Crystalline forms of a TYK2 inhibitor and uses thereof

Abstract

The disclosure is in part directed to crystalline forms of N-(4-((3-methoxy-4-(1-(methyld3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropane carboxamide, free base, pharmaceutical compositions thereof, and methods of use.

Description

Attorney Docket No.: ESK-026WO CRYSTALLINE FORMS OF A TYK2 INHIBITOR AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 671,864, filed on July 16, 2024; the content of which is hereby incorporated by reference herein in its entirety. BACKGROUND

[0002] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. TYK2 activation has been linked to diseases and disorders such as, for example, autoimmune disorders, inflammatory disorders, proliferative disorders (e.g., cancer), endocrine disorders, and neurological disorders. For example, TYK2 activation has been linked to 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. Accordingly, compounds that inhibit the activity of TYK2 are beneficial, especially those with selectivity over JAK2. Such compounds should deliver a pharmacological response that favorably treats one or more of the conditions described herein without the side-effects associated with the inhibition of JAK2.

[0003] Polymorphism is the ability of a substance to crystallize in more than one crystal lattice arrangement. Crystallization, or polymorphism, can influence many aspects of the solid- state properties of a drug substance. A crystalline substance may differ considerably from an amorphous form, and different crystal modifications of a substance may differ considerably from one another 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- state forms. It is even more difficult to predict the physical properties of these crystalline solid- state forms. Therefore, it can be advantageous to have a crystalline form of a therapeutic agent for certain formulations and / or for manufacturing processes. 1 IPTS / 128645169.1Attorney Docket No.: ESK-026WO SUMMARY

[0004] The present disclosure is directed, at least in part, to crystalline forms of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base.

[0005] For example, disclosed herein is a crystalline form of N-(4-((3-methoxy-4-(1- (methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 11.4, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 11.4, 20.9, and 22.9, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 11.0. 11.4, 17.2, 20.9, 22.9, and 25.0, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 11.0, 11.4, 13.3, 17.2, 20.9, 21.9, 22.9, 25.0, and 27.2, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 11.0, 11.4, 13.3, 17.2, 20.9, 21.9, 22.9, 23.4, 25.0, 27.2, 28.0, and 30.4.

[0006] N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5- propionylpyridin-2-yl)cyclopropanecarboxamide is, for example, a modulator of tyrosine kinase 2 (TYK2), e.g., an inhibitor of TYK2, and is represented by: .

[0007] Further contemplated a composition comprising a disclosed crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, and a pharmaceutically acceptable excipient, for example, a composition that is formulated for oral administration. Further contemplated herein is a drug substance comprising at least a detectable amount of a 2 IPTS / 128645169.1Attorney Docket No.: ESK-026WO disclosed crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base. For example, disclosed herein is a drug substance comprising substantially pure crystalline form of N-(4-((3-methoxy-4- (1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base.

[0008] 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 a disclosed crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base.

[0009] For example, provided herein is a method of treating a neuroinflammatory disease, for example, multiple sclerosis, in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed crystalline form of N-(4-((3-methoxy-4-(1- (methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 depicts an X-ray powder diffraction (XRPD) pattern of N-(4-((3-methoxy- 4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 1).

[0011] FIG. 2 depicts the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base (Form 1).

[0012] FIG. 3 depicts an X-ray powder diffraction (XRPD) pattern of N-(4-((3-methoxy- 4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 2).

[0013] FIG. 4 depicts the differential scanning calorimetry (DSC) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 2). 3 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0014] FIG. 5 depicts the thermogravimetric analysis (TGA) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 2).

[0015] FIG. 6 depicts the dynamic vapor sorption (DVS) profile of N-(4-((3-methoxy-4- (1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 2).

[0016] FIG. 7 depicts an X-ray powder diffraction (XRPD) pattern of N-(4-((3-methoxy- 4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 3).

[0017] FIG. 8 depicts the differential scanning calorimetry (DSC) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 3).

[0018] FIG. 9 depicts the thermogravimetric analysis (TGA) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 3).

[0019] FIG. 10 depicts an X-ray powder diffraction (XRPD) pattern of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 4).

[0020] FIG. 11 depicts the differential scanning calorimetry (DSC) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 4).

[0021] FIG. 12 depicts the thermogravimetric analysis (TGA) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 4).

[0022] FIG. 13 depicts an X-ray powder diffraction (XRPD) pattern of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 5). 4 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0023] FIG. 14 depicts the differential scanning calorimetry (DSC) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 5).

[0024] FIG. 15 depicts the thermogravimetric analysis (TGA) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 5).

[0025] FIG. 16 depicts an X-ray powder diffraction (XRPD) pattern of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 6).

[0026] FIG. 17 depicts the differential scanning calorimetry (DSC) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 6).

[0027] FIG. 18 depicts the thermogravimetric analysis (TGA) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 6).

[0028] FIG. 19 depicts the dynamic vapor sorption (DVS) profile of N-(4-((3-methoxy-4- (1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 6).

[0029] FIG. 20 depicts an X-ray powder diffraction (XRPD) pattern of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 7).

[0030] FIG. 21 depicts the differential scanning calorimetry (DSC) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 7).

[0031] FIG. 22 depicts an X-ray powder diffraction (XRPD) pattern of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 8). 5 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0032] FIG. 23 depicts the differential scanning calorimetry (DSC) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 8).

[0033] FIG. 24 depicts the thermogravimetric analysis (TGA) profile of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base (Form 8). DETAILED DESCRIPTION

[0034] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. Definitions

[0035] The term “crystalline form” refers to a crystal form or modification that can be characterized by analytical methods such as, e.g., X-ray powder diffraction (XRPD) and / or Differential scanning calorimetry (DSC). The crystalline compounds disclosed herein can exist in solvated as well as unsolvated forms with solvents such as water, ethanol, and the like. Unless otherwise indicated or inferred, it is intended that disclosed crystalline compounds include both solvated and unsolvated forms.

[0036] “Treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0037] The term “disorder” refers to and is used interchangeably with, the terms “disease,” “condition,” or “illness,” unless otherwise indicated.

[0038] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards. 6 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0039] The term “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, 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 compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0040] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0041] “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the present disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The mammal treated in the methods of the present disclosure is desirably a mammal in which treatment, for example, of a cancer or a blood disorder is desired. “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0042] In the present specification, the terms “effective amount” or “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the present disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect.

[0043] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. 7 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0044] As used herein, the words “a” and “an” are meant to include one or more unless otherwise specified. For example, the term “an agent” encompasses both a single agent and a combination of two or more agents.

[0045] Where the use of the term “about” is 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 ± 10% variation from the nominal value unless otherwise indicated or inferred. The term “about” in the context of peaks at degrees 2θ means that there is an uncertainty in the measurements of the 2θ of ± 0.2 (expressed in 2θ). Generally, a DSC thermogram may have a variation in the range of ± 2 °C. Therefore, the temperature values should be understood as including values in the range of about ± 2 °C.

[0046] In general, provided herein are crystalline forms of N-(4-((3-methoxy-4-(1- (methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base, that are substantially free of any other crystalline forms, unless indicated otherwise. As used herein, “substantially free” or substantially free of any other crystalline forms” 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 other crystalline forms of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5- propionylpyridin-2-yl)cyclopropanecarboxamide, free base, as measured, for example, 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 forms of N-(4- ((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base, as measured, for example, by XRPD. Thus, a disclosed crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, described herein as substantially free of any other crystalline forms would be understood to contain 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 said crystalline forms of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol- 3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base. Accordingly, in some embodiments, a disclosed crystalline form of N-(4-((3-methoxy-4-(1- (methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- 8 IPTS / 128645169.1Attorney Docket No.: ESK-026WO yl)cyclopropanecarboxamide, free base, may contain from 1% to 20% (w / w), from 5% to 20% (w / w), or from 5% to 10% (w / w) of one or more other crystalline forms of N-(4-((3-methoxy-4- (1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base.

[0047] Compounds of the disclosure may comprise one or more isotopic substitutions. For example, the disclosure also embraces crystalline forms of N-(4-((3-methoxy-4-(1-(methyl- d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base, which are identical to those recited herein, except that one or more atoms different from the atomic mass or mass number usually found in nature (e.g.,2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl) are replaced by an atom having an atomic mass or mass number usually found in nature (e.g., hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively). Crystalline Forms

[0048] The present disclosure is directed, at least in part, to crystalline forms of N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base. Also disclosed are crystalline hydrates, anhydrates, hemihydrates, solvates, tautomers and cocrystals of any of the crystalline forms described herein.

[0049] For example, disclosed herein is a crystalline form of N-(4-((3-methoxy-4-(1- (methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 6.8 (referred to herein as “Form 1”).

[0050] In one embodiment, the crystalline Form 1 of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 6.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 6.8, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 9.7, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 12.5, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 13.0, is 9 IPTS / 128645169.1Attorney Docket No.: ESK-026WO characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 13.7, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 15.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 17.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 20.7, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 21.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 23.2, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 24.1.

[0051] In another embodiment, crystalline Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 6.8, 13.7, and 24.1. In a further embodiment, crystalline Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 6.4, 6.8, 13.0, 13.7, 23.2, and 24.1. In yet another embodiment, crystalline Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 6.4, 6.8, 9.7, 12.5, 13.0, 13.7, 20.7, 23.2, and 24.1. In another embodiment, crystalline Form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 6.4, 6.8, 9.7, 12.5, 13.0, 13.7, 15.3, 17.0, 20.7, 21.4, 23.2, and 24.1. For example, a contemplated crystalline form has a 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.

[0052] The contemplated crystalline Form 1 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic exotherm with an onset of about 138 °C and a peak of about 159 °C, and a characteristic endotherm with an onset of about 236 °C and a peak of about 237 °C. Form 1, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 2.

[0053] The contemplated crystalline Form 1 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free 10 IPTS / 128645169.1Attorney Docket No.: ESK-026WO base, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.5 wt. % between about 112 °C to about 200 °C. Form 1, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 2. In certain embodiments, the contemplated crystalline Form 1 is an anhydrous crystalline form.

[0054] Also disclosed herein is a crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 11.4 (referred to herein as “Form 2”).

[0055] In one embodiment, the crystalline Form 2 of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 11.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 11.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 13.3, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 17.2, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 20.9, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 21.9, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 22.9, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 23.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 25.0, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 27.2, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 28.0, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 30.4. In another embodiment, crystalline Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 11.4, 20.9, and 22.9. In a further embodiment, crystalline Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 11.0. 11.4, 17.2, 20.9, 22.9, and 25.0. In yet another embodiment, crystalline Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic 11 IPTS / 128645169.1Attorney Docket No.: ESK-026WO peaks in degrees 2θ at about 11.0, 11.4, 13.3, 17.2, 20.9, 21.9, 22.9, 25.0, and 27.2. In another embodiment, crystalline Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 11.0, 11.4, 13.3, 17.2, 20.9, 21.9, 22.9, 23.4, 25.0, 27.2, 28.0, and 30.4. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 3. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0056] The contemplated crystalline Form 2 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with an onset of about 236 °C and a peak of about 237 °C (enthalpy 124.1 J / g). Form 2, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 4.

[0057] The contemplated crystalline Form 2 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.5 wt. % between about 27 °C to about 150 °C. Form 2, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 5.

[0058] In some embodiments, crystalline Form 2 may be characterized by a dynamic vapor sorption (DVS) profile showing a reversable total mass change of about 0.35 wt.% between about 0% to about 95% relative humidity (RH) at 25 °C. In certain embodiments, the contemplated crystalline Form 2 is an anhydrous crystalline form. Form 2, for example, may be characterized by the dynamic vapor sorption shown in FIG. 6.

[0059] Also disclosed herein is a crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.2 (referred to herein as “Form 3”).

[0060] In one embodiment, the crystalline Form 3 of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in 12 IPTS / 128645169.1Attorney Docket No.: ESK-026WO degrees 2θ at about 7.2, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 9.1, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 12.7, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 13.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 14.6, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 17.2, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 18.5, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 22.6, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 23.4, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 25.6, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 25.9, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 26.7.

[0061] In another embodiment, crystalline Form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.2, 25.6, and 26.7. In a further embodiment, crystalline Form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.2, 9.1, 13.3, 22.6, 25.6, and 26.7. In yet another embodiment, crystalline Form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.2, 9.1, 12.7, 13.3, 18.5, 22.6, 25.6, 25.9, and 26.7. In another embodiment, crystalline Form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.2, 9.1, 12.7, 13.3, 14.6, 17.2, 18.5, 22.6, 23.4, 25.6, 25.9, and 26.7. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 7. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0062] The contemplated crystalline Form 3 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a differential scanning calorimetry (DSC) profile showing a 13 IPTS / 128645169.1Attorney Docket No.: ESK-026WO characteristic endotherm with an onset of about 84 °C and a peak of about 94 °C, a characteristic exotherm with an onset of about 156 °C and a peak of about 169 °C, a characteristic endotherm with a peak of about 223 °C, a characteristic endotherm with a peak of about 237 °C, and a characteristic endotherm with a peak of about 240 °C. Form 3, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 8.

[0063] The contemplated crystalline Form 3 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.1 wt. % between about 25 °C to about 117 °C. Form 3, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 9. In certain embodiments, the contemplated crystalline Form 3 is a hydrate crystalline form.

[0064] Also disclosed herein is a crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 23.8 (referred to herein as “Form 4”).

[0065] In one embodiment, the crystalline Form 4 of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 7.1, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 10.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 10.3, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 11.2, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 17.1, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 18.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 19.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 21.8, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 23.8, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 27.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 27.3, 14 IPTS / 128645169.1Attorney Docket No.: ESK-026WO and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 30.3.

[0066] In another embodiment, crystalline Form 4 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.1, 10.0, and 23.8. In a further embodiment, crystalline Form 4 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.1, 10.0, 11.2, 18.3, 19.3, and 23.8. In yet another embodiment, crystalline Form 4 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.1, 10.0, 11.2, 17.1, 18.3, 19.3, 21.8, 23.8, and 27.0. In another embodiment, crystalline Form 4 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.1, 10.0, 10.3, 11.2, 17.1, 18.3, 19.3, 21.8, 23.8, 27.0, 27.3, and 30.3. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 10. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0067] The contemplated crystalline Form 4 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with an onset of about 113 °C and a peak of about 125 °C, and a characteristic endotherm with an onset of about 239 °C and a peak of about 240 °C. Form 4, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 11.

[0068] The contemplated crystalline Form 4 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 8.3 wt. % between about 66 °C to about 150 °C. Form 4, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 12. In certain embodiments, the contemplated crystalline Form 4 is a 1,4-dioxane solvate crystalline form, with 7.8 residual solvent wt. % as determined by1H NMR.

[0069] Also disclosed herein is a form of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, 15 IPTS / 128645169.1Attorney Docket No.: ESK-026WO free base, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.5 (referred to herein as “Form 5”).

[0070] In one embodiment, the crystalline Form 5 of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 5.1, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 6.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 7.0, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 7.5, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 10.2, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 11.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 11.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 12.6, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 13.5, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 15.9, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 18.9, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 21.5.

[0071] In another embodiment, crystalline Form 5 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.0, 7.5, and 10.2. In a further embodiment, crystalline Form 5 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 6.3, 7.0, 7.5, 10.2, 12.6, and 13.5. In yet another embodiment, crystalline Form 5 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 5.0, 6.3, 7.0, 7.5, 10.2, 12.6, 13.5, 15.9, and 18.9. In another embodiment, crystalline Form 5 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 5.0, 6.3, 7.0, 7.5, 10.2, 11.0, 11.3, 12.6, 13.5, 15.9, 18.9, and 21.5. For example, a contemplated crystalline form has a powder X-ray diffraction 16 IPTS / 128645169.1Attorney Docket No.: ESK-026WO pattern shown in FIG. 13. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0072] The contemplated crystalline Form 5 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with an onset of about 83 °C and a peak of about 104 °C, and a characteristic endotherm with an onset of about 224 °C and a peak of about 230 °C. Form 5, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 14.

[0073] The contemplated crystalline Form 5 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 20.8 wt. % between about 25 °C to about 184 °C. Form 5, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 15. In certain embodiments, the contemplated crystalline Form 5 is a hydrate crystalline form.

[0074] Also disclosed herein is a crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 9.8 (referred to herein as “Form 6”).

[0075] In one embodiment, the crystalline Form 6 of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 7.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 9.8, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 12.8, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 14.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 17.9, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 22.5, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 23.1, is characterized by a powder X-ray diffraction pattern that has a 17 IPTS / 128645169.1Attorney Docket No.: ESK-026WO characteristic peak in degrees 2θ at about 23.6, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 23.9, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 24.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 30.2, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 31.3.

[0076] In another embodiment, crystalline Form 6 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 9.8, 17.9, and 24.4. In a further embodiment, crystalline Form 6 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 9.8, 14.3, 17.9, 23.6, 23.9, and 24.4. In another embodiment, crystalline Form 6 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.4, 9.8, 12.8, 14.3, 17.9, 23.6, 23.9, 24.4, and 30.2. In a further embodiment, crystalline Form 6 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.4, 9.8, 12.8, 14.3, 17.9, 22.5, 23.1, 23.6, 23.9, 24.4, 30.2, and 31.3. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 16. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0077] The contemplated crystalline Form 6 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with an onset of about 136 °C and a peak of about 152 °C (enthalpy 154.8 J / g), and a characteristic endotherm with an onset of about 240 °C and a peak of about 241 °C (enthalpy 110.6 J / g). Form 6, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 17.

[0078] The contemplated crystalline Form 6 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.7 wt. % between about 18 °C to about 150 °C. Form 6, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 18. 18 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0079] In some embodiments, crystalline Form 6 may be characterized by a dynamic vapor sorption (DVS) profile showing a reversable total mass change of about 0.05 wt.% between about 0% to about 95% relative humidity (RH) at 25 °C. In certain embodiments, the contemplated crystalline Form 6 is a hydrate crystalline form. Form 6, for example, may be characterized by the dynamic vapor sorption shown in FIG. 19.

[0080] Also disclosed herein is a crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.2 (referred to herein as “Form 7”).

[0081] In one embodiment, the crystalline Form 7 of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 7.2, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 8.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 10.1, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 11.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 12.1, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 14.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 16.6, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 18.7, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 24.1, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 25.5, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 25.8, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 27.1.

[0082] In another embodiment, crystalline Form 7 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.2, 24.1, and 25.5. In a further embodiment, crystalline Form 7 is characterized by a powder X-ray 19 IPTS / 128645169.1Attorney Docket No.: ESK-026WO diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.2, 10.1, 14.0, 16.6, 24.1, and 25.5. In yet another embodiment, crystalline Form 7 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.2, 8.4, 10.1, 14.0, 16.6, 24.1, 25.5, 25.8, and 27.1. In another embodiment, crystalline Form 7 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.2, 8.4, 10.1, 11.4, 12.1, 14.0, 16.6, 18.7, 24.1, 25.5, 25.8, and 27.1. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 20. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0083] The contemplated crystalline Form 7 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with an onset of about 239 °C and a peak of about 240 °C. Form 7, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 21. In certain embodiments, the contemplated crystalline Form 7 is an anhydrous crystalline form.

[0084] Also disclosed herein is a crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.9 (referred to herein as “Form 8”).

[0085] In one embodiment, the crystalline Form 8 of N-(4-((3-methoxy-4-(1-(methyl-d3)- 1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 7.9, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 14.2, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 14.8, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 15.8, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 18.7, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 19.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 19.6, is characterized by a powder X-ray diffraction pattern that has a 20 IPTS / 128645169.1Attorney Docket No.: ESK-026WO characteristic peak in degrees 2θ at about 22.1, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 23.6, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 23.8, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 26.9, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 27.4.

[0086] In another embodiment, crystalline Form 8 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.9, 14.8, and 19.4. In a further embodiment, crystalline Form 8 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.9, 14.8, 15.8, 19.4, 23.6, and 23.8. In yet another embodiment, crystalline Form 8 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.9, 14.8, 15.8, 18.7, 19.4, 19.6, 22.1, 23.6, and 23.8. In another embodiment, crystalline Form 8 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.9, 14.2, 14.8, 15.8, 18.7, 19.4, 19.6, 22.1, 23.6, 23.8, 26.9, and 27.4. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 22. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0087] The contemplated crystalline Form 8 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 144 °C and a peak of about 151 °C, and a characteristic endotherm with an onset of about 236 °C and a peak of about 237 °C. Form 8, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 23.

[0088] The contemplated crystalline Form 8 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 15.7 wt. % between about 137 °C to about 154 °C. Form 8, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 24. In certain embodiments, the contemplated crystalline Form 8 is a DMSO solvate. 21 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0089] In a further embodiment, a pharmaceutical composition comprising a disclosed crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, and a pharmaceutically acceptable excipient is disclosed herein. In another embodiment, a pharmaceutical composition formed from a disclosed crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol- 3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, disclosed herein.

[0090] In an embodiment, a drug substance comprising at least a detectable amount of a disclosed crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, is disclosed herein. In another embodiment, a drug substance comprising a substantially pure crystalline form of N-(4- ((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide, free base, is disclosed herein. Compositions

[0091] Another aspect of the disclosure provides pharmaceutical compositions comprising crystalline compounds as disclosed herein formulated together with a pharmaceutically acceptable excipient. In particular, the present disclosure provides pharmaceutical compositions comprising crystalline compounds as disclosed herein formulated together with one or more pharmaceutically acceptable excipients. These formulations include those suitable for oral, topical (e.g., transdermal), buccal, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and / or may be formulated for oral, subcutaneous or intravenous administration.

[0092] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic excipient or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, 22 IPTS / 128645169.1Attorney Docket No.: ESK-026WO pharmaceutically acceptable excipients for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0093] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0094] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), 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 starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0095] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or 23 IPTS / 128645169.1Attorney Docket No.: ESK-026WO hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine 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, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0096] 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, nano-suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, 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.

[0097] 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.

[0098] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or excipients comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0099] Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable excipient, and with any preservatives, buffers, or propellants which may be required. 24 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0100] The ointments, pastes, creams and gels may contain, in addition to a 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.

[0101] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0102] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable excipients and stabilizers. The excipients and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0103] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0104] Examples of suitable aqueous and non-aqueous excipients which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures 25 IPTS / 128645169.1Attorney Docket No.: ESK-026WO thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. For example, crystalline forms provided herein may be milled to obtain a particular particle size, and in at least some embodiments, such crystalline forms may remain substantially stable upon milling.

[0105] Amounts of a crystalline compound as described herein in a formulation may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, a single bolus can be administered, several divided doses may be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active crystalline compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0106] The specification for the dosage unit forms of the disclosure is dictated by and directly dependent on (a) the unique characteristics of the crystalline compound selected and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active crystalline compound for the treatment of sensitivity in individuals.

[0107] Disclosed compositions can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it is suitable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. 26 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0108] A disclosed crystalline compound can be administered in a time release formulation, for example in a composition which includes a slow release polymer. The crystalline compound can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are generally known to those skilled in the art.

[0109] In accordance with an alternative aspect of the disclosure, a disclosed crystalline compound can be formulated with one or more additional compounds that enhance the solubility of the compound. Methods

[0110] The crystalline forms disclosed herein are useful for the inhibition of kinase activity of one or more enzymes. In some embodiments the kinase inhibited by the crystalline forms and methods is TYK2.

[0111] Provided herein are crystalline forms of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, that are inhibitors of TYK2 and are therefore useful for treating one or more disorders associated with activity of TYK2 or mutants thereof.

[0112] Provided herein are methods for treating a disease or disorder in a patient in need thereof, wherein the disease or disorder is an autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, neuroinflammatory diseases or disorders, or disorders associated with transplantation, 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.

[0113] In some embodiments, the disease or disorder is a neuroinflammatory disease or disorder. In some embodiments, the neuroinflammatory disease or disorder is, for example, multiple sclerosis. For example, provided herein is a method of treating a neuroinflammatory disease or disorder in a patient in need thereof, comprising administering to the patient an effective amount of a crystalline form described herein, or a pharmaceutical composition 27 IPTS / 128645169.1Attorney Docket No.: ESK-026WO comprising an effective amount of a disclosed crystalline form. Also provided herein is a method of treating multiple sclerosis in a patient in need thereof, comprising administering to the patient an effective amount of a crystalline form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline form.

[0114] 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.

[0115] 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.

[0116] In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocytosis.

[0117] 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.

[0118] In some embodiments, the disease or disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[0119] 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, 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. 28 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0120] In some embodiments, the disease or disorder is associated with transplantation. In some embodiments the disease or disorder associated with transplantation is transplant rejection, or graft versus host disease.

[0121] In some embodiments the disease or disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments the disease or disorder is associated with type I interferon signaling. In some embodiments the disease or disorder is associated with IL-10 signaling. In some embodiments the disorder is associated with IL-12 signaling. In some embodiments the disease or disorder is associated with IL-23 signaling.

[0122] Provided herein are methods for treating an inflammatory or allergic condition of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0123] Provided herein are methods for treating other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, 29 IPTS / 128645169.1Attorney Docket No.: ESK-026WO interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease, incontinentia pigmenti, 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, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction 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, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein 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, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0124] 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.

[0125] 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 30 IPTS / 128645169.1Attorney Docket No.: ESK-026WO erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0126] In some embodiments the inflammatory disease is Sjogren's syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, or diseases affecting the nose such as allergic rhinitis.

[0127] For example, disclosed herein is a method of inhibiting a TYK2 enzyme in a patient or biological sample, comprising contacting said patient or biological sample with a therapeutically effective amount of a crystalline form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline form.

[0128] Also disclosed herein is 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 disorder selected from the group consisting of, e.g., Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, multiple sclerosis, and systemic sclerosis.

[0129] Further disclosed herein is a TYK2-mediated disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline form. In some embodiments, a contemplated TYK2-mediated disorder may be, for example, an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, a neuroinflammatory disease or disorder, or a disorder associated with transplantation. In other embodiments, a contemplated disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signalling.

[0130] 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, multiple sclerosis, and systemic sclerosis in a patient in need thereof, comprising administering to the patient an effective amount of a crystalline form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline form. 31 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0131] In particular, in certain embodiments, the 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 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.

[0132] The crystalline compounds disclosed herein can be used as a medicament or pharmaceutically acceptable composition, e.g., in the form of pharmaceutical preparations for oral, enteral, parenteral, or topical administration, and the contemplated methods disclosed herein may include administering orally, enterally, parenterally, or topically a disclosed crystalline compound, or a composition comprising or formed from such a disclosed crystalline compound. For example, a disclosed crystalline form may be capable of controlling one or more pharmacokinetic properties (e.g., a longer or shorter release profile) when administered by a certain route (e.g., oral) or in a certain formulation, as compared to a different route (e.g., subcutaneous) or other formulation e.g., a formulation having the amorphous form. In one embodiment, a disclosed crystalline form may afford substantial reproducibility from one formulation to another. EXAMPLES

[0133] The compounds and crystalline forms described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. The following non-limiting examples illustrate the disclosure. Instruments and Methods

[0134] PANalytical X-ray powder diffractometers were used for XRPD analysis. The XRPD parameters are listed in Table 1. 32 IPTS / 128645169.1Attorney Docket No.: ESK-026WO TABLE 1 ParametersXRPDXRPD (Reflection Mode) (Variable Temperature model)

[0135] TGA data were collected using a TA Discovery TGA5500 / TGA550 from TA Instruments. DSC was performed using a TA Discovery DSC2500 / DSC250 from TA Instruments. Detailed parameters used are listed in Table 2. TABLE 2 Parameters TGA DSC

[0136] DVS was measured via a SMS (Surface Measurement Systems) DVS Intrinsic Plus. The relative humidity at 25 °C were calibrated against deliquescence point of LiCl, Mg(NO3)2 and KCl. The DVS test parameters are listed in Table 3. 33 IPTS / 128645169.1Attorney Docket No.: ESK-026WO TABLE 3 Parameters Value Tem erature 25 °C )Example 1

[0137] Crystalline Form 1 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was prepared as followed. A 20 mg sample of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol- 3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was weighed into a vial and toluene was added to form a slurry. The slurry was stirred at room temperature for 4 days. The solids were collected by filtration. XRPD analysis indicated that the solid material was crystalline with a pattern consistent with Form 1.

[0138] The XRPD pattern of crystalline Form 1 is shown in FIG. 1. Characteristic peaks include one or more of the peaks shown in Table 4. TABLE 4 Pos. [°2θ] d-spacing [Å] Height [cts] Rel. Int. [%]34 IPTS / 128645169.1Attorney Docket No.: ESK-026WO 12.525 7.06146 124.938 7.7 13.008 6.80037 164.256 12.3

[0139] FIG. 2 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 1. As shown in FIG. 2, crystalline Form 1 shows a characteristic exotherm with an onset of about 138 °C and a peak of about 159 °C, and a characteristic endotherm with an onset of about 236 °C and a peak of about 237 °C.

[0140] Crystalline Form 1 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.5 wt. % between about 112 °C to about 200 °C (FIG. 2). Crystalline Form 1 was observed to be an anhydrous crystalline form. Form 1 was observed to convert to Form 2 upon heating to 200 ºC. Example 2

[0141] Crystalline Form 2 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was prepared as followed. A 20 mg sample of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol- 3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was weighed into a vial and isopropyl acetate was added to form a slurry. The slurry was stirred at 35 IPTS / 128645169.1Attorney Docket No.: ESK-026WO room temperature for 4 days. The solids were collected by filtration. XRPD analysis indicated that the dried material was crystalline with a pattern consistent with Form 2.

[0142] The XRPD pattern of crystalline Form 2 is shown in FIG. 3. Characteristic peaks include one or more of the peaks shown in Table 5. TABLE 5 Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 88909 22346 995 02536 IPTS / 128645169.1Attorney Docket No.: ESK-026WO Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 30.8121 335.44 2.90 0.38

[0143] FIG. 4 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 2. As shown in FIG. 4, crystalline Form 2 shows a characteristic endotherm with an onset of about 236 °C and a peak of about 237 °C (enthalpy 124.1 J / g).

[0144] Crystalline Form 2 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.5 wt. % between about 27 °C to about 150 °C (FIG. 5).

[0145] Crystalline Form 2 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, displayed a dynamic vapor sorption (DVS) profile showing a reversable total mass change of about 0.35 wt.% between about 0% to about 95% relative humidity (RH) at 25 °C (FIG. 6), with no observed form change. Crystalline Form 2 was observed to be an anhydrous crystalline form.

[0146] Form 2 was observed to be chemically and physically stable at 40 °C / 90% RH in the solid form for at least one month. When mixed with the pharmaceutical excipient microcrystalline cellulose (1:2 API:excipient molar ratio), Form 2 converted to Form 6 after 1 week of being exposed under the condition of 40 °C / 75%RH (open). When mixed with the pharmaceutical excipients mannitol and dibasic calcium phosphate (1:2:2 API: excipient: excipient molar ratio), Form 2 converted to Form 6 after 1 week of being exposed under the condition of 40 °C / 75%RH (open). In addition, competitive slurry studies showed that Form 2 was the preferred form aw of 0, and Form 6 was the preferred form aw of 0.08~1.0. 37 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0147] The approximate solubility of Form 2 was measured in solvents at RT. For each experiment, approximately 2 mg of sample was added into a 3 mL glass vial. Solvents were then added stepwise and sonicated or oscillated. Addition of solvent was stopped when the solids dissolved or the total volume reached 1.0 mL. Crystalline Form 2 displayed a solubility of < 2.0 mg / mL in MeOH, a solubility of < 2.0 mg / mL in EtOH at RT, a solubility of < 2.3 mg / mL in IPA at RT, a solubility of < 2.2 mg / mL in acetone at RT, a solubility of < 2.1 mg / mL in MIBK at RT, a solubility of < 2.0 mg / mL in IPAc at RT, a solubility of < 2.2 mg / mL in MTBE at RT, a solubility between about 4.8 mg / mL and about 9.5 mg / mL in THF at RT, a solubility of < 2.3 mg / mL in 2-MeTHF at RT, a solubility between about 2.2 mg / mL and about 5.5 mg / mL in 1,4- dioxane at RT, a solubility of < 2.3 mg / mL in MeCN at RT, a solubility between about 23.0 mg / mL and about 46.0 mg / mL in CHCl3at RT, a solubility between about 4.8 mg / mL and about 9.5 mg / mL in CH2Cl2 at RT, a solubility of < 2.1 mg / mL in n-heptane at RT, a solubility of < 2.0 mg / mL in toluene at RT, a solubility of < 42.0 mg / mL in DMAc at RT, a solubility between about 19.0 mg / mL and about 38.0 mg / mL in DMSO at RT, a solubility between about 20.0 mg / mL and about 40.0 mg / mL in NMP at RT, and a solubility of < 2.2 mg / mL in H2O at RT. Example 3

[0148] Crystalline Form 3 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was prepared as followed. A 20 mg sample of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol- 3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was weighed into a vial and methanol was added to form a slurry. The slurry was stirred at room temperature for 4 days. The solids were collected by filtration. XRPD analysis indicated that the solid material was crystalline with a pattern consistent with Form 3.

[0149] The XRPD pattern of crystalline Form 3 is shown in FIG. 7. Characteristic peaks include one or more of the peaks shown in Table 6. TABLE 6 Pos. [°2θ] d-spacing [Å] Height [cts] Rel. Int. [%]38 IPTS / 128645169.1Attorney Docket No.: ESK-026WO 9.604 9.20207 45.4722 0.6 12.662 6.98550 138.042 4.8

[0150] FIG. 8 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 3. As shown in FIG. 8, crystalline Form 3 shows a characteristic endotherm with an onset 39 IPTS / 128645169.1Attorney Docket No.: ESK-026WO of about 84 °C and a peak of about 94 °C, a characteristic exotherm with an onset of about 156 °C and a peak of about 169 °C, a characteristic endotherm with a peak of about 223 °C, a characteristic endotherm with a peak of about 237 °C, and a characteristic endotherm with a peak of about 240 °C.

[0151] Crystalline Form 3 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.1 wt. % between about 25 °C to about 117 °C (FIG. 9). Crystalline Form 3 was observed to be a hydrate crystalline form. Form 3 was observed to convert to Form 2 upon heating to 165 ºC. Example 4

[0152] Crystalline Form 4 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was prepared as followed. A 20 mg sample of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol- 3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was weighed into a vial and taken up in 1,4-dioxane (2 mL). The mixture was heated to 50 ºC and then slowly cooled to 20 ºC at a rate of 0.1 ºC / min. The solids were then collected by filtration. XRPD analysis indicated that the solid material was crystalline with a pattern consistent with Form 4.

[0153] The XRPD pattern of crystalline Form 4 is shown in FIG. 10. Characteristic peaks include one or more of the peaks shown in Table 7. TABLE 7 Pos. [°2θ] d-spacing [Å] Height [cts] Rel. Int. [%]40 IPTS / 128645169.1Attorney Docket No.: ESK-026WO 15.845 5.58851 32.0926 7.3 16.310 5.43024 30.38 6.4

[0154] FIG. 11 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 4. As shown in FIG. 11, crystalline Form 4 shows a characteristic endotherm with an onset of about 113 °C and a peak of about 125 °C, and a characteristic endotherm with an onset of about 239 °C and a peak of about 240 °C.

[0155] Crystalline Form 4 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 8.3 wt. % between about 66 °C to about 150 °C (FIG. 12). Crystalline Form 4 was observed to be a 1,4-dioxane solvate crystalline form, with 7.8 residual solvent wt. % as determined by1H NMR.Example 5

[0156] Crystalline Form 5 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was prepared as followed. A 20 mg sample of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol- 3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was weighed into a vial and taken up in acetic acid (0.5 mL). The solvent was allowed to slowly 41 IPTS / 128645169.1Attorney Docket No.: ESK-026WO evaporate at room temperature. The solids were then collected. XRPD analysis indicated that the solid material was crystalline with a pattern consistent with Form 5.

[0157] The XRPD pattern of crystalline Form 5 is shown in FIG. 13. Characteristic peaks include one or more of the peaks shown in Table 8. TABLE 8 Pos. [°2θ] d-spacing [Å] Height [cts] Rel. Int. [%] 5053 1747366 10271 157

[0158] FIG. 14 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 5. As shown in FIG. 14, crystalline Form 5 shows a characteristic endotherm with an onset of about 83 °C and a peak of about 104 °C, and a characteristic endotherm with an onset of about 224 °C and a peak of about 230 °C.

[0159] Crystalline Form 5 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 20.8 wt. % between about 25 °C to about 184 °C (FIG. 15). Crystalline Form 5 was observed to be a hydrate crystalline form. Form 5 was observed to convert to Form 2 upon heating to 145 ºC. Example 6 42 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0160] Crystalline Form 6 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was prepared as followed. A slurry of crystalline Form 2 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, in EtOH:H2O (4:1, v:v) was stirred for three days at room temperature. The solids were filtered and dried at room temperature under vacuum. XRPD analysis indicated that the dried material was crystalline with a pattern consistent with Form 6.

[0161] The XRPD pattern of crystalline Form 6 is shown in FIG. 16. Characteristic peaks include one or more of the peaks shown in Table 9. TABLE 9 Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%]43 IPTS / 128645169.1Attorney Docket No.: ESK-026WO Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 22.5031 1181.71 3.95 4.95

[0162] FIG. 17 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 6. As shown in FIG. 17, crystalline Form 6 shows a characteristic endotherm with an onset of about 136 °C and a peak of about 152 °C (enthalpy 154.8 J / g), and a characteristic endotherm with an onset of about 240 °C and a peak of about 241 °C (enthalpy 110.6 J / g).

[0163] Crystalline Form 6 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, displayed a 44 IPTS / 128645169.1Attorney Docket No.: ESK-026WO thermogravimetric analysis (TGA) profile showing a mass loss of about 4.7 wt. % between about 18 °C to about 150 °C. (FIG. 18).

[0164] Crystalline Form 6 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, displayed a dynamic vapor sorption (DVS) profile showing a reversable total mass change of about 0.05 wt.% between about 0% to about 95% relative humidity (RH) at 25 °C (FIG. 19), with no observed form change. Crystalline Form 6 was observed to be a hydrate crystalline form. Example 7

[0165] Crystalline Form 7 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was prepared as followed. A sample of crystalline Form 4 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was heated from room temperature to 160 °C at a rate of 10 °C / min, then cooled back to room temperature at a rate of 3 °C / min. The solids were then collected. XRPD analysis indicated that the solid material was crystalline with a pattern consistent with Form 7.

[0166] The XRPD pattern of crystalline Form 7 is shown in FIG. 20. Characteristic peaks include one or more of the peaks shown in Table 10. TABLE 10 Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%]45 IPTS / 128645169.1Attorney Docket No.: ESK-026WO 16.567 5.34662 254.278 7.7 17.124 5.17400 66.6531 0.8

[0167] FIG. 21 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 7. As shown in FIG. 21, crystalline Form 7 shows a characteristic endotherm with an onset of about 239 °C and a peak of about 240 °C. Crystalline Form 7 was observed to be an 46 IPTS / 128645169.1Attorney Docket No.: ESK-026WO anhydrous crystalline form. Example 8

[0168] Crystalline Form 8 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, was prepared as followed. Dimethyl sulfoxide (approximately 8 volume) was added to N-(4-((3- methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2- yl)cyclopropanecarboxamide. The mixture was heated to 40 °C and then heated to approximately 90 °C for approximately 10 minutes. The mixture was filtered and rinsed with DMSO (approximately 2 volume). 1-Propanol (approximately 2 volume) was slowly added and the mixture was cooled to room temperature. The solid was filtered, the filter cake washed with 1-propanol, and the solid dried under vacuum at 50 °C. XRPD analysis indicated that the solid material was crystalline with a pattern consistent with Form 8.

[0169] The XRPD pattern of crystalline Form 8 is shown in FIG. 22. Characteristic peaks include one or more of the peaks shown in Table 11. TABLE 11 Pos. [° 2θ] Height [cts] d-spacing, [Å] Rel. Int. [%]47 IPTS / 128645169.1Attorney Docket No.: ESK-026WO 20.7958 48.10 4.27 0.16 21.0102 287.60 4.22 0.9848 IPTS / 128645169.1Attorney Docket No.: ESK-026WO

[0170] FIG. 23 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 8. As shown in FIG. 23, crystalline Form 8 shows a characteristic endotherm with an onset of about 144 °C and a peak of about 151 °C, and a characteristic endotherm with an onset of about 236 °C and a peak of about 237 °C.

[0171] Crystalline Form 8 of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3- yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 15.7 wt. % between about 137 °C to about 154 °C (FIG. 24). Crystalline Form 8 was observed to be a DMSO solvate. INCORPORATION BY REFERENCE

[0172] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS

[0173] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0174] 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 indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

[0175] What is claimed is: 49 IPTS / 128645169.1

Claims

Attorney Docket No.: ESK-026WO CLAIMS 1. A crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base (Form 2), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 11.

4.

2. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 11.4, 20.9, and 22.

9.

3. The crystalline form of claim 1 or 2, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 11.

0. 11.4, 17.2, 20.9, 22.9, and 25.

0.

4. The crystalline form of any one of claims 1-3, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 11.0, 11.4, 13.3, 17.2, 20.9, 21.9, 22.9, 25.0, and 27.

2.

5. The crystalline form of any one of claims 1-4, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 11.0, 11.4, 13.3, 17.2, 20.9, 21.9, 22.9, 23.4, 25.0, 27.2, 28.0, and 30.

4.

6. The crystalline form of any one of claims 1-5, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

7. The crystalline form of any one of claims 1-6, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 236 °C and a peak of about 237 °C.

8. The crystalline form of any one of claims 1-7, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.5 wt. % between about 27 °C to about 150 °C.

9. The crystalline form of any one of claims 1-9, wherein the crystalline form is an anhydrate crystalline form.

10. A crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base (Form 6), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 9.

8. 50 IPTS / 128645169.1Attorney Docket No.: ESK-026WO 11. The crystalline form of claim 10, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 9.8, 17.9, and 24.

4.

12. The crystalline form of claim 10 or 11, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 9.8, 14.3, 17.9, 23.6, 23.9, and 24.

4.

13. The crystalline form of any one of claims 10-12, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.4, 9.8, 12.8, 14.3, 17.9, 23.6, 23.9, 24.4, and 30.

2.

14. The crystalline form of any one of claims 10-13, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.4, 9.8, 12.8, 14.3, 17.9, 22.5, 23.1, 23.6, 23.9, 24.4, 30.2, and 31.

3.

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

16. The crystalline form of any one of claims 10-15, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 136 °C and a peak of about 152 °C, and a characteristic endotherm with an onset of about 240 °C and a peak of about 241 °C.

17. The crystalline form of any one of claims 10-16, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.7 wt. % between about 18 °C to about 150 °C.

18. The crystalline form of any one of claims 10-17, wherein the crystalline form is a hydrate crystalline form.

19. A crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base (Form 1), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 6.4, 6.8, 9.7, 12.5, 13.0, 13.7, 20.7, 23.2, and 24.1, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation. 51 IPTS / 128645169.1Attorney Docket No.: ESK-026WO 20. The crystalline form of claim 19, characterized by a differential scanning calorimetry (DSC) profile having a characteristic exotherm with an onset of about 138 °C and a peak of about 159 °C, and a characteristic endotherm with an onset of about 236 °C and a peak of about 237 °C.

21. The crystalline form of claim 19 or 20, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.5 wt. % between about 112 °C to about 200 °C.

22. The crystalline form of any one of claims 19-21, wherein the crystalline form is an anhydrate crystalline form.

23. A crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base (Form 3), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.2, 9.1, 12.7, 13.3, 18.5, 22.6, 25.6, 25.9, and 26.7, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

24. The crystalline form of claim 23, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 84 °C and a peak of about 94 °C, a characteristic exotherm with an onset of about 156 °C and a peak of about 169 °C, a characteristic endotherm with a peak of about 223 °C, a characteristic endotherm with a peak of about 237 °C, and a characteristic endotherm with a peak of about 240 °C.

25. The crystalline form of claim 23 or 24, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.1 wt. % between about 25 °C to about 117 °C.

26. The crystalline form of any one of claims 23-25, wherein the crystalline form is a hydrate crystalline form.

27. A crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base (Form 4), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.1, 10.0, 11.2, 17.1, 18.3, 19.3, 21.8, 23.8, and 27.0, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

28. The crystalline form of claim 27, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 113 °C and a peak of about 125 °C, and a characteristic endotherm with an onset of about 239 °C and a peak of about 240 °C. 52 IPTS / 128645169.1Attorney Docket No.: ESK-026WO 29. The crystalline form of claim 27 or 28, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 8.3 wt. % between about 66 °C to about 150 °C.

30. A crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base (Form 5), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 5.1, 6.3, 7.0, 7.5, 10.2, 12.6, 13.5, 15.9, and 18.9, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

31. The crystalline form of claim 30, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 83 °C and a peak of about 104 °C, and a characteristic endotherm with an onset of about 224 °C and a peak of about 230 °C.

32. The crystalline form of claim 30 or 31, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 20.8 wt. % between about 25 °C to about 184 °C.

33. The crystalline form of any one of claims 30-32, wherein the crystalline form is a hydrate crystalline form.

34. A crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base (Form 7), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.2, 8.4, 10.1, 14.0, 16.6, 24.1, 25.5, 25.8, and 27.1, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

35. The crystalline form of claim 34, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 239 °C and a peak of about 240 °C.

36. The crystalline form of claim 34 or 35, wherein the crystalline form is an anhydrate crystalline form.

37. A crystalline form of N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, free base (Form 8), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.9, 53 IPTS / 128645169.1Attorney Docket No.: ESK-026WO 14.8, 15.8, 18.7, 19.4, 19.6, 22.1, 23.6, and 23.8, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

38. The crystalline form of claim 37, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 144 °C and a peak of about 151 °C, and a characteristic endotherm with an onset of about 236 °C and a peak of about 237 °C.

39. The crystalline form of claim 37 or 38, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 15.7 wt. % between about 137 °C to about 154 °C.

40. A pharmaceutical composition comprising a crystalline form of any one of claims 1-39, and a pharmaceutically acceptable excipient.

41. A pharmaceutical composition formed from the crystalline form of any one of claims 1-39.

42. 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 of any one of claims 1-39, or the pharmaceutical composition of claim 40 or 41.

43. A method of treating a TYK2-mediated disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of claims 1-39, or the pharmaceutical composition of claim 40 or 41.

44. A method of treating a neuroinflammatory disease in a patient in need thereof, comprising administering to the patient an effective amount of a crystalline form of any one of claims 1-39, or the pharmaceutical composition of claim 40 or 41.

45. The method of claim 44, wherein the neuroinflammatory disease is multiple sclerosis.

46. A method of treating multiple sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of claims 1-39, or the pharmaceutical composition of claim 40 or 41. 54 IPTS / 128645169.1

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