Crystalline forms of TYK2 inhibitors and uses thereof

Abstract

The present disclosure relates, in part, to crystalline free base 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, pharmaceutical compositions thereof, and methods of use thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 414,665, filed on October 10, 2022, and U.S. Provisional Patent Application No. 63 / 417,092, filed on October 18, 2022; the contents of each of which are incorporated herein by reference in their entirety. Background Art

[0003] 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 conditions 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 TYK2 activity are beneficial, especially those that are selective for JAK2. Such compounds should provide a pharmacological response that advantageously treats one or more of the conditions described herein without the side effects associated with inhibiting JAK2.

[0004] Polymorphism is the ability of a substance to crystallize in more than one lattice arrangement. Crystallization or polymorphism can affect many aspects of the solid-state properties of a drug substance. Crystalline substances can be significantly different from amorphous forms, and different crystalline variants of a substance can differ significantly 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 form. It is even more difficult to predict the physical properties of these crystalline solid-state forms. Therefore, crystalline forms of therapeutic agents can be advantageous for certain formulations and / or for manufacturing processes. Summary of the Invention

[0005] 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 free base.

[0006] 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 free base, characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 11.0 degrees 2θ, for example, the powder X-ray diffraction pattern has characteristic peaks at about 11.0, 20.8, and 22.2 degrees 2θ, for example, the powder X-ray diffraction pattern has characteristic peaks at about 11.0, 20.8, 21.9, 22.2, 23.6, and 24.8 degrees 2θ, for example, the powder X-ray diffraction pattern has characteristic peaks at about 11.0, 20.8, 21.9, 22.2, 23.6, and 24.8 degrees 2θ, for example, the powder X-ray diffraction pattern has characteristic peaks at about 11.0, 20.8, 21.9, 22.2, 23.6, and 24.8 degrees 2θ. The powder X-ray diffraction pattern has characteristic peaks at 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, and 27.3 degrees 2θ, for example, it is characterized in that the powder X-ray diffraction pattern has characteristic peaks at 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 degrees 2θ.

[0007] For example, 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 a modulator of tyrosine kinase 2 (TYK2), such as an inhibitor of TYK2, and is represented by:

[0008]

[0009] Further contemplated 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-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide free base and a pharmaceutically acceptable excipient, such as a composition formulated for oral administration. Further contemplated 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-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide free base. 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 free base.

[0010] Also provided herein is a method of 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-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide free base.

[0011] For example, provided herein is a method of 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 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 free base. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] 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 free base (Form 1).

[0013] Figure 2 The differential scanning calorimetry (DSC) curve of Form 1 is depicted.

[0014] Figure 3 Thermogravimetric analysis (TGA) curve of Form 1 is depicted.

[0015] Figure 4 The single crystal X-ray structure of Form 1 with prismatic crystal orientation is depicted.

[0016] Figure 5 A diagram depicting the unit cell structure of Form 1 prismatic single crystal orientation. Detailed Description of the Invention

[0018] The features and other details of the present disclosure will now be described more specifically. Before further describing the present disclosure, certain terms used in this specification, examples, and appended claims are summarized here. These definitions should be read in light of the remainder of this 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 skilled in the art.

[0019] definition

[0020] The term "crystalline form" refers to a crystalline 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 can exist in solvated and unsolvated forms 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.

[0021] "Treatment" includes any effect that results in improvement of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, or elimination.

[0022] Unless otherwise indicated, the term "disorder" refers to and is used interchangeably with the terms "disease," "condition," or "illness."

[0023] "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 administration to humans, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by the FDA Office of Biologics standards.

[0024] As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, isotonic agents, absorption delaying agents, and the like that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic function.

[0025] 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.

[0026] "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 most preferably humans. The compounds of the present disclosure can be administered to mammals, such as humans, but 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.), can also be administered. The mammals treated with the methods of the present disclosure are ideally mammals in need of treatment for, for example, cancer or a blood disorder. "Modulate" includes antagonism (e.g., inhibition), agonism, partial antagonism, and / or partial agonism.

[0027] In this specification, the term "effective amount" or "therapeutically effective amount" refers to the amount of the subject compound that will elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or human) that a researcher, veterinarian, medical doctor, or other clinician is seeking. 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.

[0028] The term "and / or" as used in this disclosure means "and" or "or" unless indicated otherwise.

[0029] Unless otherwise specified, the terms "a" and "an" as used herein are intended to include one or more. For example, the term "an agent" encompasses a single agent and a combination of two or more agents.

[0030] When the term "about" is used before a quantitative value, unless otherwise specifically stated, the present disclosure also includes the specific quantitative value itself. Unless otherwise indicated or inferred, as used herein, the term "about" refers to a variation of ±10% relative to the nominal value. In the context of a peak value in 2θ degrees, the term "about" means that there is an uncertainty of ±0.2 (expressed in 2θ) in the measurement of 2θ. In general, DSC thermograms can have a variation within the range of ±2°C. Therefore, temperature values ​​should be understood to include values ​​within the range of approximately ±2°C.

[0031] 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 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 about 20% or less, about 10% or less, about 5% or less, about 2% or less, or about 1% or less of any 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 free base. other crystalline forms, e.g., as measured by XRPD; 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-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, e.g., as measured by XRPD. Thus, 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 free base described herein as being substantially free of any other crystalline forms will 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 the 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 free base. 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 free base 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 free base.

[0032] The compounds of the present disclosure may comprise one or more isotopic substitutions. For example, the present invention also encompasses 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 free base that is identical to the crystalline form described herein except that one or more atoms have a different atomic mass or mass number than that typically 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 Cl) is replaced by an atom having an atomic mass or mass number typically found in nature (e.g., hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively). For example, one or more deuterium atoms in 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 free base compound may be replaced by hydrogen, e.g. 2 H (D or deuterium) can be hydrogen (H). For example, six deuterium atoms in 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 free base can be replaced by hydrogen (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, N-(4-( A crystalline form of (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 expressed in degrees 2θ that are essentially identical to the listed powder X-ray diffraction 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 free base.

[0033] Crystalline form

[0034] 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 free base. Also disclosed are crystalline hydrates, anhydrates, hemihydrates, solvates, tautomers, and co-crystals of any of the crystalline forms described herein.

[0035] 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 free base characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 11.0 degrees 2θ (referred to herein as "Form 1").

[0036] In one embodiment, the 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 free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 8.9 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at about 11.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at about 13.0 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at about 16.2 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at about 16.7 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at about 16.8 degrees 2θ. The powder X-ray diffraction pattern has a characteristic peak at about 18.8 degrees 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 19.0 degrees 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 20.8 degrees 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 21.9 degrees 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 22.2 degrees 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 23.6 degrees 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 24.8 degrees 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 25.9 degrees 2θ, and / or the powder X-ray diffraction pattern has a characteristic peak at about 27.3 degrees 2θ. In another embodiment, crystalline Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 11.0, 20.8, and 22.2 degrees 2θ. In another embodiment, crystalline Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 11.0, 20.8, 21.9, 22.2, 23.6, and 24.8 degrees 2θ. In yet another embodiment, crystalline Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 11.0, 13.0, 16.8, 20.8, 21.9, 22.2, 23.6, 24.8, and 27.3 degrees 2θ. In another embodiment, crystalline Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at approximately 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 degrees 2Θ.In another embodiment, the crystalline Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 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 degrees 2θ. For example, the contemplated crystalline forms have. Figure 1 In one embodiment, the powder X-ray diffraction pattern of the crystalline form is obtained using Cu Ka radiation.

[0037] 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 free base is characterized by a differential scanning calorimetry (DSC) curve exhibiting a characteristic endotherm with an onset of about 219° C. and a peak at about 221° C. (enthalpy 118.2 J / g). For example, Form 1 is characterized by Figure 2 The differential scanning calorimetry curves are shown in .

[0038] 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 free base is characterized by a thermogravimetric analysis (TGA) curve showing a mass loss of about 1.91 wt % between about 24° C. and about 150° C. For example, Form 1 is characterized by Figure 3 Thermogravimetric analysis curves are shown in FIG. In certain embodiments, the crystalline Form 1 encompassed is an anhydrous crystalline form. In certain other embodiments, the crystalline Form 1 is an ethyl acetate solvate (3.3%). In yet other embodiments, the crystalline Form 1 exhibits a plate-like morphology. In other embodiments, the crystalline Form 1 exhibits a prismatic morphology.

[0039] 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-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide free base characterized by a powder X-ray diffraction pattern having a characteristic peak at approximately 7.8 degrees 2θ (referred to herein as "Form 2").

[0040] In one embodiment, the 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 free base is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 7.8 degrees 2θ, a powder X-ray diffraction pattern having a characteristic peak at about 12.2 degrees 2θ, and a powder X-ray diffraction pattern having a characteristic peak at about 12.2 degrees 2θ. The powder X-ray diffraction pattern has a characteristic peak at about 12.7 degrees at 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 13.6 degrees at 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 14.3 degrees at 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 15.6 degrees at 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 16.5 degrees at 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 17.2 degrees at 2θ. The powder X-ray diffraction pattern has a characteristic peak at about 18.5 degrees in 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 19.4 degrees in 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 20.1 degrees in 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 21.4 degrees in 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 22.0 degrees in 2θ, the powder X-ray diffraction pattern has a characteristic peak at about 2 The powder X-ray diffraction pattern has a characteristic peak at about 2θ of about 24.3 degrees, is characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 24.7 degrees 2θ, is characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 25.6 degrees 2θ, is characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 27.5 degrees 2θ, is characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 28.1 degrees 2θ, and / or is characterized in that the powder X-ray diffraction pattern has a characteristic peak at about 31.5 degrees 2θ.

[0041] In another embodiment, the crystalline Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 7.8, 12.2, 12.7, 24.3, 25.6, and 26.5 degrees 2θ. In another embodiment, the crystalline Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 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 degrees 2θ. In one embodiment, the powder X-ray diffraction pattern of the crystalline form is obtained using Cu Ka radiation.

[0042] 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 free base is characterized by a differential scanning calorimetry (DSC) curve 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).

[0043] 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 free base 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 free base. In some embodiments, the disclosed pharmaceutical composition may be a formulation for oral administration.

[0044] In an 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 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-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide free base.

[0045] Composition

[0046] Another aspect of the present disclosure provides a pharmaceutical composition comprising a crystalline compound as disclosed herein formulated with a pharmaceutically acceptable excipient. In particular, the present disclosure provides a pharmaceutical composition comprising a crystalline compound as disclosed herein formulated with one or more pharmaceutically acceptable excipients. These preparations include those suitable for oral, topical (e.g., transdermal), buccal, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous), rectal, vaginal or aerosol administration, but the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and the properties of the specific compound used. For example, the disclosed composition can be formulated into a unit dosage form, and / or can be formulated for oral, subcutaneous or intravenous administration.

[0047] The exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations, for example, in solid, semisolid or liquid forms, containing one or more compounds of the present disclosure as active ingredients mixed with one or more organic or inorganic excipients suitable for external, enteral or parenteral application. The active ingredients can be mixed with, for example, conventional non-toxic pharmaceutically acceptable excipients to form tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other suitable forms for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0048] To prepare solid compositions such as tablets, the main active ingredient can be mixed with pharmaceutical excipients (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 homogeneous mixture of the compound of the present disclosure. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0049] In solid dosage forms for oral administration (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 carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (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 retarding agents. agents), such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as 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. For capsules, tablets, and pills, the composition may also contain a buffering agent. 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 galactose and high molecular weight polyethylene glycols.

[0050] Tablet can be made by optionally compressing or molding together with one or more auxiliary components.Binding agent (for example gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (for example sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfactant or dispersant can be used to prepare compressed tablets.Molded tablets can be made by molding the mixture of the subject composition moistened with an inert liquid diluent in a suitable machine.Tablet and other solid dosage forms, for example dragee, capsule, pill and granule, can optionally be scored or prepared with coating and shell, for example enteric coating and other pharmaceutical preparation fields known coating.

[0051] 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 composition, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0052] Suspensions, in addition to the subject composition, 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.

[0053] Formulations for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing the subject composition with one or more suitable non-irritating excipients or excipients including, for example, cocoa butter, polyethylene glycol, suppository waxes or salicylates, 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.

[0054] Dosage forms for transdermal administration of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable excipient and any preservatives, buffers or propellants that may be required.

[0055] Ointments, pastes, creams and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0056] Powders and sprays may contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may also contain customary propellants, for example chlorofluorocarbons and volatile unsubstituted hydrocarbons, for example butane and propane.

[0057] The compositions and compounds of the present disclosure can be applied alternatively by aerosol. This can be achieved by preparing aqueous aerosols, liposome preparations or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellants) suspensions can be used. Sonic wave atomizers can be used because they can minimize the effect of shear forces on the medicament, which may cause degradation of the compound contained in the subject composition. Typically, aqueous aerosols are formulated with an aqueous solution or suspension of the subject composition together with conventional pharmaceutically acceptable excipients and stabilizers. Excipients and stabilizers vary according to the requirements of the specific subject composition, but typically include nonionic surfactants (Tween, Pluronic or Polyethylene Glycol), harmless proteins (e.g., serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (e.g., glycine), buffers, salts, sugars or sugar alcohols. Aerosols are typically prepared by isotonic solutions.

[0058] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the subject compositions 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 before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0059] The example of suitable aqueous and non-aqueous excipients that can be used for the pharmaceutical composition of the present disclosure includes water, ethanol, polyol (such as glycerol, propylene glycol, polyethylene glycol etc.) and suitable mixture thereof, vegetable oil (such as olive oil) and injectable organic ester (such as ethyl oleate and cyclodextrin). Suitable mobility can be by, for example, using coating material (such as lecithin), maintaining required particle size and using surfactant to keep in the case of dispersion. For example, crystalline form provided herein can be ground to obtain specific particle size, and in at least some embodiments, such crystalline form can keep substantially stable after grinding.

[0060] The amount of the crystalline compound described herein in the formulation may vary depending on factors such as the individual's disease state, age, sex, and weight. The dosage regimen may be adjusted to achieve the optimal therapeutic effect. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the parenteral composition in unit dosage form. As used herein, unit dosage form refers to a physically discrete unit suitable as a unit dosage 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 combination with the desired pharmaceutical carrier.

[0061] The specifications for the dosage unit forms of the present disclosure are dictated by and directly dependent on (a) the unique characteristics of the selected crystalline compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of formulating such active crystalline compounds for the treatment of individual sensitivity.

[0062] The disclosed compositions can be formulated into solutions, microemulsions, liposomes or other ordered structures suitable for high drug concentrations. 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 suitable mixtures thereof. Suitable fluidity can be maintained by, for example, using a coating (such as lecithin), maintaining the required particle size in the case of a dispersion, and using a surfactant. 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. By including an agent (such as monostearate and gelatin) that delays absorption in the composition, the absorption of the injectable composition can be prolonged.

[0063] The disclosed crystalline compound can be administered in the form of a time release formulation, for example, in a composition comprising a slow-release polymer. The crystalline compound can be prepared together with a carrier that protects the compound from rapid release, such as a controlled release formulation, including implants and microcapsule delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic-polyglycolic acid copolymers (PLG) can be used. A variety of methods for preparing such preparations are generally known to those skilled in the art.

[0064] According to alternative aspects of the present disclosure, the disclosed crystalline compounds can be formulated with one or more additional compounds that enhance the solubility of the compound.

[0065] method

[0066] 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.

[0067] 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 free base, which are TYK2 inhibitors and are therefore useful in treating one or more disorders related to the activity of TYK2 or a mutant thereof.

[0068] 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, or a transplantation-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 a disclosed crystalline form.

[0069] In some embodiments, the disease or disorder is an autoimmune disorder. In some embodiments, the disease or disorder 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.

[0070] 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.

[0071] In some embodiments, the disease or condition is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the disease or condition 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, primary myelofibrosis, or thrombocythemia.

[0072] 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.

[0073] In some embodiments, the disease or disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[0074] 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.

[0075] In some embodiments, the disease or disorder is associated with transplantation. In some embodiments, the disease or disorder is transplant rejection or graft-versus-host disease.

[0076] In some embodiments, the disease or condition is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disease or condition is associated with type I interferon signaling. In some embodiments, the disease or condition is associated with IL-10 signaling. In some embodiments, the condition is associated with IL-12 signaling. In some embodiments, the disease or condition is associated with IL-23 signaling.

[0077] 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, acquired epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0078] Provided herein is a method for treating other diseases or conditions, such as those with an inflammatory component, for example, treating 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 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, Stevens-Johnson syndrome, and inflammatory diseases of the eye. syndrome), idiopathic sprue, autoimmune inflammatory bowel disease (such as 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 eye disease, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, anterior and posterior uveitis, Sjögren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryptopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome),Examples include idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis, kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscle atrophy, metabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease 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, hypersensitivities, allergies, sinusitis, eye allergies, silica-induced disease, COPD (damage reduction, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease exacerbation), 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 mellitus, 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-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, intermittent Laryngitis, mastitis, meningitis, myelitis, myocarditis, myelitis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, localized pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0079] 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 Syndrome (CAPS), or osteoarthritis.

[0080] 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).

[0081] In some embodiments, the inflammatory disease is Sjogren's syndrome, an allergic disorder, osteoarthritis, an ocular condition (such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis), or a disease affecting the nose (such as allergic rhinitis).

[0082] For example, disclosed herein is a method of inhibiting the TYK2 enzyme in a patient or biological sample, 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.

[0083] Also disclosed herein is a method of 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 a disclosed crystalline form. In some embodiments, inhibiting TYK2 activity is associated with treating a disease or condition selected from the group consisting of: for example, Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis.

[0084] Further disclosed herein is a method of treating a TYK2-mediated disorder in a patient in need thereof, wherein the method comprises 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, or a transplant-related disorder. In other embodiments, the contemplated disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

[0085] For example, provided herein is a method of 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 a crystalline form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline form.

[0086] In particular, in certain embodiments, the present disclosure provides a method of 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 a disclosed crystalline form. In certain other embodiments, the present disclosure provides a method of 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 a disclosed crystalline form.

[0087] 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 methods encompassed herein can include oral, enteral, parenteral or topical administration of the disclosed crystalline compounds or compositions comprising or formed from such disclosed crystalline compounds. For example, the disclosed crystalline forms, when administered by a certain route (e.g., oral) or in a certain formulation, can 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 with an amorphous form). In one embodiment, the disclosed crystalline forms can provide substantial reproducibility from one formulation to another. Example

[0088] 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.

[0089] Example 1

[0090] 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 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-(propionyl-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 K2CO3 (1.1 equiv) 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, thereby forming crystals. The solid was filtered off, and the wet cake was washed with n-propanol (50 mL) and water (50 mL) and dried under vacuum at 45° C. XRPD analysis indicated that the dried material was crystalline, and its pattern was consistent with Form 1.

[0091] The XRPD pattern of crystalline form 1 is shown in Figure 1 The characteristic peaks include one or more peaks shown in Table 1.

[0092] Table 1

[0093]

[0094]

[0095]

[0096] Figure 2 Depicted is the differential scanning calorimetry (DSC) curve of crystalline Form 1. Figure 2 As shown in , crystalline Form 1 exhibits a characteristic endotherm with an onset of about 219° C. and a peak at about 221° C. (enthalpy 118.2 J / g).

[0097] The 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 free base exhibits a thermogravimetric analysis (TGA) curve showing a mass loss of about 1.91 wt % between about 24° C. and about 150° C. ( Figure 3 ). The solid form of Form 1 was observed to remain chemically and physically stable at 40°C / 75% RH and 60°C for at least 10 days.

[0098] Crystalline Form 1 exhibits a solubility of 3.97-4.28 mg / mL in SGF, a solubility of 0.03-0.05 mg / mL in FeSSIF, a low solubility of 0.002-0.0004 mg / mL in water, and a solubility of 0.001-0.002 mg / mL in FaSSIF. Crystalline Form 1 exhibits a high solubility of >43 mg / mL in MeOH / DCM (1 / 1), a solubility of <17 mg / mL in THF, a solubility of <3 mg / mL in acetone, a solubility of <3 mg / mL in MeOH, and a solubility of <1 mg / mL in acetonitrile, isopropanol, ethanol, methyl tert-butyl ether, ethyl acetate, and heptane.

[0099] Single crystals of 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 free base were grown and analyzed by single crystal X-ray analysis. Crystalline Form 1 was observed to have both prismatic and plate-like morphologies under polarized light microscopy, resulting in additional peaks in the XRPD pattern arising from different crystal orientations. A comparison of the unit cell dimensions of the plate-like and prismatic single crystals is shown in Table 2.

[0100] Table 2

[0101]

[0102]

[0103] Further details of the crystallization parameters of Form 1 prismatic single crystals are shown in Table 3.

[0104] Table 3

[0105]

[0106] Figure 4 The single crystal X-ray structure of prismatic crystals of Form 1 is shown. Figure 4 As shown in , the asymmetric unit of the free base I single crystal structure consists of only one 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 free base molecule, which indicates that the free base form I is an anhydrate.

[0107] Figure 5 The unit cell structure diagram of the prismatic single crystal of Form 1 is shown in FIG. Figure 5As shown in , 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-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide free base.

[0108] Example 2

[0109] 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 free base 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-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (25 g) portionwise at 10 to 15°C. The mixture was stirred for 5 to 10 min, then warmed to 25 to 30°C and maintained under stirring for 1 h (CO2 gas evolution was observed). The solid was filtered off, and the wet cake was washed with water (2 x 20 ml) and dried for 30 min. The solid was dried under vacuum at 45°C to 50°C until 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-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide free base. XRPD analysis indicated that the dried material was crystalline with a pattern consistent with Form 2. Characteristic peaks include one or more of the peaks shown in Table 4.

[0110] Table 4

[0111]

[0112]

[0113] Crystalline Form 2 exhibits 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).

[0114] Incorporated by Reference

[0115] 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 specifically and individually indicated to be incorporated by reference. In the event of a conflict, the present application, including any definitions herein, will control.

[0116] Equivalent

[0117] While specific embodiments of the present disclosure have been discussed, the foregoing description is illustrative and not limiting. Numerous variations of the present disclosure will become apparent to those skilled in the art upon reading this description. The full scope of the present disclosure should be determined by reference to the full scope of the claims and their equivalents, as well as the description and variations thereof.

[0118] 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 attached claims are approximations that may vary depending upon the desired properties to be obtained by the present disclosure.

[0119] What is sought to be protected is:

Claims

1. 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 free base (Form 1), characterized in that The powder X-ray diffraction pattern has a characteristic peak at about 11.0 degrees 2θ.

2. The crystalline form according to claim 1, characterized in that The powder X-ray diffraction pattern has characteristic peaks at approximately 11.0, 20.8 and 22.2 degrees 2θ.

3. The crystalline form according to claim 1 or 2, characterized in that The powder X-ray diffraction pattern has characteristic peaks at approximately 11.0, 20.8, 21.9, 22.2, 23.6, and 24.8 degrees 2θ.

4. The crystalline form according to any one of claims 1 to 3, characterized in that The powder X-ray diffraction pattern has characteristic peaks at approximately 11.0, 13.0, 16.8, 20.8, 21.9, 22.2, 23.6, 24.8, and 27.3 degrees 2θ.

5. The crystalline form according to any one of claims 1 to 4, characterized in that The powder X-ray diffraction pattern has characteristic peaks at approximately 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 degrees 2θ.

6. The crystalline form according to any one of claims 1 to 5, characterized in that The powder X-ray diffraction pattern has characteristic peaks at approximately 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 degrees 2θ.

7. The crystalline form according to any one of claims 1 to 6, characterized in that The powder X-ray diffraction pattern was obtained using Cu Kα radiation.

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

9. The crystalline form according to any one of claims 1 to 8, characterized in that Thermogravimetric analysis (TGA) curves showed a mass loss of about 1.91 wt % between about 24°C and about 150°C.

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

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

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

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

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

15. A method of 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 a crystalline form according to any one of claims 1 to 9, or a pharmaceutical composition according to claim 10 or 11.

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