Crystalline forms of TYK2 inhibitors and their uses

Abstract

This disclosure is directed, in part, to crystalline free base forms of N-(4-((2-methoxy-3-(1-(methyl-d / 3)-1H,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d / 3)pyridin-2-yl)cyclopropanecarboxamide, pharmaceutical compositions thereof, and methods of use.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 414,665, filed October 10, 2022, and U.S. Provisional Patent Application No. 63 / 417,092, filed October 18, 2022, the contents of each of which are hereby incorporated by reference in their entirety into this specification. [Background technology]

[0002] background TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. TYK2 activation has been associated with diseases and disorders, such as autoimmune disorders, inflammatory disorders, proliferative disorders (e.g., cancer), endocrine disorders, and neurological disorders. For example, TYK2 activation has been 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 the activity of TYK2, particularly those that are selective for JAK2, would be beneficial. Such compounds should produce pharmacological responses that advantageously treat one or more of the conditions described herein without the side effects associated with JAK2 inhibition.

[0003]

[0003] Polymorphism is the ability of a substance to crystallize in more than one crystal lattice structure. Crystallization or polymorphism can affect many aspects of the solid-state properties of a drug substance. Crystalline forms can differ significantly from amorphous forms, and different crystalline polymorphs of a substance can differ significantly from each other in many respects, including solubility, dissolution rate, and / or bioavailability. In general, it is difficult to predict whether a given compound will form crystalline solid-state forms. It is even more difficult to predict the physical properties of these crystalline solid-state forms. Therefore, it can be advantageous for certain formulations and / or manufacturing processes to have a therapeutic agent in a crystalline form. Summary of the Invention [Means for solving the problem]

[0004] overview

[0004] The present disclosure is directed, at least in part, to a 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, free base.

[0005] For example, the compound is characterized by a powder X-ray diffraction pattern having characteristic peaks at a 2θ angle of about 11.0; for example, by a powder X-ray diffraction pattern having characteristic peaks at 2θ angles of about 11.0, 20.8, and 22.2; for example, by a powder X-ray diffraction pattern having characteristic peaks at 2θ angles of about 11.0, 20.8, 21.9, 22.2, 23.6, and 24.8; for example, by a powder X-ray diffraction pattern having characteristic peaks at 2θ angles of about 11.0, 13.0, 16.8, 20.8, 21.9, 22.2, 23.6, 24.8, and 27.3; for example, by a powder X-ray diffraction pattern having characteristic peaks at 2θ angles of about 8.9, 11.0, 13.0, 16.7, 16.8, 19.0, 20.8, 21.9, 22.2, 23.6, 24.8, and 27.3; 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base, characterized by a powder X-ray diffraction pattern having characteristic peaks at 2θ angles of about 8.9, 11.0, 13.0, 16.2, 16.7, 16.8, 18.8, 19.0, 20.8, 21.9, 22.2, 23.6, 24.8, 25.9, and 27.3.

[0006]

[0006] 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 is, for example, a modulator of tyrosine kinase 2 (TYK2), for example, an inhibitor of TYK2, and is represented by the following: [ka]

[0007]

[0007] Further contemplated herein are pharmaceutical compositions, e.g., compositions formulated for oral administration, comprising the disclosed 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, free base, and a pharmaceutically acceptable excipient. Further contemplated herein are drug substances comprising at least a detectable 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base. For example, disclosed herein is a drug substance comprising 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, free base, in substantially pure crystalline form.

[0008]

[0008] Also provided herein is a method for treating a TYK2-mediated disorder in a patient in need thereof, 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base.

[0009]

[0009] For example, provided herein is a method for treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis and systemic sclerosis 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base. [Brief explanation of the drawings]

[0010] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0010] Figure 1 shows 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base (Form 1). [Figure 2]

[0011] 1 shows a differential scanning calorimetry (DSC) profile of Form 1. [Figure 3]

[0012] 1 shows the thermogravimetric analysis (TGA) profile of Form 1. [Figure 4]

[0013] 1 shows the single crystal X-ray structure of Form 1 with a prismatic crystal orientation. [Figure 5]

[0014] 1 shows a diagram of the unit cell structure of a prismatic single crystal orientation of Form 1. DETAILED DESCRIPTION OF THE INVENTION

[0011] Detailed Description

[0015] 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 the specification, examples and appended claims are summarized here. These definitions should be read in light of the remainder of the disclosure as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0012] definition

[0016] The term "crystalline form" refers to a crystalline form or polymorph that can be characterized by analytical methods such as, for example, X-ray powder diffraction (XRPD) and / or differential scanning calorimetry (DSC). The crystalline compounds disclosed herein can exist in solvated and unsolvated forms, such as with solvents such as water, ethanol, etc. Unless otherwise indicated or inferred, the disclosed crystalline compounds are intended to include both solvated and unsolvated forms.

[0013]

[0017] "Treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., eg, alleviating, reducing, modulating, or eliminating.

[0014]

[0018] The term "disorder" refers to, and is used interchangeably with, the terms "disease," "condition," or "illness," unless otherwise indicated.

[0015]

[0019] "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 sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0016]

[0020] As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to any solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0017]

[0021] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0018]

[0022] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most 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 pets (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.), in need of veterinary treatment. The mammal treated in the methods of the present disclosure is preferably one in which treatment of, for example, cancer or a blood disorder is desired. "Modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism, and / or partial agonism.

[0019]

[0023] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a subject compound that will elicit the biological or medical response of a tissue, system, or animal (e.g., a mammal or human) as determined by a researcher, veterinarian, physician, or other clinician. 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 prophylactic effect.

[0020]

[0024] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0021]

[0025] As used herein, the terms "a" and "an" mean one or more, unless otherwise specified. For example, the term "an agent" includes both a single agent and a combination of two or more agents.

[0022]

[0026] When the term "about" is used before a quantitative value, the present disclosure also includes the specific quantitative value itself unless otherwise specified. As used herein, the term "about" refers to a ±10% variation from the nominal value unless otherwise indicated or inferred. The term "about," with respect to a 2θ angle peak, means that the 2θ measurement varies by ±0.2 (expressed in 2θ). Generally, DSC thermograms can have a variation in the range of ±2°C. Therefore, temperature values ​​should be understood to include values ​​in the range of about ±2°C.

[0023]

[0027] Generally, 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base, 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 no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, or no more than about 1% of 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, free base, as measured, for example, by XRPD. cyclopropanecarboxamide, the free base, or 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% of 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 as measured, for example, by XRPD. Thus, the disclosed crystalline form of N-(4-((2-methoxy-3-(l-(methyl-d3)-lH-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base, which is described herein as being substantially free of any other crystalline form, will be understood to contain more than 80% (w / w), more than 90% (w / w), more than 95% (w / w), more than 98% (w / w), or more than 99% (w / w) of said crystalline form of N-(4-((2-methoxy-3-(l-(methyl-d3)-lH-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base.Thus, in some embodiments, the disclosed 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, free base can 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base.

[0024]

[0028] The compounds of the present disclosure may contain one or more isotopic substitutions. For example, the present disclosure also includes compounds containing one or more atoms that have an atomic mass or mass number that differs from that normally found in nature (e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 The present invention encompasses crystalline forms 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, free base, which are identical to those detailed herein, except that the deuterium atoms (C1, C2, C3, C4, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C49, C49, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C51, C52, C53, C54, C55, C56, C57, C58, C69, C70, C71, C72, C73, C74, C75, C76, C77, C78, ​​C79, C81, C82, C83, C84, C95, C96, C97, C98, C9 ... 2H (D or deuterium) can be hydrogen (H). For example, the 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, free base may have six deuterium atoms replaced with hydrogen atoms (e.g., N-(4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base). For example, contemplated herein is a crystalline form of N-(4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, characterized by a powder X-ray diffraction pattern having characteristic peaks at angles 2θ that are substantially identical to the detailed powder X-ray diffraction pattern 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, free base.

[0025] Crystalline morphology

[0029] The present disclosure is directed, 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base. Also disclosed are crystalline hydrates, anhydrates, hemihydrates, solvates, tautomers, and co-crystals of any of the crystalline forms described herein.

[0026]

[0030] 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle 2θ of about 11.0 (herein referred to as "Form 1").

[0027]

[0031] In one embodiment, crystalline Form 1 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, free base, is characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 8.9; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 11.0; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 13.0; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 16.2; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 16.7; characterized by an X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 16.8; characterized by an X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 18.8. characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 19.0; characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 20.8; characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 21.9; characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 22.2; characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 23.6; characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 24.8; characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 25.9; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 27.3. In another embodiment, crystalline Form 1 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at 2-theta angles of about 11.0, 20.8, and 22.2. In a further embodiment, crystalline Form 1 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at 2-theta angles of about 11.0, 20.8, 21.9, 22.2, 23.6, and 24.8.In yet another embodiment, crystalline Form 1 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 11.0, 13.0, 16.8, 20.8, 21.9, 22.2, 23.6, 24.8, and 27.3. In another embodiment, crystalline Form 1 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 8.9, 11.0, 13.0, 16.7, 16.8, 19.0, 20.8, 21.9, 22.2, 23.6, 24.8, and 27.3. In another embodiment, crystalline Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 8.9, 11.0, 13.0, 16.2, 16.7, 16.8, 18.8, 19.0, 20.8, 21.9, 22.2, 23.6, 24.8, 25.9, and 27.3. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 1. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using CuKα radiation.

[0028]

[0032] Contemplated crystalline Form 1 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, free base, can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm (enthalpy 118.2 J / g) with an onset at about 219° C. and a peak at about 221° C. Form 1 can be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 2.

[0029]

[0033] Contemplated crystalline Form 1 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, free base, can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 1.91% by weight between about 24° C. and about 150° C. Form 1 can be characterized, for example, by the thermogravimetric analysis profile shown in FIG. 3. In certain embodiments, contemplated crystalline Form 1 is an anhydrous crystalline form. In certain other embodiments, crystalline Form 1 is an ethyl acetate solvate (3.3%). In further embodiments, crystalline Form 1 exhibits a plate-like morphology. In other embodiments, Form 1 exhibits a prismatic morphology.

[0030]

[0034] Also 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base, characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle 2θ of about 7.8 (herein referred to as "Form 2").

[0031]

[0035] In one embodiment, crystalline Form 2 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, free base, is characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of about 7.8 2θ, a powder X-ray diffraction pattern having a characteristic peak at an angle of about 12.2 2θ, or a powder X-ray diffraction pattern having a characteristic peak at an angle of about 12.7 2θ. characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 13.6; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 14.3; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 15.6; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 16.5; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 17.2; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 18.5 characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 19.4; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 20.1; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 21.4; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 22.0; characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 24.3 characterized by a powder X-ray diffraction pattern having a characteristic peak at an angle of 2θ of about 24.7; characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 25.6; characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 27.5; characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 28.1; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at an angle of 2θ of about 31.5.

[0032]

[0036] In another embodiment, crystalline Form 2 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 7.8, 12.2, 12.7, 24.3, 25.6, and 26.5. In a further embodiment, crystalline Form 2 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 7.8, 12.2, 12.7, 13.6, 14.3, 15.6, 16.5, 17.2, 18.5, 19.4, 20.1, 21.4, 22.0, 24.3, 24.7, 25.6, 26.5, 27.5, 28.1, and 31.5. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using CuKα radiation.

[0033]

[0037] Contemplated crystalline Form 2 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, free base, can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset at about 94°C and a peak at about 109°C (enthalpy 134.9 J / g), a characteristic exotherm with an onset at about 121°C and a peak at about 135°C (enthalpy 74.1 J / g), and a characteristic endotherm with an onset at about 221°C and a peak at about 222°C (enthalpy 126.3 J / g).

[0034]

[0038] In a further embodiment, disclosed herein is a pharmaceutical composition comprising the disclosed 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, free base, and a pharmaceutically acceptable excipient. In another embodiment, a pharmaceutical composition is formed from the disclosed 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, free base, disclosed herein. In some embodiments, the disclosed pharmaceutical compositions can be formulated for oral administration.

[0035]

[0039] In one embodiment, disclosed herein is a drug substance comprising at least a detectable 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base. 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base.

[0036] composition

[0040] Another aspect of the present disclosure provides pharmaceutical compositions comprising the crystalline compounds disclosed herein, formulated together with a pharmaceutically acceptable excipient. In particular, the present disclosure provides pharmaceutical compositions comprising the crystalline compounds disclosed herein, formulated together with one or more pharmaceutically acceptable excipients. These formulations include those suitable for oral, topical (e.g., transdermal), buccal, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable administration form in each case will depend on the extent and severity of the condition being treated and the properties of the particular compound used. For example, the disclosed compositions may be formulated as a unit dose and / or formulated for oral, subcutaneous, or intravenous administration.

[0037]

[0041] Exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations, for example, in solid, semi-solid, or liquid form, containing one or more compounds of the present disclosure as an active ingredient mixed with organic or inorganic excipients or excipients suitable for external, enteral, or parenteral use. The active ingredient may be compounded with conventional non-toxic pharmaceutically acceptable excipients for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0038]

[0042] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with conventional tableting ingredients, such as pharmaceutical excipients, e.g., 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 the compounds of the present disclosure. When these preformulation compositions are referred to as uniform, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0039]

[0043] In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are 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, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) sorbents, such as sorbitol, ... (5) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (6) solution retarders such as paraffin; (7) absorption accelerators such as quaternary ammonium compounds; (8) wetting agents such as acetyl alcohol and glycerol monostearate; (9) absorbents such as kaolin and bentonite clay; (10) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (11) coloring agents. In the case of capsules, tablets, and pills, the compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0040]

[0044] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersants. Molded tablets may be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as sugar-coated tablets, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0041]

[0045] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, nanosuspensions, syrups, and elixirs. In addition to the subject compositions, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0042]

[0046] Suspensions may contain, in addition to the subject composition, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0043]

[0047] Formulations for rectal or vaginal administration may be provided as suppositories, which can be prepared by mixing the subject compositions with one or more suitable non-irritating excipients or excipients including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent(s).

[0044]

[0048] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active substance may be mixed under sterile conditions with a pharmaceutically acceptable excipient and any preservatives, buffers, or propellants which may be required.

[0045]

[0049] Ointments, pastes, creams and gels may contain, in addition to the subject compositions, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0046]

[0050] Powders and sprays can contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can contain, in addition, customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0047]

[0051] Alternatively, the compositions and compounds of the present disclosure may be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. Sonic nebulizers can be used because they minimize exposure of the agent to shear, which can result in degradation of the compound contained in the subject composition. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject composition with conventional pharmaceutically acceptable excipients and stabilizers. Excipients and stabilizers vary depending on the requirements of the particular subject composition, but typically include non-ionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0048]

[0052] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the subject compositions in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders that can be reconstituted just before use into sterile injectable solutions or dispersions which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0049]

[0053] Examples of suitable aqueous and non-aqueous excipients that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (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 coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. For example, the crystalline forms provided herein can be milled to obtain a specific particle size, and in at least some embodiments, such crystalline forms can remain substantially stable upon milling.

[0050]

[0054] The amount of the crystalline compound described herein in the formulation can vary depending on factors such as individual disease state, age, sex and weight.Dosage regimen can be adjusted to provide optimal therapeutic response.For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.It is particularly advantageous to formulate parenteral compositions into dosage unit form for ease of administration and uniformity of dosage.As used herein, dosage unit form refers to a physically discrete unit suitable as a unit of administration for the mammalian subject to be treated; each unit contains a predetermined amount of active crystalline compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0051]

[0055] The specifications for the dosage unit forms of the present disclosure are dictated by and directly dependent upon (a) the unique characteristics of the crystalline compound selected and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the technology of formulating such active crystalline compounds to address sensitivities in individuals.

[0052]

[0056] The disclosed compositions can be formulated as 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, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0053]

[0057] The disclosed crystalline compounds can be administered in sustained-release formulations, for example, compositions containing 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 microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic acid polyglycol copolymers (PLG).Many methods for preparing such formulations are generally known to those skilled in the art.

[0054]

[0058] According to an alternative aspect of the present disclosure, the disclosed crystalline compounds can be formulated with one or more additional compounds that enhance the solubility of the compound.

[0055] method

[0059] The crystalline forms disclosed herein are useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the crystalline forms and methods is TYK2.

[0056]

[0060] 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-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, free base, which is an inhibitor of TYK2 and is therefore useful for treating one or more disorders associated with the activity of TYK2 or a mutant thereof.

[0057]

[0061] Provided herein is a method 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, or a transplant-related disorder, comprising administering to the patient an effective amount of a crystalline form described herein or a pharmaceutical composition comprising an effective amount of the disclosed crystalline form.

[0058]

[0062] In some embodiments, the disease or disorder is an autoimmune disorder, hi some embodiments, the disease or disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0059]

[0063] In some embodiments, the disease or disorder is an inflammatory disorder, hi some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, or inflammatory bowel disease.

[0060]

[0064] 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 hematological cancer. In some embodiments, the proliferative disorder is leukemia. In some embodiments, the leukemia is T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, or essential thrombocythemia.

[0061]

[0065] In some embodiments, the disease or disorder is an endocrine disorder, hi some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0062]

[0066] In some embodiments, the disease or disorder is a neurological disorder, hi some embodiments, the neurological disorder is Alzheimer's disease.

[0063]

[0067] 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, JH2 domain, or kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0064]

[0068] In some embodiments, the disease or disorder is transplant-related. In some embodiments, the transplant-related disease or disorder is transplant rejection or graft-versus-host disease.

[0065]

[0069] 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 disorder is associated with IL-12 signaling. In some embodiments, the disease or disorder is associated with IL-23 signaling.

[0066]

[0070] 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, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0067]

[0071] Methods for treating other diseases or conditions, e.g., diseases or conditions having an inflammatory component, e.g., diseases and conditions of the eye such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis ulcerative colitis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis , diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephrosis), chronic granulomatous disease, endometriosis, kidney disease due to leptospirosis, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hyperchloresterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, rhinosinusitis, ocular allergies, silica-induced disease, COPD (reduced damage, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis,Cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, Provided herein are methods for the treatment of meningitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0068]

[0072] 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), cryopyrin-associated periodic syndromes (CAPS), or osteoarthritis.

[0069]

[0073] In some embodiments, the inflammatory disease is a Th1 or Th17 mediated disease, hi 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).

[0070]

[0074] In some embodiments, the inflammatory disease is Sjogren's syndrome, an allergic disease, osteoarthritis, an eye condition such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, or a disease affecting the nose such as allergic rhinitis.

[0071]

[0075] For example, disclosed herein are methods for inhibiting the TYK2 enzyme in a patient or biological sample, comprising contacting said patient or biological sample with a therapeutically effective amount of a crystalline form described herein or a pharmaceutical composition comprising an effective amount of the disclosed crystalline form.

[0072]

[0076] Also disclosed herein are methods for inhibiting TYK2 activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form described herein or a pharmaceutical composition comprising an effective amount of the disclosed crystalline form. In some embodiments, the inhibition of TYK2 activity is associated with treating a disease or disorder selected from the group consisting of, for example, Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis.

[0073]

[0077] Further disclosed herein is a method for treating a TYK2-mediated disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form described herein or a pharmaceutical composition comprising an effective amount of the disclosed crystalline form. In some embodiments, the TYK2-mediated disorder contemplated may be, for example, an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In other embodiments, the disorder contemplated is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

[0074]

[0078] For example, provided herein are methods for treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need thereof, 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.

[0075]

[0079] In particular, in certain embodiments, the present disclosure provides methods for treating the above medical indications, comprising administering to a patient in need thereof an effective amount of a 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 methods for treating the above medical conditions in a patient in need thereof, comprising orally, subcutaneously, or intravenously administering to the patient a composition comprising a crystalline form described herein or a pharmaceutical composition comprising an effective amount of the disclosed crystalline form.

[0076]

[0080] The crystalline compounds disclosed herein can be used as drugs or pharmaceutically acceptable compositions, for example, in the form of pharmaceutical preparations for oral, enteral, parenteral, or topical administration, and contemplated methods disclosed herein can include oral, enteral, parenteral, or topical administration of the disclosed crystalline compounds or compositions containing or formed from such disclosed crystalline compounds. For example, when administered via a specific route (e.g., oral) or in a specific formulation, the disclosed crystalline forms may be able to control one or more pharmacokinetic properties (e.g., a longer or shorter release profile) compared to a different route (e.g., subcutaneous) or other formulation, e.g., a formulation having an amorphous form. In one embodiment, the disclosed crystalline forms can provide substantial reproducibility between formulations. [Example]

[0077] Example

[0081] The compounds and crystalline forms described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. The following non-limiting examples illustrate the present disclosure.

[0078] Example 1

[0082] Crystalline Form 1 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, free base, was prepared as follows: To a 500 mL reactor was added 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 (10 g), ethyl acetate (300 mL), and water (200 mL). The mixture was stirred and heated to 35° C. To the heated mixture was added KCO (1.1 equivalents) and n-propanol (200 mL). Stirring was stopped and the aqueous phase was separated. The organic phase was concentrated under reduced pressure until the ethyl acetate was removed, resulting in the formation of crystals. The solid was filtered, and the wet cake was washed with n-propanol (50 mL) and water (50 mL) and dried under vacuum at 45° C. XRPD analysis showed that the dried material was crystalline, with a pattern consistent with Form 1.

[0079]

[0083] The XRPD pattern of crystalline Form 1 is shown in Figure 1. Characteristic peaks include one or more of the peaks shown in Table 1.

[0080] [Table 1]

[0081]

[0084] Figure 2 shows the differential scanning calorimetry (DSC) profile of crystalline Form 1. As shown in Figure 2, crystalline Form 1 exhibits a characteristic endotherm (enthalpy 118.2 J / g) with an onset at about 219°C and a peak at about 221°C.

[0082]

[0085] Crystalline Form 1 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, free base, exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 1.91 wt % between about 24 °C and about 150 °C (Figure 3). Form 1 was observed to be chemically and physically stable in solid form at 40 °C / 75% RH and 60 °C for at least 10 days.

[0083]

[0086] Crystalline Form 1 exhibited solubilities of 3.97-4.28 mg / mL in SGF, 0.03-0.05 mg / mL in FeSSIF, low solubility of 0.002-0.0004 mg / mL in water, and 0.001-0.002 mg / mL in FaSSIF. Crystalline Form 1 exhibited high solubility of >43 mg / mL in MeOH / DCM (1 / 1), <17 mg / mL in THF, <3 mg / mL in acetone, <3 mg / mL in MeOH, and <1 mg / mL in acetonitrile, isopropyl alcohol, ethanol, methyl t-butyl ether, ethyl acetate, and heptane.

[0084]

[0087] Single crystals of Form 1 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, free base, were grown and analyzed by single crystal X-ray analysis. Crystalline Form 1 was observed to have both prismatic and plate-like shapes under polarized light microscopy, resulting in additional peaks in the XRPD pattern from different crystal orientations. A comparison of the unit cell dimensions of the plate-like and prismatic single crystals is shown in Table 2.

[0085] [Table 2]

[0086]

[0088] Further details of the crystallographic parameters of the prismatic single crystals of Form 1 are given in Table 3.

[0087] [Table 3]

[0088]

[0089] Figure 4 shows the single crystal X-ray structure of prismatic crystals of Form 1. As shown in Figure 4, the asymmetric unit of the free base I single crystal structure consisted of only one molecule 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, free base, indicating that free base Form I is an anhydrate.

[0089]

[0090] Figure 5 shows a diagram of the unit cell structure of a prismatic single crystal of Form 1. As shown in Figure 5, the unit cell of the Form I single crystal structure contains four molecules 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, free base.

[0090] Example 2

[0091] Crystalline Form 2 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 was prepared as follows: To a cooled solution of Na2CO3 (8.6 g, 1.5 eq) in water (250 ml, 10 vol) was added 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 (25 g) in small portions at 10-15 °C. The mixture was stirred for 5-10 minutes, then warmed to 25-30°C and maintained with stirring for 1 hour (CO gas liberation was observed). The solid was filtered, and the wet cake was washed with water (2 x 20 ml) and dried for 30 minutes. The solid was dried under vacuum at 45-50°C until a constant weight was observed, yielding 20.2 g 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, free base. XRPD analysis showed that the dried material was crystalline and the pattern was consistent with Form 2. Characteristic peaks included one or more of the peaks shown in Table 4.

[0091] [Table 4]

[0092]

[0092] Crystalline form 2 exhibits a characteristic endotherm (enthalpy 134.9 J / g) with an onset at about 94°C and peaking at about 109°C, a characteristic exotherm (enthalpy 74.1 J / g) with an onset at about 121°C and peaking at about 135°C, and a characteristic endotherm (enthalpy 126.3 J / g) with an onset at about 221°C and peaking at about 222°C.

[0093] Incorporation by Reference All publications and patents referred to 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 specifically and individually incorporated by reference. In the case of conflict, the present application, including any definitions herein, will control.

[0094] equivalent Although specific embodiments of the present disclosure have been discussed, the above specification is illustrative and not restrictive. Upon reviewing this specification, many variations of the present disclosure will become apparent to those skilled in the art. The full scope of the present disclosure should be determined by reference to the claims, together with the full scope of their equivalents, and this specification together with such variations.

[0095]

[0095] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, 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 of N-(4-((2-methoxy-3-(1-methyl-d 3 )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d 3 )pyridin-2-yl)cyclopropanecarboxamide, free base (Form 1).

2. 2. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern having characteristic peaks at 2θ angles of about 11.0, 20.8, and 22.

2.

3. 3. The crystalline form of claim 1 or 2, characterized by a powder X-ray diffraction pattern having characteristic peaks at 2θ angles of about 11.0, 20.8, 21.9, 22.2, 23.6, and 24.

8.

4. 4. The crystalline form of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern having characteristic peaks at angles 2θ of about 11.0, 13.0, 16.8, 20.8, 21.9, 22.2, 23.6, 24.8, and 27.

3.

5. 5. The crystalline form of any one of claims 1 to 4, characterized by a powder X-ray diffraction pattern having characteristic peaks at angles 2θ of about 8.9, 11.0, 13.0, 16.7, 16.8, 19.0, 20.8, 21.9, 22.2, 23.6, 24.8 and 27.

3.

6. 6. The crystalline form of any one of claims 1 to 5, characterized by a powder X-ray diffraction pattern having characteristic peaks at angles 2θ of about 8.9, 11.0, 13.0, 16.2, 16.7, 16.8, 18.8, 19.0, 20.8, 21.9, 22.2, 23.6, 24.8, 25.9 and 27.

3.

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

8. 8. The crystalline form of any one of claims 1 to 7, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 219°C and a peak at about 221°C.

9. 9. The crystalline form of any one of claims 1 to 8, characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 1.91 wt% between about 24°C and about 150°C.

10. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 9 and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition formed from the crystalline form of any one of claims 1 to 9.

12. 12. The pharmaceutical composition of claim 10 or 11, wherein the composition is formulated for oral administration.

13. 12. A method for inhibiting TYK2 activity in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the crystalline form of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 or 11.

14. 12. A method for treating a TYK2-mediated disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the crystalline form of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 or 11.

15. 12. A method for treating one or more of the following: Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need thereof, comprising administering to the patient an effective amount of a crystalline form of any one of claims 1 to 9 or a pharmaceutical composition of claim 10 or 11.

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