21.0, 23.0, and 27.0. In yet another embodiment, Form 5 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 6.8, 10.5, 13.6, 17.6, 19.8, 21.0, 23.0, 23.4, and 27.0. In another embodiment, Form 5 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 6.8, 10.5, 1.3, 13.6, 16.7, 17.6, 19.8, 21.0, 23.0, 23.4, 27.0, and 27.4. For example, the contemplated forms have Fig. 9 The powder X-ray diffraction pattern shown is: In one embodiment, the powder X-ray diffraction pattern of the crystalline form is obtained using Cu Ka radiation.

[0055] The contemplated crystalline Form 5 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride can be characterized by a differential scanning calorimetry (DSC) curve showing a characteristic endotherm with an onset of about 141° C. and a peak at about 144° C. (enthalpy 140.7 J / g) and a characteristic endotherm with a peak at about 231° C. For example, Form 5 can be characterized by Fig.10 The differential scanning calorimetry curves are shown.

[0056] The contemplated crystalline Form 5 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride can be characterized by a thermogravimetric analysis (TGA) curve showing a mass loss of about 23.0 wt.% between about 23°C and about 150°C. For example, Form 5 can be characterized by Fig.11 In certain embodiments, the contemplated crystalline Form 5 is a benzyl alcohol solvate.

[0057] In another embodiment, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 8.2 degrees 2θ (referred to herein as "Form 6").

[0058] In one embodiment, Form 6 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 4.2 2θ degrees, a powder X-ray diffraction pattern having a characteristic peak at about 8.2 2θ degrees, and a powder X-ray diffraction pattern having a characteristic peak at about 8.4 2θ degrees. , characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 11.7 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 12.7 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 16.4 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 21.2 2θ degrees, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 21.7 2θ degrees, and / or characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 26.7 2θ degrees. In one embodiment, Form 6 is characterized in that the powder X-ray diffraction pattern has at least one or more characteristic peaks at about 4.2, 8.2 and 8.4 2θ degrees. In another embodiment, Form 6 is characterized in that the powder X-ray diffraction pattern has at least one or more characteristic peaks at about 4.2, 8.2, 8.4, 11.7, 12.7 and 16.4 2θ degrees. In yet another embodiment, Form 6 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ degrees of about 4.2, 8.2, 8.4, 11.7, 12.7, 6.4, 21.2, 21.7, and 26.7. For example, the contemplated form has Fig.12 The powder X-ray diffraction pattern shown is: In one embodiment, the powder X-ray diffraction pattern of the crystalline form is obtained using Cu Ka radiation.

[0059] The contemplated crystalline Form 6 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride can be characterized by a differential scanning calorimetry (DSC) curve showing a characteristic endotherm with a peak of about 96° C., a characteristic endotherm with a peak of about 166° C., and a characteristic endotherm with a peak of about 271° C. For example, Form 6 can be characterized by Fig.13 The differential scanning calorimetry curves are shown.

[0060] The contemplated crystalline Form 6 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride can be characterized by a thermogravimetric analysis (TGA) curve showing a mass loss of about 8.70 wt.% between about 25°C and about 120°C. For example, Form 6 can be characterized by the thermogravimetric analysis curve shown in 14.

[0061] In another embodiment, disclosed herein is a pharmaceutical composition comprising a disclosed crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride and a pharmaceutically acceptable excipient. For example, disclosed herein is a pharmaceutical composition comprising Form 1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride and a pharmaceutically acceptable excipient. In another embodiment, disclosed herein is a pharmaceutical composition formed from a disclosed crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride. For example, disclosed herein is a pharmaceutical composition formed from Form 1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride. In some embodiments, the disclosed pharmaceutical composition may be a formulation for oral administration.

[0062] In one embodiment, disclosed herein is a drug substance comprising at least a detectable amount of a disclosed crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride. In another embodiment, disclosed herein is a drug substance comprising a substantially pure crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride. For example, disclosed herein is a drug substance comprising substantially pure Form 1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride.

[0063] Composition

[0064] Another aspect of the present disclosure provides a pharmaceutical composition comprising a crystalline compound as disclosed herein formulated with a pharmaceutically acceptable excipient. Specifically, the present disclosure provides a pharmaceutical composition comprising a crystalline compound as disclosed herein formulated with one or more pharmaceutically acceptable excipients. These formulations include those suitable for oral, topical (e.g., transdermal), oral, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) rectal, vaginal or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the properties of the specific compound used. For example, the disclosed composition can be formulated into a unit dose, and / or can be formulated for oral, subcutaneous or intravenous administration.

[0065] Exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations (e.g., in solid, semisolid or liquid form) containing one or more compounds of the present disclosure as active ingredients mixed with organic or inorganic excipients or excipients suitable for in vitro, enteral or parenteral administration. The active ingredients can be compounded with, for example, conventional non-toxic, pharmaceutically acceptable excipients for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. The active compound of interest is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course of the disease or condition.

[0066] To prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical excipient (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums and other pharmaceutical diluents (e.g., water)) to form a solid preformulation composition containing a uniform mixture of a compound of the present disclosure (or a non-toxic pharmaceutically acceptable salt thereof). When referring to these preformulation compositions as uniform, it is meant that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equivalent unit dosage forms (such as tablets, pills, and capsules).

[0067] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compound is mixed with one or more pharmaceutically acceptable excipients (such as sodium citrate or dicalcium phosphate) and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants, Such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the composition may also include a buffer. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycols.

[0068] Tablets can be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant or a dispersant. Molded tablets can be made by molding a mixture of the subject compound moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms such as dragees, capsules, pills, and granules can be scored or prepared with coatings and shells (such as enteric coatings and other coatings well known in the art of pharmaceutical formulations) as needed.

[0069] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, nanosuspensions, syrups and elixirs. In addition to the subject compound, the liquid dosage form may contain an inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuran methanol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0070] Suspensions, in addition to the subject compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0071] Formulations for rectal or vaginal administration may be presented as suppositories, which may be prepared by mixing the subject compound with one or more suitable non-irritating excipients or excipients including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent.

[0072] Dosage forms for transdermal administration of the subject compounds include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable excipient and with any preservatives, buffers or propellants that may be required.

[0073] Ointments, pastes, creams and gels may contain, in addition to the subject compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicon, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0074] In addition to the subject compound, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0075] The compositions and compounds disclosed herein can be alternately administered by aerosol. This is achieved by preparing aqueous aerosols, liposome preparations or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellants) suspensions can be used. Sonic nebulizers can be used because they minimize exposure of the agent to shear, which can cause degradation of the compound contained in the subject compound. Typically, aqueous aerosols are prepared by mixing an aqueous solution or suspension of the subject compound with a commonly used pharmaceutically acceptable excipient and stabilizer. Excipients and stabilizers vary with the requirements of the specific subject compound, but typically include nonionic surfactants (Tween, pluronic or polyethylene glycol), harmless proteins such as serum albumin, sorbitol esters, oleic acid, lecithin, amino acids such as glycine, buffer, salt, sugar or sugar alcohol. Aerosols are generally prepared by isotonic solutions.

[0076] Pharmaceutical compositions suitable for parenteral administration of the present disclosure include a combination of the subject compound and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0077] Examples of suitable aqueous and non-aqueous excipients that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters, such as ethyl oleate and cyclodextrins. Appropriate fluidity can be maintained, for example, by using a coating material (such as lecithin), by maintaining a desired particle size in the case of a dispersion, and by using a surfactant. For example, the crystalline forms provided herein can be milled to obtain a specific particle size, and in at least some embodiments, these crystalline forms can remain generally stable during milling.

[0078] The amount of the crystalline compound as described herein in the formulation may vary according to factors such as the disease state, age, sex, and weight of the individual. The dosage regimen may be adjusted to provide the preferred therapeutic response. For example, a single bolus may be administered, multiple divided doses may be administered over time, or the dose may be proportionally reduced or increased depending on the exigencies of the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unit doses for mammalian subjects to be treated; each unit contains a predetermined amount of active crystalline compound calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier.

[0079] The instructions for the dosage unit forms of the present disclosure are dictated and directly determined by (a) the unique characteristics of the crystalline compound selected and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such active crystalline compounds for treating individual sensitivity.

[0080] The disclosed composition can be formulated into a solution, microemulsion, liposome or other ordered structure suitable for high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol, etc.) and a suitable mixture thereof. Appropriate fluidity can be maintained by, for example, using a coating (such as lecithin), by maintaining the desired particle size and by using a surfactant in the case of dispersion. In many cases, it is suitable to include an isotonic agent, such as sugar, polyols such as mannitol, sorbitol or sodium chloride in the composition. The extended absorption of the injectable composition can be achieved by including a medicament (such as monostearate and gelatin) that delays absorption in the composition.

[0081] The disclosed crystalline compounds can be administered in delayed release formulations, for example, in compositions comprising slow release polymers. The crystalline compounds can be prepared with carriers that protect the compound from rapid release, such as controlled release formulations, including implants and microencapsulation delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, pectin, polyorthoesters, polylactic acid and polylactic acid, polyethanol copolymers (PLG) can be used. Many methods for preparing these formulations are generally known to those skilled in the art.

[0082] According to another aspect of the present disclosure, the disclosed crystalline compounds may be formulated with one or more additional compounds that enhance the solubility of the compound.

[0083] method

[0084] The crystalline forms disclosed herein can be used to inhibit the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the crystalline forms and methods is TYK2.

[0085] Provided herein are crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride, which are inhibitors of TYK2 and are therefore useful in treating one or more disorders associated with the activity of TYK2 or a mutant thereof.

[0086] Provided herein are methods for treating a disease or disorder in a patient in need thereof, wherein the disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a transplantation-related disorder, the method comprising administering to the patient an effective amount of a crystalline form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline form.

[0087] In some embodiments, the disease or condition is an autoimmune disorder. In some embodiments, the disease or condition is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease ( disease), POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0088] In some embodiments, the disease or disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

[0089] In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a blood cancer. In some embodiments, the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocythemia.

[0090] In some embodiments, the disease or disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

[0091] In some embodiments, the disease or disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[0092] In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation in the FERM domain, the JH2 domain, or the kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0093] In some embodiments, the disease or disorder is associated with transplantation. In some embodiments, the disease or disorder associated with transplantation is transplant rejection or graft-versus-host disease.

[0094] In some embodiments, the disease or disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disease or disorder is associated with type I interferon signaling. In some embodiments, the disease or disorder is associated with IL-10 signaling. In some embodiments, the disease or disorder is associated with IL-12 signaling. In some embodiments, the disease or disorder is associated with IL-23 signaling.

[0095] Provided herein are methods for treating inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, pemphigus with tumors, epidermolysis bullosa acquired, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0096] Provided herein are methods for treating other diseases or conditions, such as those with an inflammatory component, e.g., treating eye diseases and conditions, such as eye allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases in which an autoimmune response is involved or has an autoimmune component or etiology, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, syndrome), idiopathic steatorrhea, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, drusenosis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disease, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, periodic syndromes associated with pyrogenic agents, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without renal syndrome,Examples include primary nephrotic syndrome or minimal change disease), chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypersterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinence pigmenti, Paget's disease disease), pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchial and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, severe allergies, sinusitis, eye allergies, silica-induced disease, COPD (reduction damage, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease disease), lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura purpura), hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0097] In some embodiments, the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), chillin-associated periodic syndrome (CAPS), or osteoarthritis.

[0098] In some embodiments, the inflammatory disease is a Th1 or Th17 mediated disease. In some embodiments, the Th17 mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0099] In some embodiments, the inflammatory disease is Sjögren's syndrome, an allergic disorder, osteoarthritis, a condition of the eye (such as eye allergies, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis), or a disease affecting the nose (such as allergic rhinitis).

[0100] For example, disclosed herein is a method of inhibiting a TYK2 enzyme in a patient or biological sample, the method comprising contacting the patient or biological sample with a therapeutically effective amount of a crystalline form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline form.

[0101] Also disclosed herein is a method of inhibiting TYK2 activity in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a crystalline form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline form. In some embodiments, inhibiting TYK2 activity is associated with treating a disease or condition selected from, for example, Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis.

[0102] Further disclosed herein are methods of treating a TYK2-mediated disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a crystalline form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline form. In some embodiments, the contemplated TYK2-mediated disorder may be, for example, an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a transplant-related disorder. In other embodiments, the contemplated disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

[0103] For example, provided herein is a method of treating one or more of the following in a patient in need thereof: Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis, the method comprising administering to the patient an effective amount of a crystalline form described herein or a pharmaceutical composition comprising an effective amount of a disclosed crystalline form.

[0104] Specifically, in certain embodiments, the present disclosure provides a method for treating the above-mentioned medical indications, the method comprising administering to a patient in need thereof an effective amount of the crystalline form described herein or a pharmaceutical composition comprising an effective amount of the disclosed crystalline form. In certain other embodiments, the present disclosure provides a method for treating the above-mentioned medical conditions in a patient in need thereof, the method comprising orally, subcutaneously or intravenously administering to the patient a composition comprising the crystalline form described herein, or a pharmaceutical composition comprising an effective amount of the disclosed crystalline form.

[0105] The crystalline compounds disclosed herein can be used as medicaments or pharmaceutically acceptable compositions, for example, in the form of pharmaceutical preparations for oral, enteral, parenteral or topical administration, and the contemplated methods disclosed herein may comprise oral, enteral, parenteral or topical administration of the disclosed crystalline compounds, or compositions comprising or formed from such disclosed crystalline compounds. For example, when administered by a certain route (e.g., oral) or in a certain formulation, the disclosed crystalline form can control one or more pharmacokinetic properties (e.g., longer or shorter release profiles) compared to a different route (e.g., subcutaneous) or other formulations, such as formulations having an amorphous form. In one embodiment, the disclosed crystalline form can provide substantial reproducibility from one formulation to another.

[0106] Example

[0107] The compounds and crystalline forms described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art.The following non-limiting examples illustrate the present disclosure.

[0108] X-ray powder diffraction was performed using a Bruker D8 Advance X-ray diffractometer equipped with a LynxEye detector. The samples were scanned from 3 to 40° 2θ with a step size of 0.02° 2θ. The radiation was Cu / K-α1 The tube voltage and current are 40kV and 40mA respectively.

[0109] Differential scanning calorimetry (DSC) was performed using a Discovery DSC 250 (TA Instruments, USA) calorimeter. The sample was placed in an aluminum pinhole sealed pan and the weight was accurately recorded. The sample was heated from 25°C to the final temperature at a rate of 10°C / min.

[0110] Thermogravimetric analysis (TGA) was performed on a Discovery TGA55 (TAInstruments, USA). The sample was placed in an open tared aluminum pan, weighed automatically, and then inserted into a TGA furnace. The sample was heated from ambient temperature to the final temperature at a rate of 10°C / min.

[0111] Example 1

[0112] Form 1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride was prepared as follows. N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (3.4 g) was added to 14 mL MeOH (5V) at 50° C. and a suspension was obtained. Then 7.5 mL 1M HCl / ethyl acetate was added. After the addition of the acid and an additional 2 mL MeOH, the mixture became turbid. The mixture was filtered and then 8.5 mL ethyl acetate was added. Precipitation occurred after the addition of HCl salt Form I seeds at 50° C. The mixture was slowly cooled to RT in 3 hours, 16mL ethyl acetate was added and the mixture was stirred at room temperature for 3 hours. Solid was collected by filtration. The filter cake (1.9g) was analyzed by XPRD and a mixture of Form I and Form II (1.9g) was observed. The solid was re-slurried in the mother liquor at 50°C for 2 hours, and re-slurried for 30min at RT and then collected by filtration. XRPD analysis indicated that the dried material was crystallized, and its figure was consistent with Form 1.

[0113] The XRPD pattern of Form 1 is as follows: Figure 1 The characteristic peaks include one or more of the peaks shown in Table 1.

[0114] Table 1

[0115]

[0116]

[0117]

[0118] Figure 2 Describe the differential scanning calorimetry (DSC) curve of Form 1. Figure 2 As shown, Form 1 exhibits a characteristic endotherm with an onset of about 237°C and a peak of about 243°C (enthalpy 179.57 J / g).

[0119] Form 1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride shows a thermogravimetric analysis (TGA) curve showing a mass loss of about 0.67 wt.% between about 22° C. and about 160° C. ( Figure 3Form 1 exhibits a dynamic vapor sorption (DVS) curve showing a reversible total mass change of about 0.3 wt.% between about 0% and about 90% relative humidity (RH) at 25°C ( Figure 4 ). No form changes were observed after DVS analysis.

[0120] Form 1 was observed to be an anhydrate and only slightly hygroscopic. Form 1 showed irregular crystalline morphology observed by polarized light microscopy. Form 1 was observed to be chemically and physically stable as a solid at 40°C / 75%RH and 60°C for at least 10 days and at ambient temperature and humidity for at least 12 months.

[0121] Form 1 was also obtained from single solvent slurry experiments in tetrahydrofuran, methyl ethyl ketone, acetone, acetonitrile, ethyl acetate, isopropyl acetate, isobutyl alcohol, isopropyl alcohol, toluene, methyl tert-butyl ether and n-heptane at room temperature for 3 days or at 50°C for 1 day. Form 1 was also obtained by anti-solvent precipitation in MeOH / ethyl acetate (1 / 5 v / v) and MeOH / isopropyl acetate (1 / 5 v / v). Form 1 was also obtained from mixed solvent slurry experiments in MeOH / isopropyl alcohol, MeOH / methyl ethyl ketone, MeOH / methyl tert-butyl ether, MeOH / toluene, MeOH / ethyl acetate, water / acetone and water / THF (all 1 / 9 v / v) at room temperature for 3 days.

[0122] Example 2

[0123] Form 2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride was prepared as follows. N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (280 mg) was added to 2.6 mL of acetone / water (9 / 1) at 50°C. A clear solution was obtained after adding 55.3 μL (1 equivalent) of HCl acid and precipitation occurred within about 1 minute at 50°C. After stirring at 50°C for about 1 hour, the solid was collected by filtration and then characterized after drying under vacuum at 50°C overnight. XRPD analysis indicated that the dried material was crystalline with a pattern consistent with Form 2.

[0124] The XRPD pattern of Form 2 is as follows: Figure 5 The characteristic peaks include one or more of the peaks shown in Table 2.

[0125] Table 2

[0126]

[0127]

[0128] Figure 6 Describe the differential scanning calorimetry (DSC) curve of Form 2. Figure 2 As shown, Form 1 exhibits a characteristic endotherm with an onset of about 226°C and a peak of about 237°C (enthalpy 197.35 J / g).

[0129] Form 2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride shows a thermogravimetric analysis (TGA) curve showing a mass loss of about 0.77 wt.% between about 22°C and about 160°C ( Figure 7 ). Form 2 was observed to be a dehydrate and showed a needle-like crystalline morphology as observed by polarized light microscopy.

[0130] Pure Form 2 was also obtained by dissolving Form 1 in MeOH at room temperature, filtering and allowing the filtrate to evaporate at ambient conditions. A mixture of Form 2 and free base material was obtained from a single solvent slurry in water at room temperature for 3 days. A mixture of Forms 1 and 2 was obtained by anti-solvent precipitation from MeOH / ethyl acetate (1 / 5 v / v) at room temperature.

[0131] In the interconversion study, equal amounts of Form 1 and Form 2 were added to various solvents and stirred at different temperatures for several days. Form 1 was obtained from isopropanol (50°C, 7 days), acetone (50°C, 3 days), acetone / water (9 / 1 v / v, 50°C, 1 day) and acetone / water (9 / 1 v / v, room temperature, 1 day), indicating that Form 1 is a more stable crystalline form.

[0132] Example 3

[0133] Form 3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride was prepared as follows. Form 1 (20.8 mg) of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride was added to a 1.5 mL glass vial, dissolved in MeOH (0.5 mL), and the resulting solution was filtered through a 0.45 μm PTFE membrane. The filtered solution was then added to anisole (4.5 mL) with stirring. The combined solution was evaporated at room temperature for 7 days to form a solid and collected. XRPD analysis indicated that the dried solid material was crystalline with a pattern consistent with Form 3.

[0134] The XRPD pattern of Form 3 is as follows: Figure 8 The characteristic peaks include one or more of the peaks shown in Table 3.

[0135] Table 3

[0136]

[0137]

[0138] Example 4

[0139] Form 5 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride was prepared as follows. Form 1 (21.4 mg) of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride was added to a 3 mL glass vial containing benzyl alcohol (0.5 mL), stirred at 50° C. for 2 hours, and the resulting solution was filtered through a 0.45 μm PTFE membrane. The filtered solution was rapidly cooled to −20° C. and then evaporated at room temperature for 13 days to form a solid. The solid was collected and dried under vacuum at room temperature for 3 days. XRPD analysis indicated that the dried solid material was crystalline with a pattern consistent with Form 5.

[0140] The XRPD pattern of Form 5 is as follows: Fig. 9 The characteristic peaks include one or more of the peaks shown in Table 4.

[0141] Table 4

[0142]

[0143]

[0144] Fig.10 Describe the differential scanning calorimetry (DSC) curve of Form 5. Fig.10 As shown, Form 5 exhibits a characteristic endotherm with an onset of about 141°C and a peak value of about 144°C (enthalpy 140.7 J / g) and a characteristic endotherm with a peak value of about 231°C.

[0145] Form 5 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride shows a thermogravimetric analysis (TGA) curve showing a mass loss of about 23.0 wt.% between about 23° C. and about 150° C. ( Fig.11 ). Form 5 was observed to be a benzyl alcohol solvate (22.4% residual solvent). IC / HPLC test showed Cl - The stoichiometric ratio to the free base was 0.9.

[0146] Example 5

[0147] Form 6 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride was prepared as follows. N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (20.0 mg) was added to isopropanol (0.25 mL) to form a suspension. In a separate vial, a solution was prepared by diluting 0.0282 mL of HCl / EtOAc (4 M) in 0.25 mL of isopropanol. The diluted HCl solution was added dropwise to the suspension under stirring. After the resulting slurry was stirred at room temperature for 13 days, the solid was collected by filtration and air-dried at room temperature for 1 hour. XRPD analysis indicated that the dried solid material was crystalline with a pattern consistent with Form 6.

[0148] The XRPD pattern of Form 6 is as follows: Fig.12 The characteristic peaks include one or more of the peaks shown in Table 5.

[0149] Table 5

[0150]

[0151] Fig.13 Describe the differential scanning calorimetry (DSC) curve of Form 6. Fig.13 As shown, Form 6 exhibits a characteristic endotherm with a peak value of about 96°C, a characteristic endotherm with a peak value of about 166°C, and a characteristic endotherm with a peak value of about 271°C.

[0152] Form 6 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride shows a thermogravimetric analysis (TGA) curve showing a mass loss of about 8.70 wt.% between about 25° C. and about 120° C. ( Fig.14 ). IC / HPLC test showed Cl - The stoichiometric ratio to the free base was 1.6.

[0153] Incorporate by reference

[0154] All publications and patents mentioned herein, including those listed below, are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent was individually and individually incorporated by reference. In the event of a conflict, the present application, including any definitions herein, will control.

[0155] Equivalent

[0156] Although specific embodiments of the subject invention have been discussed, the above description is illustrative rather than restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon reviewing the specification. The full scope of the present disclosure should be determined by reference to the scope of the claims and the full scope of their equivalents and the specification and such variations.

[0157] Unless otherwise indicated, all numerical values ​​expressing amounts of ingredients, reaction conditions, and so forth, used in the specification and claims are to be understood as modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. A crystalline form (Form 1) of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride, characterized in that The powder X-ray diffraction pattern has a characteristic peak at about 9.7 degrees 2θ.

2. The crystalline form of claim 1, wherein the powder X-ray diffraction pattern has characteristic peaks at 2θ degrees of about 9.7, 20.8 and 22.

9.

3. The crystalline form of claim 1 or 2, wherein the powder X-ray diffraction pattern has characteristic peaks at 2θ degrees of about 9.3, 9.7, 19.6, 20.3, 20.8 and 22.

9.

4. The crystalline form of any one of claims 1 to 3, wherein the powder X-ray diffraction pattern has characteristic peaks at 2θ degrees of about 8.3, 9.3, 9.7, 17.6, 19.6, 20.3, 20.8, 21.3 and 22.

9.

5. The crystalline form of any one of claims 1 to 4, wherein the powder X-ray diffraction pattern has characteristic peaks at 2θ degrees of about 8.3, 9.3, 9.7, 13.6, 17.2, 17.6, 19.6, 20.3, 20.8, 21.3, 22.9 and 27.

4.

6. The crystalline form of any one of claims 1 to 5, wherein the powder X-ray diffraction pattern has characteristic peaks at 2θ degrees of about 8.3, 9.3, 9.7, 13.6, 14.8, 15.5, 17.2, 17.6, 19.6, 20.3, 20.8, 21.3, 22.9, 27.4 and 30.

5.

7. The crystalline form of any one of claims 1 to 6, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

8. The crystalline form of any one of claims 1 to 7, wherein the differential scanning calorimetry (DSC) curve has a characteristic endotherm with an onset of about 237°C and a peak of about 243°C.

9. The crystalline form of any one of claims 1 to 8, wherein a thermogravimetric analysis (TGA) curve shows a mass loss of about 0.66 wt.% between about 22°C and about 160°C.

10. A crystalline form (Form 2) of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride, characterized in that The powder X-ray diffraction pattern has a characteristic peak at about 7.7 degrees 2θ.

11. The crystalline form of claim 10, wherein the powder X-ray diffraction pattern has characteristic peaks at about 7.7, 11.5 and 25.9 degrees 2θ.

12. The crystalline form of claim 10 or 11, wherein the powder X-ray diffraction pattern has characteristic peaks at 2θ degrees of about 7.7, 9.9, 11.5, 19.9, 25.9 and 27.

8.

13. The crystalline form of any one of claims 10 to 12, wherein the powder X-ray diffraction pattern has characteristic peaks at 2θ degrees of about 7.7, 9.9, 11.5, 15.2, 15.5, 19.9, 22.2, 25.9 and 27.

8.

14. The crystalline form of any one of claims 10 to 13, wherein the powder X-ray diffraction pattern has characteristic peaks at 2θ degrees of about 7.7, 9.9, 11.5, 15.2, 15.5, 17.6, 19.9, 22.2, 23.4, 25.9, 27.8 and 31.

4.

15. The crystalline form of any one of claims 10 to 14, wherein the powder X-ray diffraction pattern is obtained using Cu Ka radiation.

16. The crystalline form of any one of claims 10 to 15, wherein the differential scanning calorimetry (DSC) curve has a characteristic endotherm with an onset of about 226°C and a peak of about 237°C.

17. The crystalline form of any one of claims 10 to 16, wherein a thermogravimetric analysis (TGA) curve shows a mass loss of about 0.76 wt.% between about 22°C and about 160°C.

18. A crystalline form (Form 3) of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride, characterized in that The powder X-ray diffraction pattern has characteristic peaks at about 5.6, 6.6, 8.9, 10.9, 13.1, 13.8, 16.7, 17.8, 19.7, 23.6, 30.2 and 34.6 degrees 2θ; wherein the powder X-ray diffraction pattern is obtained using Cu Ka radiation.

19. A crystalline form (Form 5) of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride, characterized in that The powder X-ray diffraction pattern has characteristic peaks at about 6.8, 10.5, 1.3, 13.6, 16.7, 17.6, 19.8, 21.0, 23.0, 23.4, 27.0 and 27.4 degrees 2θ; wherein the powder X-ray diffraction pattern is obtained using Cu Ka radiation.

20. The crystalline form of claim 19, wherein the differential scanning calorimetry (DSC) curve has a characteristic endotherm with an onset of about 144°C and a peak value of about 144°C and a characteristic endotherm with a peak value of about 231°C.

21. The crystalline form of claim 19 or 20, wherein a thermogravimetric analysis (TGA) curve shows a mass loss of about 23.0 wt.% between about 23°C and about 150°C.

22. A crystalline form (Form 6) of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride, characterized in that The powder X-ray diffraction pattern has characteristic peaks at about 4.2, 8.2, 8.4, 11.7, 12.7, 6.4, 21.2, 21.7 and 26.7 degrees 2θ; wherein the powder X-ray diffraction pattern is obtained using Cu Ka radiation.

23. The crystalline form of claim 22, wherein the differential scanning calorimetry (DSC) curve has a characteristic endotherm with a peak value of about 96°C, a characteristic endotherm with a peak value of about 166°C, and a characteristic endotherm with a peak value of about 271°C.

24. The crystalline form of claim 22 or 23, wherein a thermogravimetric analysis (TGA) curve shows a mass loss of about 8.70 wt.% between about 25°C and about 120°C.

25. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 24 and a pharmaceutically acceptable excipient.

26. A pharmaceutical composition formed from the crystalline form of any one of claims 1 to 24.

27. The pharmaceutical composition of claim 25 or 26, wherein the composition is formulated for oral administration.

28. A drug substance comprising at least a detectable amount of the crystalline form of any one of claims 1 to 17.

29. A drug substance comprising substantially pure crystals as claimed in any one of claims 1 to 24.

30. A method of inhibiting TYK2 activity in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of any one of claims 1 to 24 or the pharmaceutical composition of any one of claims 25 to 27.

31. A method of treating a TYK2-mediated disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of any one of claims 1 to 24 or the pharmaceutical composition of any one of claims 25 to 27.

32. A method of treating one or more of the following in a patient in need thereof: Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis and systemic sclerosis, the method comprising administering to the patient an effective amount of the crystalline form of any one of claims 1 to 24 or the pharmaceutical composition of any one of claims 25 to 27.

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