Crystalline forms of TYK2 inhibitors and uses thereof

Abstract

The present disclosure is directed, in part, to crystalline salt forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, pharmaceutical compositions thereof, and methods of use.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 405,582, filed September 12, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. TYK2 activation is associated with diseases and disorders, such as autoimmune disorders, inflammatory disorders, proliferative disorders (e.g., cancer), endocrine disorders, and neurological disorders. For example, TYK2 activation is associated with inflammatory bowel disease (IBD), Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis. TYK2 also plays a role in respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Therefore, compounds that inhibit the activity of TYK2, particularly those that are selective for JAK2, would be beneficial. Such compounds would provide pharmacological responses that favorably treat one or more of the conditions described herein without the side effects associated with JAK2 inhibition.

[0003]

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

[0004]

[0004] The present disclosure is directed, at least in part, to a crystalline salt form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide.

[0005] For example, the present specification refers to a powder X-ray diffraction pattern having characteristic peaks at about 24.0 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 12.7, 17.1, and 24.0 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 9.5, 12.7, 17.1, 19.1, 20.5, and 24.0 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 9.5, 12.7, 15.5, 17.1, 19.1, 20.5, 24.0, 24.3, and 26.9 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 7.8, ... Disclosed is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate, characterized by a powder X-ray diffraction pattern having characteristic peaks at 0.5, 21.0, 23.7, 24.0, 24.3, and 26.9 degrees two-theta, for example, by a powder X-ray diffraction pattern having characteristic peaks at about 7.8, 9.5, 12.7, 15.5, 17.1, 19.1, 19.4, 20.5, 20.8, 21.0, 23.7, 24.0, 24.3, 25.5, and 26.9 degrees two-theta.

[0006]

[0006] As used herein, the term "powder X-ray diffraction" refers to a powder X-ray diffraction pattern having characteristic peaks at about 9.9 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 7.5, 9.9, and 20.0 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 7.5, 9.9, 13.7, 18.2, 20.0, and 22.5 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 7.5, 9.2, 9.9, 13.7, 18.2, 20.0, 23.9, 22.5, and 26.5 degrees 2θ. Also disclosed are different crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate, characterized by an X-ray diffraction pattern, for example, a powder X-ray diffraction pattern having characteristic peaks at about 7.5, 8.3, 9.2, 9.9, 10.4, 13.7, 18.2, 20.0, 21.1, 23.9, 22.5, and 26.5 degrees 2θ.

[0007]

[0007] As used herein, the term "aluminum fluoride" refers to a compound characterized by a powder X-ray diffraction pattern having characteristic peaks at about 21.0 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.0, 18.0, and 21.0 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.1, 8.1, 9.0, 18.0, 21.0, and 23.3 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.1, 8.1, 9.0, 10.4, 18.0, 20.6, 21.0, 23.3, and 28.5 ...6.5, 18.0, 20.6, 21.0, 23.3, and 28.5 degrees 2θ. Further disclosed are different crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate, characterized by a powder X-ray diffraction pattern having characteristic peaks at 0, 23.3, 24.0, 24.2, and 28.5 degrees two-theta, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.1, 8.1, 9.0, 10.4, 11.1, 15.6, 16.5, 17.5, 18.0, 20.6, 21.0, 23.3, 24.0, 24.2, and 28.5 degrees two-theta.

[0008] As used herein, there is provided a compound characterized by a powder X-ray diffraction pattern having characteristic peaks at about 26.1 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 8.0, 23.3, and 26.1 degrees 2θ, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 8.0, 13.5, 22.3, 23.3, 25.6, and 26.1 degrees 2θ, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 4.2, 8.0, 8.3, 13.5, 21.0 ... Also disclosed is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, fumarate, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 4.2, 8.0, 8.3, 10.7, 12.5, 13.5, 18.5, 21.0, 22.0, 21.3, 21.7, 22.3, 23.3, 25.6, and 26.1 degrees two-theta, for example, a powder X-ray diffraction pattern having characteristic peaks at about 4.2, 8.0, 8.3, 10.7, 12.5, 13.5, 18.5, 21.0, 22.0, 21.3, 21.7, 22.3, 23.3, 25.6, and 26.1 degrees two-theta.

[0009]

[0009] As used herein, the term "a compound" refers to a compound characterized, for example, by a powder X-ray diffraction pattern having characteristic peaks at about 9.7 degrees 2θ; for example, by a powder X-ray diffraction pattern having characteristic peaks at about 9.7, 19.5, and 20.5 degrees 2θ; for example, by a powder X-ray diffraction pattern having characteristic peaks at about 9.7, 19.5, 20.5, 21.2, 23.3, and 26.4 degrees 2θ; for example, by a powder X-ray diffraction pattern having characteristic peaks at about 9.7, 17.4, 19.5, 20.5, 21.2, 23.3, 26.4, 27.8, and 29.4 degrees 2θ; for example, by a powder X-ray diffraction pattern having characteristic peaks at about 9.7, 17.1, 17.4, 19.5, 20.5, 20. Disclosed is N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, hydrobromide, characterized by a powder X-ray diffraction pattern having characteristic peaks at 9, 21.2, 22.9, 23.3, 26.4, 27.8, and 29.4 degrees two-theta, for example, by a powder X-ray diffraction pattern having characteristic peaks at about 9.7, 17.1, 17.4, 19.5, 20.5, 20.9, 21.2, 22.9, 23.3, 24.8, 26.4, 27.8, 29.4, 30.8, and 32.2 degrees two-theta.

[0010]

[0010] As used herein, the term "aluminum fluoride" refers to a compound characterized by a powder X-ray diffraction pattern having characteristic peaks at about 4.8 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 4.8, 6.2, and 9.6 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 4.8, 6.2, 7.9, 9.6, 12.6, and 22.2 .... Further disclosed is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, phosphate salt, characterized by a powder X-ray diffraction pattern having characteristic peaks at 9, 9.6, 12.6, 16.7, 18.5, 21.5, and 22.2 degrees 2θ.

[0011] Further provided herein is a compound characterized by a powder X-ray diffraction pattern having characteristic peaks at about 21.2 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 8.4, 16.9, and 21.2 degrees 2θ, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 8.4, 16.9, 20.9, 21.2, 22.2, and 23.5 degrees 2θ, for example, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.3, 8.4, 16.9, 18.0, 20.9, 21.2, 21.8 ... , 20.9, 21.2, 21.8, 22.2, 23.1, 23.5, and 23.5 degrees two-theta, for example, a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.3, 8.4, 9.0, 15.4, 15.9, 16.9, 18.0, 20.6, 20.9, 21.2, 21.8, 22.2, 23.1, 23.5, and 27.8 degrees two-theta.

[0012]

[0012] As used herein, the term "aluminum fluoride" refers to a compound characterized by a powder X-ray diffraction pattern having characteristic peaks at about 16.1 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 16.1, 19.2, and 23.9 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.6, 16.1, 19.2, 19.9, 21.6, and 23.9 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.6, 12.6, 16.1, 19.2, 19.9, 21.6, 23.9, 24.2, and 25.4 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 8.2, 9.6, 12.6, 16.1, 18.0 .... Also disclosed are different crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate, characterized by a powder X-ray diffraction pattern having characteristic peaks at 9.9, 21.6, 23.9, 24.2, 24.6, and 25.4 degrees two-theta, for example, by a powder X-ray diffraction pattern having characteristic peaks at about 8.2, 9.6, 12.6, 15.4, 16.1, 18.0, 19.2, 19.9, 20.3, 21.6, 23.9, 24.2, 24.6, 25.4, and 28.2 degrees two-theta.

[0013] As used herein, the term "aluminum fluoride" refers to a compound characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.8 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.8, 19.8, and 22.7 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.6, 7.2, 9.8, 19.8, 20.2, and 22.7 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.6, 7.2, 9.8, 16.1, 19.8, 20.2, 22.7, 24.9, and 25.4 degrees 2θ, e.g., characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.6, 7.2, 9.8, 15.1, 15.8, 16.1, 19.5, 19.8 Further disclosed is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, p-toluenesulfonate, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.6, 7.2, 9.8, 13.3, 15.1, 15.8, 16.1, 19.5, 19.8, 20.2, 21.4, 22.7, 24.9, 25.4, and 26.5 degrees two-theta, for example, a powder X-ray diffraction pattern having characteristic peaks at about 6.6, 7.2, 9.8, 13.3, 15.1, 15.8, 16.1, 19.5, 19.8, 20.2, 21.4, 22.7, 24.9, 25.4, and 26.5 degrees two-theta.

[0014]

[0014] As used herein, the term "powder X-ray diffraction" refers to a powder X-ray diffraction pattern having characteristic peaks at about 9.4 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 5.4, 6.2, and 9.4 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 5.4, 6.2, 9.4, 24.3, 26.2, and 26.7 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 5.4, 6.2, 9.4, 10.3, 24.3, 24.7, 26.2, 26.7, and 31.0 degrees 2θ. Further disclosed is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, bis-hydrochloride, characterized by an X-ray diffraction pattern, for example, a powder X-ray diffraction pattern having characteristic peaks at about 5.4, 6.2, 9.4, 10.3, 10.8, 16.0, 18.5, 24.3, 24.7, 26.2, 26.7, and 31.0 degrees 2θ.

[0015] N-(4-((2-Methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, for example, is a modulator of tyrosine kinase 2 (TYK2), for example, an inhibitor of TYK2;

[0016] [ka] is expressed by

[0017] Further contemplated herein are pharmaceutical compositions, e.g., compositions formulated for oral administration, comprising the disclosed crystalline salt forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide and a pharmaceutically acceptable excipient. Further contemplated herein are drug substances comprising at least a detectable amount of the disclosed crystalline salt forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide. For example, disclosed herein is a drug substance comprising a substantially pure crystalline salt form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide.

[0018]

[0017] Also provided herein is a method for treating a TYK2-mediated disorder in a patient in need thereof, comprising administering to the patient an effective amount of the disclosed crystalline salt form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide.

[0019]

[0018] For example, provided herein is a method for treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need thereof, the method comprising administering to the patient an effective amount of the disclosed crystalline salt form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide. [Brief explanation of the drawings]

[0020] [Figure 1]

[0019] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonic acid (Form 1-1). [Figure 2] FIG. 1 shows the differential scanning calorimetry (DSC) profile of Form 1-1. [Figure 3]

[0021] FIG. 1 shows the thermogravimetric analysis (TGA) profile of Form 1-1. [Figure 4]

[0022] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate salt (Form 1-2). [Figure 5]

[0023] FIG. 1 shows the differential scanning calorimetry (DSC) profile of Form 1-2. [Figure 6]

[0024] FIG. 1 shows the thermogravimetric analysis (TGA) profile of Form 1-2. [Figure 7]

[0025] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate salt (Form 1-3). [Figure 8]

[0026] FIG. 1 shows the differential scanning calorimetry (DSC) profile of Forms 1-3. [Figure 9]

[0027] FIG. 1 shows the thermogravimetric analysis (TGA) profiles of Forms 1-3. [Figure 10]

[0028] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, fumarate salt (Form 2). [Figure 11]

[0029] FIG. 1 shows the differential scanning calorimetry (DSC) profile of Form 2. [Figure 12]

[0030] FIG. 1 shows the thermogravimetric analysis (TGA) profile of Form 2. [Figure 13]

[0031] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, hydrobromide salt (Form 3). [Figure 14]

[0032] FIG. 1 shows the differential scanning calorimetry (DSC) profile of Form 3. [Figure 15]

[0033] FIG. 1 shows the thermogravimetric analysis (TGA) profile of Form 3. [Figure 16]

[0034] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, phosphate salt (Form 4). [Figure 17]

[0035] FIG. 1 shows the differential scanning calorimetry (DSC) profile of Form 4. [Figure 18]

[0036] FIG. 1 shows the thermogravimetric analysis (TGA) profile of Form 4. [Figure 19]

[0037] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate salt (Form 5-1). [Figure 20]

[0038] FIG. 1 shows the differential scanning calorimetry (DSC) profile of Form 5-1. [Figure 21]

[0039] FIG. 1 shows the thermogravimetric analysis (TGA) profile of Form 5-1. [Figure 22]

[0040] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate salt (Form 5-2). [Figure 23]

[0041] FIG. 1 shows the differential scanning calorimetry (DSC) profile of Form 5-2. [Figure 24]

[0042] FIG. 1 shows the thermogravimetric analysis (TGA) profile of Form 5-2. [Figure 25]

[0043] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, p-toluenesulfonate salt (Form 6). [Figure 26]

[0044] FIG. 1 shows the differential scanning calorimetry (DSC) profile of Form 6. [Figure 27]

[0045] FIG. 1 shows the thermogravimetric analysis (TGA) profile of Form 6. [Figure 28]

[0046] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, bis-hydrochloride salt (Form 7). [Figure 29]

[0047] FIG. 1 shows the differential scanning calorimetry (DSC) profile of Form 7. [Figure 30]

[0048] FIG. 1 shows the thermogravimetric analysis (TGA) profile of Form 7. DETAILED DESCRIPTION OF THE INVENTION

[0021]

[0049] The features and other details of the present disclosure will be described more specifically.Before further describing the present disclosure, certain terms used in the present specification, examples, and appended claims will be collected here.These definitions should be read in light of the remainder of the present disclosure and as understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0022] definition

[0050] The term "crystalline form" refers to a crystalline form or crystalline modification that may be characterized by analytical methods such as, for example, X-ray powder diffraction (XRPD) and / or differential scanning calorimetry (DSC). The crystalline compounds disclosed herein can exist in solvated and unsolvated forms with solvents such as water, ethanol, and the like. Unless otherwise indicated or inferred, the disclosed crystalline compounds are intended to include both solvated and unsolvated forms.

[0023]

[0051] "Treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., e.g., "lessening," "reducing," "modulating," or "eliminating."

[0024]

[0052] The term "disorder" refers to, and is used interchangeably with, the terms "disease," "condition," or "illness," unless otherwise indicated.

[0025]

[0053] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0026]

[0054] The terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier," as used herein, refer 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 can also include other active compounds that provide supplementary, additional, or enhanced therapeutic functions.

[0027]

[0055] The term "pharmaceutical composition," as used herein, refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0028]

[0056] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans. The compounds of the present disclosure can be administered to mammals such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, for example, domestic animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated with the methods of the present disclosure is preferably one in which treatment of, for example, cancer or a blood disorder is desired. "Modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism, and / or partial agonism.

[0029]

[0057] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a subject compound that elicits the biological or medical response of a tissue, system, or animal (e.g., a mammal or human) that is sought by a researcher, veterinarian, physician, or other clinician. The compounds of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount necessary to achieve the desired therapeutic and / or prophylactic effect.

[0030]

[0058] The term "pharmaceutically acceptable salts" as used herein refers to salts of basic groups that may be present in compounds used in the compositions. Compounds included in the compositions that are basic in nature can form a wide variety of salts with various inorganic and organic acids.

[0031]

[0059] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0032]

[0060] As used herein, the words "a" and "an" mean one or more, unless otherwise specified. For example, the term "drug" includes both a single drug and a combination of two or more drugs.

[0033]

[0061] When the term "about" is used before a quantitative value, the present disclosure also includes the specific quantitative value itself unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value unless otherwise indicated or inferred. In the context of a peak at degrees 2θ, the term "about" means that there is an uncertainty of ±0.2 (expressed in 2θ) in the 2θ measurement. Generally, DSC thermograms can have a variation in the range of ±2°C. Therefore, temperature values ​​should be understood to include values ​​in the range of about ±2°C.

[0034]

[0062] Generally, provided herein, unless otherwise indicated, are crystalline salt forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide that are substantially free of any other crystalline forms. As used herein, "substantially free" or "substantially free of any other crystalline forms" means that the disclosed crystalline forms contain no more than about 20%, no more than about 10%, no more than about 5%, no more than about 10%, no more than about 15%, no more than about 20 ... It means containing about 2% or less, or about 1% or less, or less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of any other crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide as measured, for example, by XRPD. Thus, the disclosed crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide described herein, which are substantially free of any other crystalline forms, are 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 crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide.Thus, in some embodiments, the disclosed crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide may contain 1% to 20% (w / w), 5% to 20% (w / w), or 5% to 10% (w / w) of one or more other crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide.

[0035] Crystalline morphology

[0063] The present disclosure is directed, at least in part, to crystalline salt forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide. Also disclosed are crystalline hydrates, anhydrates, hemihydrates, solvates, tautomers, and co-crystals of any of the crystalline forms described herein.

[0036]

[0064] For example, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate (referred to herein as "Form 1-1"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.0 degrees 2θ.

[0037]

[0065] In one embodiment, crystalline Form 1-1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 6.9 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 7.8 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.5 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 12.7 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 15.5 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 17.1 degrees 2θ; and characterized by a powder X-ray diffraction pattern having a characteristic peak at about 19.1 degrees 2θ. characterized by an X-ray diffraction pattern, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 19.4 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 20.5 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 20.8 degrees 2θ, characterized by an X-ray diffraction pattern having a characteristic peak at about 21.0 degrees 2θ, characterized by an X-ray diffraction pattern having a characteristic peak at about 23.7 degrees 2θ, characterized by an X-ray diffraction pattern having a characteristic peak at about 24.0 degrees 2θ, characterized by an X-ray diffraction pattern having a characteristic peak at about 24.3 degrees 2θ, characterized by an X-ray diffraction pattern having a characteristic peak at about 25.5 degrees 2θ, and / or characterized by a powder X-ray diffraction pattern having a characteristic peak at about 26.9 degrees 2θ. In another embodiment, crystalline form 1-1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 12.7, 17.1, and 24.0 degrees 2θ.In a further embodiment, crystalline Form 1-1 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 9.5, 12.7, 17.1, 19.1, 20.5, and 24.0 degrees 2θ. In yet another embodiment, crystalline Form 1-1 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 9.5, 12.7, 15.5, 17.1, 19.1, 20.5, 24.0, 24.3, and 26.9 degrees 2θ. In another embodiment, crystalline Form 1-1 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.9, 7.8, 9.5, 12.7, 15.5, 17.1, 19.1, 20.5, 21.0, 23.7, 24.0, 24.3, and 26.9 degrees 2θ. In another embodiment, crystalline Form 1-1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 6.9, 7.8, 9.5, 12.7, 15.5, 17.1, 19.1, 19.4, 20.5, 20.8, 21.0, 23.7, 24.0, 24.3, 25.5, and 26.9 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 1. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0038]

[0066] The assumed crystalline Form 1-1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm (enthalpy 98.7 J / g) with an onset of about 200° C. and a peak at about 202° C. Form 1-1 may be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 2.

[0039]

[0067] The postulated crystalline Form 1-1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate, may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.27 wt.% between about 20°C and about 180°C. Form 1-1 may be characterized, for example, by the thermogravimetric analysis profile shown in Figure 3.

[0040]

[0068] In some embodiments, crystalline Form 1-1 may be characterized by a dynamic vapor sorption (DVS) profile exhibiting a reversible total mass change of about 0.6 wt.% between about 0% and about 80% relative humidity (RH) at 25° C., and about 1.3 wt.% between about 0% and about 90% relative humidity (RH) at 25° C. In certain embodiments, the assumed crystalline Form 1-1 is an anhydrous crystalline form.

[0041]

[0069] In another embodiment, disclosed herein is a different crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 9.9 degrees two-theta (referred to herein as "Form 1-2").

[0042]

[0070] In one embodiment, crystalline Form 1-2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate, is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 7.5 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 8.3 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.2 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.9 degrees 2θ, and characterized by a powder X-ray diffraction pattern having a characteristic peak at about 10.4 degrees 2θ. In one embodiment, crystalline Form 1-2 is characterized by an X-ray powder diffraction pattern having at least one characteristic peak at about 13.7 degrees 2θ, an X-ray powder diffraction pattern having at least one characteristic peak at about 18.2 degrees 2θ, an X-ray powder diffraction pattern having at least one characteristic peak at about 20.0 degrees 2θ, an X-ray powder diffraction pattern having at least one characteristic peak at about 21.1 degrees 2θ, an X-ray powder diffraction pattern having at least one characteristic peak at about 23.9 degrees 2θ, an X-ray powder diffraction pattern having at least one characteristic peak at about 22.2 degrees 2θ, and / or an X-ray powder diffraction pattern having at least one characteristic peak at about 26.5 degrees 2θ. In one embodiment, crystalline Form 1-2 is characterized by an X-ray powder diffraction pattern having at least one characteristic peak at about 7.5, 9.9, and 20.0 degrees 2θ. In another embodiment, crystalline Form 1-2 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.5, 9.9, 13.7, 18.2, 20.0, and 22.5 degrees 2θ. In yet another embodiment, crystalline Form 1-2 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.5, 9.2, 9.9, 13.7, 18.2, 20.0, 23.9, 22.5, and 26.5 degrees 2θ.In a further embodiment, crystalline Form 1-2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 7.5, 8.3, 9.2, 9.9, 10.4, 13.7, 18.2, 20.0, 21.1, 23.9, 22.5, and 26.5 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 4. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0043]

[0071] The postulated crystalline form 1-2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset at about 66° C. (enthalpy 7.45 J / g), a characteristic endotherm with an onset at about 122° C. and a peak at about 132° C. (enthalpy 2.68 J / g), a characteristic endotherm with an onset at about 153° C. and a peak at about 161° C. (enthalpy 27.8 J / g), and a characteristic endotherm with an onset at about 195° C. and a peak at about 195° C. (enthalpy 3.15 J / g). Form 1-2 may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0044]

[0072] The assumed crystalline Form 1-2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate, may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.70 wt. % between about 20° C. and about 75° C., and a mass loss of about 1.24 wt. % between about 75° C. and about 160° C. Form 1-2 may be characterized, for example, by the thermogravimetric analysis profile shown in FIG. 6. In certain embodiments, the assumed crystalline Form 1-2 is a tetrahydrofuran solvate (0.1 mol).

[0045]

[0073] In another embodiment, disclosed herein are different crystalline forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 21.0 degrees two-theta (referred to herein as "Forms 1-3").

[0046]

[0074] In one embodiment, crystalline Form 1-3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 7.1 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 8.1 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.0 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 10.4 degrees 2θ; characterized by an X-ray diffraction pattern having a characteristic peak at about 11.1 degrees 2θ; characterized by an X-ray diffraction pattern having a characteristic peak at about 15.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.2 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.5 degrees 2θ. In another embodiment, crystalline Form 1-3 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 9.0, 18.0, and 21.0 degrees 2θ. In a further embodiment, crystalline Form 1-3 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.1, 8.1, 9.0, 18.0, 21.0, and 23.3 degrees 2θ.In yet another embodiment, crystalline Form 1-3 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.1, 8.1, 9.0, 10.4, 18.0, 20.6, 21.0, 23.3, and 28.5 degrees 2θ. In another embodiment, crystalline Form 1-3 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.1, 8.1, 9.0, 10.4, 16.5, 18.0, 20.6, 21.0, 23.3, 24.0, 24.2, and 28.5 degrees 2θ. In another embodiment, crystalline Forms 1-3 are characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 7.1, 8.1, 9.0, 10.4, 11.1, 15.6, 16.5, 17.5, 18.0, 20.6, 21.0, 23.3, 24.0, 24.2, and 28.5 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 7. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0047]

[0075] The postulated crystalline Form 1-3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm (enthalpy 92.0 J / g) with an onset of about 208° C. and a peak at about 209° C. Form 1-3 may be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 8.

[0048]

[0076] The assumed crystalline Form 1-3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate salt may be characterized by a thermogravimetric analysis (TGA) profile exhibiting no mass loss (0% wt.) between about 20° C. and about 150° C. Form 1-3 may be characterized, for example, by the thermogravimetric analysis profile shown in FIG. 9. In some embodiments, the assumed crystalline Form 1-3 is an anhydrous crystalline form.

[0049]

[0077] In another embodiment, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, fumarate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.1 degrees two-theta (referred to herein as "Form 2").

[0050]

[0078] In one embodiment, crystalline Form 2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, fumarate is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 4.2 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 8.0 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 8.3 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 10.7 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 12.5 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 13.5 degrees 2θ; and characterized by a powder X-ray diffraction pattern having a characteristic peak at about 18.5 degrees 2θ. 3 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.0 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.0 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.3 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.7 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.3 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.3 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.6 degrees 2θ, and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.1 degrees 2θ. In another embodiment, crystalline Form 2 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 8.0, 23.3, and 26.1 degrees 2θ. In a further embodiment, crystalline Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 8.0, 13.5, 22.3, 23.3, 25.6, and 26.1 degrees 2θ.In yet another embodiment, crystalline Form 2 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.2, 8.0, 8.3, 13.5, 21.0, 22.3, 23.3, 25.6, and 26.1 degrees 2θ. In another embodiment, crystalline Form 2 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.2, 8.0, 8.3, 10.7, 13.5, 18.5, 21.0, 21.3, 22.3, 23.3, 25.6, and 26.1 degrees 2θ. In another embodiment, crystalline Form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 4.2, 8.0, 8.3, 10.7, 12.5, 13.5, 18.5, 21.0, 22.0, 21.3, 21.7, 22.3, 23.3, 25.6, and 26.1 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 10. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0051]

[0079] The expected crystalline Form 2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, fumarate salt exhibits a characteristic endotherm (enthalpy 7.74 J / g) with an onset of about 36°C and a peak at about 57°C, a characteristic endotherm with an onset of about 196°C and a peak at about 199°C. It may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm (enthalpy 11.2 J / g) with an onset of about 202° C. and a peak at about 205° C. (enthalpy 37.9 J / g), a characteristic endotherm (enthalpy 15.1 J / g) with an onset of about 208° C. and a peak at about 209° C., and a characteristic endotherm (enthalpy 21.2 J / g) with an onset of about 213° C. and a peak at about 215° C. Form 2 may be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0052]

[0080] The assumed crystalline Form 2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, fumarate salt may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.42 wt.% between about 20° C. and about 50° C. Form 2 may be characterized, for example, by the thermogravimetric analysis profile shown in FIG. 12. In certain embodiments, the assumed crystalline Form 2 is an anhydrous crystalline form.

[0053]

[0081] In another embodiment, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, hydrobromide, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 9.7 degrees two-theta (referred to herein as "Form 3").

[0054]

[0082] In one embodiment, crystalline Form 3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, hydrobromide is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.7 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 17.1 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 17.4 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 19.5 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 20.5 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 20.9 degrees 2θ, and characterized by a powder X-ray diffraction pattern having a characteristic peak at about 21. In another embodiment, crystalline Form 3 is characterized by an X-ray powder diffraction pattern having at least one characteristic peak at about 2 degrees 2θ, at about 22.9 degrees 2θ, at about 23.3 degrees 2θ, at about 24.8 degrees 2θ, at about 26.4 degrees 2θ, at about 27.8 degrees 2θ, at about 29.4 degrees 2θ, at about 30.8 degrees 2θ, and / or at about 32.2 degrees 2θ. In another embodiment, crystalline Form 3 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 9.7, 19.5, and 20.5 degrees 2θ. In a further embodiment, crystalline Form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 9.7, 19.5, 20.5, 21.2, 23.3, and 26.4 degrees 2θ.In yet another embodiment, crystalline Form 3 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 9.7, 17.4, 19.5, 20.5, 21.2, 23.3, 26.4, 27.8, and 29.4 degrees 2θ. In another embodiment, crystalline Form 3 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 9.7, 17.1, 17.4, 19.5, 20.5, 20.9, 21.2, 22.9, 23.3, 26.4, 27.8, and 29.4 degrees 2θ. In another embodiment, crystalline Form 3 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 9.7, 17.1, 17.4, 19.5, 20.5, 20.9, 21.2, 22.9, 23.3, 24.8, 26.4, 27.8, 29.4, 30.8, and 32.2 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 13. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0055]

[0083] The postulated crystalline Form 3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, hydrobromide salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm (enthalpy 82.4 J / g) with an onset of about 247° C. and a peak at about 249° C. Form 3 may be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 14.

[0056]

[0084] The assumed crystalline Form 3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, hydrobromide salt may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.86 wt.% between about 20° C. and about 180° C. Form 3 may be characterized, for example, by the thermogravimetric analysis profile shown in FIG. 15. In certain embodiments, the assumed crystalline Form 3 is an anhydrous crystalline form.

[0057]

[0085] In another embodiment, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, phosphate salt, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 4.8 degrees two-theta (referred to herein as "Form 4").

[0058]

[0086] In one embodiment, crystalline Form 4 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, phosphate salt is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 4.8 degrees two-theta, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 6.2 degrees two-theta, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 7.9 degrees two-theta, and characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.6 degrees two-theta.

[0023] Crystalline Form 4 is characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.8, 6.2, and 9.6 degrees 2θ;

[0024] Crystalline Form 4 is characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.8, 6.2, and 9.6 degrees 2θ;

[0025] Crystalline Form 4 is characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.8, 6.2, 7.9, 9.6, 12.6, and 22.2 degrees 2θ;

[0026] Crystalline Form 4 is characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.8, 6.2, 7.9, 9.6, 12.6, and 22.2 degrees 2θ;

[0027] Crystalline Form 4 is characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.8, 6.2, 7.9, 9.6, 12.6, and 22.2 degrees 2θ;

[0028] Crystalline Form 4 is characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.8, 6.2, 7.9, 9.6, 12.6, and 22.2 degrees 2θ; [0029 ... In yet another embodiment, crystalline Form 4 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 4.8, 6.2, 7.9, 9.6, 12.6, 16.7, 18.5, 21.5, and 22.2 degrees 2θ. For example, the postulated crystalline form has the powder X-ray diffraction pattern shown in Figure 16. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0059]

[0087] The postulated crystalline Form 4 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, phosphorus salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm (enthalpy 47.2 J / g) with an onset of about 172° C. and a peak at about 275° C., a characteristic exotherm (enthalpy 36.6 J / g) with a peak at about 182° C., and a characteristic endotherm (enthalpy 81.8 J / g) with an onset of about 200° C. and a peak at about 204° C. Form 4 may be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 17.

[0060]

[0088] The assumed crystalline Form 4 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, phosphate salt may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.26 wt.% between about 20° C. and about 185° C. Form 4 may be characterized, for example, by the thermogravimetric analysis profile shown in FIG. 18. In certain embodiments, the assumed crystalline Form 4 is an anhydrous crystalline form.

[0061]

[0089] In another embodiment, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate salt, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 21.2 degrees two-theta (referred to herein as "Form 5-1").

[0062]

[0090] In one embodiment, crystalline Form 5-1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 7.3 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 8.4 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.0 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 15.4 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 15.9 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 16.9 degrees 2θ; and characterized by a powder X-ray diffraction pattern having a characteristic peak at about 18.0 degrees 2θ. degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.6 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.9 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.2 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.8 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.2 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.1 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.5 degrees 2θ, and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.8 degrees 2θ. In another embodiment, crystalline Form 5-1 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 8.4, 16.9, and 21.2 degrees 2θ. In a further embodiment, crystalline form 5-1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 8.4, 16.9, 20.9, 21.2, 22.2, and 23.5 degrees 2θ.In yet another embodiment, crystalline form 5-1 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.3, 8.4, 16.9, 18.0, 20.9, 21.2, 21.8, 22.2, and 23.5 degrees 2θ. In another embodiment, crystalline form 5-1 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.3, 8.4, 9.0, 15.9, 16.9, 18.0, 20.9, 21.2, 21.8, 22.2, 23.1, and 23.5 degrees 2θ. In another embodiment, crystalline form 5-1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 7.3, 8.4, 9.0, 15.4, 15.9, 16.9, 18.0, 20.6, 20.9, 21.2, 21.8, 22.2, 23.1, 23.5, and 27.8 degrees 2θ. For example, the postulated crystalline form has the powder X-ray diffraction pattern shown in Figure 19. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0063]

[0091] The postulated crystalline Form 5-1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 91° C. and a peak at about 117° C. (enthalpy 58.0 J / g), and a characteristic endotherm with an onset of about 231° C. and a peak at about 236° C. (enthalpy 111.5 J / g). Form 5-1 may be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 20.

[0064]

[0092] The assumed crystalline form 5-1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate salt may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 4.33 wt.% between about 20°C and about 130°C. Form 5-1 may be characterized, for example, by the thermogravimetric analysis profile shown in Figure 21. In certain embodiments, the assumed crystalline form 5-1 is a methanol solvate form (2 / 3 mol).

[0065]

[0093] In another embodiment, disclosed herein is a different crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate salt, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 16.1 degrees two-theta (referred to herein as "Form 5-2").

[0066]

[0094] In one embodiment, crystalline Form 5-2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 8.2 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.6 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 12.6 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 15.4 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 16.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.2 degrees 2θ; degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.9 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.3 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.6 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.9 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.2 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.6 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.4 degrees 2θ, and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.2 degrees 2θ. In another embodiment, crystalline Form 5-2 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 16.1, 19.2, and 23.9 degrees 2θ. In a further embodiment, crystalline form 5-2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 9.6, 16.1, 19.2, 19.9, 21.6, and 23.9 degrees 2θ.In yet another embodiment, crystalline form 5-2 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 9.6, 12.6, 16.1, 19.2, 19.9, 21.6, 23.9, 24.2, and 25.4 degrees 2θ. In another embodiment, crystalline form 5-2 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 8.2, 9.6, 12.6, 16.1, 18.0, 19.2, 19.9, 21.6, 23.9, 24.2, 24.6, and 25.4 degrees 2θ. In another embodiment, crystalline form 5-2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 8.2, 9.6, 12.6, 15.4, 16.1, 18.0, 19.2, 19.9, 20.3, 21.6, 23.9, 24.2, 24.6, 25.4, and 28.2 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 22. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0067]

[0095] The postulated crystalline Form 5-2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm (enthalpy 100.2 J / g) with an onset of about 229° C. and a peak at about 233° C. Form 5-2 may be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 23.

[0068]

[0096] The assumed crystalline form 5-2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate, may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.3 wt.% between about 20°C and about 150°C. Form 5-2 may be characterized, for example, by the thermogravimetric analysis profile shown in Figure 24. In some embodiments, crystalline form 5-2 may be characterized by a dynamic vapor sorption (DVS) profile exhibiting a reversible total mass change of about 1.4 wt.% between 25°C and about 0% to about 90% relative humidity (RH). In certain embodiments, the assumed crystalline form 5-2 is an anhydrous crystalline form.

[0069]

[0097] In another embodiment, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, p-toluenesulfonate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 9.8 degrees two-theta (referred to herein as "Form 6").

[0070]

[0098] In one embodiment, crystalline Form 6 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, p-toluenesulfonate is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 6.6 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 7.2 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.8 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 13.3 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 15.1 degrees 2θ; characterized by an X-ray diffraction pattern having a characteristic peak at about 15.8 degrees 2θ; In another embodiment, crystalline Form 6 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 9.8, 19.8, and 22.7 degrees 2θ. In a further embodiment, crystalline Form 6 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 6.6, 7.2, 9.8, 19.8, 20.2, and 22.7 degrees 2θ.In yet another embodiment, crystalline Form 6 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.6, 7.2, 9.8, 16.1, 19.8, 20.2, 22.7, 24.9, and 25.4 degrees 2θ. In another embodiment, crystalline Form 6 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.6, 7.2, 9.8, 15.1, 15.8, 16.1, 19.5, 19.8, 20.2, 22.7, 24.9, and 25.4 degrees 2θ. In another embodiment, crystalline Form 6 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 6.6, 7.2, 9.8, 13.3, 15.1, 15.8, 16.1, 19.5, 19.8, 20.2, 21.4, 22.7, 24.9, 25.4, and 26.5 degrees 2θ. For example, the postulated crystalline form has the powder X-ray diffraction pattern shown in Figure 25. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0071]

[0099] The postulated crystalline Form 6 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, p-toluenesulfonate salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm (enthalpy 79.5 J / g) with an onset of about 215° C. and a peak at about 217° C. Form 6 may be characterized, for example, by the DSC profile shown in FIG. 26.

[0072]

[0100] The assumed crystalline Form 6 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, p-toluenesulfonate, may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.6 wt.% between about 20° C. and about 200° C. Form 6 may be characterized, for example, by the thermogravimetric analysis profile shown in FIG. 27. In some embodiments, crystalline Form 6 may be characterized by a dynamic vapor sorption (DVS) profile exhibiting a reversible total mass change of about 0.7 wt.% between 25° C. and about 0% to about 90% relative humidity (RH). In certain embodiments, the assumed crystalline Form 6 is an anhydrous crystalline form.

[0073]

[0101] In another embodiment, disclosed herein is a crystalline form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, bis-hydrochloride salt, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 9.4 degrees two-theta (referred to herein as "Form 7").

[0074]

[0102] In one embodiment, crystalline Form 7 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, bis-hydrochloride salt is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 5.4 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 6.2 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.4 degrees 2θ, characterized by a powder X-ray diffraction pattern having a characteristic peak at about 10.3 degrees 2θ, and characterized by a powder X-ray diffraction pattern having a characteristic peak at about 10.8 degrees 2θ. In another embodiment, crystalline Form 7 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 5.4, 6.2, and 9.4 degrees 2θ. In a further embodiment, crystalline Form 7 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 5.4, 6.2, 9.4, 24.3, 26.2, and 26.7 degrees 2θ. In yet another embodiment, crystalline Form 6 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 5.4, 6.2, 9.4, 10.3, 24.3, 24.7, 26.2, 26.7, and 31.0 degrees 2θ.In another embodiment, crystalline Form 7 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at about 5.4, 6.2, 9.4, 10.3, 10.8, 16.0, 18.5, 24.3, 24.7, 26.2, 26.7, and 31.0 degrees 2θ. For example, the postulated crystalline form has the powder X-ray diffraction pattern shown in Figure 28. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0075]

[0103] The postulated crystalline Form 7 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, bis-hydrochloride salt may be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with a peak at about 111° C., a characteristic endotherm with a peak at about 179° C., and a characteristic endotherm with a peak at about 188° C. Form 7 may be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 29.

[0076]

[0104] The postulated crystalline Form 7 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, bis-hydrochloride salt may be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 8.63 wt.% between about 29°C and about 80°C. Form 7 may be characterized, for example, by the thermogravimetric analysis profile shown in Figure 30.

[0077]

[0105] In a further embodiment, disclosed herein is a pharmaceutical composition comprising the disclosed crystalline salt form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide and a pharmaceutically acceptable excipient. In another embodiment, a pharmaceutical composition is formed from the disclosed crystalline salt form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide disclosed herein. In some embodiments, the disclosed pharmaceutical compositions can be formulated for oral administration.

[0078]

[0106] In embodiments, disclosed herein is a drug substance comprising at least a detectable amount of the disclosed crystalline salt form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide. In another embodiment, disclosed herein is a drug substance comprising a substantially pure crystalline salt form of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide.

[0079] composition

[0107] Another aspect of the present disclosure provides pharmaceutical compositions comprising the crystalline compounds disclosed herein, formulated with pharmaceutically acceptable excipients.In particular, the present disclosure provides pharmaceutical compositions comprising the crystalline compounds disclosed herein, formulated with one or more pharmaceutically acceptable excipients.These formulations include those suitable for oral administration, topical administration (e.g., transdermal administration), buccal administration, ocular administration, parenteral administration (e.g., subcutaneous administration, intramuscular administration, intradermal administration, or intravenous administration), rectal administration, intravaginal administration, or aerosol administration, although the most suitable administration form in any given case depends on the degree and severity of the condition being treated and the properties of the specific compound used.For example, the disclosed compositions can be formulated as a unit dose and / or can be formulated for oral administration, subcutaneous administration, or intravenous administration.

[0080]

[0108] Exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations, for example, in solid, semi-solid, or liquid form, which contain one or more compounds of the present disclosure as active ingredients mixed with organic or inorganic excipients or vehicles suitable for external, enteral, or parenteral use. The active ingredient can be compounded with conventional non-toxic, pharmaceutically acceptable excipients for, for example, tablets, pellets, capsules, suppositories, liquids, emulsions, suspensions, and any other form suitable for use. The active compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0081]

[0109] In preparing solid compositions such as tablets, the principal active ingredient can be mixed with pharmaceutical excipients, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g., water, to form solid preformulation compositions containing a homogeneous mixture of a compound of the present disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition, and that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0082]

[0110] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders. (5) additives, such as sorbent, sorbent, sorbent (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols, for example.

[0083]

[0111] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be produced by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as sugar-coated tablets, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field.

[0084]

[0112] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or their mixtures, as well as powders.Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, nanosuspensions, syrups, and elixirs.In addition to the subject composition, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrin, and mixtures thereof.

[0085]

[0113] Suspensions may contain, in addition to the subject composition, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0086]

[0114] Formulations for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing the subject compositions with one or more suitable non-irritating excipients, or excipients including, for example, cocoa butter, polyethylene glycol, a suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature and therefore melt in the body cavity and release the active agent.

[0087]

[0115] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable excipient, and with any preservatives, buffers, or propellants which may be required.

[0088]

[0116] Ointments, pastes, creams, and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0089]

[0117] Powders and sprays may contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0090]

[0118] Alternatively, the compositions and compounds of the present disclosure can be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal formulation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. Sonic nebulizers can be used to minimize drug exposure to shear, which can lead to degradation of the compounds contained in the composition. Typically, aqueous aerosols are produced by formulating an aqueous solution or suspension of the composition with conventional pharmaceutically acceptable excipients and stabilizers. Excipients and stabilizers vary depending on the requirements of the particular composition, but typically include non-ionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0091]

[0119] Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise the subject compositions in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted immediately before use into sterile injectable solutions or dispersions, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0092]

[0120] Examples of suitable aqueous and non-aqueous excipients that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin.For example, appropriate fluidity can be maintained by using coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.For example, the crystalline forms provided herein can be milled to obtain a specific particle size, and in at least some embodiments, such crystalline forms can remain substantially stable even after milling.

[0093]

[0121] The amount of the crystalline compound described herein in the formulation can vary depending on factors such as individual's condition, age, sex, and weight.Dosage regimen can be adjusted to achieve optimal therapeutic response.For example, a single bolus can be administered, or several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the needs of the therapeutic situation.For ease of administration and uniformity of dosage, it is particularly advantageous to formulate parenteral compositions into dosage unit form.Dosage unit form, as used herein, refers to a physically separate unit suitable for a single dosage to the mammalian subject being treated, each unit containing a predetermined amount of active crystalline compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0094]

[0122] The specifications for the dosage unit forms of the present disclosure are dictated by and directly depend upon (a) the unique characteristics of the selected crystalline compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of formulating such active crystalline compounds for the treatment of sensitivities in individuals.

[0095]

[0123] The disclosed compositions can be formulated as solutions, microemulsions, liposomes, or other ordered structures suitable for high drug concentrations. The carrier can be a solvent or dispersion medium, including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by using a coating such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants. In many cases, it is appropriate to include isotonic agents, such as sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption, such as monostearate salts and gelatin, in the composition.

[0096]

[0124] The disclosed crystalline compounds can be administered in time-release formulations, such as compositions containing slow-release polymers.Crystalline compounds can be prepared with carriers that protect the compound from rapid release, such as controlled-release formulations, including implants and microencapsulated delivery systems.Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic-polyglycolic acid copolymers (PLG).Many methods for preparing such formulations are commonly known to those skilled in the art.

[0097]

[0125] According to an alternative aspect of the present disclosure, the disclosed crystalline compounds can be formulated with one or more additional compounds that enhance the solubility of the compound.

[0098] method

[0126] The crystalline forms disclosed herein are useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the crystalline forms and methods is TYK2.

[0099]

[0127] Provided herein are crystalline salt forms of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, which are inhibitors of TYK2 and are therefore useful for treating one or more disorders associated with the activity of TYK2 or a mutant thereof.

[0100]

[0128] Provided herein are methods for treating a disease or disorder in a patient in need thereof, wherein the disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder, comprising administering to the patient an effective amount of a crystalline salt form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline salt form.

[0101]

[0129] In some embodiments, the disease or disorder is an autoimmune disorder. In some embodiments, the disease or disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0102]

[0130] In some embodiments, the disease or disorder is an inflammatory disorder, hi some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, or inflammatory bowel disease.

[0103]

[0131] In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments, the proliferative disorder is leukemia. In some embodiments, the leukemia is T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, essential thrombocytosis, or thrombocytosis.

[0104]

[0132] In some embodiments, the disease or disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0105]

[0133] In some embodiments, the disease or disorder is a neurological disorder, hi some embodiments, the neurological disorder is Alzheimer's disease.

[0106]

[0134] In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation in the FERM domain, JH2 domain, or kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0107]

[0135] In some embodiments, the disease or disorder is transplant-related. In some embodiments, the transplant-related disease or disorder is transplant rejection or graft-versus-host disease.

[0108]

[0136] 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.

[0109]

[0137] Provided herein are methods for treating inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0110]

[0138] Provided herein are methods for treating other diseases or conditions, e.g., diseases or conditions having an inflammatory component, e.g., diseases and conditions of the eye, such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, e.g., autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wege syndrome, and the like. Nurr granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, renal disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, keratoconjunctivitis sicca and vernal catarrhal keratoconjunctivitis keratoconjunctivitis), interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic fever, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g., idiopathic nephrotic syndrome or minimal change nephropathy) nephropathy), chronic granulomatous disease, endometriosis, leptospirosis, kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory syndrome, eosinophilia, hypersensitivity reactions, anaphylaxis, nasalsinusitis), eye allergies, silica-induced disease, COPD (reduction of damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, and dermatitis Methods for treating dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myelitis, myocarditis, 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 are provided.

[0111]

[0139] 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 fever syndrome (CAPS), or osteoarthritis.

[0112]

[0140] 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).

[0113]

[0141] In some embodiments, the inflammatory disease is Sjogren's syndrome, an allergic disorder, osteoarthritis, an ocular condition such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, or a disease affecting the nose such as allergic rhinitis.

[0114]

[0142] For example, disclosed herein is a method of inhibiting the TYK2 enzyme in a patient or biological sample, comprising contacting the patient or biological sample with a therapeutically effective amount of a crystalline salt form described herein, or a pharmaceutical composition comprising an effective amount of the disclosed crystalline salt form.

[0115]

[0143] Also disclosed herein are methods of inhibiting TYK2 activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline salt form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline salt form. In some embodiments, inhibiting TYK2 activity is associated with treating a disease or disorder selected from the group consisting of, for example, Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis.

[0116]

[0144] 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 salt form described herein or a pharmaceutical composition comprising an effective amount of the disclosed crystalline salt form. In some embodiments, the TYK2-mediated disorder is, for example, an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In other embodiments, the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

[0117]

[0145] For example, provided herein are methods of treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need thereof, comprising administering to the patient an effective amount of a crystalline salt form described herein, or a pharmaceutical composition comprising an effective amount of a disclosed crystalline salt form.

[0118]

[0146] In particular, in certain embodiments, the present disclosure provides methods of treating the above medical indications, comprising administering to a patient in need thereof an effective amount of a crystalline salt form described herein, or a pharmaceutical composition comprising an effective amount of the disclosed crystalline salt form. In certain other embodiments, the present disclosure provides methods 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 salt form described herein, or a pharmaceutical composition comprising an effective amount of the disclosed crystalline salt form.

[0119]

[0147] The crystalline compounds disclosed herein can be used as medicines or pharmaceutically acceptable compositions, for example, in the form of pharmaceutical preparations for oral, enteral, parenteral, or topical administration, and contemplated methods disclosed herein can include administering the disclosed crystalline compounds or compositions containing or formed from such disclosed crystalline compounds orally, enterally, parenterally, or topically. For example, the disclosed crystalline salt forms, when administered by a particular route (e.g., oral) or in a particular formulation, may be able to control one or more pharmacokinetic properties (e.g., a longer or shorter release profile) compared to a different route (e.g., subcutaneous) or other formulation, such as a formulation having an amorphous form. In one embodiment, the disclosed crystalline salt forms may provide substantial reproducibility from one formulation to another. [Example]

[0120]

[0148] The compounds and crystalline salt forms described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art. The following non-limiting examples illustrate the present disclosure.

[0121]

[0149] X-ray powder diffraction was performed using a Bruker D8 Advance X-ray diffractometer equipped with a LynxEye detector. Samples were scanned from 3 to 40° 2θ with a step size of 0.02° 2θ. The radiation was Cu / K-alpha 1 (λ = 1.5406 Å). The tube voltage and current were 40 kV and 40 mA, respectively.

[0122]

[0150] Differential scanning calorimetry (DSC) was performed using a Discovery DSC 250 (TA Instruments, US) calorimeter. Samples were placed in aluminum pinhole hermetic pans and their weights were accurately recorded. The samples were heated from 25°C to the final temperature at a rate of 10°C / min.

[0123]

[0151] Thermogravimetric analysis (TGA) was performed on a TGA Q500 or Discovery TGA 55 (TA Instruments, US). Samples were placed in tared open aluminum pans, automatically weighed, and inserted into the TGA furnace. The samples were heated from ambient temperature to the final temperature at a rate of 10 °C / min.

[0124]

[0152] Dynamic vapor sorption analysis (DVS) was performed on a DVS Intrinsic PLUS (SMS, UK). Samples were placed in a tared sample chamber and automatically weighed. Samples were dried at 40°C until dm / dt was less than 0.002% and cooled to 25°C. Instrument parameters were as follows: Step time (min) = 60 min, Sample temperature = 25°C; Cycle = Full cycle; Adsorption (%RH) = 0, 10, 20, 30, 40, 50, 60, 70, 80, 90; Desorption (%RH) = 80, 70, 60, 50, 40, 30, 20, 10, 0; Data storage rate = 5 s; Total flow rate = 200 sccm; Post-experiment flow rate = 200 sccm.

[0125]

[0153] Polarized light microscopy (PLM) was performed using a polarized light microscope ECLIPSE LV100POL (Nikon, Japan).

[0126] Example 1

[0154] Crystalline Form 1-1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate salt, was prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (30-45 mg) was added to MeOH (9 V). After the addition of 1.1 equivalents of methanesulfonic acid, precipitation occurred after adding 19 volumes of ethyl acetate. The mixture was concentrated to approximately 3 volumes at room temperature and stirred. The solid was collected and dried under vacuum. XRPD analysis showed the dried material to be crystalline with a pattern consistent with Form 1-1.

[0127]

[0155] Crystalline Form 1-1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate, was also prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (30-45 mg) was added to MeOH (5 V) with heating. After the addition of 1.1 equivalents of methanesulfonic acid, a precipitate formed after the addition of ethyl acetate (14 V). The mixture was cooled and stirred at room temperature, and then an additional 10 volumes of ethyl acetate were added. The solid was collected and dried under vacuum. XRPD analysis showed the dried material to be crystalline with a pattern consistent with Form 1-1.

[0128]

[0156] The XRPD pattern of crystalline form 1-1 is shown in Figure 1. Characteristic peaks include one or more of the peaks shown in Table 1.

[0129] [Table 1-1]

[0130] [Table 1-2]

[0131]

[0157] Figure 2 shows the differential scanning calorimetry (DSC) profile of crystalline form 1-1. As shown in Figure 2, crystalline form 1-1 exhibits a characteristic endotherm (enthalpy 98.7 J / g) with an onset of about 200°C and a peak at about 202°C.

[0132]

[0158] Crystalline Form 1-1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide methanesulfonate exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of approximately 0.27 wt.% between approximately 20 °C and approximately 180 °C (Figure 3). Crystalline Form 1-1 exhibited a dynamic vapor sorption (DVS) profile showing a reversible total mass change of approximately 0.6 wt.% between approximately 0% and approximately 80% relative humidity (RH) at 25 °C, and a reversible total mass change of approximately 1.3 wt.% between approximately 0% and approximately 90% relative humidity (RH) at 25 °C. No morphology change was observed after DVS analysis.

[0133]

[0159] Crystalline Form 1-1 exhibited solubilities of greater than 4.1 mg / mL in SGF, 0.02-0.03 mg / mL in FeSSIF, 2.06-0.93 mg / mL in water, and 0.001-0.002 mg / mL in FaSSIF. Crystalline Form 1-1 was observed to dissociate to the free base in FaSSIF, FeSSIF, and water.

[0134]

[0160] Crystalline Form 1-1 was observed to be anhydrous and only slightly hygroscopic. Form 1-1 was observed to be chemically and physically stable in solid form at 40°C / 75% RH and 60°C for at least 10 days.

[0135] Example 2

[0161] Crystalline Form 1-2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate salt, was prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (30-45 mg) was added to THF (9 mL). After the addition of 1.1 equivalents of methanesulfonic acid, the formation of a slurry was observed, and the solid was collected and dried under vacuum. XRPD analysis showed the dried material to be crystalline with a pattern consistent with Form 1-2.

[0136]

[0162] The XRPD pattern of crystalline form 1-2 is shown in Figure 4. Characteristic peaks include one or more of the peaks shown in Table 2.

[0137] [Table 2]

[0138]

[0163] Figure 5 shows the differential scanning calorimetry (DSC) profile of crystalline form 1-2. As shown in Figure 5, crystalline form 1-2 exhibits a characteristic endotherm with a peak at about 66°C (enthalpy 7.45 J / g), a characteristic endotherm with an onset of about 122°C and a peak at about 132°C (enthalpy 2.68 J / g), a characteristic endotherm with an onset of about 153°C and a peak at about 161°C (enthalpy 27.8 J / g), and a characteristic endotherm with an onset of about 195°C and a peak at about 195°C (enthalpy 3.15 J / g).

[0139]

[0164] Crystalline form 1-2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate, exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of approximately 0.70 wt.% between about 20 °C and about 75 °C, and a mass loss of approximately 1.24 wt.% between about 75 °C and about 160 °C (Figure 6). Crystalline form 1-2 was observed to be a tetrahydrofuran solvate (0.1 mol).

[0140] Example 3

[0165] Crystalline Form 1-3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate salt, was prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (30-45 mg) was added to acetone / water (9:1, 14V). After the addition of 1.1 equivalents of methanesulfonic acid, precipitation occurred after stirring at room temperature for 2 days. The solid was collected and dried under vacuum. XRPD analysis showed the dried material to be crystalline with a pattern consistent with Forms 1-3.

[0141]

[0166] The XRPD patterns of crystalline forms 1-3 are shown in Figure 7. Characteristic peaks include one or more of the peaks shown in Table 3.

[0142] [Table 3-1]

[0143] [Table 3-2]

[0144]

[0167] Figure 8 shows the differential scanning calorimetry (DSC) profile of crystalline form 1-3. As shown in Figure 8, crystalline form 1-3 exhibits a characteristic endotherm (enthalpy 92.0 J / g) with an onset of about 208°C and a peak at about 209°C.

[0145]

[0168] Crystalline Form 1-3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide methanesulfonate exhibited a thermogravimetric analysis (TGA) profile showing no mass loss (0% wt.) between about 20 °C and about 150 °C (Figure 9). Crystalline Form 1-3 was observed to be anhydrous.

[0146] Example 4

[0169] Crystalline Form 2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, fumarate salt, was prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (32 mg) was dissolved in DCM / MeOH (1:1, 19 V) at room temperature. Then, 1.1 equivalents of 0.25 M fumaric acid / MeOH were added. Precipitation occurred immediately after the addition of the acid. The mixture was stirred at room temperature for 2 hours and the solid was collected by filtration and dried under vacuum at 50° C. XRPD analysis showed the dried material to be crystalline with a pattern consistent with Form 2.

[0147]

[0170] The XRPD pattern of crystalline Form 2 is shown in Figure 10. Characteristic peaks include one or more of the peaks shown in Table 4.

[0148] [Table 4-1]

[0149] [Table 4-2]

[0150]

[0171] Figure 11 shows the differential scanning calorimetry (DSC) profile of crystalline Form 2. As shown in Figure 11, crystalline Form 2 exhibits a characteristic endotherm with an onset of about 36°C and a peak at about 57°C (enthalpy 7.74 J / g), a characteristic endotherm with an onset of about 196°C and a peak at about 199°C (enthalpy 11.2 J / g), a characteristic endotherm with an onset of about 202°C and a peak at about 205°C (enthalpy 37.9 J / g), a characteristic endotherm with an onset of about 208°C and a peak at about 209°C (enthalpy 15.1 J / g), and a characteristic endotherm with an onset of about 213°C and a peak at about 215°C (enthalpy 21.2 J / g).

[0151]

[0172] Crystalline Form 2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, fumarate salt exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of approximately 0.42 wt.% between about 20 °C and about 50 °C (Figure 12). Crystalline Form 2 was observed to be anhydrous. Crystalline Form 2 may be characterized as having a rod-like crystalline morphology as observed by polarized light microscopy.

[0152] Example 5

[0173] Crystalline Form 3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, hydrobromide salt was prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (21 mg) was taken up in acetone / water (9:1, 14V) at 50° C. After addition of 1.1 equivalents of hydrobromic acid, precipitation occurred immediately. The mixture was stirred at 50° C. for 30 minutes and then cooled to room temperature. The solid was collected by filtration and dried under vacuum at 40° C. before analysis. XRPD analysis showed the dried material to be crystalline with a pattern consistent with Form 3.

[0153]

[0174] The XRPD pattern of crystalline Form 3 is shown in Figure 13. Characteristic peaks include one or more of the peaks shown in Table 5.

[0154] [Table 5-1]

[0155] [Table 5-2]

[0156]

[0175] Figure 14 shows the differential scanning calorimetry (DSC) profile of crystalline Form 3. As shown in Figure 14, crystalline Form 3 exhibits a characteristic endotherm (enthalpy 82.4 J / g) with an onset of about 247°C and a peak at about 249°C.

[0157]

[0176] Crystalline Form 3 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, hydrobromide salt exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.86 wt.% between about 20 °C and about 180 °C (Figure 15). Crystalline Form 3 was observed to be anhydrous.

[0158] Example 6

[0177] Crystalline Form 4 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, phosphate salt, was prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (30 mg) was taken up in MeOH / water (9:1, 14V) at 50° C. One equivalent of phosphoric acid was added, followed by cooling to 35° C., and precipitation occurred after cooling to room temperature. The mixture was stirred at 50° C. for 30 minutes and then cooled to room temperature. The solid was collected by filtration and dried under vacuum. XRPD analysis showed that the dried material was crystalline and had a pattern consistent with Form 4.

[0159]

[0178] Crystalline Form 4 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, phosphate salt, was prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (30 mg) was taken up in DCM / MeOH (1:1, 22 V) at room temperature. After adding one equivalent of phosphoric acid, precipitation occurred immediately. The solid was collected by filtration and dried under vacuum. XRPD analysis showed that the dried material was crystalline and had a pattern consistent with Form 4.

[0160]

[0179] The XRPD pattern of crystalline Form 4 is shown in Figure 16. Characteristic peaks include one or more of the peaks shown in Table 6.

[0161] [Table 6-1]

[0162] [Table 6-2]

[0163]

[0180] Figure 17 shows the differential scanning calorimetry (DSC) profile of crystalline Form 4. As shown in Figure 17, crystalline Form 4 exhibits a characteristic endotherm (enthalpy 47.2 J / g) with an onset of about 172°C and a peak at about 275°C, a characteristic exotherm (enthalpy 36.6 J / g) with a peak at about 182°C, and a characteristic endotherm (enthalpy 81.8 J / g) with an onset of about 200°C and a peak at about 204°C.

[0164]

[0181] Crystalline Form 4 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, phosphate salt, exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.26 wt.% between about 20 °C and about 185 °C (Figure 18). Crystalline Form 4 was observed to be anhydrous.

[0165] Example 7

[0182] Crystalline form 5-1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate salt, was prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (32 mg) was taken up in MeOH (10 V) at 50 °C. After addition of 1.1 equivalents of 2 M sulfuric acid in ethyl acetate, precipitation occurred after addition of 8 volumes of ethyl acetate at 50 °C. The mixture was stirred at 50 °C for 5 minutes and then cooled to room temperature. The solid was collected by filtration and dried under vacuum. XRPD analysis showed the dried material to be crystalline with a pattern consistent with Form 5-1.

[0166]

[0183] The XRPD pattern of crystalline form 5-1 is shown in Figure 19. Characteristic peaks include one or more of the peaks shown in Table 7.

[0167] [Table 7-1]

[0168] [Table 7-2]

[0169]

[0184] Figure 20 shows the differential scanning calorimetry (DSC) profile of crystalline form 5-1. As shown in Figure 20, crystalline form 5-1 exhibits a characteristic endotherm with an onset of about 91°C and a peak at about 117°C (enthalpy 58.0 J / g), and a characteristic endotherm with an onset of about 231°C and a peak at about 236°C (enthalpy 111.5 J / g).

[0170]

[0185] Crystalline form 5-1 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate salt, exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of approximately 4.33 wt.% between about 20 °C and about 130 °C (Figure 21). Crystalline form 5-1 was observed to be a methanol solvate (3.7%, 2 / 3 mol).

[0171] Example 8

[0186] Crystalline Form 5-2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate salt, was prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (32 mg) was taken up in acetone (13 V) at 50° C. After adding 1.1 equivalents of 2 M sulfuric acid in water, precipitation occurred after 20 minutes at 50° C. The mixture was cooled to room temperature, and the solid was collected by filtration and dried under vacuum. XRPD analysis showed the dried material to be crystalline with a pattern consistent with Form 5-2.

[0172]

[0187] The XRPD pattern of crystalline form 5-2 is shown in Figure 22. Characteristic peaks include one or more of the peaks shown in Table 8.

[0173] [Table 8-1]

[0174] [Table 8-2]

[0175]

[0188] Figure 23 shows the differential scanning calorimetry (DSC) profile of crystalline form 5-2. As shown in Figure 23, crystalline form 5-2 exhibits a characteristic endotherm (enthalpy 100.2 J / g) with an onset of about 229°C and a peak at about 233°C.

[0176]

[0189] Crystalline Form 5-2 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, sulfate salt, exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of approximately 0.3 wt.% between about 20 °C and about 150 °C (Figure 24). Crystalline Form 5-2 exhibited a dynamic vapor sorption (DVS) profile showing a reversible total mass change of approximately 0.9 wt.% between about 0% and about 80% relative humidity (RH) at 25 °C, and a reversible total mass change of approximately 1.4 wt.% between about 0% and about 90% relative humidity (RH) at 25 °C. No morphology change was observed following DVS analysis. Crystalline Form 5-2 was observed to be anhydrous.

[0177] Example 9

[0190] Crystalline Form 6 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, p-toluenesulfonate, was prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (32 mg) was taken up in MeOH (6 V) at 50 °C. 1.1 equivalents of 2 M p-toluenesulfonic acid in MeOH were added, followed by the addition of 25 volumes of ethyl acetate, resulting in precipitation. The mixture was cooled to room temperature, and the solid was collected by filtration and dried under vacuum. XRPD analysis showed that the dried material was crystalline and had a pattern consistent with Form 6.

[0178]

[0191] The XRPD pattern of crystalline Form 6 is shown in Figure 25. Characteristic peaks include one or more of the peaks shown in Table 9.

[0179] [Table 9-1]

[0180] [Table 9-2]

[0181]

[0192] Figure 26 shows the differential scanning calorimetry (DSC) profile of crystalline Form 6. As shown in Figure 26, crystalline Form 6 exhibits a characteristic endotherm (enthalpy 79.5 J / g) with an onset of about 215°C and a peak at about 217°C.

[0182]

[0193] Crystalline Form 6 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, p-toluenesulfonate, exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.6 wt.% between about 20 °C and about 200 °C (Figure 27). Crystalline Form 6 exhibited a dynamic vapor sorption (DVS) profile showing a reversible total mass change of about 0.6 wt.% between about 0% and about 80% relative humidity (RH) at 25 °C and about 0% and about 0.7 wt.% between about 0% and about 90% relative humidity (RH) at 25 °C. No morphological change was observed following DVS analysis. Crystalline Form 6 was observed to be anhydrous.

[0183] Example 10

[0194] Crystalline Form 7 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, bis-hydrochloride salt, was prepared as follows: N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (20.0 mg) was added to isopropyl acetate (0.25 mL) to form a suspension. In a separate vial, a solution was prepared by diluting 0.0094 mL of aqueous HCl (12 M) with 0.25 mL of isopropyl acetate. The diluted HCl solution was added dropwise to the suspension with stirring. The resulting slurry was stirred at room temperature for 3 days, after which the solid was collected by filtration and air-dried at room temperature for 1 hour. XRPD analysis showed that the dried solid material was crystalline and had a pattern consistent with Form 7.

[0184]

[0195] The XRPD pattern of crystalline form 7 is shown in Figure 28. Characteristic peaks include one or more of the peaks shown in Table 10.

[0185] [Table 10]

[0186]

[0196] Figure 29 shows the differential scanning calorimetry (DSC) profile of crystalline form 7. As shown in Figure 29, crystalline form 7 exhibits a characteristic endotherm with a peak at about 111°C, a characteristic endotherm with a peak at about 179°C, and a characteristic endotherm with a peak at about 188°C.

[0187]

[0197] Crystalline Form 7 of N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide, bis-hydrochloride salt, exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 8.63 wt.% between about 29 °C and about 80 °C (Figure 30). IC / HPLC testing showed a Cl-based mass loss of about 8.63 wt.% relative to the free base. - It was shown that the stoichiometric ratio of

[0188] Incorporation by Reference

[0198] All publications and patents mentioned in this specification, including those listed below, are incorporated herein by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0189] equivalent

[0199] While specific embodiments of the subject disclosure have been described, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the present disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0190]

[0200] 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 the specification and appended claims are approximations and may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. N-(4-((2-methoxy-3-(1-methyl-d), characterized by a powder X-ray diffraction pattern having a characteristic peak at about 24.0 degrees 2θ. ３ )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d ３ )pyridin-2-yl)cyclopropanecarboxamide, a crystalline form of methanesulfonate salt (Form 1-1).

2. 10. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 12.7, 17.1, and 24.0 degrees 2θ.

3. 3. The crystalline form of claim 1 or 2, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.5, 12.7, 17.1, 19.1, 20.5, and 24.0 degrees 2θ.

4. 4. The crystalline form of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.5, 12.7, 15.5, 17.1, 19.1, 20.5, 24.0, 24.3, and 26.9 degrees 2θ.

5. 5. The crystalline form of any one of claims 1 to 4, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.9, 7.8, 9.5, 12.7, 15.5, 17.1, 19.1, 20.5, 21.0, 23.7, 24.0, 24.3, and 26.9 degrees 2θ.

6. 6. The crystalline form of any one of claims 1 to 5, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.9, 7.8, 9.5, 12.7, 15.5, 17.1, 19.1, 19.4, 20.5, 20.8, 21.0, 23.7, 24.0, 24.3, 25.5, and 26.9 degrees 2θ.

7. 7. The crystalline form of any one of claims 1 to 6, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 201°C and a peak at about 202°C.

8. 8. The crystalline form of any one of claims 1 to 7, characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.20 wt. % between about 100°C and about 201°C.

9. N-(4-((2-methoxy-3-(1-methyl-d), characterized by a powder X-ray diffraction pattern with a characteristic peak at about 9.9 degrees 2θ ３ )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d ３ )pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate salt crystalline form (Form 1-2).

10. 10. The crystalline form of claim 9, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.5, 9.9, and 20.0 degrees 2θ.

11. 11. The crystalline form of claim 9 or 10, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.5, 9.9, 13.7, 18.2, 20.0, and 22.5 degrees 2θ.

12. 12. The crystalline form of any one of claims 9 to 11, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.5, 9.2, 9.9, 13.7, 18.2, 20.0, 23.9, 22.5, and 26.5 degrees 2θ.

13. 13. The crystalline form of any one of claims 9 to 12, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.5, 8.3, 9.2, 9.9, 10.4, 13.7, 18.2, 20.0, 21.1, 23.9, 22.5, and 26.5 degrees 2θ.

14. 14. The crystalline form of any one of claims 9 to 13, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with a peak at about 66°C, a characteristic endotherm with an onset of about 122°C and a peak at about 132°C, a characteristic endotherm with an onset of about 153°C and a peak at about 161°C, and a characteristic endotherm with an onset of about 195°C and a peak at about 195°C.

15. 15. The crystalline form of any one of claims 9 to 14, characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.70 wt. % between about 20°C and about 75°C, and a mass loss of about 1.24 wt. % between about 75°C and about 160°C.

16. N-(4-((2-methoxy-3-(1-methyl-d), characterized by a powder X-ray diffraction pattern having a characteristic peak at about 21.0 degrees 2θ. ３ )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d ３ )pyridin-2-yl)cyclopropanecarboxamide, methanesulfonate salt crystalline forms (Forms 1-3).

17. 17. The crystalline form of claim 16, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.0, 18.0, and 21.0 degrees 2θ.

18. 18. The crystalline form of claim 16 or 17, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.1, 8.1, 9.0, 18.0, 21.0, and 23.3 degrees 2θ.

19. 19. The crystalline form of any one of claims 16 to 18, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.1, 8.1, 9.0, 10.4, 18.0, 20.6, 21.0, 23.3, and 28.5 degrees 2θ.

20. 20. The crystalline form of any one of claims 16 to 19, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.1, 8.1, 9.0, 10.4, 16.5, 18.0, 20.6, 21.0, 23.3, 24.0, 24.2, and 28.5 degrees 2θ.

21. 21. The crystalline form of any one of claims 16 to 20, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.1, 8.1, 9.0, 10.4, 11.1, 15.6, 16.5, 17.5, 18.0, 20.6, 21.0, 23.3, 24.0, 24.2, and 28.5 degrees 2θ.

22. 22. The crystalline form of any one of claims 16 to 21, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 208°C and a peak at about 209°C.

23. 23. The crystalline form of any one of claims 16 to 22, characterized by a thermogravimetric analysis (TGA) profile exhibiting no mass loss (0% wt.) between about 20°C and about 150°C.

24. N-(4-((2-methoxy-3-(1-methyl-d), characterized by a powder X-ray diffraction pattern having a characteristic peak at about 26.1 degrees 2θ. ３ )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d ３ )pyridin-2-yl)cyclopropanecarboxamide, a crystalline form of fumarate salt (Form 2).

25. 25. The crystalline form of claim 24, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 8.0, 23.3, and 26.1 degrees 2θ.

26. 26. The crystalline form of claim 24 or 25, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 8.0, 13.5, 22.3, 23.3, 25.6, and 26.1 degrees 2θ.

27. 27. The crystalline form of any one of claims 24 to 26, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 4.2, 8.0, 8.3, 13.5, 21.0, 22.3, 23.3, 25.6, and 26.1 degrees 2θ.

28. 28. The crystalline form of any one of claims 24 to 27, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 4.2, 8.0, 8.3, 10.7, 13.5, 18.5, 21.0, 21.3, 22.3, 23.3, 25.6, and 26.1 degrees 2θ.

29. 29. The crystalline form of any one of claims 24 to 28, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 4.2, 8.0, 8.3, 10.7, 12.5, 13.5, 18.5, 21.0, 22.0, 21.3, 21.7, 22.3, 23.3, 25.6, and 26.1 degrees 2θ.

30. 30. The crystalline form of any one of claims 24 to 29, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 36°C and a peak at about 57°C, a characteristic endotherm with an onset of about 196°C and a peak at about 199°C, a characteristic endotherm with an onset of about 202°C and a peak at about 205°C, a characteristic endotherm with an onset of about 208°C and a peak at about 209°C, and a characteristic endotherm with an onset of about 213°C and a peak at about 215°C.

31. 31. The crystalline form of any one of claims 24 to 30, characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.42 wt. % between about 20°C and about 50°C.

32. N-(4-((2-methoxy-3-(1-methyl-d), characterized by a powder X-ray diffraction pattern with a characteristic peak at about 9.7 degrees 2θ ３ )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d ３ )pyridin-2-yl)cyclopropanecarboxamide, a crystalline form of hydrobromide salt (Form 3).

33. 33. The crystalline form of claim 32, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.7, 19.5, and 20.5 degrees 2θ.

34. 34. The crystalline form of claim 32 or 33, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.7, 19.5, 20.5, 21.2, 23.3, and 26.4 degrees 2θ.

35. 35. The crystalline form of any one of claims 32 to 34, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.7, 17.4, 19.5, 20.5, 21.2, 23.3, 26.4, 27.8, and 29.4 degrees 2θ.

36. 36. The crystalline form of any one of claims 32 to 35, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.7, 17.1, 17.4, 19.5, 20.5, 20.9, 21.2, 22.9, 23.3, 26.4, 27.8, and 29.4 degrees 2θ.

37. 37. The crystalline form of any one of claims 32 to 36, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.7, 17.1, 17.4, 19.5, 20.5, 20.9, 21.2, 22.9, 23.3, 24.8, 26.4, 27.8, 29.4, 30.8, and 32.2 degrees 2θ.

38. 38. The crystalline form of any one of claims 32 to 37, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 247°C and a peak at about 249°C.

39. 39. The crystalline form of any one of claims 32 to 38, characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.86 wt. % between about 20°C and about 180°C.

40. N-(4-((2-methoxy-3-(1-methyl-d), characterized by a powder X-ray diffraction pattern with a characteristic peak at about 4.8 degrees 2θ. ３ )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d ３ )pyridin-2-yl)cyclopropanecarboxamide, a crystalline form of phosphate salt (Form 4).

41. 41. The crystalline form of claim 40, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 4.8, 6.2, and 9.6 degrees 2θ.

42. 42. The crystalline form of claim 40 or 41, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 4.8, 6.2, 7.9, 9.6, 12.6, and 22.2 degrees 2θ.

43. 43. The crystalline form of any one of claims 40 to 42, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 4.8, 6.2, 7.9, 9.6, 12.6, 16.7, 18.5, 21.5, and 22.2 degrees 2θ.

44. 44. The crystalline form of any one of claims 40 to 43, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 172°C and a peak at about 275°C, a characteristic exotherm with a peak at about 182°C, and a characteristic endotherm with an onset of about 200°C and a peak at about 204°C.

45. 45. The crystalline form of any one of claims 40 to 44, characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.26 wt. % between about 20°C and about 185°C.

46. N-(4-((2-methoxy-3-(1-methyl-d), characterized by a powder X-ray diffraction pattern having a characteristic peak at about 21.2 degrees 2θ. ３ )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d ３ )pyridin-2-yl)cyclopropanecarboxamide, a crystalline form of sulfate salt (Form 5-1).

47. 47. The crystalline form of claim 46, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 8.4, 16.9, and 21.2 degrees 2θ.

48. 48. The crystalline form of claim 46 or 47, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 8.4, 16.9, 20.9, 21.2, 22.2, and 23.5 degrees 2θ.

49. 49. The crystalline form of any one of claims 46 to 48, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.3, 8.4, 16.9, 18.0, 20.9, 21.2, 21.8, 22.2, and 23.5 degrees 2θ.

50. 50. The crystalline form of any one of claims 46 to 49, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.3, 8.4, 9.0, 15.9, 16.9, 18.0, 20.9, 21.2, 21.8, 22.2, 23.1, and 23.5 degrees 2θ.

51. 51. The crystalline form of any one of claims 46 to 50, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.3, 8.4, 9.0, 15.4, 15.9, 16.9, 18.0, 20.6, 20.9, 21.2, 21.8, 22.2, 23.1, 23.5, and 27.8 degrees 2θ.

52. 52. The crystalline form of any one of claims 46-51, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 91°C and a peak at about 117°C, and a characteristic endotherm with an onset of about 231°C and a peak at about 236°C.

53. 53. The crystalline form of any one of claims 46 to 52, characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 4.33 wt.% between about 20°C and about 130°C.

54. N-(4-((2-methoxy-3-(1-methyl-d), characterized by a powder X-ray diffraction pattern having a characteristic peak at about 16.1 degrees 2θ. ３ )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d ３ )pyridin-2-yl)cyclopropanecarboxamide, a crystalline form of sulfate salt (Form 5-2).

55. 55. The crystalline form of claim 54, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 16.1, 19.2, and 23.9 degrees 2θ.

56. 56. The crystalline form of claim 54 or 55, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.6, 16.1, 19.2, 19.9, 21.6, and 23.9 degrees 2θ.

57. 57. The crystalline form of any one of claims 54 to 56, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.6, 12.6, 16.1, 19.2, 19.9, 21.6, 23.9, 24.2, and 25.4 degrees 2θ.

58. 58. The crystalline form of any one of claims 54 to 57, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 8.2, 9.6, 12.6, 16.1, 18.0, 19.2, 19.9, 21.6, 23.9, 24.2, 24.6, and 25.4 degrees 2θ.

59. 59. The crystalline form of any one of claims 54 to 58, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 8.2, 9.6, 12.6, 15.4, 16.1, 18.0, 19.2, 19.9, 20.3, 21.6, 23.9, 24.2, 24.6, 25.4, and 28.2 degrees 2θ.

60. 60. The crystalline form of any one of claims 54 to 59, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 229°C and a peak at about 233°C.

61. 61. The crystalline form of any one of claims 54 to 60, characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.31 wt. % between about 20°C and about 150°C.

62. N-(4-((2-methoxy-3-(1-methyl-d), characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.8 degrees 2θ. ３ )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d ３ )pyridin-2-yl)cyclopropanecarboxamide, p-toluenesulfonate salt crystalline form (Form 6).

63. 63. The crystalline form of claim 62, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.8, 19.8, and 22.7 degrees 2θ.

64. 64. The crystalline form of claim 62 or 63, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.6, 7.2, 9.8, 19.8, 20.2, and 22.7 degrees 2θ.

65. 65. The crystalline form of any one of claims 62 to 64, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.6, 7.2, 9.8, 16.1, 19.8, 20.2, 22.7, 24.9, and 25.4 degrees 2θ.

66. 66. The crystalline form of any one of claims 62 to 65, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.6, 7.2, 9.8, 15.1, 15.8, 16.1, 19.5, 19.8, 20.2, 22.7, 24.9, and 25.4 degrees 2θ.

67. 67. The crystalline form of any one of claims 62 to 66, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.6, 7.2, 9.8, 13.3, 15.1, 15.8, 16.1, 19.5, 19.8, 20.2, 21.4, 22.7, 24.9, 25.4, and 26.5 degrees 2θ.

68. 68. The crystalline form of any one of claims 62 to 67, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 215°C and a peak at about 217°C.

69. 69. The crystalline form of any one of claims 62 to 68, characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.6 wt. % between about 20°C and about 200°C.

70. N-(4-((2-methoxy-3-(1-methyl-d), characterized by a powder X-ray diffraction pattern having a characteristic peak at about 9.4 degrees 2θ. ３ )-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d ３ )pyridin-2-yl)cyclopropanecarboxamide, bis-hydrochloride salt crystalline form (Form 7).

71. 71. The crystalline form of claim 70, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 5.4, 6.2, and 9.4 degrees 2θ.

72. 72. The crystalline form of claim 70 or 71, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 5.4, 6.2, 9.4, 24.3, 26.2, and 26.7 degrees 2θ.

73. 73. The crystalline form of any one of claims 70 to 72, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 5.4, 6.2, 9.4, 10.3, 24.3, 24.7, 26.2, 26.7, and 31.0 degrees 2θ.

74. 74. The crystalline form of any one of claims 70 to 73, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 5.4, 6.2, 9.4, 10.3, 10.8, 16.0, 18.5, 24.3, 24.7, 26.2, 26.7, and 31.0 degrees 2θ.

75. 75. The crystalline form of any one of claims 70-74, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with a peak at about 111 °C, a characteristic endotherm with a peak at about 179 °C, and a characteristic endotherm with a peak at about 188 °C.

76. 76. The crystalline form of any one of claims 70 to 75, characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 8.63 wt. % between about 29°C and about 80°C.

77. 77. The crystalline form of any one of claims 1 to 76, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

78. 78. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 77 and a pharmaceutically acceptable excipient.

79. 78. A pharmaceutical composition formed from the crystalline form of any one of claims 1 to 77.

80. 80. The pharmaceutical composition of claim 78 or 79, formulated for oral administration.

81. 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 to 77, or a pharmaceutical composition of any one of claims 78 or 79.

82. 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 to 77, or a pharmaceutical composition of any one of claims 78 or 79.

83. 80. A method of treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need thereof, comprising administering to the patient an effective amount of a crystalline form of any one of claims 1 to 77, or a pharmaceutical composition of any one of claims 78 or 79.

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