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 hydrogen fumarate, pharmaceutical compositions thereof, and methods of use.

Description

Attorney Docket No.: ESK-027WO 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 / 671,870, 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 / 128645171.1Attorney Docket No.: ESK-027WO 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 hemi-fumaric acid, N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4- triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide mono- fumaric acid, and N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)- 5-propionylpyridin-2-yl)cyclopropanecarboxamide bis-fumaric acid. Also disclosed are crystalline hydrates, anhydrates, hemihydrates, solvates, tautomers and cocrystals of any of the crystalline forms described herein.

[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, hemi-fumaric acid, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 24.2, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 7.5, 11.8, and 24.2, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 7.5, 8.0, 11.8, 22.6, 22.8, and 24.2, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 7.5, 8.0, 11.8, 13.8, 16.4, 22.6, 22.8, 23.2, and 24.2, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 7.5, 8.0, 9.0, 11.8, 13.8, 15.3, 16.4, 22.6, 22.8, 23.2, 24.2, and 27.1.

[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: .2 IPTS / 128645171.1Attorney Docket No.: ESK-027WO

[0007] Further contemplated herein is 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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid, 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 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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid. 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 hemi-fumaric acid, mono-fumaric acid, or bis- fumaric acid.

[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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid.

[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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid. 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, hemi-fumaric acid (Form 1).

[0011] FIG. 2 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, hemi-fumaric acid (Form 1). 3 IPTS / 128645171.1Attorney Docket No.: ESK-027WO

[0012] FIG. 3 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, hemi-fumaric acid (Form 1).

[0013] FIG. 4 depicts the asymmetric unit of the N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, hemi- fumaric acid (Form 1) single X-ray co-crystal structure.

[0014] FIG. 5 depicts the unit cell of the N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4- triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide and fumaric acid molecule in the Form 1 single X-ray co-crystal structure.

[0015] FIG. 6 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, hemi-fumaric acid (Form 2).

[0016] FIG. 7 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, hemi-fumaric acid (Form 2).

[0017] FIG. 8 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, hemi-fumaric acid (Form 2).

[0018] FIG. 9 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, hemi-fumaric acid (Form 3).

[0019] FIG. 10 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, hemi-fumaric acid (Form 3).

[0020] FIG. 11 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, hemi-fumaric acid (Form 3). 4 IPTS / 128645171.1Attorney Docket No.: ESK-027WO

[0021] FIG. 12 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, hemi-fumaric acid (Form 4).

[0022] FIG. 13 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, hemi-fumaric acid (Form 4).

[0023] FIG. 14 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, hemi-fumaric acid (Form 4).

[0024] FIG. 15 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, bis-fumaric acid (Form 5).

[0025] FIG. 16 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, bis-fumaric acid (Form 5).

[0026] FIG. 17 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, bis-fumaric acid (Form 5).

[0027] FIG. 18 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, mono-fumaric acid (Form 6).

[0028] FIG. 19 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, mono-fumaric acid (Form 6).

[0029] FIG. 20 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, mono-fumaric acid (Form 6). 5 IPTS / 128645171.1Attorney Docket No.: ESK-027WO

[0030] FIG. 21 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, hemi-fumaric acid (Form 7).

[0031] FIG. 22 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, hemi-fumaric acid (Form 7).

[0032] FIG. 23 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, hemi-fumaric acid (Form 7).

[0033] FIG. 24 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, mono-fumaric acid (Form 8).

[0034] FIG. 25 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, mono-fumaric acid (Form 8).

[0035] FIG. 26 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, mono-fumaric acid (Form 8). DETAILED DESCRIPTION

[0036] 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

[0037] 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 6 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 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.

[0038] “Treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0039] The term “disorder” refers to and is used interchangeably with, the terms “disease,” “condition,” or “illness,” unless otherwise indicated.

[0040] “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.

[0041] 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.

[0042] 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.

[0043] “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 7 IPTS / 128645171.1Attorney Docket No.: ESK-027WO cancer or a blood disorder is desired. “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0044] 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.

[0045] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0046] 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.

[0047] 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.

[0048] 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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid, 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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid, as measured, for example, by XRPD, 8 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid, 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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid, 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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid,. 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- yl)cyclopropanecarboxamide hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid, 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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid.

[0049] 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 fumaric acid, mono-fumaric acid, or bis-fumaric acid, 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

[0050] 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- 9 IPTS / 128645171.1Attorney Docket No.: ESK-027WO yl)cyclopropanecarboxamide hemi-fumaric acid, N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4- triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide mono- fumaric acid, and N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)- 5-propionylpyridin-2-yl)cyclopropanecarboxamide bis-fumaric acid. Also disclosed are crystalline hydrates, anhydrates, hemihydrates, solvates, tautomers and cocrystals of any of the crystalline forms described herein.

[0051] 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, hemi-fumaric acid, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 24.2 (referred to herein as “Form 1”).

[0052] 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, hemi-fumaric acid, 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 8.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 9.0, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 11.8, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 13.8, 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 16.4, 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 22.8, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 23.2, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 24.2, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 27.1. 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 7.5, 11.8, and 24.2. 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 10 IPTS / 128645171.1Attorney Docket No.: ESK-027WO about 7.5, 8.0, 11.8, 22.6, 22.8, and 24.2. 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 7.5, 8.0, 11.8, 13.8, 16.4, 22.6, 22.8, 23.2, and 24.2. 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 7.5, 8.0, 9.0, 11.8, 13.8, 15.3, 16.4, 22.6, 22.8, 23.2, 24.2, and 27.1. 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.

[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, hemi- fumaric acid, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with an onset of about 242 °C and a peak of about 243 °C (enthalpy 168.2 J / g). Form 1, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 2.

[0054] 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, hemi- fumaric acid, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.3 wt. % between about 19 °C to about 120 °C. Form 1, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 3. In certain embodiments, the contemplated crystalline Form 1 is an anhydrous crystalline form.

[0055] In some embodiments, contemplated crystalline Form 1 displays a molar ratio of fumaric acid 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, free base of about 0.5. In some embodiments, 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, hemi-fumaric acid, is an anhydrous co-crystal 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 fumaric acid; wherein the wherein the crystalline form is characterized by the following unit cell parameters: cell dimensions: a = 8.62960(10) Å, α = 106.4580(10)º, b = 12.1329(2) Å, β = 97.2400(10)º, c =12.6652(2) Å, γ = 105.1200(10)º; space group = P ̅1 ̅ ;volume = 1198.75(3) Å3; and crystal11 IPTS / 128645171.1Attorney Docket No.: ESK-027WO system = triclinic. For example, Form 1 may be characterized by the single X-ray co-crystal structures shown in FIG. 4 and FIG. 5.

[0056] 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, hemi-fumaric acid, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.7, 20.1, and 26.6 (referred to herein as “Form 2”).

[0057] 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, hemi-fumaric acid, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 7.7, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 8.1, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 13.1, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 13.8, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 15.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 16.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 20.1, 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 23.2, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 26.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 26.6, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 27.5.

[0058] 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 7.7, 15.4, 16.3, 20.1, 26.6, and 27.5. 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 7.7, 8.1, 15.4, 16.3, 20.1, 23.2, 26.3, 26.6, and 27.5. In a further embodiment, crystalline Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more 12 IPTS / 128645171.1Attorney Docket No.: ESK-027WO characteristic peaks in degrees 2θ at about 7.7, 8.1, 13.1, 13.8, 15.4, 16.3, 20.1, 20.9, 23.2, 26.3, 26.6, and 27.5. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 6. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0059] 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, hemi- fumaric acid, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with an onset of about 129 °C and a peak of about 134 °C (enthalpy 62.2 J / g), and a characteristic endotherm with an onset of about 240 °C and a peak of about 242 °C (enthalpy 118.9 J / g). Form 2, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 7.

[0060] 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, hemi- fumaric acid, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.8 wt. % between about 31 °C to about 90 °C, and a mass loss of about 14.8 wt. % between about 90 °C to about 180 °C. Form 2, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 8.

[0061] In some embodiments, contemplated crystalline Form 2 displays a molar ratio of fumaric acid 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, free base of about 0.5. In certain embodiments, the contemplated crystalline Form 2 is a dichloromethane solvate crystalline form, with 14.2 residual solvent wt. % as determined by1H NMR.

[0062] 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, hemi-fumaric acid, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.5, 7.8, and 14.6 (referred to herein as “Form 3”).

[0063] 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, hemi-fumaric acid, is characterized by a powder X-ray diffraction pattern that has a characteristic 13 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 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 7.8, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 8.9, 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 15.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 16.1, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 22.0, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 29.3.

[0064] 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 7.5, 7.8, 8.9, 14.6, 15.0, and 22.0. 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 7.5, 7.8, 8.9, 14.6, 15.0, 16.1, 22.0, and 29.3. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 9. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0065] 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, hemi- fumaric acid, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with a peak of about 76 °C, a characteristic endotherm with a peak of about 102 °C, and a characteristic endotherm with an onset of about 236 °C and a peak of about 238 °C (enthalpy 120.1 J / g). Form 3, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 10.

[0066] 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, hemi- fumaric acid, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.7 wt. % between about 27 °C to about 130 °C. Form 3, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 11. 14 IPTS / 128645171.1Attorney Docket No.: ESK-027WO

[0067] In some embodiments, contemplated crystalline Form 3 displays a molar ratio of fumaric acid 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, free base of about 0.5. In certain embodiments, the contemplated crystalline Form 3 is a hydrate crystalline form.

[0068] 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, hemi-fumaric acid, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 13.3, 20.1, and 25.3 (referred to herein as “Form 4”).

[0069] 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, hemi-fumaric acid, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 8.2, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 8.8, 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 13.3, is 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 16.7, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 18.4, 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 20.1, 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 25.3, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 25.8.

[0070] 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 12.5, 13.3, 16.7, 20.1, 22.6, and 25.3. 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 15 IPTS / 128645171.1Attorney Docket No.: ESK-027WO about 8.2, 8.8, 12.5, 13.3, 13.7, 16.7, 20.1, 22.6, and 25.3. 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 8.2, 8.8, 12.5, 13.3, 13.7, 16.7, 18.4, 19.3, 20.1, 22.6, 25.3, and 25.8. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 12. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0071] 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, hemi- fumaric acid, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with a peak of about 76 °C, a characteristic endotherm with a peak of about 102 °C, and a characteristic endotherm with an onset of about 119 °C and a peak of about 123 °C (enthalpy 36.5 J / g), and a characteristic endotherm with an onset of about 246 °C and a peak of about 248 °C (enthalpy 105.8 J / g). Form 4, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 13.

[0072] 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, hemi- fumaric acid, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.0 wt. % between about 25 °C to about 80 °C, and a mass loss of about 16.6 wt. % between about 80 °C to about 180 °C. Form 4, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 14.

[0073] In some embodiments, contemplated crystalline Form 4 displays a molar ratio of fumaric acid 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, free base of about 0.5. In certain embodiments, the contemplated crystalline Form 4 is a dibromomethane solvate crystalline form, with 19.8 residual solvent wt. % as determined by1H NMR.

[0074] 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, bis-fumaric acid, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.8, 26.1, and 27.7 (referred to herein as “Form 5”). 16 IPTS / 128645171.1Attorney Docket No.: ESK-027WO

[0075] 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, bis-fumaric acid, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 8.8, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 15.7, 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 17.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 19.9, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 20.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 22.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 22.8, 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 25.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 26.1, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 27.7.

[0076] 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 8.8, 15.7, 15.9, 23.6, 26.1, and 27.7. 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 8.8, 15.7, 15.9, 19.9, 20.4, 23.6, 25.0, 26.1, and 27.7. 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 8.8, 15.7, 15.9, 17.0, 19.9, 20.4, 22.3, 22.8, 23.6, 25.0, 26.1, and 27.7. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 15. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0077] 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, bis- fumaric acid, may be characterized by a differential scanning calorimetry (DSC) profile showing 17 IPTS / 128645171.1Attorney Docket No.: ESK-027WO a characteristic endotherm with a peak of about 231 °C, and a characteristic endotherm with a peak of about 234 °C. Form 5, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 16.

[0078] 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, bis- fumaric acid, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.0 wt. % between about 25 °C to about 80 °C, and a mass loss of about 2.8 wt. % between about 23 °C to about 160 °C. Form 5, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 17.

[0079] In some embodiments, contemplated crystalline Form 5 displays a molar ratio of fumaric acid 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, free base of about 2.1. In certain embodiments, the contemplated crystalline Form 5 is an anhydrate crystalline form.

[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, mono-fumaric acid, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.6, 15.6, and 26.7 (referred to herein as “Form 6”).

[0081] 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, mono-fumaric acid, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 7.6, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 12.9, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 13.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 13.9, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 14.1, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 15.6, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 16.1, 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- 18 IPTS / 128645171.1Attorney Docket No.: ESK-027WO ray diffraction pattern that has a characteristic peak in degrees 2θ at about 20.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 20.5, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 24.2, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 26.7.

[0082] 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 7.6, 15.6, 16.1, 20.0, 24.2, and 26.7. 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 7.6, 12.9, 14.1, 15.6, 16.1, 20.0, 20.5, 24.2, and 26.7. 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 7.6, 12.9, 13.4, 13.9, 14.1, 15.6, 16.1, 17.0, 20.0, 20.5, 24.2, and 26.7. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 18. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0083] 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, mono-fumaric acid, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with an onset of about 142 °C and a peak of about 158 °C (enthalpy 38.2 J / g), a characteristic endotherm with a peak of about 228 °C, and a characteristic endotherm with a peak of about 232 °C. Form 6, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 19.

[0084] 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, mono-fumaric acid, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 9.1 wt. % between about 26 °C to about 180 °C. Form 6, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 20.

[0085] In some embodiments, contemplated crystalline Form 6 displays a molar ratio of fumaric acid to N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5- 19 IPTS / 128645171.1Attorney Docket No.: ESK-027WO propionylpyridin-2-yl)cyclopropanecarboxamide, free base of about 1.0. In certain embodiments, the contemplated crystalline Form 6 is a 1,4-dioxane solvate crystalline form, with 7.5 residual solvent wt. % as determined by1H NMR.

[0086] Also disclosed herein is aform 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, hemi-fumaric acid, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.5, 9.0, and 14.6 (referred to herein as “Form 7”).

[0087] 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, hemi-fumaric acid, 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 7.7, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 9.0, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 11.8, 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 14.6, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 15.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 16.1, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 22.0, is characterized by a powder X- ray diffraction pattern that has a characteristic peak in degrees 2θ at about 22.7, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 24.2, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 25.7.

[0088] In a further 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 7.5, 9.0, 14.6, 16.1, 22.0, and 24.2. 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 7.5, 9.0, 11.8, 14.6, 15.0, 16.1, 22.0, 22.7, and 24.2. In another embodiment, crystalline 20 IPTS / 128645171.1Attorney Docket No.: ESK-027WO Form 7 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 2θ at about 7.5, 7.7, 9.0, 11.8, 14.2, 14.6, 15.0, 16.1, 22.0, 22.7, 24.2, and 25.7. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 21. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0089] 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, hemi- fumaric acid, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with an onset of about 229 °C and a peak of about 235 °C (enthalpy 115.6 J / g). Form 7, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 22.

[0090] 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, hemi- fumaric acid, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.5 wt. % between about 20 °C to about 150 °C. Form 7, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 23.

[0091] In some embodiments, contemplated crystalline Form 7 displays a molar ratio of fumaric acid 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, free base of about 0.5. In certain embodiments, the contemplated crystalline Form 7 is an anhydrate crystalline form.

[0092] 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, mono-fumaric acid, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.0, 13.5, and 25.0 (referred to herein as “Form 8”).

[0093] 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, mono-fumaric acid, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 8.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 8.5, is characterized by a powder X- 21 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 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 14.1, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 14.5, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 16.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 16.7, 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 20.7, 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 25.0, and / or is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 2θ at about 29.8.

[0094] 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 8.0, 8.5, 13.5, 16.7, 25.0, and 29.8. 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 8.0, 8.5, 13.5, 14.1, 16.7, 20.7, 22.6, 25.0, and 29.8. 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 8.0, 8.5, 13.5, 14.1, 14.5, 16.0, 16.7, 17.9, 20.7, 22.6, 25.0, and 29.8. For example, a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 24. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0095] 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, hemi- fumaric acid, may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with a peak of about 228 °C, and a characteristic endotherm with a peak of about 232 °C. Form 8, for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 25. 22 IPTS / 128645171.1Attorney Docket No.: ESK-027WO

[0096] 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, mono-fumaric acid, may be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 1.5 wt. % between about 32 °C to about 150 °C. Form 8, for example, may be characterized by the thermogravimetric analysis profile shown in FIG. 26.

[0097] In some embodiments, contemplated crystalline Form 8 displays a molar ratio of fumaric acid 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, free base of about 1.0. In certain embodiments, the contemplated crystalline Form 8 is an anhydrate crystalline form.

[0098] 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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid, 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 hemi-fumaric acid, mono-fumaric acid, or bis- fumaric acid, disclosed herein.

[0099] 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 hemi-fumaric acid, mono-fumaric acid, or bis-fumaric acid, 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 hemi- fumaric acid, mono-fumaric acid, or bis-fumaric acid, is disclosed herein. Compositions

[0100] 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 23 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 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.

[0101] 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, 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.

[0102] 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.

[0103] 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) 24 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 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.

[0104] 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 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.

[0105] 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.

[0106] Suspensions, in addition to the subject composition, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and 25 IPTS / 128645171.1Attorney Docket No.: ESK-027WO sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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 26 IPTS / 128645171.1Attorney Docket No.: ESK-027WO acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0112] 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.

[0113] 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 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.

[0114] 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.

[0115] 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 27 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 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.

[0116] 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.

[0117] 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.

[0118] 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

[0119] 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.

[0120] 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 hemi- 28 IPTS / 128645171.1Attorney Docket No.: ESK-027WO fumaric acid, mono-fumaric acid, or bis-fumaric acid, that are inhibitors of TYK2 and are therefore useful for treating one or more disorders associated with activity of TYK2 or mutants thereof.

[0121] 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.

[0122] 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 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.

[0123] 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.

[0124] 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.

[0125] 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 29 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 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.

[0126] 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.

[0127] In some embodiments, the disease or disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] Provided herein are methods for treating other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases 30 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 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, 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, 31 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 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.

[0133] 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.

[0134] In some embodiments the inflammatory disease is a Th1 or Th17 mediated disease. In some embodiments the Th17 mediated disease is selected from Systemic lupus erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0135] 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.

[0136] 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.

[0137] 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. 32 IPTS / 128645171.1Attorney Docket No.: ESK-027WO

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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 33 IPTS / 128645171.1Attorney Docket No.: ESK-027WO embodiment, a disclosed crystalline form may afford substantial reproducibility from one formulation to another. EXAMPLES

[0142] 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

[0143] PANalytical X-ray powder diffractometers were used for XRPD analysis. The XRPD parameters are listed in Table 1. TABLE 1 ParametersXRPDXRPD (Reflection Mode) (Variable Temperature model)

[0144] 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. 34 IPTS / 128645171.1Attorney Docket No.: ESK-027WO TABLE 2 Parameters TGA DSC Method Ram Ram

[0145] 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. TABLE 3 Parameters Value )Example 1

[0146] 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, hemi-fumaric acid, was prepared as followed. A slurry of 5 g 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 fumaric acid (1.1 equiv) in THF was stirred at 50 °C for 1 hour, then at room temperature for 35 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 4 days. The solids were filtered and dried at 40 °C under vacuum for 3 hours. XRPD analysis indicated that the dried material was crystalline with a pattern consistent with Form 1.

[0147] 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] Height [cts] d-spacing [Å] Rel. Int. [%] 74761 277545 1183 377336 IPTS / 128645171.1Attorney Docket No.: ESK-027WO Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 22.7857 2272.18 3.90 30.89

[0148] FIG. 2 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 1. As shown in FIG. 2, crystalline Form 1 shows a characteristic endotherm with an onset of about 242 °C and a peak of about 243 °C (enthalpy 168.2 J / g).

[0149] 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, hemi-fumaric acid, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.3 wt. % between about 19 °C to about 120 °C (FIG. 3).

[0150] Crystalline Form 1 displayed a molar ratio of fumaric acid 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, free base of about 0.5. Form 1 was observed to be an anhydrate crystalline form. 37 IPTS / 128645171.1Attorney Docket No.: ESK-027WO

[0151] Form 1 was observed to be chemically and physically stable at 60 °C (closed), 40 °C / 90%RH (open), and 40 °C / 90%RH (closed) in the solid form for at least six weeks, with no observed change in polymorphic form. When mixed with the pharmaceutical excipient microcrystalline cellulose (1:2 API:excipient molar ratio), Form 1 was observed to be chemically and physically stable after being exposed under the condition of 40 °C / 75%RH (open) at least 8 weeks, with no observed change in polymorphic form. When mixed with the pharmaceutical excipient microcrystalline cellulose (1:2 API:excipient molar ratio), Form 1 was also observed to be chemically and physically stable after being exposed under the condition of 40 °C / 75%RH (open) at least 8 weeks, with no observed change in polymorphic form.

[0152] The approximate solubility of Form 1 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 1 displayed a solubility between about 1.9 mg / mL and about 4.75 mg / mL in MeOH, a solubility of < 2.1 mg / mL in EtOH at RT, a solubility of < 1.7 mg / mL in IPA at RT, a solubility of < 1.7 mg / mL in acetone at RT, a solubility of < 2.2 mg / mL in MIBK at RT, a solubility of < 2.1 mg / mL in EtOAc at RT, a solubility of < 2.2 mg / mL in IPAc at RT, a solubility of < 1.8 mg / mL in MTBE at RT, a solubility between about 2.3 mg / mL and about 5.8 mg / mL in 1,4-dioxane at RT, a solubility between about 5.0 mg / mL and about 10.1 mg / mL in THF at RT, a solubility of < 2.1 mg / mL in 2-MeTHF at RT, a solubility between about 0.77 mg / mL and about 1.15 mg / mL in 1-propanol at RT, a solubility of < 2.2 mg / mL in MeCN at RT, a solubility of < 1.9 mg / mL in CHCl3at RT, a solubility of < 1.8 mg / mL in CH2Cl2 at RT, a solubility of < 2.2 mg / mL in n-heptane at RT, a solubility of < 2.4 mg / mL in toluene at RT, a solubility of > 40.0 mg / mL in DMAc at RT, a solubility of > 44.0 mg / mL in DMSO at RT, a solubility of > 44.0 mg / mL in NMP at RT, and a solubility of < 2.0 mg / mL in H2O at RT.

[0153] Single crystals of 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, hemi-fumaric acid, were grown and analyzed by single crystal X-ray analysis. A 3 mL glass vial was charged with 20.1 mg 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 5.8 mg of fumaric acid (molar ratio of base / acid = 1:1). The solids were taken up in THF (0.5 mL) to produce a suspension. 38 IPTS / 128645171.1Attorney Docket No.: ESK-027WO The 3 mL vial was enclosed in a 10 mL Teflon lined hydrothermal autoclave. The autoclave was then placed in an oven to conduct solvothermal synthesis by running a heating and cooling program consisting of warming from room temperature to 80 °C over 5 hours, maintaining a temperature of 80 °C for 12 hours, then cooling from 80 °C to 25 °C over 46 hours. After the heating and cooling program was completed, block-like single crystals were observed. A single crystal with suitable size was isolated and analyzed by single-crystal X-ray diffraction.

[0154] The crystal system of the single crystal was triclinic and P1 ̅ space group. The unitcell dimensions were determined as {a = 8.62960(10) Å, b = 12.1329(2) Å, c = 12.6652(2) Å, α = 106.4580(10)º, β = 97.2400(10)º, γ = 105.1200(10)º, V = 1198.75(3) Å3}. Other crystallographic data and the refinement parameters are listed in Table 5. TABLE 5 Temperature 299.08(10) W l th K λ 1 41 4 Å39 IPTS / 128645171.1Attorney Docket No.: ESK-027WO Final R indices [I ≥ 2sigma(I)]R1= 0.0497, wR2= 0.1289Final R indices [all data]R1= 0.0531, wR2= 0.1311

[0155] FIG. 4 depicts the asymmetric unit of the N-(4-((3-methoxy-4-(1-(methyl-d3)-1H- 1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide, hemi- fumaric acid (Form 1) single X-ray co-crystal structure. As shown in FIG. 4, the asymmetric unit of the hemi-fumarate Form 1 single crystal structure was comprised of one freebase neutral molecule 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 and half a fumaric acid neutral molecule, which indicated that Form 1 was an anhydrous, hemi-fumaric acid cocrystal.

[0156] FIG. 5 depicts the unit cell of the N-(4-((3-methoxy-4-(1-(methyl-d3)-1H-1,2,4- triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide and fumaric acid molecule in the Form 1 single X-ray co-crystal structure. As shown in FIG. 5, Each unit cell of the single crystal structure contains two neutral molecules 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 and one fumaric acid neutral molecule. As shown, there are 4 fumaric acid molecules shown in the diagram, and the center of the fumaric acid molecule is located on the axis of the unit cell. Example 2

[0157] 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, hemi-fumaric acid, was prepared as followed. A sample of 20 mg of 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, hemi-fumaric acid, was suspended in CH2Cl2(0.5 mL) in an HPLC vial. The suspension was stirred at room temperature for 7 days. The solids were isolated by centrifugation and air-dried at room temperature for 2 hours. XRPD analysis indicated that the dried material was crystalline with a pattern consistent with Form 2.

[0158] The XRPD pattern of crystalline Form 2 is shown in FIG. 6. Characteristic peaks include one or more of the peaks shown in Table 6. 40 IPTS / 128645171.1Attorney Docket No.: ESK-027WO TABLE 6 Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 7.7085 7861.88 11.47 100.0041 IPTS / 128645171.1Attorney Docket No.: ESK-027WO Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 38.3815 57.24 2.35 0.73

[0159] FIG. 7 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 2. As shown in FIG. 7, crystalline Form 2 shows a characteristic endotherm with an onset of about 129 °C and a peak of about 134 °C (enthalpy 62.2 J / g), and a characteristic endotherm with an onset of about 240 °C and a peak of about 242 °C (enthalpy 118.9 J / g).

[0160] 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, hemi-fumaric acid, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.8 wt. % between about 31 °C to about 90 °C, and a mass loss of about 14.8 wt. % between about 90 °C to about 180 °C (FIG. 8).

[0161] Crystalline Form 2 displayed a molar ratio of fumaric acid 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, free base of about 0.5. Form 2 was observed as a dichloromethane solvate crystalline form, with 14.2 residual solvent wt. % as determined by1H NMR. Example 3

[0162] 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, hemi-fumaric acid, was prepared as followed. A sample of 20 mg of 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, hemi-fumaric acid, was dissolved in MeOH (0.5 mL) in a mL glass vial. The clear solution was subjected to slow evaporation at room temperature. The solids were isolated by centrifugation and air-dried at room temperature for 2 hours. XRPD analysis indicated that the dried material was crystalline with a pattern consistent with Form 3.

[0163] The XRPD pattern of crystalline Form 3 is shown in FIG. 9. Characteristic peaks include one or more of the peaks shown in Table 7. 42 IPTS / 128645171.1Attorney Docket No.: ESK-027WO TABLE 7 Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 7.4858 6714.55 11.81 100.00

[0164] FIG. 10 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 3. As shown in FIG. 10, crystalline Form 3 shows a characteristic endotherm with a peak of about 76 °C, a characteristic endotherm with a peak of about 102 °C, and a characteristic endotherm with an onset of about 236 °C and a peak of about 238 °C (enthalpy 120.1 J / g).

[0165] 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, hemi-fumaric acid, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.7 wt. % between about 27 °C to about 130 °C (FIG. 11).

[0166] Crystalline Form 3 displayed a molar ratio of fumaric acid 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, free base of about 0.5. Form 3 was observed to be a hydrate. Example 4

[0167] 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, hemi-fumaric acid, was prepared as followed. A sample of 20 mg of 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, hemi-fumaric acid, was mixed with dibromomethane (0.5 mL) in a glass vial to form a suspension. The suspension was placed into a biochemical incubator of 50 °C 43 IPTS / 128645171.1Attorney Docket No.: ESK-027WO for heating and cooling temperature cycles as follows: heating to 50 °C in 7.5 hours; then holding at 50 °C for 2 hours; then cooling to 5 °C at a rate of 0.1 °C / min and then holding at 5 °C for 1 hr. The temperature cycle was repeated 8 times. The solids were isolated by centrifugation and air-dried at room temperature for 2 hours. XRPD analysis indicated that the dried material was crystalline with a pattern consistent with Form 4.

[0168] The XRPD pattern of crystalline Form 4 is shown in FIG. 12. Characteristic peaks include one or more of the peaks shown in Table 8. TABLE 8 Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%]44 IPTS / 128645171.1Attorney Docket No.: ESK-027WO Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 29.5980 82.61 3.02 2.70

[0169] FIG. 13 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 4. As shown in FIG. 13, crystalline Form 4 shows a characteristic endotherm with a peak of about 76 °C, a characteristic endotherm with a peak of about 102 °C, and a characteristic endotherm with an onset of about 119 °C and a peak of about 123 °C (enthalpy 36.5 J / g), and a characteristic endotherm with an onset of about 246 °C and a peak of about 248 °C (enthalpy 105.8 J / g).

[0170] 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, hemi-fumaric acid, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.0 wt. % between about 25 °C to about 80 °C, and a mass loss of about 16.6 wt. % between about 80 °C to about 180 °C (FIG. 14).

[0171] Crystalline Form 4 displayed a molar ratio of fumaric acid 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, free base of about 0.5. Form 4 was observed as a dibromomethane solvate crystalline form, with 19.8 residual solvent wt. % as determined by1H NMR.Example 5

[0172] 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, bis-fumaric acid, was prepared as followed. A slurry of 300 mg 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 fumaric acid (166 mg 2.0 equiv) in MeCN (10 mL) was stirred at room temperature for 6 45 IPTS / 128645171.1Attorney Docket No.: ESK-027WO days. The solids were isolated by centrifugation and vacuum dried overnight. XRPD analysis indicated that the dried material was crystalline with a pattern consistent with Form 5.

[0173] The XRPD pattern of crystalline Form 5 is shown in FIG. 15. Characteristic peaks include one or more of the peaks shown in Table 9. TABLE 9 Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 88480 493100 999 1000046 IPTS / 128645171.1Attorney Docket No.: ESK-027WO Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 26.1384 2135.32 3.41 43.30

[0174] FIG. 16 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 5. As shown in FIG. 16, crystalline Form 5 shows a characteristic endotherm with a peak of about 76 °C, a characteristic endotherm with a peak of about 231 °C, and a characteristic endotherm with a peak of about 234 °C.

[0175] 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, bis-fumaric acid, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.0 wt. % between about 25 °C to about 80 °C, and a mass loss of about 2.8 wt. % between about 23 °C to about 160 °C (FIG. 17).

[0176] Crystalline Form 5 displayed a molar ratio of fumaric acid 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, free base of about 2.1. Form 5 was observed to be an anhydrate crystalline form. Example 6

[0177] 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, mono-fumaric acid, was prepared as followed. A slurry of 20 mg 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 fumaric acid (1.1 equiv) in 1,4-dioxane (0.5 mL) was stirred at room temperature for 6 days. 47 IPTS / 128645171.1Attorney Docket No.: ESK-027WO The solids were isolated by centrifugation and air-dried for 2 hours. XRPD analysis indicated that the dried material was crystalline with a pattern consistent with Form 6.

[0178] The XRPD pattern of crystalline Form 6 is shown in FIG. 18. Characteristic peaks include one or more of the peaks shown in Table 10. TABLE 10 Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 76476 347598 1156 867148 IPTS / 128645171.1Attorney Docket No.: ESK-027WO Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 28.6131 76.44 3.12 1.91

[0179] FIG. 19 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 6. As shown in FIG. 19, crystalline Form 6 shows a characteristic endotherm with an onset of about 142 °C and a peak of about 158 °C (enthalpy 38.2 J / g), a characteristic endotherm with a peak of about 228 °C, and a characteristic endotherm with a peak of about 232 °C.

[0180] 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, mono-fumaric acid, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 9.1 wt. % between about 26 °C to about 180 °C (FIG. 20).

[0181] Crystalline Form 6 displayed a molar ratio of fumaric acid 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, free base of about 1.0. Form 6 was observed to be a 1,4-dioxane solvate crystalline form, with 7.5 residual solvent wt. % as determined by1H NMR. Example 7

[0182] 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, hemi-fumaric acid, was prepared as followed. A sample of 20 mg of 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, hemi-fumaric acid, was heated to 130 °C and then cooled to room temperature. The solid was then analyzed by XRPD, which indicated that the cooled material was crystalline with a pattern consistent with Form 7. 49 IPTS / 128645171.1Attorney Docket No.: ESK-027WO

[0183] The XRPD pattern of crystalline Form 7 is shown in FIG. 21. Characteristic peaks include one or more of the peaks shown in Table 11. TABLE 11 Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 74956 945154 1179 1000050 IPTS / 128645171.1Attorney Docket No.: ESK-027WO Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 31.1950 131.93 2.87 1.40

[0184] FIG. 22 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 7. As shown in FIG. 22, crystalline Form 7 shows a characteristic endotherm with an onset of about 229 °C and a peak of about 235 °C (enthalpy 115.6 J / g).

[0185] 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, hemi-fumaric acid, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.5 wt. % between about 20 °C to about 150 °C (FIG. 23).

[0186] Crystalline Form 7 displayed a molar ratio of fumaric acid 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, free base of about 0.5. Form 7 was observed to be an anhydrate crystalline form. Example 8

[0187] 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, mono-fumaric acid, was prepared as followed. A sample of 20 mg of 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, mono-fumaric acid, was heated to 180 °C and then cooled to room temperature. The solid was then analyzed by XRPD, which indicated that the cooled material was crystalline with a pattern consistent with Form 8.

[0188] The XRPD pattern of crystalline Form 8 is shown in FIG. 24. Characteristic peaks include one or more of the peaks shown in Table 12. 51 IPTS / 128645171.1Attorney Docket No.: ESK-027WO TABLE 12 Pos. [°2θ] Height [cts] d-spacing [Å] Rel. Int. [%] 7.9754 2563.91 11.09 22.66

[0189] FIG. 25 depicts the differential scanning calorimetry (DSC) profile of crystalline Form 8. As shown in FIG. 25, crystalline Form 8 shows a characteristic endotherm with a peak of about 228 °C, and a characteristic endotherm with a peak of about 232 °C.

[0190] 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, mono-fumaric acid, displayed a thermogravimetric analysis (TGA) profile showing a mass loss of about 1.5 wt. % between about 32 °C to about 150 °C (FIG. 26).

[0191] Crystalline Form 8 displayed a molar ratio of fumaric acid 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, free base of about 1.0. Form 8 was observed to be an anhydrate crystalline form. 52 IPTS / 128645171.1Attorney Docket No.: ESK-027WO INCORPORATION BY REFERENCE

[0192] 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

[0193] 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.

[0194] 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.

[0195] What is claimed is: 53 IPTS / 128645171.1

Claims

Attorney Docket No.: ESK-027WO 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, hemi-fumaric acid (Form 1), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 24.

2.

2. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 7.5, 11.8, and 24.

2.

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 7.5, 8.0, 11.8, 22.6, 22.8, and 24.

2.

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 7.5, 8.0, 11.8, 13.8, 16.4, 22.6, 22.8, 23.2, and 24.

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 7.5, 8.0, 9.0, 11.8, 13.8, 15.3, 16.4, 22.6, 22.8, 23.2, 24.2, and 27.

1.

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 242 °C and a peak of about 243 °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 0.3 wt. % between about 19 °C to about 120 °C.

9. The crystalline form of any one of claims 1-8, wherein the crystalline form is an anhydrate crystalline form.

10. The crystalline form of any one of claims 1-9, wherein the molar ratio of fumaric acid 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, free base is about 0.

5. 54 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 11. The crystalline form of any one of claims 1-10, characterized by the following unit cell parameters: cell dimensions a = 8.62960(10) Å, α = 106.4580(10)º b = 12.1329(2) Å, β = 97.2400(10)º c = 12.6652(2) Å, γ = 105.1200(10)º; space group = P ̅1 ̅ ;volume = 1198.75(3) Å3; and crystal system = triclinic.

12. 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, hemi-fumaric acid (Form 2), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.7, 20.1, and 26.

6.

13. The crystalline form of claim 12, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.7, 15.4, 16.3, 20.1, 26.6, and 27.

5.

14. The crystalline form of claim 12 or 13, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.7, 8.1, 15.4, 16.3, 20.1, 23.2, 26.3, 26.6, and 27.

5.

15. The crystalline form of any one of claims 12-14, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.7, 8.1, 13.1, 13.8, 15.4, 16.3, 20.1, 20.9, 23.2, 26.3, 26.6, and 27.

5.

16. The crystalline form of any one of claims 12-15, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

17. The crystalline form of any one of claims 12-16, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 129 °C and a peak of about 134 °C, and a characteristic endotherm with an onset of about 240 °C and a peak of about 242 °C. 55 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 18. The crystalline form of any one of claims 12-17, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.8 wt. % between about 31 °C to about 90 °C, and a mass loss of about 14.8 wt. % between about 90 °C to about 180 °C.

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, hemi-fumaric acid (Form 3), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.5, 7.8, and 14.

6.

20. The crystalline form of claim 19, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.5, 7.8, 8.9, 14.6, 15.0, and 22.

0.

21. The crystalline form of claim 19 or 20, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.5, 7.8, 8.9, 14.6, 15.0, 16.1, 22.0, and 29.

3.

22. The crystalline form of any one of claims 19-21, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

23. The crystalline form of any one of claims 19-22, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with a peak of about 76 °C, a characteristic endotherm with a peak of about 102 °C, and a characteristic endotherm with an onset of about 236 °C and a peak of about 238 °C.

24. The crystalline form of any one of claims 19-23, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.7 wt. % between about 27 °C to about 130 °C.

25. The crystalline form of any one of claims 19-24, wherein the crystalline form is a hydrate crystalline form.

26. 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, hemi-fumaric acid (Form 4), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 13.3, 20.1, and 25.

3.

27. The crystalline form of claim 26, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 12.5, 13.3, 16.7, 20.1, 22.6, and 25.

3. 56 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 28. The crystalline form of claim 26 or 27, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.2, 8.8, 12.5, 13.3, 13.7, 16.7, 20.1, 22.6, and 25.

3.

29. The crystalline form of any one of claims 26-28, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.2, 8.8, 12.5, 13.3, 13.7, 16.7, 18.4, 19.3, 20.1, 22.6, 25.3, and 25.

8.

30. The crystalline form of any one of claims 26-29, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

31. The crystalline form of any one of claims 26-30, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 119 °C and a peak of about 123 °C, and a characteristic endotherm with an onset of about 246 °C and a peak of about 248 °C.

32. The crystalline form of any one of claims 26-31, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.0 wt. % between about 25 °C to about 80 °C, and a mass loss of about 16.6 wt. % between about 80 °C to about 180 °C.

33. 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, bis-fumaric acid (Form 5), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.8, 26.1, and 27.

7.

34. The crystalline form of claim 33, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.8, 15.7, 15.9, 23.6, 26.1, and 27.

7.

35. The crystalline form of claim 33 or 34, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.8, 15.7, 15.9, 19.9, 20.4, 23.6, 25.0, 26.1, and 27.

7.

36. The crystalline form of any one of claims 33-35, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.8, 15.7, 15.9, 17.0, 19.9, 20.4, 22.3, 22.8, 23.6, 25.0, 26.1, and 27.

7. 57 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 37. The crystalline form of any one of claims 33-36, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

38. The crystalline form of any one of claims 33-37, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 231 °C and a peak of about 234 °C.

39. The crystalline form of any one of claims 33-38, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 2.8 wt. % between about 23 °C to about 160 °C.

40. The crystalline form of any one of claims 33-39, wherein the crystalline form is an anhydrate crystalline form.

41. 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, mono-fumaric acid (Form 6), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.6, 15.6, and 26.

7.

42. The crystalline form of claim 41, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.6, 15.6, 16.1, 20.0, 24.2, and 26.

7.

43. The crystalline form of claim 41 or 42, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.6, 12.9, 14.1, 15.6, 16.1, 20.0, 20.5, 24.2, and 26.

7.

44. The crystalline form of any one of claims 41-43, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.6, 12.9, 13.4, 13.9, 14.1, 15.6, 16.1, 17.0, 20.0, 20.5, 24.2, and 26.

7.

45. The crystalline form of any one of claims 41-44, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

46. The crystalline form of any one of claims 41-45, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 142 °C and a peak of about 158 °C, a characteristic endotherm with a peak of about 228 °C, and a characteristic endotherm with a peak of about 232 °C. 58 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 47. The crystalline form of any one of claims 41-46, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 9.1 wt. % between about 26 °C to about 180 °C.

48. 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, hemi-fumaric acid (Form 7), characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.5, 9.0, and 14.

6.

49. The crystalline form of claim 48, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.5, 9.0, 14.6, 16.1, 22.0, and 24.

2.

50. The crystalline form of claim 48 or 49, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.5, 9.0, 11.8, 14.6, 15.0, 16.1, 22.0, 22.7, and 24.

2.

51. The crystalline form of any one of claims 48-50, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 7.5, 7.7, 9.0, 11.8, 14.2, 14.6, 15.0, 16.1, 22.0, 22.7, 24.2, and 25.

7.

52. The crystalline form of any one of claims 48-51, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

53. The crystalline form of any one of claims 48-52, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 229 °C and a peak of about 235 °C.

54. The crystalline form of any one of claims 48-53, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.5 wt. % between about 20 °C to about 150 °C.

55. The crystalline form of any one of claims 48-54, wherein the crystalline form in an anhydrate crystalline form.

56. 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, mono-fumaric acid (Form 8), 59 IPTS / 128645171.1Attorney Docket No.: ESK-027WO characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.0, 13.5, and 25.

0.

57. The crystalline form of claim 56, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.0, 8.5, 13.5, 16.7, 25.0, and 29.

8.

58. The crystalline form of claim 56 or 57, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.0, 8.5, 13.5, 14.1, 16.7, 20.7, 22.6, 25.0, and 29.

8.

59. The crystalline form of any one of claims 56-58, characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 2θ at about 8.0, 8.5, 13.5, 14.1, 14.5, 16.0, 16.7, 17.9, 20.7, 22.6, 25.0, and 29.

8.

60. The crystalline form of any one of claims 56-59, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

61. The crystalline form of any one of claims 56-60, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with a peak of about 228 °C, and a characteristic endotherm with a peak of about 232 °C.

62. The crystalline form of any one of claims 56-61, characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 1.5 wt. % between about 32 °C to about 150 °C.

63. The crystalline form of any one of claims 56-62, wherein the crystalline form in an anhydrate crystalline form.

64. A pharmaceutical composition comprising a crystalline form of any one of claims 1-63, and a pharmaceutically acceptable excipient.

65. A pharmaceutical composition formed from the crystalline form of any one of claims 1-63.

66. 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 1-63, or the pharmaceutical composition of claim 64 or 65. 60 IPTS / 128645171.1Attorney Docket No.: ESK-027WO 67. 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 1-63, or the pharmaceutical composition of claim 64 or 65.

68. 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 1-63, or the pharmaceutical composition of claim 64 or 65.

69. The method of claim 68, wherein the neuroinflammatory disease is multiple sclerosis.

70. 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 1-63, or the pharmaceutical composition of claim 64 or 65. 61 IPTS / 128645171.1

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