Crystalline form of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-B][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Abstract

Described herein are crystalline forms of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide, processes for preparing the forms, and pharmaceutical compositions and methods of their use.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 298,816, filed January 12, 2022, and U.S. Provisional Patent Application No. 63 / 386,113, filed December 5, 2022, each of which is incorporated by reference in its entirety for all purposes.

[0002] Described herein are crystalline forms of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide, processes for preparing the forms, pharmaceutical compositions, and methods of their use. [Background technology]

[0003] Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of inflammation, apoptosis, and necroptosis. RIPK1 has a key role in regulating inflammatory responses mediated by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). More recent studies have shown that its kinase activity controls necroptosis, a form of necrotic cell death. Furthermore, RIPK1 is part of a proapoptotic complex that exhibits its activity in regulating apoptosis. Dysregulation of receptor-interacting protein kinase 1 signaling can result in excessive inflammation or cell death. Studies suggest that inhibition of RIPK1 is a potential clinical target for diseases involving inflammation or cell death. RIPK1 kinase has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases.

[0004] Compound (I) is a RIPK1 inhibitor and may be useful in the treatment of RIPK1-mediated diseases or disorders. Compound (I) is disclosed in WO 2017 / 136727 (and also in U.S. Pat. No. 9,815,850) and has the following structure: [ka]

[0005] Solid forms (e.g., crystalline forms) of bioactive compounds such as Compound (I) are of interest in the pharmaceutical industry, where solid forms with certain physical, chemical, or pharmaceutical properties, such as solubility, dissociation, true density, dissolution, melting point, morphology, compression behavior, particle size, flow properties, or solid state stability, may be desirable or required for pharmaceutical development. Although it is known that the preparation of crystalline forms may improve the physical or pharmaceutical properties of a pharma- ceutical active compound, it is not possible to predict whether a compound will exist in a crystalline form, or which crystalline form may have advantages for a particular purpose, prior to the actual preparation and characterization of the crystalline form. In particular, such advantages may include, in a non-limiting manner, better processability, solubility, or shelf-life stability, to name just a few. Other advantages may also include biological properties such as improved bioavailability, reduced adverse reactions in the GI tract (e.g., irritation of the GI tract, partial degradation of the compound, etc.), or improved delivery of the drug to its intended target site, among other advantages. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure relates to various solid forms of the RIPK1 inhibitor (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (also referred to as Compound (I)), processes for preparing the forms, and pharmaceutical compositions and methods of their use.

[0007] The present disclosure provides a crystalline form of Compound (I), characterized as Form A.

[0008] The present disclosure provides a crystalline form of Compound (I), characterized as Form B.

[0009] The present disclosure provides a crystalline form of Compound (I), characterized as Form C.

[0010] The present disclosure provides a crystalline form of Compound (I), characterized as Form D.

[0011] The present disclosure provides a crystalline form of Compound (I), characterized as Form E.

[0012] The present disclosure provides a crystalline form of Compound (I), characterized as Form F.

[0013] Crystalline Form B of Compound (I) has a high melting point, is less hygroscopic and appears to be the most suitable for industrial use and storage. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 is an X-ray powder diffraction pattern of crystalline Form A of Compound (I). [Diagram 2] 1 is a differential scanning calorimetry / thermogravimetric analysis (DSC / TGA) thermogram of crystalline Form A of Compound (I). [Diagram 3] FIG. 1 is an X-ray powder diffraction pattern of crystalline form B of compound (I). [Figure 4] 1 is a differential scanning calorimetry / thermogravimetric analysis (DSC / TGA) thermogram of crystalline Form B of Compound (I). [Diagram 5] FIG. 1 is an X-ray powder diffraction pattern of crystalline Form C of Compound (I). [Figure 6] 1 is a 1H NMR spectrum of Form C of Compound (I). [Figure 7] 1 is a differential scanning calorimetry / thermogravimetric analysis (DSC / TGA) thermogram of crystalline Form C of Compound (I). [Figure 8] FIG. 1 is an X-ray powder diffraction pattern of crystalline form D of compound (I). [Figure 9] 1 is a differential scanning calorimetry / thermogravimetric analysis (DSC / TGA) thermogram of crystalline Form D of Compound (I). [Figure 10] 1 is a 1H NMR spectrum of Form D of Compound (I). [Figure 11] FIG. 1 is an X-ray powder diffraction pattern of crystalline form E of compound (I). [Figure 12] FIG. 1 is an X-ray powder diffraction pattern of crystalline form F of compound (I). [Figure 13] It is a mutual conversion relationship between different forms. [Figure 14] 1 is a thermal ellipsoid drawing of a single crystal of crystalline Form B of Compound (I). [Figure 15] Hydrogen bonds in the single crystal structure of crystalline form B of Compound (I). [Figure 16] 1 is a calculated XRPD generated from the single crystal structure of crystalline Form B of Compound (I). [Figure 17] 1 is a thermal ellipsoid drawing of a single crystal of crystalline Form E of Compound (I). [Figure 18] 1 is a calculated XRPD generated from the single crystal structure of crystalline Form E of Compound (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The details of the present disclosure are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used to practice or test the present disclosure, exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular form also includes the plural form unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.

[0016] The present disclosure provides crystalline solid forms of Compound (I). The present disclosure also provides pharmaceutical compositions comprising one or more crystalline solid forms of Compound (I). The present disclosure also provides processes for making the crystalline solid forms and methods for using them.

[0017] Also provided herein are pharmaceutical compositions comprising one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F, and a pharma- ceutically acceptable excipient.

[0018] Also provided herein is a method of preparing a pharmaceutical composition, comprising mixing one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F, and a pharma- ceutically acceptable excipient.

[0019] Also provided herein is a process for preparing a pharmaceutical composition comprising mixing Form B of Compound (I) and a pharma- ceutically acceptable excipient.

[0020] Also provided herein is a method of treating a disease associated with RIPK1 in a patient in need thereof, comprising administering to the patient an effective amount of one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F.

[0021] Also provided herein is a method of treating a disease associated with RIPK1 in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F.

[0022] Also provided herein is a method of inhibiting RIPK1. The method includes administering to a patient in need thereof a therapeutically effective amount of one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F.

[0023] Also provided herein is a method of inhibiting RIPK1, comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F.

[0024] Another aspect of the present disclosure relates to one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F for use in the treatment of diseases associated with RIPK1. One aspect of the present disclosure relates to a pharmaceutical composition comprising one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F for use in diseases or disorders associated with RIPK1, and a pharma- ceutically acceptable excipient.

[0025] Also provided herein is the use of one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F in the manufacture of a medicament for treating a disease associated with RIPK1. Another aspect of the present disclosure relates to the use of a pharmaceutical composition comprising one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F in the manufacture of a medicament for treating a disease or disorder associated with RIPK1, and a pharma- ceutical composition comprising a pharma-ceutical acceptable excipient.

[0026] Also provided herein is one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F for use as a medicament. Another aspect of the disclosure relates to a pharmaceutical composition comprising one or more compounds selected from the group consisting of Compound (I) Form A, Compound (I) Form B, Compound (I) Form C, Compound (I) Form D, Compound (I) Form E, and Compound (I) Form F for use as a medicament. In some embodiments, the medicament is used to treat a disease or disorder mediated by RIPK1.

[0027] Provided herein are methods for treating a disease or disorder mediated by receptor interacting protein kinase 1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.

[0028] In certain embodiments, the disease or disorder is inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), systemic lupus erythematosus, cutaneous lupus erythematosus, Sjogren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis. , nephritis, celiac disease, autoimmune ITP, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, cytokine release syndrome, COVID-19 infection, cerebrovascular disease, myocardial infarction, Huntington's disease, Parkinson's disease, allergic disease, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, or periodontitis.

[0029] In certain embodiments, the disease or disorder is trauma, ischemia, stroke, myocardial infarction, infection, lysosomal storage disease, Gaucher disease, Krabbe disease, Niemann-Pick disease, sepsis, Parkinson's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Huntington's disease, HIV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis, or inflammatory bowel disease.

[0030] In certain embodiments, the disease or disorder is ALS, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, or spinal muscular atrophy. In certain embodiments, the disease or disorder is brain injury, spinal cord injury, dementia, stroke, ALS, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, or prion disorder.

[0031] The disclosure also provides compounds and pharmaceutical compositions that are useful in inhibiting RIPK1.

[0032] Each embodiment described herein may be used alone or in combination with one or more other embodiments.

[0033] term The articles "a" and "an" are used to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0034] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise stated.

[0035] The terms "article of manufacture" and "kit" are used synonymously.

[0036] "Pharmaceutically acceptable excipient" means a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing a pharmaceutical composition, and includes carriers or excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0037] As used herein, the term "crystalline" or "crystalline solid form" refers to a solid form that is substantially free of any amorphous solid form. In some embodiments, the crystalline solid form is a single solid form, e.g., crystalline form A.

[0038] In some embodiments, "substantially free" refers to less than about 10% w / w, less than about 9% w / w, less than about 8% w / w, less than about 7% w / w, less than about 6% w / w, less than about 5% w / w, less than about 4% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1% w / w, less than about 0.75% w / w, less than about 0.50% w / w, less than about 0.25% w / w, less than about 0.10% w / w, or less than about 0.05% w / w of other crystalline forms and amorphous compounds of the compound. In some embodiments, "substantially free" refers to undetectable amounts of other crystalline forms and amorphous compounds of the compound.

[0039] As used herein, the term "substantially pure" means that a crystalline form contains at least 90 weight percent, preferably at least 95 weight percent, more preferably at least 97 weight percent, and most preferably at least 99 weight percent of the indicated crystalline form relative to the total weight of all forms of the compound.

[0040] Alternatively, "substantially pure" will be understood to mean that the crystalline form contains less than 10 weight percent, preferably less than 5 weight percent, more preferably less than 3 weight percent, and most preferably less than 1 weight percent of impurities, including other polymorphs, solvates or amorphous forms, relative to the total weight of the compound in all forms.

[0041] An "XRPD pattern" or "X-ray powder diffraction pattern" is an XY graph with the diffraction angle (i.e., °2θ) on the X-axis and the intensity on the Y-axis. Peaks in this pattern can be used to characterize crystalline solid forms. As with any data measurement, there is variability in XRPD data. Data are often expressed only by the diffraction angle of the peaks, rather than including their intensity, because peak intensities are particularly sensitive to sample preparation (e.g., particle size, water content, solvent content, and preferred orientation, which affects sensitivity), so samples of the same material prepared under different conditions may produce slightly different patterns, and this variability is usually greater than the variability in the diffraction angle. Variability in diffraction angle may also be sensitive to sample preparation. Other sources of variability arise from instrument parameters and processing of raw X-ray data: different X-ray instruments operate using different parameters, which can result in slightly different XRPD patterns from the same solid form, and similarly different software packages process X-ray data in different ways, which also result in variability. These and other sources of variability are known to those skilled in the pharmaceutical arts, and due to such sources of variability, it is common to assign a variability of about ±0.2° θ to the diffraction angles of XRPD patterns.

[0042] solid form Forms A and B are anhydrous polymorphs of Compound (I). Form C is a hydrate of Compound (I), and Forms D, E and F are solvates of Compound (I).

[0043] The preparation and use of Compound (I) has been previously described (see WO 2017 / 136727; U.S. Pat. No. 9,815,850).

[0044] In some embodiments provided herein, Compound (I) is crystalline.

[0045] In some embodiments, the crystallinity of the solid form is characterized by X-ray powder diffraction (XRPD).

[0046] In some embodiments, the crystallinity of the solid form is determined by thermogravimetric analysis (TGA).

[0047] In some embodiments, the crystallinity of the solid form is determined by differential scanning calorimetry (DSC).

[0048] Provided herein is a crystalline form selected from the group consisting of: (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide form A; (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide form B; (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide form C; (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide form D; Form E of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide; and Form F of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.

[0049] Provided herein is crystalline Form A of Compound (I).

[0050] In some embodiments, crystalline Form A of Compound (I) is characterized as having one or more of the following: a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 1; b) an X-ray powder diffraction (XRPD) pattern derived using Cu(Kα) radiation, with peaks in degrees 2θ at about 6.9, 13.0, 16.6, and 23.4±0.2°; c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG. 2; d) A differential scanning calorimetry (DSC) thermogram with three endothermic events, with an onset at about 186.7° C. and a peak at about 188.9° C.; e) Thermogravimetric analysis (TGA) pattern substantially identical to that shown in Figure 2; f) a thermogravimetric analysis (TGA) pattern having a loss of about 1.0% w / w from about 27.8° C. to about 150° C.; or g) any combination thereof.

[0051] In one embodiment is crystalline Form A of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes 1, 2, 3, 4, 5, 6, 7 or more peaks selected from the group consisting of 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in °2θ±0.2 °2θ).

[0052] In one embodiment is crystalline Form A of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes one peak selected from the group consisting of 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0053] In one embodiment is crystalline Form A of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes two peaks selected from the group consisting of 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in °2θ±0.2 °2θ).

[0054] In one embodiment is crystalline Form A of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes three peaks selected from the group consisting of 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0055] In one embodiment is crystalline Form A of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes four peaks selected from the group consisting of 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0056] In one embodiment is crystalline Form A of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes five peaks selected from the group consisting of 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0057] In one embodiment is crystalline Form A of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes six peaks selected from the group consisting of 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0058] In one embodiment is crystalline Form A of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes seven or more peaks selected from the group consisting of 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0059] In one embodiment is crystalline Form A of Compound (I) having an X-ray powder diffraction pattern including a peak at about 6.9 (±0.2 each time) 2θ degrees.

[0060] In one embodiment is crystalline Form A of Compound (I) having an X-ray powder diffraction pattern containing peaks at about 6.9 and about 13.0 (+ / - 0.2 each time) degrees 2θ.

[0061] In one embodiment is crystalline Form A of Compound (I) having one or more X-ray powder diffraction peaks displayed as °2θ° at about 6.9, 13.0, 16.6 and 23.4 (+ / - 0.2 each time).

[0062] In one embodiment, the crystalline form A of compound (I) has an X-ray powder diffraction pattern comprising one or more 2θ degrees selected from the group comprising about 13.9, 16.6, 19.4, and 23.4 (each time + / - 0.2).

[0063] In one embodiment is crystalline Form A of Compound (I) having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.

[0064] Also provided herein is crystalline Form A of Compound (I), characterized by a differential scanning calorimetry (DSC) curve having an onset at about 186.7°C and an endothermic peak at 188.9°C.

[0065] Also provided herein is a process for the preparation of crystalline Form A of Compound (I), comprising at least the following steps: a) dissolving compound (I) in a solvent selected from CPME, EtOH, IPA, acetone, MIBK, EtOAc, IPAc, ACN, MTBE, THF, n-heptane, MeOAc, 2-MeTHF and toluene at a set temperature in the range of 50° C. to 70° C.; b) slowly cooling to room temperature; c) filtering, washing with a solvent, and drying to provide crystalline Form A of Compound (I) formed in step 2.

[0066] Provided herein is crystalline Form B of Compound (I).

[0067] In some embodiments, crystalline Form B of Compound (I) is characterized as having one or more of the following: a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 3; b) an X-ray powder diffraction (XRPD) pattern derived using Cu(Kα) radiation, with peaks in degrees 2θ at about 9.6, 11.5, 16.4, 19.2, and 23.8±0.2°; c) unit cell parameters substantially the same as those shown in Table 25; d) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG. 4; e) A differential scanning calorimetry (DSC) thermogram having three endothermic events with an onset at about 189.2°C and a peak at about 191.9°C; f) Thermogravimetric analysis (TGA) pattern substantially identical to that shown in Figure 4; g) a thermogravimetric analysis (TGA) pattern having a loss of about 1.0% w / w from about 23.8° C. to about 150° C.; or h) any combination thereof.

[0068] Also provided herein is a crystalline form of Compound (I), characterized as Form B.

[0069] In one embodiment, crystalline Form B of Compound (I) consists of one tautomer.

[0070] In one embodiment, the crystalline form B of compound (I) has at least 90% (w / w) of one tautomer, where the hydrogen is at the 4-position of the triazole ring of the tautomer.

[0071] In one embodiment, the crystalline form B of compound (I) has at least 95% (w / w) of one tautomer, where the hydrogen is at the 4-position of the triazole ring of the tautomer.

[0072] In one embodiment, the crystalline form B of compound (I) has at least 97% (w / w) of one tautomer, where the hydrogen is at the 4-position of the triazole ring of the tautomer.

[0073] In one embodiment is crystalline Form B of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes 1, 2, 3, 4, 5, 6 or more peaks selected from the group consisting of 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in °2θ±0.2 °2θ).

[0074] In one embodiment is crystalline Form B of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes one peak selected from the group consisting of 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2θ±0.2 degrees 2θ).

[0075] In one embodiment is crystalline Form B of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes two peaks selected from the group consisting of 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in °2θ±0.2 °2θ).

[0076] In one embodiment is crystalline Form B of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes three peaks selected from the group consisting of 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2θ±0.2 degrees 2θ).

[0077] In one embodiment is crystalline Form B of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes four peaks selected from the group consisting of 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2θ±0.2 degrees 2θ).

[0078] In one embodiment is crystalline Form B of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes five peaks selected from the group consisting of 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2θ±0.2 degrees 2θ).

[0079] In one embodiment is crystalline Form B of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes six or more peaks selected from the group consisting of 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2θ±0.2 degrees 2θ).

[0080] Also provided herein is crystalline Form B of Compound (I), having an X-ray powder diffraction pattern including peaks at about 9.6 and about 16.4 (+ / - 0.2 each time) 2θ degrees.

[0081] Also provided herein is crystalline Form B of Compound (I) having an X-ray powder diffraction displaying one or more peaks expressed as degrees 2θ at about 9.6, 11.5, 16.4, 19.2, 23.2 and 23.8 (+ / −0.2 in each case).

[0082] Also provided herein is crystalline Form B of Compound (I) having an X-ray powder diffraction pattern comprising one or more 2θ degrees selected from the group comprising about 11.5, 19.2, 23.2, and 23.8 (+ / - 0.2 each time).

[0083] Also provided herein is crystalline Form B of Compound (I), having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.

[0084] In this specification, a=5.0418(8)Å, b=15.320(3)Å, c=11.599(2)Å, α=90°, β=98.383(5)°, γ=90°, V=886.3(3)Å 3 Also provided is crystalline Form B of Compound (I), having substantially the same lattice parameters as

[0085] In this specification, a = 5.0418 Å, b = 15.320 Å, c = 11.599 Å, α = 90°, β = 98.383°, γ = 90°, V = 886.3 Å 3 Also provided is crystalline Form B of Compound (I), having substantially the same lattice parameters as

[0086] In this specification, a = 5.04 Å, b = 15.32 Å, c = 11.60 Å, α = 90°, β = 98.38°, γ = 90°, and V = 886.33 Å. 3 Also provided is crystalline Form B of Compound (I), having substantially the same lattice parameters as

[0087] Also provided herein is crystalline Form B of Compound (I), characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 189.2°C and an endothermic peak at 191.9°C.

[0088] Also provided herein is a process for the preparation of crystalline Form B of Compound (I), comprising at least the following steps: a) dissolving compound (I) in a solvent selected from MIBK, IPAc, HO and dimethyl carbonate to form a slurry; b) stirring the slurry at room temperature; c) filtering, washing with a solvent and drying to provide crystalline Form B of Compound (I).

[0089] Also provided herein is a process for the preparation of crystalline Form B of Compound (I), comprising at least the following steps: a) dissolving compound (I) in a solvent selected from EtOH, IPA, EtOAc, n-PrOAc, IPA / HO, EtOH / IPAc, MeOH / toluene, MIBK, IPAc, HO and methyl carbonate to form a slurry; b) stirring the slurry at room temperature; c) filtering, washing with a solvent and drying to provide crystalline Form B of Compound (I).

[0090] Also provided herein is a process for the preparation of crystalline Form B of Compound (I), comprising at least the following steps: a) dissolving compound (I) in a solvent selected from IPAc, EtOH, MIBK, EtOAc, HO, MeOH / IPAc, EtOH / MeOAc, and THF / HO to form a slurry; b) stirring the slurry at a set temperature in the range of 40°C to 60°C; c) filtering, washing with a solvent and drying to provide crystalline Form B of Compound (I).

[0091] Also provided herein is a process for the preparation of crystalline Form B of Compound (I), comprising at least the following steps: a) dissolving compound (I) in a solvent selected from MIBK, IPAc, HO and dimethyl carbonate to form a slurry; b) stirring the slurry at a set temperature in the range of 40°C to 60°C; c) slowly cooling to 1-10°C; d) filtering, washing with a solvent and drying to provide crystalline Form B of Compound (I).

[0092] Also provided herein is a process for the preparation of crystalline Form B of Compound (I), comprising at least the following steps: a) dissolving compound (I) in a mixture of DMAc and HO to obtain a suspension; b) stirring the suspension at a set temperature in the range of 40°C to 60°C; c) filtering, washing with a solvent and drying to provide crystalline Form B of Compound (I).

[0093] Also provided herein is a process for the preparation of crystalline Form B of Compound (I), comprising at least the following steps: a) placing compound (I) into a first container; b) placing the first container into a second container containing MeOH; c) sealing the second container and maintaining the second container at room temperature for 10 to 16 days; d) isolating the solid to provide crystalline Form B of Compound (I).

[0094] Provided herein is crystalline Form C of Compound (I).

[0095] In some embodiments, crystalline Form C of Compound (I) is characterized as having one or more of the following: a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 5; b) an X-ray powder diffraction (XRPD) pattern derived using Cu(Kα) radiation, with peaks in degrees 2θ at about 9.8, 10.2, 14.8, 15.2, and 20.4±0.2°; c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG. 7; d) A differential scanning calorimetry (DSC) thermogram with three endothermic events, with an onset at about 124.9° C. and a peak at about 131.3° C.; e) Thermogravimetric analysis (TGA) pattern substantially identical to that shown in Figure 7; f) a thermogravimetric analysis (TGA) pattern having a loss of about 5.7% w / w from about 22.4° C. to about 100° C.; or g) any combination thereof.

[0096] Also provided herein is a crystalline form of Compound (I), characterized as Form C.

[0097] In one embodiment is crystalline Form C of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes 3, 4, 5, 6 or more peaks selected from the group consisting of 9.8, 10.2, 14.8, 15.2, 18.1, 20.4, and 22.3 (expressed in °2θ±0.2 °2θ).

[0098] In one embodiment is crystalline Form C of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes one peak selected from the group consisting of 9.8, 10.2, 14.8, 15.2, 18.1, 20.4, and 22.3 (expressed in degrees 2θ±0.2 degrees 2θ).

[0099] In one embodiment is crystalline Form C of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes two peaks selected from the group consisting of 9.8, 10.2, 14.8, 15.2, 18.1, 20.4, and 22.3 (expressed in °2θ±0.2 °2θ).

[0100] In one embodiment, the crystalline form C of Compound (I) has an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes three peaks selected from the group consisting of 9.8, 10.2, 14.8, 15.2, 18.1, 20.4, and 22.3 (expressed in degrees 2θ±0.2 degrees 2θ).

[0101] In one embodiment is crystalline Form C of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes four peaks selected from the group consisting of 9.8, 10.2, 14.8, 15.2, 18.1, 20.4, and 22.3 (expressed in degrees 2θ±0.2 degrees 2θ).

[0102] In one embodiment, the crystalline form C of Compound (I) has an X-ray powder diffraction pattern, derived using Cu(Kα) radiation, that includes five peaks selected from the group consisting of 9.8, 10.2, 14.8, 15.2, 18.1, 20.4, and 22.3 (expressed in degrees 2θ±0.2 degrees 2θ).

[0103] In one embodiment is crystalline Form C of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes six or more peaks selected from the group consisting of 9.8, 10.2, 14.8, 15.2, 18.1, 20.4, and 22.3 (expressed in degrees 2θ±0.2 degrees 2θ).

[0104] Also provided herein is crystalline Form C of Compound (I), having an X-ray powder diffraction pattern including peaks for degrees 2θ at about 9.8 and about 10.2 (+ / −0.2 each time).

[0105] Also provided herein is crystalline Form C of Compound (I), having an X-ray powder diffraction pattern comprising peaks at degrees 2θ selected from the group consisting of about 9.8, 10.2, 14.8, 15.2 and 20.4 (+ / - 0.2 each time).

[0106] Also provided herein is crystalline Form C of Compound (I), having an X-ray powder diffraction pattern comprising one or more 2θ degrees selected from the group comprising about 14.8, 15.2, 18.1, 20.4, and 22.3 (each time + / - 0.2).

[0107] Also provided herein is crystalline Form C of Compound (I), having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.

[0108] Also provided herein is crystalline Form C of Compound (I), characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 124.9°C and an endothermic peak at 131.3°C.

[0109] Also provided herein is a process for the preparation of crystalline Form C of Compound (I), comprising at least the following steps: a) dissolving compound (I) in MeOH / HO to obtain a slurry; b) stirring the slurry at a set temperature in the range of 40°C to 60°C; c) slowly cooling to 1-10°C; d) filtering, washing with a solvent and drying to provide crystalline Form C of Compound (I).

[0110] Provided herein is crystalline Form D of Compound (I).

[0111] In some embodiments, crystalline Form D of Compound (I) is characterized as having one or more of the following: a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 7; b) an X-ray powder diffraction (XRPD) pattern derived using Cu(Kα) radiation, with peaks in terms of degrees 2θ at about 8.2, 10.4, 12.1, 16.3, and 19.9±0.2°; c) unit cell parameters substantially equal to those shown in Table 27; d) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG. 9; e) a differential scanning calorimetry (DSC) thermogram having an endothermic event with an onset at about 93.0° C. and a peak at about 96.7° C.; f) Thermogravimetric analysis (TGA) pattern substantially identical to that shown in FIG. 9; g) a thermogravimetric analysis (TGA) pattern having a loss of about 3.8% w / w from about 23.5° C. to about 85.0° C., and a loss of about 11.5% w / w from about 85.0° C. to about 120° C.; or h) any combination thereof.

[0112] Also provided herein is a crystalline form of Compound (I), characterized as Form D.

[0113] In one embodiment, the crystalline form D of Compound (I) has an X-ray powder diffraction pattern, derived using Cu(Kα) radiation, that includes 3, 4, 5 or more peaks selected from the group consisting of 8.2, 10.4, 12.1, 16.3, 19.9, and 21.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0114] In one embodiment, the crystalline form D of Compound (I) has an X-ray powder diffraction pattern, derived using Cu(Kα) radiation, that includes one peak selected from the group consisting of 8.2, 10.4, 12.1, 16.3, 19.9, and 21.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0115] In one embodiment, the crystalline form D of Compound (I) has an X-ray powder diffraction pattern, derived using Cu(Kα) radiation, that includes two peaks selected from the group consisting of 8.2, 10.4, 12.1, 16.3, 19.9, and 21.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0116] In one embodiment, the crystalline form D of Compound (I) has an X-ray powder diffraction pattern, derived using Cu(Kα) radiation, that includes three peaks selected from the group consisting of 8.2, 10.4, 12.1, 16.3, 19.9, and 21.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0117] In one embodiment, the crystalline form D of Compound (I) has an X-ray powder diffraction pattern, derived using Cu(Kα) radiation, that includes four peaks selected from the group consisting of 8.2, 10.4, 12.1, 16.3, 19.9, and 21.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0118] In one embodiment, the crystalline form D of Compound (I) has an X-ray powder diffraction pattern, derived using Cu(Kα) radiation, that includes five or more peaks selected from the group consisting of 8.2, 10.4, 12.1, 16.3, 19.9, and 21.0 (expressed in degrees 2θ±0.2 degrees 2θ).

[0119] Also provided herein is crystalline Form D of Compound (I), having an X-ray powder diffraction pattern including peaks at about 8.2 and about 16.3 degrees 2θ.

[0120] Also provided herein is crystalline Form D of Compound (I), having an X-ray powder diffraction pattern comprising one or more 2θ degrees selected from the group comprising about 8.2, 10.4, 12.1, 16.3, and 19.9 (each time + / - 0.2).

[0121] Also provided herein is crystalline Form D of Compound (I), having unit cell parameters substantially equal to those set forth in Table 27.

[0122] Also provided herein is crystalline Form D of Compound (I), having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.

[0123] Also provided herein is crystalline Form D of Compound (I), characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 93.0°C and an endothermic peak at 96.7°C.

[0124] Also provided herein is a process for the preparation of crystalline Form D of Compound (I), comprising at least the following steps: a) placing crystalline Form C of Compound (I) into a first vial; b) placing the first vial into a second vial containing isopropyl alcohol; c) sealing the second vial and maintaining the second vial at room temperature for 10 to 16 days; d) isolating the solid to provide crystalline Form D of Compound (I).

[0125] Provided herein is crystalline Form E of Compound (I).

[0126] In some embodiments, crystalline Form E of Compound (I) is characterized as having one or more of the following: (a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 11 ; (b) X-ray powder diffraction (XRPD) pattern derived using Cu(Kα) radiation with peaks in terms of degrees 2θ at approximately 9.5, 17.1, 20.1, 20.6, and 24.6±0.2°.

[0127] Also provided herein is a crystalline form of Compound (I), characterized as Form E.

[0128] In one embodiment is crystalline Form E of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes 3, 4, 5, 6 or more peaks selected from the group consisting of 8.11, 9.5, 10.0, 17.1, 20.1, 20.6, 24.6, and 30.1 (expressed in °2θ±0.2 °2θ).

[0129] In one embodiment is crystalline form E of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes one peak selected from the group consisting of 8.11, 9.5, 10.0, 17.1, 20.1, 20.6, 24.6, and 30.1 (expressed in degrees 2θ±0.2 degrees 2θ).

[0130] In one embodiment is crystalline form E of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes two peaks selected from the group consisting of 8.11, 9.5, 10.0, 17.1, 20.1, 20.6, 24.6, and 30.1 (expressed in °2θ±0.2 °2θ).

[0131] In one embodiment is crystalline form E of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes three peaks selected from the group consisting of 8.11, 9.5, 10.0, 17.1, 20.1, 20.6, 24.6, and 30.1 (expressed in degrees 2θ±0.2 degrees 2θ).

[0132] In one embodiment is crystalline form E of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes four peaks selected from the group consisting of 8.11, 9.5, 10.0, 17.1, 20.1, 20.6, 24.6, and 30.1 (expressed in degrees 2θ±0.2 degrees 2θ).

[0133] In one embodiment is crystalline form E of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes five peaks selected from the group consisting of 8.11, 9.5, 10.0, 17.1, 20.1, 20.6, 24.6, and 30.1 (expressed in degrees 2θ±0.2 degrees 2θ).

[0134] In one embodiment is crystalline form E of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes six or more peaks selected from the group consisting of 8.11, 9.5, 10.0, 17.1, 20.1, 20.6, 24.6, and 30.1 (expressed in degrees 2θ±0.2 degrees 2θ).

[0135] Also provided herein is crystalline Form E of Compound (I), having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.

[0136] Also provided herein is crystalline Form E of Compound (I) having an X-ray powder diffraction pattern including peaks in terms of degrees 2θ at about 9.5, 17.1, 20.1, 20.6, and 24.6±0.2 degrees.

[0137] Also provided herein is a process for the preparation of crystalline Form E of Compound (I), comprising at least the following steps: a) dissolving compound (I) in dichloromethane to obtain a suspension; b) filtering the suspension to obtain a filtrate; c) placing the filtrate in a vial and covering with a film; d) Evaporation at room temperature to obtain crystalline Form E of Compound (I).

[0138] In one aspect, provided herein is crystalline Form F of Compound (I). In some embodiments, crystalline Form F of Compound (I) is characterized as having one or more of the following: (a) X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 12; (b) X-ray powder diffraction (XRPD) pattern derived using Cu(Kα) radiation with peaks in terms of degrees 2θ at approximately 9.8, 10.2, 17.8, 22.3, and 24.9±0.2°.

[0139] Also provided herein is a crystalline form of Compound (I), characterized as Form F.

[0140] In one embodiment is crystalline Form F of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes 3, 4, 5, 6 or more peaks selected from the group consisting of 9.8, 10.2, 17.8, 20.9, 21.1, 21.8, 22.3, and 24.9 (expressed in °2θ±0.2 °2θ).

[0141] In one embodiment is crystalline form F of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes one peak selected from the group consisting of 9.8, 10.2, 17.8, 20.9, 21.1, 21.8, 22.3, and 24.9 (expressed in degrees 2θ±0.2 degrees 2θ).

[0142] In one embodiment is crystalline form F of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes two peaks selected from the group consisting of 9.8, 10.2, 17.8, 20.9, 21.1, 21.8, 22.3, and 24.9 (expressed in degrees 2θ±0.2 degrees 2θ).

[0143] In one embodiment is crystalline form F of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes three peaks selected from the group consisting of 9.8, 10.2, 17.8, 20.9, 21.1, 21.8, 22.3, and 24.9 (expressed in degrees 2θ±0.2 degrees 2θ).

[0144] In one embodiment is crystalline form F of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes four peaks selected from the group consisting of 9.8, 10.2, 17.8, 20.9, 21.1, 21.8, 22.3, and 24.9 (expressed in degrees 2θ±0.2 degrees 2θ).

[0145] In one embodiment is crystalline form F of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes five peaks selected from the group consisting of 9.8, 10.2, 17.8, 20.9, 21.1, 21.8, 22.3, and 24.9 (expressed in degrees 2θ±0.2 degrees 2θ).

[0146] In one embodiment is crystalline form F of Compound (I) having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes six or more peaks selected from the group consisting of 9.8, 10.2, 17.8, 20.9, 21.1, 21.8, 22.3, and 24.9 (expressed in degrees 2θ±0.2 degrees 2θ).

[0147] Also provided herein is crystalline Form F of Compound (I), having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.

[0148] Also provided herein is crystalline Form F of Compound (I) having an X-ray powder diffraction pattern including peaks in degrees 2θ at about 9.8, 10.2, 17.8, 22.3, and 24.9 (expressed in degrees 2θ±0.2 degrees 2θ).

[0149] Also provided herein is a process for the preparation of crystalline Form F of Compound (I), comprising at least the following steps: a) dissolving compound (I) in a solvent selected from MeOH and MeOH / HO to form a slurry; b) stirring the slurry at a set temperature in the range of 40°C to 60°C; c) slowly cooling to 1-10°C; d) filtering, washing with a solvent and drying to provide crystalline Form F of Compound (I).

[0150] Preparation of Compound (I) The compounds described herein may be made from commercially available starting materials or may be synthesized using known organic, inorganic, and / or enzymatic processes.For example, compound (I) can be synthesized using the method described in WO2017 / 136727 (see also US Pat. No. 9,815,850), as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereof recognized by those skilled in the art.

[0151] Pharmaceutical Compositions In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharma- ceutical acceptable inactive ingredients that facilitate the processing of active compounds into medicament-use preparations. Appropriate formulation depends on the route of administration selected. Overviews of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0152] In some embodiments, the compounds described herein are administered in a pharmaceutical formulation, either alone or in combination with a pharma- ceutically acceptable excipient. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compound to the site of action.

[0153] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

[0154] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules in a suitable machine, and optionally mixing with a binder, an inert diluent, or a lubricating surface-active or dispersing agent. Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine.

[0155] In some embodiments, the tablets are coated or divided and formulated to provide a delayed or controlled release of the active ingredient therein. All formulations for oral administration should be in a suitable form for such administration. Push-fit capsules may contain the active ingredient mixed with binders such as lactose, starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used that may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of doses of the active compound.

[0156] It will be understood that in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0157] Also provided herein is a pharmaceutical composition comprising crystalline Form A of Compound (I) and a pharma- ceutically acceptable excipient. In one embodiment, in the pharmaceutical composition, the crystalline Form A is substantially pure and substantially free of other crystalline forms of Compound (I). In another embodiment, in the pharmaceutical composition, the crystalline Form A comprises at least 90 percent by weight of all forms.

[0158] Also provided herein is a pharmaceutical composition comprising crystalline Form B of Compound (I) and a pharma- ceutically acceptable excipient. In one embodiment, in the pharmaceutical composition, the crystalline Form B is substantially pure and substantially free of other forms. In another embodiment, in the pharmaceutical composition, the crystalline Form B comprises at least 90 percent by weight of all forms.

[0159] Also provided herein is a pharmaceutical composition comprising crystalline Form C of Compound (I) and a pharma- ceutically acceptable excipient. In one embodiment, in the pharmaceutical composition, the crystalline Form C is substantially pure and substantially free of other forms. In another embodiment, in the pharmaceutical composition, the crystalline Form C comprises at least 90 percent by weight of all forms.

[0160] Also provided herein is a pharmaceutical composition comprising crystalline Form D of Compound (I) and a pharma- ceutically acceptable excipient. In one embodiment, in the pharmaceutical composition, the crystalline Form D is substantially pure and substantially free of other forms. In another embodiment, in the pharmaceutical composition, the crystalline Form D comprises at least 90 percent by weight of all forms.

[0161] Also provided herein is a pharmaceutical composition comprising crystalline Form E of Compound (I) and a pharma- ceutically acceptable excipient. In one embodiment, in the pharmaceutical composition, the crystalline Form E is substantially pure and substantially free of other forms. In another embodiment, in the pharmaceutical composition, the crystalline Form E comprises at least 90 percent by weight of all forms.

[0162] Also provided herein is a pharmaceutical composition comprising crystalline Form F of Compound (I) and a pharma- ceutically acceptable excipient. In one embodiment, in the pharmaceutical composition, the crystalline Form F is substantially pure and substantially free of other forms. In another embodiment, in the pharmaceutical composition, the crystalline Form F comprises at least 90 percent by weight of all forms.

[0163] Methods of Administration and Treatment Regimens The daily dosage may be described as the total amount of the compounds disclosed herein administered per dose or per day. The daily dosage of the compounds disclosed herein may be about 1 mg to 4,000 mg, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0164] When administered orally, the total daily dosage for a human patient can be 1 mg to 1,000 mg, about 1,000 to 2,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day.

[0165] In certain embodiments, the method includes administering to the patient an initial daily dose of about 1-800 mg of a compound described herein, and increasing the dose incrementally until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice a week, or once a week.

[0166] Also provided herein is a method of treating a disease or disorder mediated by RIPK1 in a patient in need thereof, comprising administering to the patient an effective amount of crystalline Form A of Compound (I).

[0167] Also provided herein is crystalline Form A of Compound (I) for use as a medicament, for use as an inhibitor of the RIPK1 receptor, and for use in the treatment of various diseases in which the RIPK1 receptor is involved.

[0168] Also provided herein is the use of crystalline Form A of Compound (I) for the manufacture of a medicament for the treatment of a disease involving inhibition of the RIPK1 receptor.

[0169] Also provided herein is a method of treating a disease or disorder mediated by RIPK1 in a patient in need thereof, comprising administering to the patient an effective amount of crystalline Form B of Compound (I).

[0170] Also provided herein is crystalline Form B of Compound (I) for use as a medicament, for use as an inhibitor of the RIPK1 receptor, and for use in the treatment of various diseases in which the RIPK1 receptor is involved.

[0171] Also provided herein is the use of crystalline form B of compound (I) for the manufacture of a medicament for the treatment of a disease involving inhibition of the RIPK1 receptor.

[0172] Also provided herein is a method of treating a disease or disorder mediated by RIPK1 in a patient in need thereof, comprising administering to the patient an effective amount of crystalline Form C of Compound (I).

[0173] Also provided herein is crystalline Form C of Compound (I) for use as a medicament, for use as an inhibitor of the RIPK1 receptor, and for use in the treatment of various diseases in which the RIPK1 receptor is involved.

[0174] Also provided herein is the use of crystalline Form C of Compound (I) for the manufacture of a medicament for the treatment of a disease involving inhibition of the RIPK1 receptor.

[0175] Also provided herein is a method of treating a disease or disorder mediated by RIPK1 in a patient in need thereof, comprising administering to the patient an effective amount of crystalline Form D of Compound (I).

[0176] Also provided herein is crystalline form D of Compound (I) for use as a medicament, for use as an inhibitor of the RIPK1 receptor, and for use in treating various diseases in which the RIPK1 receptor is involved.

[0177] Also provided herein is the use of crystalline form D of compound (I) for the manufacture of a medicament for the treatment of a disease involving inhibition of the RIPK1 receptor.

[0178] Also provided herein is a method of treating a disease or disorder mediated by RIPK1 in a patient in need thereof, comprising administering to the patient an effective amount of crystalline Form E of Compound (I).

[0179] Also provided herein is crystalline form E of Compound (I) for use as a medicament, for use as an inhibitor of the RIPK1 receptor, and for use in treating various diseases in which the RIPK1 receptor is involved.

[0180] Also provided herein is the use of crystalline form E of compound (I) for the manufacture of a medicament for the treatment of a disease involving inhibition of the RIPK1 receptor.

[0181] Also provided herein is a method of treating a disease or disorder mediated by RIPK1 in a patient in need thereof, comprising administering to the patient an effective amount of crystalline Form F of Compound (I).

[0182] Also provided herein is crystalline form F of Compound (I) for use as a medicament, for use as an inhibitor of the RIPK1 receptor, and for use in treating various diseases in which the RIPK1 receptor is involved.

[0183] Also provided herein is the use of crystalline form F of compound (I) for the manufacture of a medicament for the treatment of a disease involving inhibition of the RIPK1 receptor.

[0184] Manufactured Products and Kits In certain embodiments, kits and articles of manufacture are disclosed herein for use in one or more of the methods described herein.In some embodiments, the additional components of the kit include packaging or containers that are compartmentalized to receive one or more containers, such as vials, tubes, etc., each of which contains one of the separate elements used in the methods described herein.Suitable containers include, for example, bottles, vials, plates, syringes, and test tubes.In one embodiment, the containers are formed from a variety of materials, such as glass or plastic.

[0185] The articles of manufacture provided herein contain packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, bags, containers, and any packaging material suitable for the selected formulation and intended mode of use.

[0186] For example, the container contains one or more of the compounds described herein. Such kits optionally include identifying descriptions, labels, or instructions for their use in the methods described herein.

[0187] The kit typically includes a label describing the contents and / or instructions for use, as well as a package insert containing the instructions. A set of instructions is also typically included.

[0188] In one embodiment, the label is on or associated with the container. In one embodiment, the label can be on the container if the letters, numbers or other characters forming the label are attached, molded or inscribed on the container itself, or it can be associated with the container if the label is presented in the container or in a receptacle or container that holds the container, for example, as a package insert. In one embodiment, the label is used to indicate that the contents should be used for a particular therapeutic application. The label also indicates instructions for the use of the contents, such as the methods described herein.

[0189] Abbreviation ACN or MeCN: acetonitrile; CAN: ceric ammonium nitrate; CPME: cyclopentyl methyl ether; DCM: dichloromethane; DMSO: dimethyl sulfoxide; DMAc: N,N-dimethylacetamide; DSC: differential scanning calorimetry; DVS: Dynamic Vapor Sorption; Et: ethyl; EtOAc: ethyl acetate; EtOH: ethanol; equiv or eq.: equivalent; FaSSIF: fasted artificial intestinal fluid; FeSSIF: fed state artificial intestinal fluid; FTIR: Fourier transform infrared; h or hr: hours; hrs: time; HPLC: high performance liquid chromatography; IPA: Isopropyl alcohol; IPAc: isopropyl acetate; KCl: potassium chloride; LC-MS or LCMS or LC / MS: Liquid Chromatography-Mass Spectrometry; LiCl: lithium chloride; M: moles; Me: methyl; MeOH: methanol; MeOAc: methyl acetate; Mg(NO3)2: Magnesium nitrate; MIBK: methyl isobutyl ketone; MTBE: methyl tert-butyl ether; mins or min: minutes; N2: nitrogen; n-PrOAc: n-propyl acetate; NMR: nuclear magnetic resonance; RH: relative humidity; rt or RT: room temperature; SCXRD: single crystal X-ray diffraction; SGF: simulated gastric fluid; TFA: trifluoroacetic acid; TGA thermogravimetric analysis; THF: tetrahydrofuran; 2-MeTHF: 2-methyltetrahydrofuran; vol:volume; w / w: weight ratio; and XRPD: X-ray powder diffraction.

[0190] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0191] Apparatus and method 1. XRPD A PANalytical Empyrean and X'Pert3 X-ray powder diffractometer were used for the XRPD analysis. The XRPD parameters used are listed in Table 1.

[0192] [Table 1]

[0193] 2. TGA and DSC TGA data was collected using a TA Instruments TA Q500 / Q5000 TGA. DSC was performed using a TA Instruments TA Q2000 / Q200 DSC. The detailed parameters used are shown in Table 2.

[0194] [Table 2]

[0195] 3.DVS DVS was measured via a DVS Intrinsic from SMS (Surface Measurement Systems). Relative humidity was calibrated against the deliquescence points of LiCl, Mg(NO3)2 and KCl at 25° C. Parameters for the DVS test are listed in Table 3.

[0196] [Table 3]

[0197] 4. 1 H solution NMR 1 H solution NMR was collected on a Bruker 400M NMR spectrometer using DMSO-d6.

[0198] 1. HPLC Agilent HPLC was used and the detailed chromatographic conditions for purity and solubility determination are shown in Table 4.

[0199] [Table 4]

[0200] 2. SCXRD Single crystal X-ray diffraction data were collected at 175K using a Bruker D8 VENTURE diffractometer (Mo / Kα radiation, λ=0.71073 Å). Photomicrographs were captured using a Shanghai Cewei binocular stereo microscope. Experimental XRPD of single crystal samples of Compound (I) Form B and reference compounds were collected on a PANalytical X'Pert powder diffractometer. The instrument parameters are shown in Table 5.

[0201] [Table 5] EXAMPLES

[0202] Example 1: Preparation of Form A of Compound (I) To 100 mg of compound (I), 0.9 mL of toluene, 0.1 mL of methylcyclohexane were added. The mixture was heated to 60° C., dissolving the solids to give a homogeneous solution. The solution was cooled and a gummy precipitate was observed. The mixture was left stirring for 3 days, where the precipitated material remained gummy. A few drops of diisopropyl ether were added at room temperature. The mixture was then heated to 60° C., where a small amount of what appeared to be a powdery solid residue remained undissolved. Upon cooling, much precipitation occurred, but the precipitated solid appeared to be part powder / part rubber. The mixture was again heated to 60° C. and held at this temperature for 6 hours - when hot, a more powdery solid precipitated directly. The mixture was allowed to cool and stirred at room temperature overnight, then filtered and washed with toluene (1 mL) to give approximately 77 mg of a white solid.

[0203] As shown in Figure 1, XRPD revealed that Example 1 is crystalline and is therefore designated as Form A. Thus, crystalline Form A can be characterized by having one or more X-ray powder diffraction patterns displaying peaks expressed in 2θ° at about 6.9, 13.0, 16.6 and 23.4 (each time + / - 0.2), which optionally further display one or more of the following peaks expressed in 2θ° at about 13.9, 19.4, 11.5 and 24.0 (each time + / - 0.2), or optionally further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1. A characteristic X-ray powder diffraction pattern of crystalline Form A of Compound (I) can be substantially given in Figure 1, and its characteristic signals are summarized in Table 6 below.

[0204] The TGA and DSC data of Example 1 are shown in Figure 2. In the TGA curve, a weight loss of 1.0% was observed up to 150°C. The DSC results showed an endothermic onset at 186.7°C (+ / - 2°C) and an endothermic peak at 188.9°C (+ / - 2°C). As shown in Figure 2, this melting point temperature is associated with the high enthalpy of fusion AHf (nearly 91.7 J / g). According to the results, Form A is characterized as anhydrous.

[0205] [Table 6]

[0206] Example 2: Preparation of solid form by slurry method at 50°C Slurry conversion experiments were also carried out at 50° C. in 12 different solvent systems. Approximately 15 mg of starting material (Example 1) was suspended in 0.5 mL of solvent in an HPLC vial. The suspension was magnetically stirred (about 1000 rpm) at 50° C. for about 2 days, after which the remaining solid was isolated for XRPD analysis. The results of the slurry conversion experiments are summarized in Table 7.

[0207] [Table 7]

[0208] As displayed in Figure 3, XRPD revealed that Example 2-1 is crystalline and is therefore designated as Form B. Crystalline Form B can be characterized by having an X-ray powder diffraction displaying one or more peaks expressed as 2θ degrees at about 9.6, 11.5, 16.4, 19.2, 23.2, and 23.8 (+ / -0.2 each time), optionally further displaying the following peak expressed as 2θ degrees at about 13.8 (+ / -0.2 each time), optionally further characterized by a powder X-ray diffraction pattern substantially as illustrated in Figure 3, whose characteristic signals are summarized in Table 8 below.

[0209] The TGA and DSC data of Example 2-1 are shown in Table 4. A weight loss of 1.0% was observed in the TGA curve up to 150°C. The DSC results showed an endothermic onset at 189.2°C (+ / - 2°C) and an endothermic peak at 191.9°C (+ / - 2°C). As shown in Figure 4, this melting point temperature is associated with the high enthalpy of fusion AHf (nearly 93.4 J / g). According to the results, Form B is characterized as anhydrous. Examples 2-2, 2-4, 2-5, 2-8, 2-9, 2-10 and 2-12 are consistent with Figure 3.

[0210] [Table 8]

[0211] Example 3: Preparation of solid forms by slurry cycling (50-5°C) Slurry cycling (50-5°C) experiments were performed with six different solvent systems. Approximately 15 mg of starting material (Example 1) was suspended in 0.5 mL of solvent in an HPLC vial. The suspension was magnetically stirred (approximately 600 rpm) at 50°C for 1 h and then slowly cooled to 5°C at a rate of 0.1°C / min. The resulting solid was cycled between 50°C and 5°C three times and then held isothermal at 5°C. The solid was isolated for XRPD analysis. The XRPDs of Examples 3-1, 3-2, 3-3, and 3-6 are consistent with Figure 3, and therefore are also Form B. The results summarized in Table 9 indicate that Forms A, B, and A+B were produced.

[0212] [Table 9]

[0213] Example 4: Preparation of solid forms by slow cooling method Slow cooling experiments were performed with 10 solvent systems. Approximately 15 mg of starting material (Example 1) was suspended in 1.0 mL of solvent in an HPLC vial at RT. The suspension was then heated to 50° C., equilibrated for approximately 2 hours, and filtered into a new vial using a PTFE membrane (0.45 μm pore size) to remove undissolved material. The filtrate was slowly cooled to 5° C. at a rate of 0.1° C. / min. The resulting solid was kept isothermal at 5° C. and then isolated for XRPD analysis. The clear solution was evaporated to dryness at RT, and the solid was then examined by XRPD. The XRPD of Examples 4-10 is consistent with FIG. 3, so it is also Form B. The results summarized in Table 10 showed that Form A, Form B, and amorphous material were obtained.

[0214] [Table 10]

[0215] Example 5: Preparation of solid forms by slurry method at RT Slurry conversion experiments were carried out in 14 different solvent systems at RT. Approximately 15 mg of starting material (Example 1) was suspended in 0.5 mL of solution in an HPLC vial. After the suspension was magnetically stirred (approximately 1000 rpm) at RT for approximately 13 days, the remaining solid was isolated for XRPD analysis. The results summarized in Table 11 showed that Forms A and B were produced.

[0216] [Table 11]

[0217] Example 6: Preparation of solid forms by vapor-solid diffusion method Vapor-solid experiments were carried out using ten different solvents. Approximately 15 mg of sample (Example 1) was weighed into a 3 mL glass vial. The 3 mL vial was then placed into a 20 mL vial containing 4 mL of solvent. The 20 mL vial was sealed with a cap and kept at RT for 13-14 days. The solid was isolated for XRPD analysis. The results summarized in Table 12 showed that Forms A, B and A+B were observed.

[0218] [Table 12]

[0219] Example 7: Preparation of solid forms by vapor-solution diffusion method Vapor-solution diffusion experiments were performed with eight different solvents. Approximately 15 mg of starting material (Example 1) was dissolved in 0.2-1.6 mL of the appropriate solvent to obtain a clear solution in a 3 mL vial. This solution was then placed in a 20 mL vial containing 4 mL of a volatile solvent. The 20 mL vial was sealed with a cap and kept at RT for a sufficient time for the organic vapor to interact with the solution. A clear solution was obtained after 12 days and transferred to evaporate at RT. The solid was isolated for XRPD analysis. The results summarized in Table 13 showed that Forms A, B and amorphous material were observed.

[0220] [Table 13]

[0221] Example 8: Preparation of solid forms by antisolvent addition method A total of 12 anti-solvent addition experiments were performed. Approximately 20 mg of starting material (Example 1) was dissolved in 0.2-1.6 mL of solvent to obtain a clear solution, which was magnetically stirred (approximately 1000 rpm) followed by the addition of 0.1 mL of anti-solvent per step until a precipitate appeared or the total amount of anti-solvent reached 10 mL. The resulting precipitate was isolated for XRPD analysis. The results in Table 14 showed that Form A, Form A+B and amorphous material were produced.

[0222] [Table 14]

[0223] Example 9: Preparation of solid forms by the reverse antisolvent addition method Reverse anti-solvent addition experiments were carried out under 10 conditions. Approximately 15 mg of starting material (Example 1) was dissolved in 0.2-1.8 mL of each solvent to obtain a clear solution. This solution was added dropwise to a glass vial containing 5 mL of each anti-solvent at RT. The precipitate was isolated for XRPD analysis. The results summarized in Table 15 showed that Form A, Form A+B, and amorphous material were obtained.

[0224] [Table 15]

[0225] Example 10: Preparation of solid forms by slow evaporation method Slow evaporation experiments were carried out under 12 conditions. Approximately 15 mg of starting material (Example 1) was dissolved in 0.4-2.0 mL of solvent in a 3 mL glass vial. In case of complete dissolution, the suspension was filtered using a PTFE membrane (0.45 μm pore size) to obtain a clear solution, which was subjected to evaporation at RT using a vial sealed by Parafilm® (perforated with 3 pinholes). Solids formed during evaporation and were isolated for XRPD analysis, the results of which are summarized in Table 16, showed that Form A, Form A+B, and amorphous material were obtained.

[0226] [Table 16]

[0227] Example 11: Preparation of Form A of Compound (I) Form A was alternatively prepared by adding 10 g of Compound (I) to anhydrous toluene (80 mL) at RT. The mixture was heated to 80° C. to dissolve the material, then cooled to 60° C. and held at 60° C. overnight. The mixture was gradually cooled to RT, and the mixture was stirred at RT for about 18 hours. The solid was collected by vacuum filtration, washed with toluene, and dried by drawing air through the filter for 1 hour to provide the desired product as a white crystalline solid, which was characterized by XRPD, TGA, and DSC. The XRPD of Example 11 is consistent with FIG. 1. The TGA and DSC of Example 11 are consistent with FIG. 2, so Example 11 was also Form A.

[0228] Example 12: Preparation of Form B by Slurry Method at 50°C About 15 mg of starting material (Example 1) was suspended in 0.5 mL of IPAc in an HPLC vial. The suspension was magnetically stirred (about 1000 rpm) at 50° C. for about 4 days, and the solid was isolated for XRPD analysis (Example 12). The XRPD pattern and TGA / DSC curve of Example 12 are consistent with Figures 3 and 4, respectively. A weight loss of 1.0% up to 150° C. and an endotherm at 188.7° C. (onset temperature) were observed in the TGA / DSC curve.

[0229] Example 13: Preparation of Form B by slurry cycling (50 to 5°C) and slurry method at 50°C Example 13 was prepared via temperature cycling from 50° C. to 5° C. in HO, followed by slurry for 1 day at 50° C. The XRPD pattern of Example 13 matched FIG. 3, so Example 13 was Form B.

[0230] Example 14: Preparation of single crystals by slow evaporation First, 5.1 mg of compound (Example 1) starting material was weighed into a 3 mL glass vial, followed by adding 0.35 mL of MeOH. After vibrating on a vortex and shaking ultrasonically to accelerate dissolution, the solution was then filtered through a PTFE filter membrane (0.45 μm) and transferred into a 4 mL shell vial (44.6 mm×14.65 mm) with a disposable syringe. A small amount of crystal sample (Example 10-1) was added into the vial as seed crystal, and then the vial was covered using a PE-Plug with one pinhole on it and allowed to slowly evaporate at RT. After 5 days, a rod-shaped single crystal was obtained.

[0231] Example 15: Preparation of Form C of Compound (I) A crystalline form of Compound (I) was obtained via evaporation of a DCM solution at RT for 1 day, followed by drying at RT. The XRPD pattern and TGA / DSC curves are shown in Figures 5 and 7. As shown in Figure 5, XRPD revealed that Example 15 was crystalline, and was therefore designated as Form C.

[0232] Alternatively, Form C was prepared by the slow cooling method. A solution of Compound (I) in methanol-water was heated to about 50° C. The hot mixture was filtered and the filtrate was slowly cooled to 5° C. The precipitated solid was filtered and the resulting solid was mixed with water for several days. The resulting slurry was filtered to provide Form C.

[0233] Crystalline Form C is characterized by having an X-ray powder diffraction displaying peaks expressed as degrees 2θ at about 9.8, 10.2, 14.8, 15.2 and 20.4 (in each case + / - 0.2), which optionally further exhibits the following peaks expressed as degrees 2θ at about 18.1 and 22.3 (in each case + / - 0.2), optionally further characterized by an X-ray powder diffraction pattern substantially as illustrated in Figure 5, whose characteristic signals are summarized in Table 17 below.

[0234] For Form C prepared by evaporation, a weight loss of 5.7% up to 100° C. was observed in the TGA curve. DSC data showed two endotherms at 80.9° C. (peak temperature) and 124.9° C. (onset temperature). H NMR in FIG. 6 showed that DCM solvent was observed and the molar ratio of DCM:free form was about 0.04:1 (0.9 wt%). Comparative XRPD pattern showed that no morphological change was observed for Form C after heating to 100° C. and cooling to RT. TGA and DSC results of Form C after heating showed a weight loss of 2.5% up to 100° C. in the TGA curve, while two endotherms at 76.5° C. (peak temperature) and 127.0° C. (onset temperature) were observed in the DSC curve. Variable temperature XRPD (VT-XRPD) was performed on Form C for form identification. XRPD patterns showed that no changes were observed after heating Form C to 100 °C under N2. Given the large weight loss in TGA and no change in XRPD after removal of water / solvent (VT-XRPD), single crystal structure determination confirmed that Form C is a channel hydrate (no change in form after dehydration).

[0235] [Table 17]

[0236] Example 16: Preparation of Form D-IPA Solvate Generally following the procedure described in Example 6, a crystalline form of Compound (I) was obtained via vapor-solid diffusion of Form C of Compound (I) in IPA for about 6 days. As displayed in FIG. 8, XRPD revealed that Example 16 is crystalline, and was therefore designated Form D. Crystalline Form D of Compound (I) is characterized by having an X-ray powder diffraction displaying peaks expressed as 2θ° at about 8.2, 10.4, 12.1, and 16.3 (each time + / - 0.2), which optionally further displays the following peaks expressed as 2θ° at about 19.9 and 21.0 (each time + / - 0.2), and optionally further characterized by a powder X-ray diffraction pattern substantially as illustrated in FIG. 8, whose characteristic signals are summarized in Table 18 below.

[0237] The TGA / DSC curves are shown in Figure 9. Two steps of weight loss of 3.8% up to 85°C and 11.5% from 85°C to 120°C were observed in the TGA curve. The DSC data showed one endotherm at 93°C (onset temperature). 1 H NMR showed that IPA solvent was observed and the molar ratio of IPA:free form was 0.8:1 (11.3 wt%) for form D, which corresponded to the two-step weight loss in TGA ( FIG. 10 ). For form identification, form D was heated to 100° C. and cooled to RT. Comparison of XRPD shows that the D sample was converted to form C after being heated and cooled to RT. According to the results, form D was characterized as an IPA solvate.

[0238] [Table 18]

[0239] Example 17: Preparation of Form E-DCM Solvate 15 mg of starting material (Example 1) was dissolved in 0.4-2.0 mL of DCM in a 3 mL glass vial. The suspension was filtered using a PTFE membrane (0.45 μm pore size) and the filtrate was subjected to evaporation at RT with the vial sealed by Parafilm® (perforated with 3 pinholes). Some solids were observed in the solution. The XRPD pattern of the wet sample (covered with a plastic film during XRPD testing) is shown in FIG. 11 and the form was characterized as Form E. DCM solvate Form E of Compound (I) is characterized by having an X-ray powder diffraction displaying peaks expressed in degrees 2θ at about 9.5, 17.1, 20.1, 20.6 and 24.6 (in each case + / - 0.2), optionally further exhibiting the following peaks expressed in degrees 2θ at about 8.11, 10.0 and 30.1 (in each case + / - 0.2), optionally further characterized by an X-ray powder diffraction substantially as illustrated in Figure 11.

[0240] A characteristic X-ray powder diffraction diagram of the DCM solvate form E of compound (I) can be substantially provided in FIG. 11 and its characteristic signals are summarized in Table 19 below.

[0241] XRPD comparison showed that Form E converts to Form C upon exposure to ambient conditions. Therefore, TGA and DSC characterization was not performed on Form E. According to the results of single crystal structure determination, Form E is a DCM solvate.

[0242] [Table 19]

[0243] Example 18: Preparation of Form F-MeOH Solvate Generally following the procedure described in Example 4, Example 18 can be obtained via slow cooling (50° C. to 5° C.) from a MeOH or MeOH / HO (19:1) solution. Single crystal structure determination results indicate that Form F is a MeOH solvate, and the calculated XRPD pattern of Form F is shown in FIG. 12. MeOH solvate Form F of Compound (I) is characterized by having an X-ray powder diffraction pattern displaying peaks expressed as 2θ degrees at about 9.8, 10.2, 17.8, 22.3, and 24.9 (+ / −0.2 each time), which optionally further displays the following peaks expressed as 2θ degrees at about 20.9, 21.1, and 21.8 (+ / −0.2 each time), optionally further characterized by powder X-ray diffraction substantially as illustrated in FIG. 12.

[0244] A characteristic X-ray powder diffraction diagram of MeOH solvate Form F of Compound (I) can be substantially provided in Figure 12, and its characteristic signals are summarized below in Table 20. Experimental XRPD, TGA and DSC data were not collected for Form F.

[0245] [Table 20]

[0246] [Table 21]

[0247] [Table 22]

[0248] Example 19: Crystalline form interconversion studies To understand the thermodynamic stability relationship between forms A, B and C, slurry competition experiments in HO and n-heptane were carried out at RT and 70°C. Prior to the study, the starting material (form A of compound (I)) was used to saturate the corresponding solvent at RT and 70°C, followed by filtration to obtain a nearly saturated solution. Equal amounts (about 5 mg) of forms A, B and C were weighed and then added to 0.3 mL of the prepared solution to form a new suspension, which was magnetically stirred (about 1000 rpm) at RT / 70°C for about 2 days. As summarized in Table 21, form B was obtained under four conditions, indicating that form B was more thermodynamically stable than forms A and C from RT to 70°C. At room temperature (RT, 25±2° C.) and 70° C., Forms A and C were converted to Form B after 2 days in HO and n-heptane, indicating that Form B was the thermodynamically more stable form among Forms A / B / C from RT to 70° C. The detailed interconversion relationship may be referred to the schematic diagram shown in FIG.

[0249] [Table 23]

[0250] Example 20: Dynamic Vapor Sorption (DVS) To investigate the stability of the solid forms as a function of humidity, DVS isotherm plots of Form A, Form B, and Form C were collected at 25° C. from 0 to 95% RH. All samples were characterized using XRPD after DVS testing and no morphological changes were observed.

[0251] Crystalline Forms A, B, and C of Compound (I) exhibit weight gains of approximately 0.09 weight percent, 0.07 weight percent, and 5.7 weight percent, respectively, as determined by dynamic vapor sorption (DVS) at a temperature of approximately 25 degrees Celsius (+ / - 0.2°C) and in the range of 0 percent to 95 percent relative humidity.

[0252] As used herein, the term "non-hygroscopic" refers to a compound that exhibits a weight gain of less than 0.2 weight percent based on the weight of the compound when measured at about 25 degrees Celsius (+ / - 0.2°C) in the range of 0 to 95 percent relative humidity. Thus, these results demonstrate that crystalline Forms A and B of Compound (I) are non-hygroscopic.

[0253] Example 21: Physical and Chemical Stability To evaluate the physical and chemical stability, Form A, Form B and Form C were stored at three conditions (40° C. / 75% RH; 25° C. / 60% RH; and 60° C.) for 2 and 4 weeks. All samples were characterized using XRPD and HPLC. XRPD results showed that there was no observable morphological change. HPLC results showed that no significant HPLC purity change was observed.

[0254] Example 22: Kinetic Solubility Kinetic solubility studies of Forms A, B, and C were performed in biorelevant media (SGF, FaSSIF, and FeSSIF) and HO at 37°C. Solids were suspended in FaSSIF, FeSSIF, SGF, and HO at a target concentration of approximately 10 mg / mL. The suspensions were agitated in a rotary incubator at 25 rpm (incubator set at 37°C) for 1, 4, and 24 hours. At each time point, 1 mL of the suspension was removed with a pipette, centrifuged at 25000 rpm (3 min), and filtered through a 0.45 μm membrane to obtain the supernatant for HPLC solubility and pH studies. The residual solids were analyzed by XRPD. No morphological changes were observed for Forms A and B after kinetic solubility studies in biorelevant media or HO, but the sample of Form C converted to Form A after the solubility studies. The solubilities of Forms A / B / C are summarized in Tables 22-24.

[0255] [Table 24]

[0256] [Table 25]

[0257] [Table 26]

[0258] Example 23: Equilibrium Solubility The equilibrium solubility of Form B was measured in eight pH buffers (i.e., pH 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0) at RT for 24 hours. The solids were suspended in the pH buffers at a target concentration of approximately 10 mg / mL. The suspensions were slurried (1000 rpm) at RT for 24 hours, then centrifuged at 20000 rpm (2 min) and filtered through a 0.45 μm membrane to obtain the supernatant for HPLC solubility and pH testing. The residual solids were analyzed by XRPD. No morphological changes were observed for Form B after solubility evaluation in the pH buffers.

[0259] Example 24: Single crystal structure determination of Form B Suitable single crystals with good diffraction quality were selected from the rod-shaped crystal samples (Example 14), mounted on Mylar loops in random orientation, and immersed in a nitrogen stream at 175 K. Preliminary examination and data collection were performed on a Bruker D8 VENTURE diffractometer (Mo / Kα radiation, λ=0.71073 Å) and analyzed with the APEX3 software package.

[0260] The lattice parameters and orientation matrices for data collection were obtained and refined (least-squares refinement) by SAINT (Bruker, V8.37A) software using set angles of 9086 reflections in the range of 2.217°<θ<27.401°. Data were collected at 175 K up to a maximum diffraction angle (θ) of 27.549°. The data set is 99.30% complete up to 27.549° in θ, with an average I / σ of 15.3 and a D min (Mo) of 0.77 Å.

[0261] A multiple scan absorption correction was performed using SADABS-2014 / 5 (Bruker, 2014 / 5). wR2(int) was 0.1401 before correction and 0.0825 after correction. The absorption coefficient μ of this material is 0.100 mm at this wavelength ( / .: = 0.71073 Å). -1 where the minimum and maximum transmittance are 0.5818 and 0.7456. The intensities of the equivalent reflections were averaged. The agreement rate of the average was 5.22% based on the intensity.

[0262] Structure,ShelXT 1 Solved in space group P21 by Intrinsic Phasing using the structure solver OLEX2 3 ShelXL included in 2 (Sheldrick, 2015) Refined by least-squares using the refinement package version 2017 / 1. All non-hydrogen atoms were refined anisotropically. Hydrogen atom positions were freely refined according to the Fourier map.

[0263] The crystal system is monoclinic and the space group is P21. The lattice parameters are a = 5.0418(8) Å, b = 15.320(3) Å, c = 11.599(2) Å, α = 90°, β = 98.383(5)°, γ = 90°, and V = 886.3(3) Å. 3 The formula weight is 378.39 g mol at Z=2. -1 and 1.418 g cm -3 The calculated densities are given in Table 25.

[0264] [Table 27]

[0265] A thermal ellipsoid plot of the compound in the crystal lattice is shown in Figure 14. The hydrogen bonds in the single crystal structure are shown in Figure 15 and Table 26. The calculated XRPD generated from the single crystal structure data and the experimental XRPD pattern of the single crystal sample are consistent with the Form B authentic form of Compound (I) shown in Figure 16.

[0266] [Table 28]

[0267] Example 25: Single crystal structure determination of Form E Suitable single crystals with good diffraction quality were selected from the block crystal samples and analyzed by single crystal X-ray diffraction.

[0268] Lattice parameters and orientation matrices for data collection were obtained and refined (least-squares refinement) by SAINT (Bruker, V8.37A, 2013 and later) software using set angles of 4176 reflections in the range of 2.907°<θ<24.230°. Data were collected up to a maximum diffraction angle (θ) of 27.506° at 175 K. The data set is 98.4% complete up to 27.506° in θ, with an average I / σ of 7.2 and D min(Mo) of 0.77 Å.

[0269] Frames were integrated in SAINT (Bruker, V8.37A, 2013 and later). A total of 14827 reflections were collected, of which 4858 were unique. Lorentzian and polarization corrections were applied to the data. Multiscan absorption correction was performed using SADABS-2014 / 5 (Bruker, 2014 / 5). wR2(int) was 0.1189 before correction and 0.0837 after correction. The absorption coefficient μ of this material is 0.337 mm at this wavelength ( / .:=0.71073 Å). -1 where the minimum and maximum transmittance are 0.5036 and 0.7456. The intensities of the equivalent reflections were averaged. The agreement rate of the average was 8.52% based on the intensity.

[0270] Structure,ShelXT 1 The structure was solved in space group P212121 by Intrinsic Phasing using the structure solver OLEX2 3 ShelXL included in 2(Sheldrick, 2015) Refinement was by least-squares using the refinement package version 2017 / 1. All non-hydrogen atoms were refined anisotropically. The positions of hydrogen atoms present on carbon atoms were calculated geometrically and refined using a riding model, whereas hydrogen atoms present on nitrogens were refined freely according to the Fourier map.

[0271] The structure of the crystal was successfully determined. The crystal system is orthorhombic and the space group is P212121. The lattice parameters are a = 9.5908(13) Å, b = 10.2639(16) Å, c = 21.863(3) Å, α = 90°, β = 90°, γ = 90°, V = 2152.2(5) Å. 3 The formula weight is 463.32 g mol at Z=4. -1 and 1.430 g cm -3 The calculated densities are given in Table 27.

[0272] The asymmetric unit of the single crystal structure consists of one molecule of compound (I) and one molecule of DCM solvent, indicating that the crystal is a DCM solvate of compound (I). A thermal ellipsoid drawing of the molecules of compound (I) and the DCM solvent molecule in the crystal structure is shown in Figure 17. The single crystal structure determination confirmed the absolute configuration assignment (R / S) of the chiral atom in the compound as C11(S). The calculated XRPD generated from the single crystal structure data is shown in Figure 18.

[0273] [Table 29]

[0274] conclusion As shown by the above DSC and DVS results, anhydrous crystalline Forms B and A have higher melting points and lower hygroscopicity compared to Forms C, D, E and F. The slurry competition experiments shown above indicate that Forms A and C converted to Form B after 2 days of slurry in HO and n-heptane, and Form B was the more thermodynamically stable form among Forms A, B and C from RT to 70° C.

[0275] Therefore, the anhydrous crystalline form B of compound (I) is considered to be the most suitable product for use and storage on an industrial scale. Indeed, the anhydrous crystalline form B of compound (I) is not hygroscopic and is stable (melting point value) as shown above.

Claims

1. (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide form A; (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide form B; (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide form C; (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide form D; (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide form E; and Form F of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide A crystalline form selected from the group consisting of:

2. A crystalline form of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide characterized as Form A.

3. 3. The crystalline form of claim 2, having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes 3, 4, 5, 6, 7 or more peaks in degrees 2θ selected from the group consisting of 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0±0.2°.

4. 3. The crystalline form of claim 2 having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.

5. 3. The crystalline form of claim 2, characterized by a differential scanning calorimetry (DSC) curve having an onset at about 186.7°C and an endothermic peak at 188.9°C.

6. a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 1; b) an X-ray powder diffraction (XRPD) pattern derived using Cu (Kα) radiation having peaks in degrees 2θ at about 6.9, 13.0, 16.6, and 23.4±0.2°; c) a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 2; d) A differential scanning calorimetry (DSC) thermogram with three endothermic events with an onset at about 186.7° C. and a peak at about 188.9° C.; e) a thermogravimetric analysis (TGA) pattern substantially identical to that shown in FIG. 2; f) a thermogravimetric analysis (TGA) pattern having a loss of about 1.0% w / w from about 27.8° C. to about 150° C.; or g) Combinations thereof 3. The crystalline form of claim 2, characterized as having one or more of:

7. A crystalline form of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide characterized as Form B.

8. 8. The crystalline form of claim 7 having an X-ray powder diffraction pattern comprising peaks in terms of degrees 2θ at about 9.6 and 16.4±0.2 degrees.

9. 8. The crystalline form of claim 7, having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes 3, 4, 5, 6 or more peaks in degrees 2θ selected from the group consisting of 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8±0.2°.

10. 8. The crystalline form of claim 7 having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.

11. 8. The crystalline form of claim 7, characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at 189.2°C and an endotherm peak at 191.9°C.

12. a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 3; b) an X-ray powder diffraction (XRPD) pattern derived using Cu (Kα) radiation having peaks in degrees 2θ at about 9.6, 11.5, 16.4, 19.2, and 23.8±0.2 degrees; c) a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG. 4; d) A differential scanning calorimetry (DSC) thermogram with three endothermic events with an onset at about 189.2° C. and a peak at about 191.9° C.; e) a thermogravimetric analysis (TGA) pattern substantially identical to that shown in FIG. 4; f) a thermogravimetric analysis (TGA) pattern having a loss of about 1.0% w / w from about 23.8° C. to about 150° C.; or g) Combinations thereof 8. The crystalline form of claim 7, characterized as having one or more of:

13. A crystalline form of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide characterized as Form C.

14. 14. The crystalline form of claim 13, having an X-ray powder diffraction pattern derived using Cu(Kα) radiation that includes 3, 4, 5, 6 or more peaks in degrees 2θ selected from the group consisting of 9.8, 10.2, 14.8, 15.2, 18.1, 20.4, and 22.3±0.2°.

15. 14. The crystalline form of claim 13 having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.

16. 14. The crystalline form of claim 13, characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at 124.9°C and an endotherm peak at 131.3°C.

17. a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 5; b) an X-ray powder diffraction (XRPD) pattern derived using Cu (Kα) radiation having peaks in degrees 2θ at about 9.8, 10.2, 14.8, 15.2, and 20.4±0.2 degrees; c) a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG. 7; d) A differential scanning calorimetry (DSC) thermogram with three endothermic events with an onset at about 124.9° C. and a peak at about 131.3° C.; e) a thermogravimetric analysis (TGA) pattern substantially identical to that shown in FIG. 7; f) a thermogravimetric analysis (TGA) pattern having a loss of about 5.7% w / w from about 22.4° C. to about 100° C.; or g) Combinations thereof 14. The crystalline form of claim 13, characterized as having one or more of:

18. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 17 and a pharma- ceutically acceptable excipient.

19. 19. The pharmaceutical composition of claim 18, further comprising one or more crystalline forms selected from the group consisting of compound (I) Form A, compound (I) Form B, compound (I) Form C, and a pharma- ceutically acceptable excipient.

20. 20. A method of treating a disease or disorder mediated by RIPK1 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 17.

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