Crystalline form of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine-3-carboxamide

Abstract

Provided are several crystalline forms of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide: Form F, Form G, Form H, Form I, Form J, and Form K. Some of these crystalline forms are hydrates. Characterization data for each of these crystalline forms is provided.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention generally relates to crystalline forms of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. Such crystalline forms include crystalline hydrate forms of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide and crystalline anhydrous forms of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. The present invention also relates generally to pharmaceutical compositions containing said crystalline forms and to methods of obtaining such crystalline forms. [Background technology]

[0002] 2. Background of the Invention The compound 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide has the formula (I): [ka] Compound (I) has the structure: embedded image and is referred to herein as "Compound (I)". Compound (I) is disclosed in commonly assigned U.S. Patent RE47,929E. U.S. Patent RE47,929E also discloses methods of treatment using Compound (I). Compound (I) is also known as duravacitinibe.

[0003] Compound (I) is a Tyk2 inhibitor currently in clinical trials for the treatment of autoimmune and autoinflammatory diseases such as psoriasis, psoriatic arthritis, lupus, lupus nephritis, Sjogren's syndrome, inflammatory bowel disease, Crohn's disease and ankylosing spondylitis.

[0004] During the synthesis of chemical compounds intended for pharmaceutical use, it is necessary to isolate and purify the compound upon completion of the synthesis process and prior to providing the compound in a pharmaceutical formulation. The isolation and purification steps, which may be combined or separate sequential steps, ideally provide the compound as a purified solid with minimal loss of yield during isolation of the compound from other components of the reaction mixture and / or purification to remove impurities from an isolated compound sample. Summary of the Invention [Problem to be solved by the invention]

[0005] It would be desirable to provide solid forms of such compounds that can be reproducibly produced from isolation and / or purification steps.

[0006] Additionally, it is desirable to isolate the compound in a solid form that is physically and chemically stable during storage, including under various conditions of temperature and humidity. It is also desirable to provide the compound in a solid form that is amenable to further processing, for example a crystalline form that can be converted to other solid forms, such as amorphous or other crystalline forms.

[0007] As described herein, the crystalline forms of Compound (I) are surprisingly amenable to further processing and conversion to other solid forms. The present invention is directed to these and other important aspects. [Means for solving the problem]

[0008] Summary of the Invention The present invention provides crystalline forms of Compound (I), namely, Form F, Form G, Form H, Form I, Form J and Form K. The designations used herein to characterize a particular form, e.g., "Form F", "Form G", etc., should not be considered limiting with respect to any other substance having similar or identical physical and chemical characteristics, but rather, the designations are merely identifiers that should also be interpreted in accordance with the characterization information provided herein. [Brief description of the drawings]

[0009] [Figure 1] 1 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form F of Compound (I).

[0010] [Diagram 2] 1 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form G of Compound (I).

[0011] [Diagram 3] 1 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form H of Compound (I).

[0012] [Figure 4] 1 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline Form I of Compound (I).

[0013] [Diagram 5] 1 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form J of Compound (I).

[0014] [Figure 6] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form J of Compound (I).

[0015] [Figure 7] 1 shows a thermogravimetric analysis (TGA) thermogram of Form J of Compound (I).

[0016] [Figure 8] 1 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form K of Compound (I).

[0017] [Figure 9] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form K of Compound (I).

[0018] [Figure 10]1 shows a thermogravimetric analysis (TGA) thermogram of Form K of Compound (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description of the Invention The features and advantages of the present invention will be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It will also be recognized that, for reasons of clarity, certain features of the invention that are described above and below in the context of separate embodiments may be combined to form a single embodiment. Conversely, various features of the invention that are, for reasons of brevity, described in the context of a single embodiment may also be combined to form subcombinations thereof.

[0020] Designations used herein to characterize a particular form, such as "Form F," are merely identifiers that should be interpreted in accordance with the characterization information provided herein (or in references cited herein) and are not limiting to the exclusion of any other materials having similar or identical physical and chemical characteristics.

[0021] The definitions provided herein take precedence over definitions set forth in any patents, patent applications and / or patent application publications incorporated herein by reference.

[0022] All numerical values ​​preceded by the term "about" expressing amounts of ingredients, weight percentages, temperatures, and the like, should be understood to be merely approximations, such that slight variations above and below the stated numerical value can be used to produce results substantially the same as the stated numerical value. Accordingly, unless specifically indicated to the contrary, numerical parameters preceded by the term "about" are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and without limiting the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of at least the recited significant digits and by applying ordinary rounding techniques.

[0023] All measurements are subject to experimental error which is consistent with the spirit of the invention.

[0024] As used herein, "polymorph" refers to crystalline forms having the same chemical structure but differing in the spatial arrangement of the molecules and / or ions that form the crystals.

[0025] As used herein, "hydrate" refers to having a stoichiometric or non-stoichiometric amount of water molecules incorporated into a crystal lattice structure. In some embodiments, the stoichiometry can be specified (e.g., monohydrate).

[0026] As used herein, "amorphous" refers to a solid form of molecules and / or ions that is not crystalline. Amorphous solids do not exhibit a definitive X-ray diffraction pattern with a distinct maximum.

[0027] As used herein, "substantially pure" when used in reference to a crystalline form of a compound means that the crystalline form is greater than 90% pure by weight, including greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% and 99% by weight, including greater than about 100% by weight, based on the weight of the sample or specimen. The remaining material includes other forms of the compound and / or reaction impurities and / or process impurities resulting from its manufacture. For example, a crystalline form of Compound (I) can be considered substantially pure when it is greater than 90% pure by weight, as measured by means currently known and generally accepted in the art, where the remaining less than 10% by weight of the material includes amorphous and / or other forms of Compound (I) and / or reaction impurities and / or process impurities.

[0028] As used herein, a powder X-ray diffraction (PXRD) pattern that "comprises" a number of peaks selected from a specified set of peaks is intended to include PXRD patterns having additional peaks not included in the specified set of peaks. For example, a PXRD pattern that includes 4 or more (such as 5 or more) peaks or 2θ values ​​selected from a, b, c, d, e, f, g, and h is intended to include PXRD patterns that have: (a) 4 or more (such as 5 or more) 2θ values ​​selected from a, b, c, d, e, f, g, and h; and (b) 0, 1, or more peaks that are not one of the peaks a, b, c, d, e, f, g, and h.

[0029] The presence of reaction and / or process impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, and / or infrared spectroscopy.

[0030] As used herein, the unit cell parameter "molecule / unit cell" refers to the number of molecules of Compound (I) in a unit cell.

[0031] Forms of Compound (I) are described in WO2018 / 183656 (Form A), WO2019 / 232138 (Form B), WO2020 / 251911 (Forms C and D) and U.S. Provisional Application 63 / 143,769 (Form E). The present invention generally relates to Forms F, G, H, I, J and K of Compound (I).

[0032] Form F of compound (I) In certain embodiments, Compound (I) is provided as a crystalline material comprising Form F. Crystalline Form F of Compound (I) is a free base hydrate crystalline form.

[0033] In certain embodiments, crystalline form F of Compound (I) is characterized by unit cell parameters approximately equal to: Cell Dimensions (Monoclinic): a=54.50±0.10Å b = 7.83 ± 0.10 Å c=23.43±0.10Å α=90.0° β=102.4±1.0° γ=90.0° Space group: C2 / c Molecules / unit cell(Z):16 Unit cell volume = 9766 ± 20 Å 3 Density (calculated) = 1.288mg / m 3 (wherein the unit cell parameters of Form F of Compound (I) are measured at a temperature of about 296K). [Table 1]

[0034] In certain embodiments, crystalline Form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 3.3±0.2, 6.6±0.2, 7.7±0.2, 9.0±0.2, 11.2±0.2, 15.0±0.2, 18.9±0.2, 20.1±0.2, 23.8±0.2, 25.3±0.2 and 27.2±0.2, where the PXRD pattern of Form F is measured at room temperature.

[0035] In certain embodiments, crystalline Form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from: 3.3±0.2, 6.6±0.2, 7.7±0.2, 9.0±0.2, 11.2±0.2, 15.0±0.2, 18.9±0.2, 20.1±0.2, 23.8±0.2, 25.3±0.2, and 27.2±0.2, where the PXRD pattern of Form F is measured at room temperature.

[0036] In certain embodiments, crystalline Form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising four or more 2θ values ​​(°) (CuKα) selected from 3.3±0.2, 6.6±0.2, 7.7±0.2, 9.0±0.2, 11.2±0.2, 15.0±0.2, 18.9±0.2, 20.1±0.2, 23.8±0.2, 25.3±0.2 and 27.2±0.2, where the PXRD pattern of Form F is measured at room temperature.

[0037] In certain embodiments, crystalline Form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 3.3±0.2, 6.6±0.2, 7.7±0.2, 9.0±0.2, 11.2±0.2, 15.0±0.2, 18.9±0.2, 20.1±0.2, 23.8±0.2, 25.3±0.2 and 27.2±0.2, where the PXRD pattern of Form F is measured at room temperature.

[0038] In certain embodiments, crystalline Form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 6 or more 2θ values ​​(°) (CuKα) selected from 3.3±0.2, 6.6±0.2, 7.7±0.2, 9.0±0.2, 11.2±0.2, 15.0±0.2, 18.9±0.2, 20.1±0.2, 23.8±0.2, 25.3±0.2 and 27.2±0.2, where the PXRD pattern of Form F is measured at room temperature.

[0039] In certain embodiments, crystalline Form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 7 or greater 2θ values ​​(°) (CuKα) selected from 3.3±0.2, 6.6±0.2, 7.7±0.2, 9.0±0.2, 11.2±0.2, 15.0±0.2, 18.9±0.2, 20.1±0.2, 23.8±0.2, 25.3±0.2 and 27.2±0.2, where the PXRD pattern of Form F is measured at room temperature.

[0040] In certain embodiments, crystalline Form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.3±0.2 and 7.7±0.2, where the PXRD pattern of Form F is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 6.6±0.2, 9.0±0.2, 11.2±0.2, 15.0±0.2, 18.9±0.2, 20.1±0.2, 23.8±0.2, 25.3±0.2, and 27.2±0.2. For example, in certain embodiments, crystalline form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.3±0.2, 7.7±0.2, and 9.0±0.2, where the PXRD pattern of form F is measured at room temperature.

[0041] In certain embodiments, crystalline form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.3±0.2, 7.7±0.2, and 25.3±0.2, where the PXRD pattern of form F is measured at room temperature.

[0042] In a further embodiment, crystalline form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.3±0.2, 7.7±0.2, 23.8±0.2 and 25.3±0.2, where the PXRD pattern of form F is measured at room temperature.

[0043] In a further embodiment, crystalline form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.3±0.2, 7.7±0.2, 9.0±0.2, 23.8±0.2 and 25.3±0.2, where the PXRD pattern of form F is measured at room temperature.

[0044] In a further embodiment, crystalline form F of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.3±0.2, 6.6±0.2, 7.7±0.2, 9.0±0.2, 11.2±0.2, 15.0±0.2, 18.9±0.2, 20.1±0.2, 23.8±0.2, 25.3±0.2 and 27.2±0.2, where the PXRD pattern of form F is measured at room temperature.

[0045] In certain embodiments, crystalline form F of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0046] In certain embodiments, Form F of Compound (I) is substantially pure. For example, Form F of Compound (I) may be present in a sample in greater than 90%, greater than 95%, or greater than 99% purity by weight, while the remainder of the material contains other forms of the compound and / or reaction and / or processing impurities.

[0047] In certain embodiments, the crystalline form of Compound (I) consists essentially of Form F. For such embodiments, crystalline Compound (I) may contain at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, crystalline F, based on the weight of Compound (I).

[0048] An embodiment also provides a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline form F.

[0049] In a further embodiment, there is provided a pharmaceutical composition comprising Form F of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0050] In certain embodiments, the pharmaceutical composition comprises substantially pure Form F of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0051] In certain embodiments, Form F of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0052] In certain embodiments, the pharmaceutical composition comprises Form F of Compound (I) and other solid forms of Compound (I). Such other solid forms can be, for example, other crystalline forms (e.g., Form A, Form G, Form J, Form K) and / or amorphous Compound (I).

[0053] Form G of compound (I) In certain embodiments, Compound (I) is provided as a crystalline material comprising Form G. Crystalline Form G of Compound (I) is a free base hydrate crystalline form. [Table 2]

[0054] In certain embodiments, crystalline Form G of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 3.2±0.2, 5.6±0.2, 8.6±0.2, 11.7±0.2, 14.2±0.2, 15.0±0.2, 17.3±0.2, and 18.2±0.2, where the PXRD pattern of Form G is measured at room temperature.

[0055] In certain embodiments, crystalline Form G of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 3.2±0.2, 5.6±0.2, 8.6±0.2, 11.7±0.2, 14.2±0.2, 15.0±0.2, 17.3±0.2, and 18.2±0.2, where the PXRD pattern of Form G is measured at room temperature.

[0056] In certain embodiments, crystalline form G of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 3.2±0.2, 5.6±0.2, 8.6±0.2, 11.7±0.2, 14.2±0.2, 15.0±0.2, 17.3±0.2, and 18.2±0.2, where the PXRD pattern of form G is measured at room temperature.

[0057] In certain embodiments, crystalline form G of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 3.2±0.2, 5.6±0.2, 8.6±0.2, 11.7±0.2, 14.2±0.2, 15.0±0.2, 17.3±0.2, and 18.2±0.2, where the PXRD pattern of form G is measured at room temperature.

[0058] In certain embodiments, crystalline form G of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.2±0.2 and 5.6±0.2, where the PXRD pattern of form G is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 8.6±0.2, 11.7±0.2, 14.2±0.2, 15.0±0.2, 17.3±0.2, and 18.2±0.2.

[0059] In certain embodiments, crystalline form G of compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​5.6±0.2 and 8.6±0.2, where the PXRD pattern of form G is measured at room temperature.

[0060] In a further embodiment, crystalline form G of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.2±0.2, 5.6±0.2, and 8.6±0.2, where the PXRD pattern of form G is measured at room temperature.

[0061] In a further embodiment, crystalline form G of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.2±0.2, 5.6±0.2, 8.6±0.2 and 14.2±0.2, where the PXRD pattern of form G is measured at room temperature.

[0062] In a further embodiment, crystalline form G of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.2±0.2, 5.6±0.2, 8.6±0.2, 11.7±0.2, 14.2±0.2, 15.0±0.2, 17.3±0.2 and 18.2±0.2, where the PXRD pattern of form G is measured at room temperature.

[0063] In certain embodiments, crystalline form G of compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0064] In certain embodiments, Form G of Compound (I) is substantially pure. For example, Form G of Compound (I) may be present in a sample at greater than 90%, greater than 95%, or greater than 99% purity by weight, while the remainder of the material contains other forms of the compound and / or reaction and / or processing impurities.

[0065] In certain embodiments, the crystalline form of Compound (I) consists essentially of Form G. For such embodiments, crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline G, based on the weight of Compound (I).

[0066] An embodiment also provides a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline form G.

[0067] In a further embodiment, there is provided a pharmaceutical composition comprising Form G of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0068] In certain embodiments, the pharmaceutical composition comprises substantially pure Form G of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0069] In certain embodiments, Form G of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0070] In some embodiments, the pharmaceutical composition comprises Form G of Compound (I) and other solid forms of Compound (I). Such other solid forms can be, for example, other crystalline forms (e.g., Form F) and / or amorphous Compound (I).

[0071] Form H of compound (I) In certain embodiments, Compound (I) is provided as a crystalline material comprising Form H. Crystalline Form H of Compound (I) is a free base hydrate crystalline form. [Table 3]

[0072] In certain embodiments, crystalline form H of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 8.2±0.2, 9.0±0.2, 13.8±0.2, 21.2±0.2, 22.4±0.2, 23.2±0.2, 24.4±0.2, 25.0±0.2 and 27.8±0.2, where the PXRD pattern of form H is measured at room temperature.

[0073] In certain embodiments, crystalline form H of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 8.2±0.2, 9.0±0.2, 13.8±0.2, 21.2±0.2, 22.4±0.2, 23.2±0.2, 24.4±0.2, 25.0±0.2 and 27.8±0.2, where the PXRD pattern of form H is measured at room temperature.

[0074] In certain embodiments, crystalline form H of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising four or more 2θ values ​​(°) (CuKα) selected from 8.2±0.2, 9.0±0.2, 13.8±0.2, 21.2±0.2, 22.4±0.2, 23.2±0.2, 24.4±0.2, 25.0±0.2, and 27.8±0.2, where the PXRD pattern of form H is measured at room temperature.

[0075] In certain embodiments, crystalline form H of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 8.2±0.2, 9.0±0.2, 13.8±0.2, 21.2±0.2, 22.4±0.2, 23.2±0.2, 24.4±0.2, 25.0±0.2, and 27.8±0.2, where the PXRD pattern of form H is measured at room temperature.

[0076] In certain embodiments, crystalline form H of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​8.2±0.2 and 13.8±0.2, where the PXRD pattern of form H is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 9.0±0.2, 21.2±0.2, 22.4±0.2, 23.2±0.2, 24.4±0.2, 25.0±0.2, and 27.8±0.2.

[0077] In certain embodiments, crystalline form H of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​8.2±0.2 and 21.2±0.2, where the PXRD pattern of form H is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 9.0±0.2, 13.8±0.2, 22.4±0.2, 23.2±0.2, 24.4±0.2, 25.0±0.2, and 27.8±0.2.

[0078] In a further embodiment, crystalline form H of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​8.2±0.2, 21.2±0.2 and 24.4±0.2, where the PXRD pattern of form H is measured at room temperature.

[0079] In certain embodiments, crystalline form H of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​8.2±0.2, 9.0±0.2, and 13.8±0.2, where the PXRD pattern of form H is measured at room temperature.

[0080] In a further embodiment, crystalline form H of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​8.2±0.2, 9.0±0.2, 13.8±0.2 and 21.2±0.2, where the PXRD pattern of form H is measured at room temperature.

[0081] In a further embodiment, crystalline form H of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​8.2±0.2, 9.0±0.2, 13.8±0.2, 21.2±0.2 and 24.4±0.2, where the PXRD pattern of form H is measured at room temperature.

[0082] In a further embodiment, crystalline form H of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​8.2±0.2, 9.0±0.2, 13.8±0.2, 21.2±0.2, 22.4±0.2, 23.2±0.2, 24.4±0.2, 25.0±0.2 and 27.8±0.2, where the PXRD pattern of form H is measured at room temperature.

[0083] In certain embodiments, crystalline form H of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0084] In certain embodiments, Form H of Compound (I) is substantially pure. For example, Form H of Compound (I) may be present in a sample in greater than 90%, greater than 95%, or greater than 99% purity by weight, while the remainder of the material contains other forms of the compound and / or reaction and / or processing impurities.

[0085] In certain embodiments, the crystalline form of Compound (I) consists essentially of Form H. For such embodiments, crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, crystalline H, based on the weight of Compound (I).

[0086] An embodiment also provides a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline form H.

[0087] In a further embodiment, there is provided a pharmaceutical composition comprising Form H of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0088] In certain embodiments, the pharmaceutical composition comprises substantially pure Form H of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0089] In certain embodiments, Form H of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0090] In certain embodiments, the pharmaceutical composition comprises Form H of Compound (I) and other solid forms of Compound (I). Such other solid forms can be, for example, other crystalline forms and / or amorphous Compound (I).

[0091] Form I of compound (I) In certain embodiments, Compound (I) is provided as a crystalline material comprising Form I. Crystalline Form I of Compound (I) is a free base hydrate crystalline form. [Table 4]

[0092] In certain embodiments, crystalline Form I of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 3.3±0.2, 5.8±0.2, 8.9±0.2, and 14.6±0.2, where the PXRD pattern of Form I is measured at room temperature.

[0093] In certain embodiments, crystalline Form I of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 3.3±0.2, 5.8±0.2, 8.9±0.2, and 14.6±0.2, where the PXRD pattern of Form I is measured at room temperature.

[0094] In certain embodiments, crystalline Form I of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.3±0.2 and 5.8±0.2, where the PXRD pattern of Form I is measured at room temperature.

[0095] In a further embodiment, crystalline Form I of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.3±0.2, 5.8±0.2, and 8.9±0.2, where the PXRD pattern of Form I is measured at room temperature.

[0096] In certain embodiments, crystalline Form I of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​5.8±0.2 and 8.9±0.2, where the PXRD pattern of Form I is measured at room temperature.

[0097] In a further embodiment, crystalline Form I of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​5.8±0.2, 8.9±0.2, and 14.6±0.2, where the PXRD pattern of Form I is measured at room temperature.

[0098] In a further embodiment, crystalline Form I of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.3±0.2, 5.8±0.2, 8.9±0.2 and 14.6±0.2, where the PXRD pattern of Form I is measured at room temperature.

[0099] In certain embodiments, crystalline Form I of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0100] In certain embodiments, Form I of Compound (I) is substantially pure. For example, Form I of Compound (I) may be present in a sample in greater than 90%, greater than 95%, or greater than 99% purity by weight, while the remainder of the material contains other forms of the compound and / or reaction and / or processing impurities.

[0101] In certain embodiments, the crystalline form of Compound (I) consists essentially of Form I. For such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of Crystal I, based on the weight of Compound (I).

[0102] An embodiment also provides a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline Form I.

[0103] In a further embodiment, there is provided a pharmaceutical composition comprising Form I of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0104] In certain embodiments, the pharmaceutical composition comprises substantially pure Form I of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0105] In certain embodiments, Form I of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0106] In certain embodiments, the pharmaceutical composition comprises Form I of Compound (I) and other solid forms of Compound (I). Such other solid forms can be, for example, other crystalline forms (e.g., Form G) and / or amorphous Compound (I).

[0107] Form J of compound (I) In certain embodiments, Compound (I) is provided as a crystalline material comprising Form J. Crystalline Form J of Compound (I) is the free base anhydrous crystalline form. [Table 5]

[0108] In certain embodiments, crystalline Form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 4.0±0.2, 7.4±0.2, 8.1±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2 and 25.8±0.2, where the PXRD pattern of Form J is measured at room temperature.

[0109] In certain embodiments, crystalline Form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from: 4.0±0.2, 7.4±0.2, 8.1±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2, and 25.8±0.2, where the PXRD pattern of Form J is measured at room temperature.

[0110] In certain embodiments, crystalline Form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 4.0±0.2, 7.4±0.2, 8.1±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2 and 25.8±0.2, where the PXRD pattern of Form J is measured at room temperature.

[0111] In certain embodiments, crystalline Form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 4.0±0.2, 7.4±0.2, 8.1±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2 and 25.8±0.2, where the PXRD pattern of Form J is measured at room temperature.

[0112] In certain embodiments, crystalline Form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 6 or more 2θ values ​​(°) (CuKα) selected from 4.0±0.2, 7.4±0.2, 8.1±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2 and 25.8±0.2, where the PXRD pattern of Form J is measured at room temperature.

[0113] In certain embodiments, crystalline Form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 7 or greater 2θ values ​​(°) (CuKα) selected from 4.0±0.2, 7.4±0.2, 8.1±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2, and 25.8±0.2, where the PXRD pattern of Form J is measured at room temperature.

[0114] In certain embodiments, crystalline Form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2 and 8.1±0.2, where the PXRD pattern of Form J is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 4.0±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2, and 25.8±0.2.

[0115] In certain embodiments, crystalline form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2, 8.1±0.2, and 8.7±0.2, where the PXRD pattern of form J is measured at room temperature.

[0116] In certain embodiments, crystalline form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2, 8.1±0.2, and 16.0±0.2, where the PXRD pattern of form J is measured at room temperature.

[0117] In a further embodiment, crystalline form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2, 8.1±0.2, 16.0±0.2 and 23.5±0.2, where the PXRD pattern of form J is measured at room temperature.

[0118] In a further embodiment, crystalline form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2, 8.1±0.2, 16.0±0.2, 23.5±0.2 and 24.4±0.2, where the PXRD pattern of form J is measured at room temperature.

[0119] In a further embodiment, crystalline form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2, 8.1±0.2, 8.7±0.2, 16.0±0.2, 23.5±0.2 and 24.4±0.2, where the PXRD pattern of form J is measured at room temperature.

[0120] In a further embodiment, crystalline form J of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​4.0±0.2, 7.4±0.2, 8.1±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2 and 25.8±0.2, where the PXRD pattern of form J is measured at room temperature.

[0121] In certain embodiments, crystalline form J of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0122] In certain embodiments, crystalline form J of Compound (I) is characterized by an endotherm having a peak maximum in the range of approximately 261° C. to 265° C. In further embodiments, the endotherm maximum is about 263° C. For example, in certain embodiments, crystalline form J of Compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram that includes an endotherm having a maximum in the range of about 261° C. to about 265° C.; in certain embodiments, the differential scanning calorimetry (DSC) thermogram includes an endotherm having a maximum at about 263° C. It should be understood that in some cases, an endothermic event may not be detected.

[0123] In certain embodiments, crystalline Form J of Compound (I) is characterized by (i) a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2 and 8.1±0.2, where the PXRD pattern of Form J is measured at room temperature; and (ii) an endotherm having a peak maximum in the range of approximately 261° C. to 265° C. In further embodiments, the endothermic peak maximum is about 263° C.

[0124] In certain embodiments, crystalline Form J of Compound (I) is characterized by (i) a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2, 8.1±0.2, 8.7±0.2, and 16.0±0.2, where the PXRD pattern of Form J is measured at room temperature; and (ii) an endotherm having a peak maximum in the range of approximately 261° C. to 265° C. In further embodiments, the endothermic peak maximum is about 263° C.

[0125] In certain embodiments, crystalline form J of Compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with the thermogram shown in FIG.

[0126] In certain embodiments, crystalline Form J of Compound (I) is characterized by: (i) a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 4.0±0.2, 7.4±0.2, 8.1±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2 and 25.8±0.2, where the PXRD pattern of Form J is measured at room temperature; and (ii) a differential scanning calorimetry (DSC) thermogram substantially in accordance with the thermogram depicted in FIG. 6.

[0127] In certain embodiments, crystalline form J of Compound (I) is characterized by a thermogravimetric analysis (TGA) thermogram having less than 0.1% mass loss upon heating (e.g., from room temperature) to a temperature of about 150° C. In certain embodiments, crystalline form J of Compound (I) is characterized by a thermogravimetric analysis (TGA) thermogram having less than 0.1% mass loss upon heating to a temperature of about 175° C. In further embodiments, crystalline form J of Compound (I) is characterized by a thermogravimetric analysis (TGA) thermogram exhibiting less than about 0.5% mass loss at about 200° C., and in certain embodiments, less than about 0.1% mass loss.

[0128] In certain embodiments, crystalline form J of Compound (I) exhibits a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG.

[0129] In certain embodiments, Form J of Compound (I) is substantially pure. For example, Form J of Compound (I) may be present in a sample in greater than 90%, greater than 95%, or greater than 99% purity by weight, while the remainder of the material contains other forms of the compound and / or reaction and / or processing impurities.

[0130] In certain embodiments, the crystalline form of Compound (I) consists essentially of Form J. For such embodiments, crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, crystalline J, based on the weight of Compound (I).

[0131] An embodiment also provides a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline form J.

[0132] In a further embodiment, there is provided a pharmaceutical composition comprising Form J of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0133] In certain embodiments, the pharmaceutical composition comprises substantially pure Form J of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0134] In certain embodiments, Form J of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0135] In some embodiments, the pharmaceutical composition comprises Form J of Compound (I) and other solid forms of Compound (I). Such other solid forms can be, for example, other crystalline forms (e.g., Form F) and / or amorphous Compound (I).

[0136] Form K of compound (I) In certain embodiments, Compound (I) is provided as a crystalline material comprising Form K. Crystalline Form K of Compound (I) is the free base monohydrate crystalline form. [Table 6]

[0137] In certain embodiments, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 3.8±0.2, 7.7±0.2, 9.4±0.2, 12.1±0.2, 12.4±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 18.9±0.2, 23.6±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2 and 27.7±0.2, where the PXRD pattern of form K is measured at room temperature.

[0138] In certain embodiments, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from: 3.8±0.2, 7.7±0.2, 9.4±0.2, 12.1±0.2, 12.4±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 18.9±0.2, 23.6±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2, and 27.7±0.2, where the PXRD pattern of form K is measured at room temperature.

[0139] In certain embodiments, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising four or more 2θ values ​​(°) (CuKα) selected from 3.8±0.2, 7.7±0.2, 9.4±0.2, 12.1±0.2, 12.4±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 18.9±0.2, 23.6±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2, and 27.7±0.2, where the PXRD pattern of form K is measured at room temperature.

[0140] In certain embodiments, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 3.8±0.2, 7.7±0.2, 9.4±0.2, 12.1±0.2, 12.4±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 18.9±0.2, 23.6±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2, and 27.7±0.2, where the PXRD pattern of form K is measured at room temperature.

[0141] In certain embodiments, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 6 or more 2θ values ​​(°) (CuKα) selected from 3.8±0.2, 7.7±0.2, 9.4±0.2, 12.1±0.2, 12.4±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 18.9±0.2, 23.6±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2, and 27.7±0.2, where the PXRD pattern of form K is measured at room temperature.

[0142] In certain embodiments, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 7 or greater 2θ values ​​(°) (CuKα) selected from 3.8±0.2, 7.7±0.2, 9.4±0.2, 12.1±0.2, 12.4±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 18.9±0.2, 23.6±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2, and 27.7±0.2, where the PXRD pattern of form K is measured at room temperature.

[0143] In certain embodiments, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.7±0.2 and 12.1±0.2, where the PXRD pattern of form K is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 3.8±0.2, 9.4±0.2, 12.4±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 18.9±0.2, 23.6±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2, and 27.7±0.2.

[0144] In certain embodiments, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.7±0.2, 12.1±0.2, and 16.3±0.2, where the PXRD pattern of form K is measured at room temperature.

[0145] In certain embodiments, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.8±0.2, 7.7±0.2, and 12.1±0.2, where the PXRD pattern of form K is measured at room temperature.

[0146] In certain embodiments, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.7±0.2, 12.1±0.2, 16.3±0.2, and 24.3±0.2, where the PXRD pattern of form K is measured at room temperature.

[0147] In a further embodiment, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.7±0.2, 12.1±0.2, 16.3±0.2, 18.9±0.2 and 24.3±0.2, where the PXRD pattern of form K is measured at room temperature.

[0148] In a further embodiment, crystalline form K of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.8±0.2, 7.7±0.2, 9.4±0.2, 12.1±0.2, 12.4±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 18.9±0.2, 23.6±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2 and 27.7±0.2, where the PXRD pattern of form K is measured at room temperature.

[0149] In certain embodiments, crystalline form K of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0150] In certain embodiments, crystalline form K of Compound (I) is characterized by an endotherm having a peak maximum of less than about 130° C. In certain embodiments, the endotherm maximum is from room temperature to about 125° C. For example, in certain embodiments, crystalline form K of Compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram that includes an endotherm having a maximum in the range of from room temperature to about 125° C. It should be understood that in some cases, an endothermic event may not be detected.

[0151] In certain embodiments, crystalline form K of Compound (I) is characterized by (i) a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.7±0.2 and 12.1±0.2, where the PXRD pattern of form K is measured at room temperature; and (ii) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with a peak between room temperature and about 125° C.

[0152] In certain embodiments, crystalline form K of Compound (I) is characterized by (i) a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​3.8±0.2, 7.7±0.2, 12.1±0.2, and 16.3±0.2, where the PXRD pattern of form K is measured at room temperature; and (ii) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with a peak between room temperature and about 125° C.

[0153] In certain embodiments, crystalline form K of Compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with the thermogram shown in FIG.

[0154] In certain embodiments, crystalline form K of Compound (I) is characterized by: (i) a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 3.8±0.2, 7.7±0.2, 9.4±0.2, 12.1±0.2, 12.4±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 18.9±0.2, 23.6±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2 and 27.7±0.2, where the PXRD pattern of form K is measured at room temperature; and (ii) a differential scanning calorimetry (DSC) thermogram substantially in accordance with the thermogram depicted in FIG. 9.

[0155] In certain embodiments, crystalline form K of Compound (I) is characterized by a thermogravimetric analysis (TGA) thermogram having a mass loss of about 4% upon heating (e.g., from room temperature) to a temperature of about 125°C.

[0156] In certain embodiments, crystalline form K of Compound (I) exhibits a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG.

[0157] In certain embodiments, Form K of Compound (I) is substantially pure. For example, Form K of Compound (I) may be present in a sample in greater than 90%, greater than 95%, or greater than 99% purity by weight, while the remainder of the material contains other forms of the compound and / or reaction and / or processing impurities.

[0158] In certain embodiments, the crystalline form of Compound (I) consists essentially of Form K. For such embodiments, crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, crystalline K, based on the weight of Compound (I).

[0159] An embodiment also provides a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline form K.

[0160] In a further embodiment, there is provided a pharmaceutical composition comprising Form K of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0161] In certain embodiments, the pharmaceutical composition comprises substantially pure Form K of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0162] In certain embodiments, Form K of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0163] In some embodiments, the pharmaceutical composition comprises Form K of Compound (I) and other solid forms of Compound (I). Such other solid forms may be, for example, other crystalline forms (e.g., Form F) and / or amorphous Compound (I).

[0164] Crystalline forms can be produced by a variety of methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from the melt, solid state transformation from other phases, crystallization from supercritical fluids, and jet spraying. Techniques for crystallizing or recrystallizing crystalline forms from solvent mixtures include, for example, evaporation of the solvent, lowering the temperature of the solvent mixture, seeding with a supersaturated solvent mixture of the molecule and / or salt, freeze-drying the solvent mixture, and adding an anti-solvent (counter-solvent) to the solvent mixture. High-throughput crystallization techniques can be used to produce crystalline forms, including polymorphs.

[0165] Drug crystals, including polymorphs, and methods for preparing and characterizing drug crystals are described in Solid-State Chemistry of Drugs, SR Byrn, RR Pfeiffer, and JG Stowell, 2 nd Edition, SSCI, West Lafayette, Indiana (1999).

[0166] For the crystallization technique using solvent, the selection of one or more solvents typically depends on one or more factors such as the solubility of the compound, the crystallization technique and the vapor pressure of the solvent.A combination of solvents may be used, for example, the compound is dissolved in a first solvent to form a solution, and then an anti-solvent is added to reduce the solubility of the compound in the solution and form crystals.Anti-solvent is a solvent in which the compound has low solubility.

[0167] In one method of producing crystals, the compound is suspended and / or stirred in a suitable solvent to obtain a slurry, which may be heated to facilitate dissolution. As used herein, the term "slurry" refers to a saturated solution of a compound, which may also contain additional amounts of the compound, to obtain a heterogeneous mixture of the compound and the solvent at a certain temperature.

[0168] Seeds can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a particular polymorph or to control the particle size distribution of the crystalline product. Thus, the calculation of the amount of seeds required depends on the size of the available seeds and the desired size of the average product particles, as described, for example, in "Programmed Cooling of Batch Crystallizers," JW Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. In general, small size seeds are required to effectively control the growth of batch crystals. Small size seeds can be produced by sieving, milling or pulverizing large crystals or by microcrystallizing a solution. It should be noted that milling or pulverizing crystals does not result in a change in crystallinity from the desired crystal form (i.e., to amorphous or other polymorphs).

[0169] The cooled crystallization mixture may be filtered under reduced pressure, and the isolated solid may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to obtain the desired crystalline form. The isolated solid may be analyzed by one or more suitable spectroscopic or analytical techniques, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction, etc., to assess the formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70% by weight isolated yield, preferably greater than 90% by weight isolated yield, based on the weight of the compound originally used in the crystallization procedure. If necessary, the product may be co-ground or passed through a mesh screen to break up any agglomerates of the product.

[0170] The crystalline form may be prepared directly from the reaction medium of the final process for preparing compound (I). Such preparation may be achieved, for example, by using a solvent or solvent mixture from which compound (I) can crystallize at the final process step. Alternatively, the crystalline form may be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include the non-polar and polar solvents mentioned above, including, for example, protic polar solvents such as alcohols and aprotic polar solvents such as ketones.

[0171] The presence of more than one polymorph in a sample can be determined by techniques such as powder X-ray diffraction (PXRD) or solid state nuclear magnetic resonance spectroscopy (ssNMR). For example, the presence of extra peaks in a comparison of a simulated PXRD pattern with an experimentally determined PXRD pattern can indicate the presence of more than one polymorph in a sample. A simulated PXRD can be calculated from single crystal X-ray data. See Smith, DK, "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0172] Form E of compound (I) can be characterized using various techniques known to those skilled in the art to operate. Form E can be characterized and differentiated using single crystal X-ray diffraction based on unit cell measurements of a single crystal at a fixed analysis temperature. A detailed description of the unit cell is provided in Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference. Alternatively, the specific arrangement of atoms in spatial relationship within a crystal lattice can be characterized according to the observed partial atomic coordinates. Another means of characterizing the crystal structure is powder X-ray diffraction analysis, in which a diffraction profile is compared to a simulated profile representing a pure powder material, both run at the same analysis temperature, and the measured value of the form of interest is characterized as a series of 2θ values ​​(e.g., 2, 3, 4 or more).

[0173] Other methods of characterizing the forms may be used. Such methods include solid state nuclear magnetic resonance (ssNMR), differential scanning calorimetry (DSC), thermography, and visual examination of crystalline or amorphous forms. Two or more of these parameters may also be used in combination to characterize the form of interest.

[0174] usefulness The crystalline forms of Compound (I) described herein can be used to isolate Compound (I) from other components at the end of a synthetic process; and / or Compound (I) can be isolated by one or a series of crystallization steps. The isolation and purification steps can be combined or performed as separate process steps. Each of the crystalline forms described herein can also be used to prepare other solid forms of Compound (I), including, for example, Form A (described in WO2018 / 183656), one or more of the other forms described herein, and / or amorphous Compound (I). For example, in one embodiment, a method of preparing amorphous Compound (I) includes preparing crystalline Form F, where crystalline Form F is characterized as described herein. In a further embodiment, the amorphous Compound (I) is then used to prepare a dosage form for clinical use (e.g., a dosage form including a solid dispersion of amorphous Compound (I)).

[0175] Each of the crystalline forms of Compound (I) described herein can be used alone or in combination with other forms of Compound (I) (including other crystalline forms described herein) and / or formulated with one or more excipients or other active pharmaceutical ingredients to produce pharmaceutical compositions. EXAMPLES

[0176] The invention will now be further described by the following working examples of preferred embodiments of the invention. All temperatures are in degrees Celsius (° C.) unless otherwise specified. It is understood that these examples are illustrative rather than limiting, and that other embodiments may exist which fall within the spirit and scope of the invention.

[0177] For ease of reference, the following abbreviations are used herein: [Table 7]

[0178] Example 1: Preparation of Crystalline Form F of Compound (I) Approximately 80 mg of Compound (I) was dissolved in 2.5 g of isopropanol:water 50:50 (w / w) at 75° C. The solution was hot filtered. The filtered solution was rapidly cooled to 23° C. in 10 minutes and further rapidly cooled to 5° C. in 13 minutes to give a white precipitate. The solid was then isolated by vacuum filtration and air dried. The solid contained Form F. In another example, about 100 mg of Compound (I) was dissolved in about 2 g of 1-butanol:water 80:20 (wt / wt) emulsion at 75° C. The solution was hot filtered. The filtered solution was rapidly cooled to ambient temperature in less than 30 minutes to give a white suspension. The solid was then isolated by vacuum filtration and air-dried. The solid contained Form F. In another example, about 104 mg of Compound (I) was dissolved in about 2 g of 1-butanol:water 80:20 (wt / wt) emulsion at 75° C. The solution was hot filtered. The filtered solution was slowly cooled to ambient temperature over 5 hours and aged overnight without stirring. The resulting solid was then isolated by vacuum filtration and air-dried. The solid contained Form F. In another preparation, approximately 4 mg of {[(6E)-6-(cyclopropanecarbonylimino)-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}-3-[(2H3)methylcarbamoyl]-1,6-dihydropyridazin-1-yl]methoxy}phosphonic acid and 2 molar equivalents of KOH were dissolved in 0.6 mL of 50:50 NMP:water (v / v) while heating the solution to 50° C. in a 1 dram vial. The vial was partially capped and the solvent was allowed to evaporate slowly at room temperature. Crystals were obtained after 1 week and contained Form F.

[0179] Example 2: Preparation of Crystalline Form G of Compound (I) Approximately 2.0 g of Compound (I) was dissolved in 36.0 g of 1-butanol:water 80:20 (wt / wt) emulsion at 75° C. The solution was hot filtered into a new pre-warmed container and the filtered solution was allowed to cool slowly to ambient temperature over 5 hours and aged overnight without stirring. The solid was then isolated by vacuum filtration, washed twice with 10 mL of acetone:water 70:30 (v / v), air dried for approximately 10 min, and equilibrated at 84% RH for 18 days. A sample of the resulting material (4.7 g) was suspended in 20 mL of acetone:water 70:30 (v / v) and subjected to five temperature cycling experiments from 5 to 45 to (-5) °C, which gave a thick, immobile suspension. 10 mL of acetone:water 70:30 (v / v) was added and the mobile suspension was subjected to two temperature cycling experiments from 5 to 45 to 5 °C; three cycles from 5 to 35 to 5 °C; and one cycle from 10 to 35 to 10 °C. The resulting solid was isolated by vacuum filtration and washed once with 5 mL of acetone:water 70:30 (v / v), giving 2.6 g of solid. A portion of the latter solid (418.4 mg) was exposed to 84% RH for 24 hours to give 324.7 mg of solids. These solids contained Form G. Form G of compound (I) was also obtained by evaporation of the filtrate in acetone:1-butanol:water 19:56:25% (w / w / w) at ambient conditions. Form G of Compound (I) was also prepared by exposing the amorphous material to 75% RH at ambient temperature for 17 days up to 46 days. In another example, 360 mg of Compound (I) was dissolved in 24 mL of tetrahydrofuran:water 95:5 (v / v) at ambient temperature. 71 μL of 37% hydrochloric acid was added. The solid was isolated by rapid evaporation, and 90 mg of the isolated solid was suspended in 1 mL of ethanol:water 1:2 (v / v) at 60° C. and stirred overnight. The solid contained Form G. In another preparation, 360 mg of Compound (I) was dissolved in 24 mL of tetrahydrofuran:water 95:5 (v / v) at ambient temperature. 55 μL of methanesulfonic acid was added. The solid was isolated by rapid evaporation and 90 mg of the isolated solid was suspended in 1 mL of ethanol:water 1:2 (v / v) at 60° C. and stirred overnight. The suspension was then filtered and the filtered solid was dried at 50° C. overnight. The dried solid contained Form G.

[0180] Example 3: Preparation of Crystalline Form H of Compound (I) Form H of compound (I) was prepared by rotary evaporation in chloroform:methanol 50:50 (v / v) followed by drying in vacuum at elevated temperature (45° C. in this example) overnight. Specifically, about 100 mg of Compound (I) was dissolved in 2.3 mL of chloroform:methanol 50:50 (v / v). The solution was filtered into a new container and the filtered solution was rotary evaporated to dryness at 40° C. The resulting solid was dried in vacuum at 45° C. for 17 hours and stored over a strong desiccant (P2O5 in this example) to yield 95.5 mg of dry solid. The solid contained Form H. In another preparation, 700 mg of Compound (I) was added to 174.3 g of 95 wt% / 5 wt% THF / water under magnetic stirring in a flask. After stirring for at least 30 minutes, the solid was not completely dissolved, and an additional 40.10 g of 95 wt% / 5 wt% THF / water was added. After stirring for at least another 30 minutes, insoluble solid was still observed. The solution was then spray-dried. The solid contained a mixture of Form H and Form A (see WO2018 / 183656 for a description of Form A).

[0181] Example 4: Preparation of Crystalline Form I of Compound (I) Form I of Compound (I) was prepared by drying Form G under vacuum at elevated temperature (45° C. in this example) for 24 hours. Specifically, approximately 108 mg of Form G was vacuum dried at 45° C. for 24 hours and stored over a strong desiccant (P2O5 in this example) to yield 64.9 mg of dry solid. The solid contained Form I. In another preparation, 100 mg of Compound (I) was dissolved in a mixture of 4.75 mL tetrahydrofuran and 0.25 mL water. 50 μL of this solution was dispensed into the wells of a 96-well plate. The solvent was allowed to evaporate. IPA:water 1:2 (v / v) was then added to the wells. The plate was sealed and subjected to the following temperature cycling procedure repeated 9 times: 2 hours at 50° C. isothermal; linear cooling to 20° C. over 8 hours; heating to 50° C. The plate was then opened and the solvent was allowed to evaporate. The solid contained Form I.

[0182] Example 5: Preparation of Crystalline Form J of Compound (I) Form J of Compound (I) was prepared as follows: Approximately 512.0 mg of wet Compound (I) Form F was dried in vacuum at 40-48° C. for 3 hours and stored over a strong desiccant (P2O5 in this example) to give 161.5 mg of dry solid. The solid contained Form J. In another preparation, 40 mg of Compound (I) (Form A) was weighed and 500 μL of THF:water (water activity of 0.85) was added. The slurry was stirred for 3 days at 50° C. A slurry sample was collected and the sample was dried for 8 hours. The resulting solid contained a mixture of Form J and Form A. In another preparation, 40 mg of Compound (I) (Form A) was weighed and 500 μL of THF:water (water activity of 0.95) was added. The slurry was stirred for 3 days at 5° C. A slurry sample was collected and the sample was dried for 8 hours. The resulting solid contained a mixture of Form J and Form A.

[0183] Example 6: Preparation of Crystalline Form K of Compound (I) Compound (I) Form K was prepared as follows: Approximately 753.5 mg of Compound (I) Form F was dried under vacuum at 50° C. for 3 hours and exposed to 33% RH at ambient temperature for 5 days to yield 263.3 mg of a solid. The solid contained Form K. In another preparation, 100 mg of compound (I) was dissolved in a mixture of 4.75 mL tetrahydrofuran and 0.25 mL water. 50 μL of this solution was dispensed into the wells of a 96-well plate. The solvent was allowed to evaporate. THF:water 1:2 (v / v) was then added to the wells. The plate was sealed and subjected to the following temperature cycling procedure repeated 9 times: 2 hours at 50° C. isothermal; linearly cool to 20° C. over 8 hours; heat to 50° C. The plate was then opened and the solvent was allowed to evaporate. The solid contained Form K.

[0184] 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) Synthesis of pyridazine-3-carboxamide Step 1: Preparation of Compound 2 [ka] A glass lined reactor was charged with toluene (0.26 kg), sulfolane (3.4 kg), compound 1 (1.0 kg) and POCl3 (2.7 kg). The crude was cooled to 0° C. Triethylamine (0.89 kg) was charged and the resulting crude mixture was heated to 65° C. and aged until the reaction was complete. The reaction mass was cooled to 5° C. In a separate reactor, water (7.5 kg) was charged and cooled to 5°C. The reaction mass was slowly added to the aqueous solution while maintaining the internal temperature below 5°C. Additional water (0.5 kg) was used to rinse the reactor and aid transfer. The resulting mixture was stirred at 5°C for 3 h and then extracted three times with MTBE (3 x 4.5 kg). The combined organic layers were washed successively with aqueous pH 7 buffer (5.0 L / kg, 15 wt% KH2PO4 / K2HPO4) and water (2.5 kg). The crude was distilled under reduced pressure to a total volume of approximately 3 L / kg. ACN (2 x 6.3 kg) was added followed by further distillation back to approximately 3 L / kg. The crude was cooled to 20°C to give compound 2 as a 30-36 wt% solution in 90-95% yield.

[0185] Step 2: Preparation of Compound 3 [ka] ACN (2.7 kg), lithium bromide (1.18 kg) and water (0.65 kg) were charged to a glass-lined reactor at 25° C. The compound 2 crude solution prepared above (the limiting reagent) was added followed by DIPEA (1.82 kg). The resulting slurry was stirred at 25° C. until the reaction was complete. The product was isolated by filtration. The crude solid was washed with ACN (1.6 kg). The cake was dried under vacuum at 45° C. Compound 3 was isolated with 98 AP and 83% yield.

[0186] Step 3: Preparation of Compound 8 [ka] Water (6.0 kg, 6.0 L / kg) and compound 7 (1.0 kg) were charged to a glass-lined reactor at 25° C. Zinc acetate anhydrate (1.08 kg, 1.0 equiv.) was added followed by compound 3 (1.28 kg, 1.20 equiv.). The reactor lines were rinsed with 2-propanol (0.79 kg, 1.0 L / kg) and water (1.50 kg, 1.50 L / kg). The resulting homogenous solution was heated to 65° C. and aged until the reaction was complete. Water (7.0 kg, 7.0 L / kg) was added and the crude mixture was cooled to 20° C. and aged for 30 minutes. The product was isolated by filtration. The crude solid was washed successively with water (6.0 kg, 6.0 L / kg), water (6.0 kg, 6.0 L / kg), THF (5.3 kg, 6.0 L / kg) and THF (5.3 kg, 6.0 L / kg). The cake was dried under reduced pressure at 70° C. Compound 8 was isolated with 98 AP and 94% yield.

[0187] Step 4: Preparation of Compound 9 [ka] Another glass-lined reactor was flushed with nitrogen. Toluene (0.87 kg, 1.0 L / kg) and MeCN (0.79 kg, 1.0 L / kg) were charged, followed by (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (Josiphos SL-009-01) (14.1 g, 1.0 mol%) and palladium acetate (2.9 g, 0.5 mol%). The reactor lines were rinsed with toluene (0.43 kg, 0.5 L / kg). The resulting preformed catalyst solution was kept under nitrogen until further use. At 20° C., toluene (3.46 Kg, 4.0 L / kg) and ACN (1.57 kg, 2.0 L / kg) were charged to a nitrogen-flushed glass-lined reactor. Compound 8 (1.00 kg) was added, followed by DBU (0.39 kg, 1.00 equiv.). The reactor lines were rinsed with toluene (0.43 kg, 0.5 L / kg). Compound 10 (0.54 kg, 2.5 equiv.) and K2CO3 (325 mesh grade, 0.70 kg, 2.0 equiv.) were added to the reaction mixture, followed by toluene (1.30 kg, 1.5 L / kg) and ACN (0.79 kg, 1.0 L / kg). The preformed catalyst solution was transferred to the reaction mixture, which was then heated to 75° C. and aged until the reaction was complete. The reaction crude was cooled to 20° C. Aqueous acetic acid (50% by volume, 4.0 kg, 4.0 L / kg) was charged slowly over 1 hour. Glacial acetic acid (10.5 kg, 10.0 L / kg) was then added. The resulting homogenous solution was washed twice with heptane (2×3.42 kg, 2×5.0 L / kg). The bottom aqueous layer was collected and transferred to a clean reactor. Water (5.0 kg, 5.0 L / kg) was added followed by Compound 9 seeds (0.01 kg, 1.0 wt%). The slurry was aged for 2 hours at 20° C. Additional water (2.0 kg, 2.0 L / kg) was added and the slurry was aged for an additional 6 hours. The product was isolated by filtration. The crude cake was washed with aqueous ACN (50% by volume, 4.5 kg, 5.0 L / kg) followed by ACN (3.9 kg, 5.0 L / kg). The cake was dried under vacuum at 65° C. Compound 9 was isolated with 98.5 AP and 84% yield.

[0188] Step 5: Preparation of Compound (I) [ka] NMP (2.06 kg, 2.0 L / kg) and ACN (0.78 kg, 1.0 L / kg) were charged to a glass-lined reactor and stirred at 20° C. N-methylimidazole (0.13 kg, 0.7 eq.), compound 13 (0.17 kg, 1.2 eq.) and compound 9 (1.00 kg) were charged to the reaction mixture. The mixture was heated to 65° C. and aged until homogeneous. HOBt 20% wet (0.17 kg, 0.5 eq.) was then charged to the reaction mixture, followed by EDC HCl (0.54 kg, 1.4 eq.). The reactor was rinsed with ACN (0.78 kg, 1.0 L / kg) and the resulting mixture was then aged at 65° C. until the reaction was complete. The reaction was quenched by adding water (1.0 kg, 1 L / kg) and then diluted with ACN (3.0 kg, 3 L / kg). The reaction mixture was aged at 65° C. for 1 hour, then cooled to 0° C. and aged an additional 2 hours at 0° C. The product was isolated by filtration. The wet cake was washed with 2:1 water:ACN (2.8 kg, 3 L / kg), then ACN (2.4 kg, 3 L / kg), then dried under absolute vacuum at 65° C. Compound (I) was isolated in >99.5% purity and 91% yield. NMP (6.2 kg, 6.0 L / kg) and Compound (I) (1.0 kg) were charged to a glass-lined reactor. The batch was heated to 70° C. to give a pale yellow solution, which was then transferred to a clean vessel at 70° C. through a polish filter. 2-Propanol (2.4 kg, 3 L / kg) was added, followed by Compound I seeds (0.005 kg, 0.005 kg / kg). After aging for 1 hour, additional 2-propanol (4.8 kg, 6 L / kg) was added over 2 hours (3 L / kg / hr). The slurry was aged at 70° C. for 1 hour, slowly cooled to 0° C., and aged at 0° C. for an additional 12 hours. The product was isolated by filtration. The wet cake was washed with 2-propanol (2×3.1 kg, 2×4 L / kg) and then dried at 65° C. under absolute vacuum. Compound (I) was isolated in >99.9% purity and 83% yield.

[0189] Preparation of compound 7 Step 1: Preparation of N-methyl-N-formylhydrazine [ka] A glass lined reactor was charged with methanol (1.6 kg / kg, 2.0 L / kg) and methylhydrazine (1 kg) at 0° C. Methyl formate (0.57 kg / kg, 1.1 equiv.) was added dropwise. The crude was warmed up to 20° C. and aged for an additional 6 h. The crude was distilled under reduced pressure to a total volume of about 0.5 L / kg. Five put / take distillations with 2-MeTHF (5×3.6 kg / kg) were performed for azeotropic drying. The crude was cooled to 20° C. N-Methyl-N-formylhydrazine was isolated in 89–91% yield as an 89–90 wt% solution.

[0190] Step 2: Preparation of Compound 5 [ka] A glass-lined reactor was charged with potassium tert-butoxide (1.5 kg / kg, 2.4 equiv.) and THF (12.2 kg / kg) at 0° C. A mixture of compound 4 (1.0 kg), N-methyl-N-formylhydrazine (1.0 kg / kg, 2.30 equiv.) and THF (5.3 kg / kg, 6.0 L / kg) was added slowly. The reactor lines were rinsed with THF (0.5 kg / kg). The reaction crude was aged at 0° C. until the reaction was complete. Water (5.0 kg / kg) was added and the resulting mixture was aged at 0° C. for 30 min, heated to 40° C. and aged for an additional 30 min. The layers were separated and the aqueous layer was discarded. The organic layer was washed with brine (15 wt %, 5.7 kg / kg) and then distilled under reduced pressure until the total volume was about 5 L / kg. Four distillations with ethyl acetate (4×10 L / kg) were performed for azeotropic drying. The crude was cooled to 20° C. Sulfuric acid (0.66 kg / kg, 1.10 equiv.) was added and the slurry was stirred for 2-3 h. The product was isolated by filtration. The cake was successively washed with ethyl acetate (2×6.5 L / kg) and heptane (8 L / kg) and dried under reduced pressure at 45° C. Compound 5 was isolated with 99 AP and 83% yield.

[0191] Step 3: Preparation of Compound 6 [ka] A glass-lined reactor was charged with concentrated sulfuric acid (4.5 kg / kg) and compound 5 (1.0 kg) at 0-5° C. Nitric acid (68 wt%, 0.35 kg / kg, 1.2 equiv.) was added dropwise. The mixture was stirred at 0-5° C. until the reaction was complete. In a separate reactor, water (12 kg / kg) and methanol (6.5 kg / kg, 8.3 L / kg) were mixed at 20°C with good stirring. The nitrated crude was slowly transferred to the methanol water mixture. The reactor lines were rinsed with methanol (0.5 kg / kg). The crude was heated to 40-45°C. Aqueous ammonium hydroxide (25 wt%, 7.4 kg / kg) was slowly added. The resulting slurry was cooled to 20°C and stirred for 3 hours. The product was isolated by filtration. The cake was washed with water (2×6 L / kg) and dried under reduced pressure at 45°C. Compound 6 was isolated with 99 AP and 95% yield.

[0192] Step 4: Preparation of Compound 7 [ka] A nitrogen flushed high pressure reactor was charged with methanol (8.0 kg / kg) and compound 6 (1.0 kg). Sodium bicarbonate (0.6 kg / kg, 2.0 equiv.) and Pd / C (10% loading, 50% wet, 0.02 kg / kg) were added while carefully removing oxygen. The reactor was pressurized with hydrogen (41-46 psi) and the reaction mixture was aged at 20 °C for 6 h, then heated to 45 °C and aged until the reaction was complete. The reactor was flushed with nitrogen and the reaction crude was filtered to remove Pd / C. Methanol (5 kg / kg) was used to aid transfer. The combined filtrates were distilled under reduced pressure to a total volume of approximately 2.5 L / kg. Water (10 kg / kg) was added and the crude was distilled under reduced pressure to a total volume of approximately 2.5 L / kg. The crude was heated to 70 °C. Brine (25 wt%, 9.0 kg / kg) was added and the resulting crude was stirred at 70 °C for 6 h. After cooling to 0 °C, the crude was aged for an additional 6 h. The product was isolated by filtration. The cake was washed with brine (pre-cooled to 0 °C, 25 wt%, 2.0 kg / kg) and dried under reduced pressure at 45 °C. Compound 7 was isolated in 99 AP and 88% yield.

[0193] Preparation of compound 13 Step 1: Preparation of Compound 11 and Compound 12 [ka] A nitrogen flushed glass lined reactor was charged with water (16.3 L / kg) and sodium hydroxide (3.3 kg, 3.0 equiv). The mixture was aged until the sodium hydroxide was completely dissolved. The crude was cooled to 0° C. d4-methanol (1.0 kg) and THF (4.5 L / kg) were charged. A solution of TsCl (6.3 kg, 1.2 equiv) in THF (6.3 kg, 7.1 L / kg) was added over 2 hours. The crude was stirred at 0° C. until the reaction was complete. The batch was warmed to 20° C. The layers were separated. The combined organic layer was diluted with MTBE (4.0 kg, 5.4 L / kg) and washed twice with brine (25 wt%, 4.0 kg followed by 12 kg). The organic layer was distilled under reduced pressure to a total volume of approximately 10 L / kg. Two distillations with ACN (2×10 L / kg) were performed for azeotropic drying. The crude was cooled to 20° C. ACN (10.0 kg, 12.8 L / kg) and NaN(CHO)2 (3.3 kg, 1.2 equiv.) were added. The crude was heated to 65° C. and stirred until the reaction was complete. After cooling to 5° C., the mixture was filtered and the crude cake was washed twice with ACN (2×2.5 kg, 2×3.2 L / kg). The combined filtrate was distilled under reduced pressure to a total volume of about 3 L / kg. The crude was cooled to 20° C. Compound 12 was obtained as an oil in 60–70% yield with 80–85 wt%.

[0194] Step 2: Preparation of Compound 13 [ka] A glass-lined reactor was charged with compound 12 (1.0 kg) and methanol (3.9 kg, 5.0 L / kg) at 20°C. HCl in IPA (5-6N, 4.5 kg, 1.5 equiv.) was added. The resulting mixture was heated to 50°C and stirred until the reaction was complete. THF (10 kg, 11.2 L / kg) was added slowly and the crude was cooled to 0°C over 2 h to give a slurry. The product was isolated by filtration. The cake was washed with THF (3.7 kg, 4.1 L / kg) and dried under reduced pressure at 45°C. Compound 13 was isolated in 80% yield.

[0195] Optional recrystallization of compound 13: Methanol (5.6 kg, 8.3 L / kg) and compound 13 (1.0 kg) were placed in a glass-lined reactor. DBU (0.1 kg) was added slowly. The crude was stirred for 1 h. THF (12.4 kg, 13.9 L / kg) was added slowly and the resulting slurry was aged for 2 h. The product was isolated by filtration. The cake was washed with THF (2.6 kg, 2.9 L / kg) and dried under vacuum at 45° C. Compound 13 was isolated in 60% yield (first crop). The mother liquor was distilled under vacuum to a total volume of approximately 1 L / kg. A double distillation with methanol (2×2.8 kg, 2×3.6 L / kg) was performed to concentrate the solution back to approximately 1 L / kg. The crude was cooled to 20° C. THF (4.8 kg, 5.4 L / kg) was added and the resulting slurry was aged for 2 h. The product was isolated by filtration. The cake was washed with THF (1.0 kg) and dried under reduced pressure at 45° C. Compound 13 was isolated in 25% yield (2nd crop).

[0196] 1. Single crystal X-ray measurement Single crystal X-ray data for Compound (I) Form F was collected using a Bruker X8 Kappa diffractometer equipped with an APEX II CCD detector and a Microstar Rotating Anode X-ray source with monochromatic Cu Kα radiation. Indexing and processing of the measured intensity data was performed with the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). Final unit cell parameters were determined at 296 K using the complete data set. The structure was diffracted by direct methods and refined by a full matrix least-squares approach using the SHELXTL software package (GM Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA.). Structure refinement was performed using

number

number

[0197] 2. Powder X-ray diffraction PANalytical X'Pert PRO MPD Diffractometer - Transmission Geometry X-ray powder diffraction patterns were collected on a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced by an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to direct Cu Kα X-rays through the specimen and focus them onto the detector. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the Si 111 peak position. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop and short anti-scatter extensions were used to minimize background produced by air. Soller slits for the incident and diffracted beams were used to minimize spread from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software v.5.5.

[0198] 3. Differential Scanning Calorimetry Differential scanning calorimetry (DSC) was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Tau-lag adjustments were performed with indium, tin, and zinc. Temperature and enthalpy were adjusted with octane, phenyl acrylate, indium, tin, and zinc. Adjustments were then verified with octane, phenyl acrylate, indium, tin, and zinc. Samples were placed into sealed aluminum DSC pans and weights were accurately recorded. The lids of the pans were then punctured and placed into the DSC cell. A weighed aluminum pan, configured as the sample pan, was placed into the target side of the cell. Data were collected from -20°C to 350°C or room temperature to 350°C at a heating rate of 10°C / min.

[0199] 4. Thermogravimetric analysis Thermogravimetric analysis (TGA) was performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature calibration was performed using calcium oxalate, indium, tin and zinc. Samples were placed in aluminum pans. The samples were sealed, the lids were punctured and the samples were then placed in a TG furnace. The furnace was heated under nitrogen at a flow rate of 50 mg / mL. The method involved heating from ambient to 350° C. at a heating rate of 10° C. / min.

Claims

1. 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ ) Crystalline form J of pyridazine-3-carboxamide.

2. The crystalline form J according to claim 1, characterized by at least one of the following: (i) a powder X-ray diffraction pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 4.0±0.2, 7.4±0.2, 8.1±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2 and 25.8±0.2, wherein the PXRD pattern is measured at room temperature; (ii) an observed powder X-ray diffraction pattern substantially as shown in Figure 5, where the PXRD pattern is measured at room temperature; (iii) an endotherm having a peak maximum in the range of about 261° C. to about 265° C.; (iv) A Differential Scanning Calorimetry (DSC) thermogram substantially as shown in FIG.

3. 2. The crystalline form J of claim 1, characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from: 4.0±0.2, 7.4±0.2, 8.1±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2 and 25.8±0.2, wherein the PXRD pattern of the crystalline form is measured at room temperature.

4. 2. The crystalline form J of claim 1, characterized by a powder X-ray diffraction (PXRD) pattern comprising four or more 2θ values ​​(°) (CuKα) selected from: 4.0±0.2, 7.4±0.2, 8.1±0.2, 8.7±0.2, 11.4±0.2, 14.8±0.2, 16.0±0.2, 16.2±0.2, 23.2±0.2, 23.5±0.2, 24.4±0.2 and 25.8±0.2, wherein the PXRD pattern of the crystalline form is measured at room temperature.

5. 2. The crystalline form J of claim 1, characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2 and 8.1±0.2, wherein the PXRD pattern of the crystalline form is measured at room temperature.

6. 2. The crystalline form J of claim 1, characterized by: (i) a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2 and 8.1±0.2, wherein the PXRD pattern is measured at room temperature; and (ii) an endotherm having a peak maximum in the range of about 261° C. to about 265° C.

7. 2. The crystalline form J of claim 1, characterized by: (i) a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2, 8.1±0.2, and 16.0±0.2, wherein the PXRD pattern is measured at room temperature; and (ii) an endotherm having a peak maximum in the range of about 261° C. to about 265° C.

8. 2. The crystalline form J of claim 1, characterized by: (i) a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2 and 8.1±0.2, wherein the PXRD pattern is measured at room temperature; and (ii) a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

6.

9. 2. The crystalline form J of claim 1, characterized by: (i) a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2, 8.1±0.2, and 24.4±0.2, wherein the PXRD pattern is measured at room temperature; and (ii) a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

6.

10. 2. The crystalline form J of claim 1, characterized by a thermogravimetric analysis (TGA) thermogram comprising less than about 0.1% mass loss when heated from about 30° C. to about 200° C.

11. 2. The crystalline form J of claim 1, wherein said form J is in substantially pure form.

12. 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ )pyridazine-3-carboxamide, said composition comprising 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ 2.) A composition, wherein at least 90% by weight of the pyridazine-3-carboxamide is crystalline form J.

13. The 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ 13. The composition of claim 12, wherein at least 95% by weight of the pyridazine-3-carboxamide is crystalline form J.

14. 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ A composition comprising a crystal of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ ) A composition, wherein at least 95% by weight of the crystals of pyridazine-3-carboxamide is crystalline form J.

15. 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ )pyridazine-3-carboxamide, said composition comprising 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ 2.) The composition, wherein pyridazine-3-carboxamide consists essentially of crystalline form J.

16. 10. A pharmaceutical composition comprising the crystalline form of claim 1 and a pharma- ceutically acceptable carrier or diluent.

17. Crystal form J of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ３ 2.) A pharmaceutical composition comprising pyridazine-3-carboxamide and a pharma- ceutically acceptable carrier or diluent, wherein the crystalline form J is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) at ​​7.4±0.2 and 8.1±0.2, wherein the PXRD pattern is measured at room temperature.

18. Use of crystalline form J according to any one of claims 1 to 11 in a process for preparing amorphous 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide.

19. A process for preparing crystalline form J of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, comprising the steps of: (a) adding 40 mg of crystalline form A of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide to 500 μL of THF:water (water activity of 0.85) to obtain a slurry; (b) stirring the slurry for 3 days at 50° C.; and (c) drying the slurry to obtain a solid comprising crystalline form J of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide. A manufacturing method comprising:

20. The method of claim 19, wherein the drying of the slurry in step (c) is carried out for 8 hours.

21. A process for preparing crystalline form J of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, comprising the steps of: (a) adding 40 mg of crystalline form A of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide to 500 μL of THF:water (water activity of 0.95) to obtain a slurry; (b) stirring the slurry for 3 days at 5° C.; and (c) drying the slurry to obtain a solid comprising crystalline form J of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide. A manufacturing method comprising:

22. The method of claim 21, wherein the drying of the slurry in step (c) is carried out for 8 hours.

Images