Crystal Forms of TYK2 Inhibitors and Their Use

Abstract

The present disclosure is directed in part to crystalline forms 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 hydrochloride and pharmaceutical compositions thereof.

Description

Technical Field

[0001] Cross - Reference to Related Applications

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 341,528, filed May 13, 2022; and U.S. Provisional Patent Application No. 63 / 405,577, filed Sep. 12, 2022, each of which is incorporated herein by reference in its entirety.

Background Art

[0002]

[0002] TYK2 is a non - receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. TYK2 activation has been implicated in 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 implicated in 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. Thus, compounds that inhibit TYK2 activity, particularly compounds that are selective for JAK2, are beneficial. Such compounds should provide a pharmacological response that advantageously treats one or more of the conditions described herein without causing side effects associated with JAK2 inhibition.

[0003]

[0003] Polymorphism is the ability of a substance to crystallize in more than one crystal lattice arrangement. Crystallization, or polymorphism, can affect many aspects of the solid physical properties of the drug substance. Crystalline substances can be significantly different from the amorphous form, and different crystal modification forms of a substance can be significantly different from each other in many respects, including solubility, dissolution rate, and / or bioavailability. Generally, it is difficult to predict whether a given compound will form any crystalline solid form. It is even more difficult to predict the physical properties of these crystalline solid forms. Therefore, having a crystalline form of a therapeutic agent can be advantageous for a particular formulation and / or for the manufacturing process.

Summary of the Invention

Problems to be Solved by the Invention

[0004]

[0004] The present disclosure is at least partially directed to the crystalline forms 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 hydrochloride.

Means for Solving the Problems

[0005]

[0005] For example, 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)The crystalline forms of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride are disclosed herein, which are characterized by a powder X-ray diffraction pattern having a characteristic peak at about 2θ = 9.7 degrees, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 9.7, 20.8, and 22.9 degrees, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 9.3, 9.7, 19.6, 20.3, 20.8, and 22.9 degrees, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 8.3, 9.3, 9.7, 13.6, 17.2, 17.6, 19.6, 20.3, 20.8, 21.3, 22.9, and 27.4 degrees.

[0006]

[0006] 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 is, for example, a modulator of tyrosine kinase 2 (TYK2), for example, an inhibitor of TYK2,

[0007]

Chemical formula

[0008] is represented by.

[0007] 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 hydrochloride and a pharmaceutical composition comprising a pharmaceutically acceptable excipient, for example, a composition formulated for oral administration are further contemplated herein. A composition comprising at least a detectable amount 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 hydrochloride is further contemplated herein. For example, 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 hydrochloride in substantially pure crystalline form is disclosed herein.

[0009]

[0008] A method of treating a TYK2-mediated disorder in a patient in need thereof, comprising administering to the patient an effective amount 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 hydrochloride in the disclosed crystalline form is also provided herein.

[0010]

[0009] For example, 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 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 hydrochloride in the disclosed crystalline form is provided herein.

Brief Description of the Drawings

[0011]

Figure 1

[0010] The powder X-ray 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 hydrochloride (Form 1) is shown.

Figure 2

[0011] The differential scanning calorimetry (DSC) profile of Form 1 is shown.

Figure 3

[0012] The thermogravimetric analysis (TGA) profile of Form 1 is shown.

Figure 4

[0013] The dynamic vapor sorption (DVS) profile of Form 1 is shown.

Figure 5

[0014] The powder X-ray 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 hydrochloride (Form 2) is shown.

Figure 6

[0015] The differential scanning calorimetry (DSC) profile of Form 2 is shown.

Figure 7

[0016] The thermogravimetric analysis (TGA) profile of Form 2 is shown.

Figure 8

[0017] The powder X-ray 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 hydrochloride (Form 3) is shown.

Figure 9

[0018] The powder X-ray 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 hydrochloride (Form 5) is shown.

Figure 10

[0019] Represents the differential scanning calorimetry (DSC) profile of Form 5.

Figure 11

[0020] Represents the thermogravimetric analysis (TGA) profile of Form 5.

Figure 12

[0021] Represents the powder X-ray 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 hydrochloride (Form 6).

Figure 13

[0022] Represents the differential scanning calorimetry (DSC) profile of Form 6.

Figure 14

[0023] Represents the thermogravimetric analysis (TGA) profile of Form 6.

Mode for Carrying Out the Invention

[0012]

[0024] The features and other details of the present disclosure are described more specifically here. Before further description of the present disclosure, certain terms used in the specification, examples, and appended claims are collected here. These definitions should be read in view of the remainder of the present disclosure and as understood by those of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Definitions

[0025] The term "crystalline form" refers to a crystalline or modified form that can be characterized by analytical methods, such as powder X-ray diffraction (XRPD) and / or differential scanning calorimetry (DSC). The crystalline compounds disclosed herein can exist in solvated forms as well as non-solvated forms with solvents, such as water, ethanol, etc. Unless otherwise indicated or inferred, the disclosed crystalline compounds are intended to include both solvated and non-solvated forms.

[0013]

[0026] "To treat" includes any action, for example, actions such as reducing, decreasing, modulating, or eliminating, which result in the improvement of a condition, disease, disorder, etc.

[0014]

[0027] Unless otherwise indicated, the term "disorder" refers to and is used interchangeably with the terms "disease", "condition", or "illness".

[0028] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or human as appropriate. For human administration, the preparation should meet sterility, pyrogenicity, and general safety and purity standards as required by the FDA Office of Biologics.

[0015]

[0029] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier", as used herein, refers to any and all solvents, dispersion media, coatings, isotonic agents, absorption delaying agents, etc. that are compatible with the administration of a pharmaceutical. The use of such media and agents for a pharmaceutical active substance is well known in the art. The composition can also contain other active compounds that provide auxiliary, additional, or enhanced therapeutic functions.

[0016]

[0030] The term "pharmaceutical composition", as used herein, refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0017]

[0031] 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, and most preferably humans. The compounds of the present disclosure can be administered to mammals, for example, humans, but can also be administered to other mammals, such as animals in need of veterinary treatment, such as domestic animals (e.g., dogs, cats, etc.), breeding animals (e.g., female cows, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammals treated by the methods of the present disclosure are preferably mammals in which treatment, for example, treatment of cancer or blood disorders, is desired. "Modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0018]

[0032] In the specification of the present invention, the terms "effective amount" or "therapeutically effective amount" mean the amount of the subject compound that induces a biological or medical response in a tissue, system or animal (e.g., a mammal or a human), which amount is explored by a researcher, veterinarian, medical doctor 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.

[0019]

[0033] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of basic groups that may be present in the compounds used in the compositions. The compounds contained in the compositions of the present invention having basic properties are capable of forming a wide variety of salts with various inorganic acids and organic acids.

[0020]

[0034] The term "and / or" as used in the present disclosure means either "and" or "or" unless otherwise indicated.

[0035] As used herein, the words "a" and "an" are intended to include one or more, unless specifically stated otherwise. For example, the term "an agent" includes a single agent as well as combinations of two or more agents.

[0021]

[0036] When the term "about" is used before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a variation of ±10% from the nominal value, unless otherwise indicated or inferred. The term "about" means that there is an uncertainty of ±0.2 (expressed in 2θ) in the measurement of 2θ in the context of a 2θ degree peak. Generally, DSC thermograms can have a variation in the range of ±2 °C. Thus, temperature values are understood to include values in the range of about ±2 °C.

[0022]

[0037] Generally, unless otherwise indicated, crystal forms substantially free of any other crystal forms are provided herein for 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 hydrochloride. As used herein, "substantially free of" or "substantially free of any other crystal forms" means that the disclosed crystal form, when measured, for example by XRPD, is about 20% or less, about 10% or less, about 5% or less, about 2% or less, or about 1% or less of N-(4-((2-methoxy-3-(1-(methyl-d 3 )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d 3)Any other crystalline form of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride, 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 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 )means containing any other crystalline form of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride. Thus, substantially free of any other crystalline form, 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 )The disclosed crystalline form of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride is considered 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 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 )the said crystalline form of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride. Thus, in some embodiments, 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 )The disclosed crystalline form of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride is 1% - 20% (w / w), 5% - 20% (w / w), or 5% - 10% (w / w) 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) may contain one or more other crystalline forms of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride. Crystalline form

[0038] This disclosure is at least partially directed to 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 hydrochloride in crystalline form. Also disclosed are crystalline hydrates, anhydrates, hemihydrates, solvates, tautomers, and cocrystals of any of the crystalline forms described herein.

[0023]

[0039] For example, 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 hydrochloride, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 2θ = 9.7 degrees (referred to herein as "Form 1"), is disclosed herein.

[0024]

[0040] In one embodiment, 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)The crystalline form 1 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 8.3 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 9.3 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 9.7 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 13.6 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 14.8 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 15.5 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 17.2 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 17.6 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 19.6 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 20.3 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 20.8 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 21.3 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 22.9 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 27.4 degrees, and / or characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 30.5 degrees. 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 2θ = 9.7, 20.8, and 22.9 degrees. In a further embodiment, the crystalline form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 2θ = 9.3, 9.7, 19.6, 20.3, 20.8, and 22.9 degrees.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 8.3, 9.3, 9.7, 17.6, 19.6, 20.3, 20.8, 21.3, and 22.9 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 8.3, 9.3, 9.7, 13.6, 17.2, 17.6, 19.6, 20.3, 20.8, 21.3, 22.9, and 27.4 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 8.3, 9.3, 9.7, 13.6, 14.8, 15.5, 17.2, 17.6, 19.6, 20.3, 20.8, 21.3, 22.9, 27.4, and 30.5 degrees 2θ. For example, the contemplated crystalline form has the powder X-ray diffraction pattern shown in FIG. 1. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0025]

[0041] 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 hydrochloride, the contemplated crystalline Form 1, can be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm (enthalpy 179.57 J / g) starting at about 237° C. and having a peak at about 243° C. Form 1 can be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 2.

[0026]

[0042] 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)The assumed crystalline Form 1 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.67% by weight between about 22 °C and about 160 °C. Form 1 can be characterized, for example, by the thermogravimetric analysis profile shown in Figure 3. In some embodiments, crystalline Form 1 can also be characterized as having an irregular crystal form when observed by polarized light microscopy.

[0027]

[0043] In some embodiments, crystalline Form 1 can be characterized by a dynamic vapor sorption (DVS) profile showing a reversible total mass change of about 0.2% by weight at 25 °C and a relative humidity (RH) between about 0% and about 80%. In other embodiments, crystalline Form 1 can be characterized by a dynamic vapor sorption (DVS) profile showing a reversible total mass change of about 0.3% by weight at 25 °C and a relative humidity (RH) between about 0% and about 90%. In certain embodiments, the assumed crystalline Form 1 is an anhydrous crystal form. Form 1 can be characterized, for example, by the dynamic vapor sorption shown in Figure 4.

[0028]

[0044] In another embodiment, 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 hydrochloride (referred to herein as "Form 2") is disclosed herein.

[0029]

[0045] In one embodiment, 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)The crystalline form 2 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 7.7 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 9.9 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 11.5 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 15.2 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 15.5 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 17.6 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 19.9 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 22.2 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 23.4 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 25.9 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 27.8 degrees, and / or characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 31.4 degrees. In one embodiment, the crystalline form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 2θ = 7.7, 11.5, and 25.9 degrees. 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 2θ = 7.7, 9.9, 11.5, 19.9, 25.9, and 27.8 degrees. In yet 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 2θ = 7.7, 9.9, 11.5, 15.2, 15.5, 19.9, 22.2, 25.9, and 27.8 degrees.In a further embodiment, crystalline Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 7.7, 9.9, 11.5, 15.2, 15.5, 17.6, 19.9, 22.2, 23.4, 25.9, 27.8, and 31.4 degrees 2θ. For example, the assumed crystalline form has a powder X-ray diffraction pattern shown in Figure 5. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0030]

[0046] 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 hydrochloride's assumed crystalline Form 2 can be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm (enthalpy 197.35 J / g) starting at about 226 °C and having a peak at about 237 °C. Form 2 can be characterized, for example, by a differential scanning calorimetry profile shown in Figure 6.

[0031]

[0047] 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 hydrochloride's assumed crystalline Form 2 can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.76 wt% between about 22 °C and about 160 °C. Form 2 can be characterized, for example, by a thermogravimetric analysis profile shown in Figure 7. In certain embodiments, the assumed crystalline Form 2 is an anhydrous crystalline form. In some embodiments, crystalline Form 2 can be characterized as having a needle-like crystal form when observed by polarized light microscopy.

[0032]

[0048] In another embodiment, 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 hydrochloride in crystalline form (referred to herein as "Form 3") is disclosed herein.

[0033]

[0049] In one embodiment, 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)The crystalline form 3 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 5.6 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 6.6 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 8.9 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 10.9 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 13.1 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 13.8 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 16.7 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 17.8 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 19.7 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 23.6 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 30.2 degrees, and / or characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 34.6 degrees. In one embodiment, the crystalline form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 2θ = 8.9, 13.1, and 23.6 degrees. In another embodiment, the crystalline form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 2θ = 5.6, 8.9, 10.9, 13.1, 13.8, and 23.6 degrees. In yet another embodiment, the crystalline form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 2θ = 5.6, 6.6, 8.9, 10.9, 13.1, 13.8, 17.8, 23.6, and 30.2 degrees.In a further embodiment, crystalline Form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 5.6, 6.6, 8.9, 10.9, 13.1, 13.8, 16.7, 17.8, 19.7, 23.6, 30.2, and 34.6 degrees 2θ. For example, the contemplated crystalline form has the powder X-ray diffraction pattern shown in FIG. 8. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0034]

[0050] In another embodiment, 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 hydrochloride (referred to herein as "Form 5") is disclosed herein.

[0035]

[0051] In one embodiment, 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)The crystalline form 5 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 6.8 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 10.5 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 11.3 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 13.6 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 16.7 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 17.6 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 19.8 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 21.0 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 23.0 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 23.4 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 27.0 degrees, and / or characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 27.4 degrees. In one embodiment, the crystalline form 5 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 2θ = 6.8, 23.0, and 27.0 degrees. In another embodiment, the crystalline form 5 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 2θ = 6.8, 10.5, 19.8, 21.0, 23.0, and 27.0 degrees. In yet another embodiment, the crystalline form 5 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 2θ = 6.8, 10.5, 13.6, 17.6, 19.8, 21.0, 23.0, 23.4, and 27.0 degrees.In a further embodiment, crystalline Form 5 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 6.8, 10.5, 13.3, 13.6, 16.7, 17.6, 19.8, 21.0, 23.0, 23.4, 27.0, and 27.4 degrees 2θ. For example, the expected crystalline form has the powder X-ray diffraction pattern shown in Figure 9. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0036]

[0052] 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 hydrochloride's assumed crystalline Form 5 can be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm (enthalpy 140.7 J / g) starting at about 141 °C and having a peak at about 144 °C, and a characteristic endotherm having a peak at about 231 °C. Form 5 can be characterized, for example, by the differential scanning calorimetry profile shown in Figure 10.

[0037]

[0053] 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 hydrochloride's assumed crystalline Form 5 can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 23.0 wt% between about 23 °C and about 150 °C. Form 5 can be characterized, for example, by the thermogravimetric analysis profile shown in Figure 11. In certain embodiments, the assumed crystalline Form 5 is a benzyl alcohol solvate.

[0038]

[0054] In another embodiment, 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 hydrochloride (referred to herein as "Form 6") having a characteristic peak at about 2θ of 8.2 degrees is disclosed herein.

[0039]

[0055] In one embodiment, 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)The crystalline form 6 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride is characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 4.2 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 8.2 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 8.4 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 11.7 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 12.7 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 16.4 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 21.2 degrees, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 21.7 degrees, and / or characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ = 26.7 degrees. In one embodiment, crystalline form 6 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 2θ = 4.2, 8.2, and 8.4 degrees. In another embodiment, crystalline form 6 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 2θ = 4.2, 8.2, 8.4, 11.7, 12.7, and 16.4 degrees. In yet another embodiment, crystalline form 6 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 2θ = 4.2, 8.2, 8.4, 11.7, 12.7, 6.4, 21.2, 21.7, and 26.7 degrees. For example, the putative crystalline form has the powder X-ray diffraction pattern shown in Figure 12. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0040]

[0056] 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)The putative crystalline Form 6 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride can be characterized by a differential scanning calorimetry (DSC) profile showing characteristic endotherms with peaks at about 96 °C, characteristic endotherms with peaks at about 166 °C, and characteristic endotherms with peaks at about 271 °C. Form 6 can be characterized, for example, by the differential scanning calorimetry profile shown in Figure 13.

[0041]

[0057] 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 )The putative crystalline Form 6 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 8.70 wt% between about 25 °C and about 120 °C. Form 6 can be characterized, for example, by the thermogravimetric analysis profile shown in Figure 14.

[0042]

[0058] In a further embodiment, a pharmaceutical composition comprising the disclosed crystalline forms 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 hydrochloride and a pharmaceutically acceptable excipient is disclosed herein. For example, a pharmaceutical composition comprising crystalline Form 1 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 hydrochloride and a pharmaceutically acceptable excipient is disclosed herein. In another embodiment, a pharmaceutical composition comprising crystalline Form 1 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)A pharmaceutical composition formed from the disclosed crystalline forms of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride is disclosed herein. For example, 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 )A pharmaceutical composition formed from crystalline form 1 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride is disclosed herein. In some embodiments, the disclosed pharmaceutical composition may be a formulation for oral administration.

[0043]

[0059] In one embodiment, a drug substance comprising at least a detectable amount of the disclosed crystalline forms 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 hydrochloride is disclosed herein. In another embodiment, a drug substance comprising a substantially pure 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 hydrochloride is disclosed herein. For example, a drug substance comprising a substantially pure crystalline form 1 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 hydrochloride is disclosed herein. Composition

[0060] Another aspect of the present disclosure provides a pharmaceutical composition comprising a crystalline compound disclosed herein formulated together with a pharmaceutically acceptable excipient. In particular, the present disclosure provides a pharmaceutical composition comprising a crystalline compound disclosed herein formulated together with one or more pharmaceutically acceptable excipients. These formulations include formulations suitable for oral, topical (e.g., transdermal), buccal, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous), rectal, vaginal, or aerosol administration, provided that the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and the nature of the particular compound being used. For example, the disclosed compositions may be formulated as unit dosages and / or may be formulated for oral, subcutaneous or intravenous administration.

[0044]

[0061] 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, and this pharmaceutical composition is mixed with organic excipients or inorganic excipients, or excipients suitable for topical, enteral or parenteral administration, and contains one or more of the compounds of the present disclosure as active ingredients. The active ingredient may be formulated together 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 target compound is included in the pharmaceutical composition in an amount sufficient to effect the desired action in the course or condition of the disease.

[0045]

[0062] To prepare a solid composition, e.g., a tablet, the main active ingredient is mixed with a pharmaceutical excipient, e.g., a conventional tableting ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum, and other pharmaceutical diluents, e.g., water, to form a homogeneous mixture of the compounds of the present disclosure or a solid preformulation composition containing a pharmaceutically acceptable salt thereof that is non-toxic. When referring to these preformulation compositions as being homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition such that the composition can be readily divided into equally effective unit dosage forms, e.g., tablets, pills and capsules.

[0046]

[0063] In solid dosage forms for oral administration (such as capsules, tablets, pills, dragees, powders, granules, etc.), the subject composition is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethyl cellulose, 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) dissolution retardants, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the composition may also contain buffering agents. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycol, etc.

[0047]

[0064] Tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropylmethyl cellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or croscarmellose sodium), a surfactant or a dispersing agent. Molded tablets can be prepared by molding in a suitable device a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, can optionally be prepared with scoring or using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0048]

[0065] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, nanosuspensions, syrups and elixirs. In addition to the subject composition, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0049]

[0066] In addition to the subject composition, suspensions can contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0050]

[0067] Preparations for rectal or vaginal administration may be presented as suppositories, which can be prepared by mixing the subject composition with one or more suitable non-irritating excipients, or excipients such as cocoa butter, polyethylene glycol, suppository wax or excipients containing salicylates, which are solid at room temperature but liquid at body temperature and thus melt in the body cavity and release the active agent.

[0051]

[0068] 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 pharmaceutically acceptable excipients and any preservatives, buffers or propellants that may be required.

[0052]

[0069] Ointments, pastes, creams and gels can contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0053]

[0070] Powders and sprays can 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 can further contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0054]

[0071] The compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is achieved by preparing an aqueous aerosol, a liposomal preparation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. A sonic nebulizer can be used. This is because exposure to shear will degrade the compounds contained in the subject composition, and a sonic nebulizer minimizes exposure of the drug to shear. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the subject composition together with conventional pharmaceutically acceptable excipients and stabilizers. The excipients and stabilizers vary depending on the requirements of the particular subject composition, but usually include nonionic surfactants (Tweens, Pluronics®, 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.

[0055]

[0072] The pharmaceutical compositions of the present disclosure suitable for parenteral administration include the subject composition 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 into injectable sterile solutions or dispersions immediately prior to use. The pharmaceutical compositions suitable for parenteral administration can contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0056]

[0073] Examples of suitable aqueous and non-aqueous excipients that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Appropriate fluidity can be maintained, for example, by the use of coating materials such as the use of lecithin, etc., in the case of dispersions, by maintaining the required particle size, and by the use of 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.

[0057]

[0074] The amount of the crystalline compound in the formulations described herein can vary depending on factors such as the individual's condition, age, gender, and body weight. The dosage regimen can be adjusted to obtain an optimal therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally decreased or increased as indicated by the exigencies of the therapeutic situation. For the sake of simplicity of administration and uniformity of dosage, it is particularly advantageous to formulate parenteral compositions in unit dosage form. As used herein, unit dosage form refers to physically discrete units suitable as unit dosages for the mammalian subject to be treated, each unit containing a predetermined quantity of the active crystalline compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0058]

[0075] The specifications of the unit dosage forms of the present disclosure are determined by and directly depend on the following: (a) the unique characteristics of the selected crystalline compound and the specific therapeutic effect to be achieved, and (b) the limitations peculiar to the art in formulating such active crystalline compounds for the treatment of sensitivity in an individual.

[0059]

[0076] The disclosed compositions can be formulated as solutions, microemulsions, liposomes, or other ordered structures suitable for high drug concentrations. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of coatings, such as lecithin, in the case of dispersions, by maintaining the required particle size, and by the use of surfactants. In many cases, it is appropriate to include in the composition isotonic agents, such as sugars, polyalcohols, such as mannitol, sorbitol, or sodium chloride. Prolonged absorption of the injectable composition can be caused by including in the composition agents that delay absorption, such as monostearate salts and gelatin.

[0060]

[0077] The disclosed crystalline compounds can be administered in a time-release formulation, such as a composition containing a slow-release polymer. The crystalline compounds can be prepared using a carrier that protects the compound from rapid release, and can be prepared, for example, as a controlled-release formulation including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers can be used, and these are, for example, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic acid - polyglycolic acid copolymers (PLG). Many methods for the preparation of such formulations are generally known to those skilled in the art.

[0061]

[0078] According to an alternative aspect of the present disclosure, the disclosed crystalline compounds can be formulated using one or more additional compounds that enhance the solubility of the compound. Method

[0079] The crystalline forms disclosed herein are useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by this crystalline form and method is TYK2.

[0062]

[0080] An inhibitor of TYK2 and thus useful for treating one or more disorders associated with the activity of TYK2 or a mutant thereof, 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 hydrochloride in crystalline form is provided herein.

[0063]

[0081] 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 disorder associated with transplantation, and the method comprises administering to the patient an effective amount of the crystalline form described herein, or a pharmaceutical composition comprising an effective amount of the disclosed crystalline form.

[0064]

[0082] 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, Behçet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0065]

[0083] 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.

[0066]

[0084] In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a blood cancer. In some embodiments, the proliferative disorder is 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, essential thrombocythemia or thrombocytosis.

[0067]

[0085] In some embodiments, the disease or disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0086] In some embodiments, the disease or disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[0068]

[0087] 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 to 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.

[0069]

[0088] In some embodiments, the disease or disorder is associated with transplantation. In some embodiments, the disease or disorder associated with transplantation is graft rejection, or graft-versus-host disease.

[0089] In some embodiments, the disease or disorder is related to type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disease or disorder is related to type I interferon signaling. In some embodiments, the disease or disorder is related to IL-10 signaling. In some embodiments, the disorder is related to IL-12 signaling. In some embodiments, the disease or disorder is related to IL-23 signaling.

[0070]

[0090] Methods are provided herein for treating inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo vulgaris, hypersensitivity vasculitis, urticaria, bullous pemphigoid, erythema nodosum, systemic erythema nodosum, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0071]

[0091] Methods for treating other diseases or conditions, such as diseases or conditions having an inflammatory component, e.g., the treatment of eye diseases and conditions, e.g., eye allergies, conjunctivitis, dry conjunctivitis, and vernal catarrh, nasal diseases affecting the nose including allergic rhinitis, and inflammatory diseases having an autoimmune component or cause, including those in which an autoimmune reaction is suggested or autoimmune blood diseases (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, idiopathic sprue, autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary fibrosis, kidney diseases, glomerular diseases, alcoholic liver diseases, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, dry conjunctivitis and vernal catarrh, interstitial lung fibrosis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g., including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospiral kidney disease, glaucoma, retinal diseases, aging phenomena, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle fatigue, disorders of catabolism, obesity, fetal growth retardation, hyperchlolesterolemia, heart diseases, chronic heart failure, mesothelioma, anhidrotic ectodermaldysplasia), Behçet's disease, dyschromatosis, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, rhinosinusitis, ocular allergy, silica-induced disease, COPD (damage, airway inflammation, bronchial hyperreactivity, remodeling or reduction of disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataract, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enteritis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, rhinosinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0072]

[0092] In some embodiments, the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndrome (CAPS), or osteoarthritis.

[0073]

[0093] 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).

[0074]

[0094] In some embodiments, the inflammatory disease is Sjogren's syndrome, an allergic disease, osteoarthritis, an ocular condition such as ocular allergy, conjunctivitis, dry conjunctivitis, vernal catarrh, or a disease affecting the nose such as allergic rhinitis.

[0075]

[0095] Disclosed herein is a method of inhibiting the TYK2 enzyme in a patient or a biological sample, the method comprising contacting the patient or biological sample with a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form described herein or an effective amount of a disclosed crystalline form.

[0076]

[0096] Also disclosed herein is a method of inhibiting TYK2 activity in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form described herein or an effective amount of a disclosed crystalline form. In some embodiments, inhibiting TYK2 activity is related to treating a disease or disorder selected from the group consisting of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis.

[0077]

[0097] Further disclosed herein is a TYK2-mediated disorder in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form described herein or 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 disorder associated with transplantation. In other embodiments, the contemplated disorder is related to type I interferon, IL-10, IL-12, or IL-23 signaling.

[0078]

[0098] For example, 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 the crystalline form described herein, or a pharmaceutical composition comprising an effective amount of the disclosed crystalline form, is provided herein.

[0079]

[0099] In particular, in certain embodiments, the disclosure provides a method of treating the above medical indications, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of the crystalline form described herein, or an effective amount of the disclosed crystalline form. In certain other embodiments, the disclosure provides a method of treating the above medical condition in a patient in need thereof, the method comprising orally, subcutaneously, or intravenously administering to the patient a composition comprising the crystalline form described herein, or a pharmaceutical composition comprising an effective amount of the disclosed crystalline form.

[0080]

[0100] The crystalline compounds disclosed herein can be used as a medicament or a pharmaceutically acceptable composition, for example, in the form of pharmaceutical preparations for oral, enteral, parenteral, or topical administration, and the contemplated methods disclosed herein can include orally, enterally, parenterally, or topically administering the disclosed crystalline compound, or a composition comprising or formed from such disclosed crystalline compound. For example, the disclosed crystalline form may be capable of controlling one or more pharmacokinetic properties (e.g., a longer or shorter release profile) when administered via a particular route (e.g., orally) or as a particular formulation compared to a different route (e.g., subcutaneously) or another formulation, e.g., a formulation having an amorphous form. In one embodiment, the disclosed crystalline form can provide a significant reproducibility from one formulation to another.

Example

[0081]

[0101] The compounds and crystalline forms described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art. The following non-limiting examples illustrate the present disclosure.

[0082]

[0102] Powder X-ray diffraction was performed using a Bruker D8 Advance X-ray diffractometer equipped with a LynxEye detector. The sample was scanned from 3 to 40° 2θ with a step size of 0.02° 2θ. The radiation was Cu / K-alpha1 (λ = 1.5406 Å). The tube voltage and current were 40 kV and 40 mA, respectively.

[0083]

[0103] Differential scanning calorimetry (DSC) was performed using a Discovery DSC 250 (TA Instruments, US) calorimeter. The sample was placed in an aluminum pinhole-sealed pan and the weight was accurately recorded. The sample was heated from 25 °C to the final temperature at a rate of 10 °C / min.

[0084]

[0104] Thermogravimetric analysis (TGA) was performed on a Discovery TGA 55 (TA Instruments, US). The sample was placed on an open aluminum pan with tare weight, automatically weighed, and inserted into the TGA furnace. The sample was heated from ambient temperature to the final temperature at a rate of 10 °C / min.

[0085] Example 1

[0105] 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 hydrochloride, crystalline form 1, was prepared as follows. 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((2-Pyridinyl)cyclopropanecarboxamide (3.4 g) was added to 14 mL of MeOH (5V) at 50 °C to obtain a suspension. Then 7.5 mL of 1M HCl / ethyl acetate was added. After adding the acid and another 2 mL of MeOH, the mixture was turbid. The mixture was filtered and then 8.5 mL of ethyl acetate was added. After adding seed crystals of HCl salt Form I at 50 °C, precipitation occurred. The mixture was slowly cooled to room temperature over 3 hours, 16 mL of ethyl acetate was added, and the mixture was stirred at room temperature for an additional 3 hours. The solid was collected by filtration. Analysis of the filter cake (1.9 g) by XPRD revealed it to be a mixture of Form I and Form II (1.9 g). The solid was reslurried in the mother liquor at 50 °C for 2 hours and at room temperature for 30 minutes, and then collected by filtration. XRPD analysis showed that the dried material was crystalline and had a pattern consistent with Form 1.)

[0086]

[0106] The XRPD pattern of crystalline Form 1 is shown in Figure 1. The characteristic peaks include one or more of the peaks shown in Table 1.)

[0087]

Table 1-1

[0088]

Table 1-2

[0089]

[0107] Figure 2 represents the differential scanning calorimetry (DSC) profile of crystalline Form 1. As shown in Figure 2, crystalline Form 1 exhibits a characteristic endotherm (enthalpy 179.57 J / g) that starts at about 237 °C and has a peak at about 243 °C.)

[0090]

[0108] 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)The crystalline form 1 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride shows a thermogravimetric analysis (TGA) profile with a mass loss of about 0.67% by weight between about 22 °C and about 160 °C (Figure 3). The crystalline form 1 showed a dynamic vapor sorption (DVS) profile with a reversible total mass change of about 0.3% by weight at 25 °C and relative humidity (RH) between about 0% and about 90% (Figure 4). No morphological changes were observed after DVS analysis.

[0091]

[0109] The crystalline form 1 is an anhydrate and was observed to be only slightly hygroscopic. Form 1 showed an irregular crystal morphology when observed by polarized light microscopy. Form 1 was observed to be chemically and physically stable in the solid form at 40 °C / 75% RH and 60 °C for at least 10 days, as well as at ambient temperature and ambient humidity for at least 12 months.

[0092]

[0110] The crystalline form 1 was also obtained from single solvent slurry experiments in tetrahydrofurn, methyl ethyl ketone, acetone, acetonitrile, ethyl acetate, isopropyl acetate, isobutanol, isopropanol, toluene, methyl t-butyl ether, and n-heptane at room temperature for 3 days or at 50 °C for 1 day. The crystalline form 1 was also obtained from poor solvent precipitation in MeOH / ethyl acetate (1 / 5 v / v) and MeOH / isopropyl acetate (1 / 5 v / v). The crystalline form 1 was also obtained from mixed solvent slurry experiments in MeOH / isopropanol, MeOH / methyl ethyl ketone, MeOH / methyl t-butyl ether, MeOH / toluene, MeOH / ethyl acetate, water / acetone and water / THF (all 1 / 9 v / v) at room temperature for 3 days.

[0093] Example 2

[0111] 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 hydrochloride Crystal Form 2 was prepared as follows. 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 (280 mg) was added to 2.6 mL of acetone / water (9 / 1) at 50 °C. After adding 55.3 μL (1 equivalent) of HCl acid and obtaining a clear solution, precipitation occurred at 50 °C in about 1 minute. After stirring at 50 °C for about 1 hour, the solid was collected by filtration and then dried under vacuum at 50 °C overnight, and then characterized. XRPD analysis showed that the dried material was crystalline and had a pattern consistent with Form 2.

[0094]

[0112] The XRPD pattern of Crystal Form 2 is shown in Figure 5. The characteristic peaks include one or more of the peaks shown in Table 2.

[0095]

Table 2-1

[0096]

Table 2-2

[0097]

[0113] Figure 6 represents the differential scanning calorimetry (DSC) profile of Crystal Form 2. As shown in Figure 2, Crystal Form 1 shows a characteristic endotherm (enthalpy 197.35 J / g) starting at about 226 °C and having a peak at about 237 °C.

[0098]

[0114] 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)The crystalline form 2 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride showed a thermogravimetric analysis (TGA) profile with a mass loss of about 0.77% by weight between about 22 °C and about 160 °C (Figure 7). It was observed that crystalline form 2 is an anhydrate and showed a needle-like crystal form when observed by polarized light microscopy.

[0099]

[0115] Pure crystalline form 2 was also obtained by dissolving form 1 in MeOH at room temperature, filtering, and evaporating the filtrate under ambient conditions. A mixture of form 2 and the free base material was obtained from a single-solvent slurry in water over 3 days at room temperature. A mixture of forms 1 and 2 was obtained from a poor-solvent precipitation in MeOH / ethyl acetate (1 / 5 v / v) at room temperature.

[0100]

[0116] In the interconversion experiments, equal amounts of form 1 and form 2 were added to various solvents and stirred at various temperatures for several days. Form 1 was obtained from isopropanol (50 °C, 7 days), acetone (50 °C, 3 days), acetone / water (9 / 1 v / v, 50 °C, 1 day), and acetone / water (9 / 1 v / v, room temperature, 1 day). This suggested that form 1 is the more stable crystalline form.

[0101] Example 3

[0117] 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 )The crystalline form 3 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride was prepared as follows. 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)The crystalline form 1 of (pyridin-2-yl)cyclopropanecarboxamide hydrochloride (20.8 mg) was added to a 1.5 mL glass vial, dissolved in MeOH (0.5 mL), and the resulting solution was filtered through a 0.45 μm PTFE membrane. Subsequently, the filtered solution was added to anisole (4.5 mL) with stirring. The combined solution was allowed to evaporate at room temperature for 7 days, after which a solid was formed and collected. XRPD analysis showed that the dried solid was crystalline and had a pattern consistent with form 3.

[0102]

[0118] The XRPD pattern of crystalline form 3 is shown in Figure 8. The characteristic peaks include one or more of the peaks shown in Table 3.

[0103]

Table 3

[0104] Example 4

[0119] 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 hydrochloride crystalline form 5 was prepared as follows. The crystalline form 1 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 hydrochloride (21.4 mg) was added to a 3 mL glass vial containing benzyl alcohol (0.5 mL), stirred at 50 °C for 2 hours, and the resulting solution was filtered through a 0.45 μm PTFE membrane. The filtered solution was quickly cooled to -20 °C and then allowed to evaporate at room temperature for 13 days, after which a solid was formed. The solid was collected and dried under vacuum at room temperature for 3 days. XRPD analysis showed that the dried solid was crystalline and had a pattern consistent with form 5.

[0105]

[0120] The XRPD pattern of crystalline form 5 is shown in Figure 9. The characteristic peaks include one or more of the peaks shown in Table 4.

[0106]

Table 4-1

[0107]

Table 4-2

[0108]

[0121] Figure 10 represents the differential scanning calorimetry (DSC) profile of crystalline form 5. As shown in Figure 10, crystalline form 5 shows a characteristic endotherm (enthalpy 140.7 J / g) starting at about 141 °C and having a peak at about 144 °C, and a characteristic endotherm having a peak at about 231 °C.

[0109]

[0122] 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 hydrochloride in crystalline form 5 showed a thermogravimetric analysis (TGA) profile with a mass loss of about 23.0 wt% between about 23 °C and about 150 °C (Figure 11). It was observed that crystalline form 5 is a benzyl alcohol solvate (22.4% residual solvent). The IC / HPLC test showed that the stoichiometric ratio of Cl - to the free base is 0.9.

[0110] Example 5

[0123] 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 hydrochloride in crystalline form 6 was prepared as follows. N-(4-((2-Methoxy-3-(1-(methyl-d3 )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d 3 )Pyridin-2-yl)cyclopropanecarboxamide (20.0 mg) was added to isopropyl alcohol (0.25 mL) to form a suspension. A solution was prepared in a separate vial by diluting 0.0282 mL of HCl / EtOAc (4 M) in 0.25 mL of isopropyl alcohol. The diluted HCl solution was added dropwise to the suspension with stirring. The resulting slurry was stirred at room temperature for 13 days, after which the solid was collected by filtration and air-dried at room temperature for 1 hour. XRPD analysis showed that the dried solid was crystalline and had a pattern consistent with Form 6.

[0111]

[0124] The XRPD pattern of crystalline Form 6 is shown in Figure 12. The characteristic peaks include one or more of the peaks shown in Table 5.

[0112]

Table 5

[0113]

[0125] Figure 13 represents the differential scanning calorimetry (DSC) profile of crystalline Form 6. As shown in Figure 13, crystalline Form 6 exhibits characteristic endotherms with peaks at approximately 96 °C, approximately 166 °C, and approximately 271 °C.

[0114]

[0126] 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 hydrochloride in crystalline Form 6 showed a thermogravimetric analysis (TGA) profile with a mass loss of approximately 8.70 wt% between approximately 25 °C and approximately 120 °C (Figure 14). The IC / HPLC test showed that the stoichiometric ratio of Cl - to the free base is 1.6. Incorporation by Reference

[0127] All publications and patents described herein, including the items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent were specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalents

[0128] Particular embodiments of the disclosed subject matter have been discussed, but the above specification is illustrative and not limiting. Many variations of the present disclosure will be apparent to those skilled in the art upon reviewing this specification. The full scope of the present disclosure should be determined by reference to the claims, along with such variations, their equivalents, and the full scope of this specification.

[0115]

[0129] Unless otherwise indicated, all numbers expressing amounts 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 indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. Characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.7 degrees 2θ, the crystalline form (Form 1) 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 hydrochloride.

2. The crystalline form according to claim 1, characterized by a powder X-ray diffraction pattern having characteristic peaks at 2θ of about 9.7, 20.8, and 22.9 degrees.

3. The crystalline form according to claim 1 or 2, characterized by a powder X-ray diffraction pattern having characteristic peaks at 2θ of about 9.3, 9.7, 19.6, 20.3, 20.8, and 22.9 degrees.

4. The crystalline form according to any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern having characteristic peaks at 2θ of about 8.3, 9.3, 9.7, 17.6, 19.6, 20.3, 20.8, 21.3, and 22.9 degrees.

5. The crystalline form according to any one of claims 1 to 4, characterized by a powder X-ray diffraction pattern having characteristic peaks at 2θ of about 8.3, 9.3, 9.7, 13.6, 17.2, 17.6, 19.6, 20.3, 20.8, 21.3, 22.9, and 27.4 degrees.

6. The crystalline form according to any one of claims 1 to 5, characterized by a powder X-ray diffraction pattern having characteristic peaks at 2θ of about 8.3, 9.3, 9.7, 13.6, 14.8, 15.5, 17.2, 17.6, 19.6, 20.3, 20.8, 21.3, 22.9, 27.4, and 30.5 degrees.

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

8. The crystalline form according to any one of claims 1 to 7, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm starting at about 237 °C and having a peak at about 243 °C.

9. The crystalline form according to any one of claims 1 to 8, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.66 wt% between about 22 °C and about 160 °C.

10. Characterized by a powder X-ray diffraction pattern having a characteristic peak at about 7.7 degrees 2θ, a crystalline form (Form 2) 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 hydrochloride.

11. The crystalline form according to claim 10, characterized by a powder X-ray diffraction pattern having characteristic peaks at 2θ of about 7.7, 11.5, and 25.9 degrees.

12. The crystalline form according to claim 10 or 11, characterized by a powder X-ray diffraction pattern having characteristic peaks at 2θ of about 7.7, 9.9, 11.5, 19.9, 25.9, and 27.8 degrees.

13. The crystalline form according to any one of claims 10 to 12, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.7, 9.9, 11.5, 15.2, 15.5, 19.9, 22.2, 25.9, and 27.8 degrees of 2θ.

14. The crystalline form according to any one of claims 10 to 13, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.7, 9.9, 11.5, 15.2, 15.5, 17.6, 19.9, 22.2, 23.4, 25.9, 27.8, and 31.4 degrees of 2θ.

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

16. The crystalline form according to any one of claims 10 to 15, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm starting at about 226 °C and having a peak at about 237 °C.

17. The crystalline form according to any one of claims 10 to 16, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.76 wt% between about 22 °C and about 160 °C.

18. Characterized by a powder X-ray diffraction pattern having characteristic peaks at about 5.6, 6.6, 8.9, 10.9, 13.1, 13.8, 16.7, 17.8, 19.7, 23.6, 30.2, and 34.6 degrees in 2θ, the powder X-ray diffraction pattern being obtained using Cu Kα radiation, 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 hydrochloride in crystalline form (Form 3).

19. Characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.8, 10.5, 1.3, 13.6, 16.7, 17.6, 19.8, 21.0, 23.0, 23.4, 27.0, and 27.4 degrees, the powder X-ray diffraction pattern obtained using Cu Kα radiation, 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 hydrochloride crystal form (Form 5).

20. The crystalline form according to claim 19, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm starting at about 141 °C and having a peak at about 144 °C, and a characteristic endotherm having a peak at about 231 °C.

21. The crystalline form according to claim 19 or 20, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 23.0 wt% between about 23 °C and about 150 °C.

22. Characterized by a powder X-ray diffraction pattern having characteristic peaks at about 2θ of 2, 8.2, 8.4, 11.7, 12.7, 6.4, 21.2, 21.7, and 26.7 degrees, the powder X-ray diffraction pattern obtained using Cu Kα radiation, 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 hydrochloride crystal form (Form 6).

23. The crystalline form according to claim 22, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm having a peak at about 96 °C, a characteristic endotherm having a peak at about 166 °C, and a characteristic endotherm having a peak at about 271 °C.

24. The crystalline form according to claim 22 or 23, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 8.70 wt% between about 25 °C and about 120 °C.

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

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

27. The pharmaceutical composition according to claim 25 or 26, formulated for oral administration.

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

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

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

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

32. 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 the crystalline form according to any one of claims 1 to 24, or the pharmaceutical composition according to any one of claims 25 to 27.

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