Solid form of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-benzylacetamide

Abstract

The present application provides a solid form of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide and methods for preparing and using same.

Description

[Technical Field]

[0001] Related applications This application claims priority and benefits of U.S. Provisional Application No. 62 / 555,390, filed on 7 September 2017, the entirety of which is incorporated herein by reference. [Background technology]

[0002] background Signal transduction is the process by which cells convert one type of signal or stimulus into another. Protein kinases are involved in signal transduction. Tyrosine kinases are enzymes that can transfer phosphate groups from ATP to tyrosine residues in proteins through a process called phosphorylation, which is a crucial mechanism in signal transduction for regulating enzyme activity. Because kinases are involved in regulating a wide range of normal cellular signaling pathways, they are thought to play a role in many diseases and disorders. Approximately 50% of known oncogene products are protein tyrosine kinases (PTKs), and their kinase activity has been shown to induce cell transformation. For this reason, regulating the kinase signaling cascade may be an important means of treating or preventing diseases and disorders.

[0003] Various known protein kinase inhibitors have a variety of therapeutic applications. One promising therapeutic application of protein kinase inhibitors is as anticancer agents. 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-benzylacetamide is a tyrosine kinase inhibitor that can modulate the kinase cascade. The free base compound is disclosed in U.S. Patent No. 7,300,931 (Patent Document 1).

[0004] The polymorphism of a compound affects many of its properties, including solubility, hygroscopicity, chemical reactivity, and stability. Many of the inconsistencies encountered in drug performance can be attributed to polymorphism. Regardless of the importance of polymorphism, methods for predicting the existence of possible polymorphs of a compound and the conditions under which they can form are unreliable, and methods for producing polymorphs often fail to consistently and reliably generate them.

[0005] Therefore, there is an urgent need to discover a solid form of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-benzylacetamide that exhibits desirable physicochemical properties. This invention addresses this need. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] U.S. Patent No. 7,300,931 [Overview of the project]

[0007] overview This application has the following structure: The solid form of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-benzylacetamide (compound A) is provided at TIFF0007843116000001.tif28128.

[0008] In one embodiment, the present application provides a crystalline form of compound A. In one embodiment, the present application provides a polymorph of compound A.

[0009] In one embodiment, the present invention provides a morphology A polymorph of compound A characterized by an X-ray powder diffraction ("XRPD") pattern containing peaks at approximately 4.3, 17.0, and 21.1°2θ using Cu Kα irradiation. In one embodiment, morphology A is characterized by an XRPD pattern substantially similar to that described in Figures 1, 5, 7, 9, 11, 13, or 18. In one embodiment, morphology A is evident by PLM and appears as birefringent particles as shown in Figure 23.

[0010] In one embodiment, the morphology A polymorph is characterized by a single endothermic event that begins at approximately 124°C to approximately 135°C or approximately 135°C to approximately 139°C, as measured by DSC. In one embodiment, the morphology A polymorph is characterized by multiple endothermic events that begin at approximately 124°C to approximately 135°C and approximately 135°C to approximately 139°C, as measured by DSC. In one embodiment, the morphology A polymorph is characterized by a TGA or DSC thermogram substantially similar to that described in Figure 12 or 14.

[0011] In one embodiment, the present application provides a morphology B polymorph of compound A, characterized by an XRPD pattern containing peaks at approximately 6.4, 19.3 and 19.9°2θ using Cu Kα irradiation. In one embodiment, the morphology B polymorph is characterized by an XRPD pattern substantially similar to that described in Figures 1, 6, 8, 10, 15, or 20. In one embodiment, morphology B appears as a birefringent particle clearly visible by PLM, as shown in Figure 24.

[0012] In one embodiment, the morphology B polymorph is characterized by an endothermic event that begins at approximately 133°C to approximately 138°C, as measured by DSC. In one embodiment, the morphology B polymorph is characterized by a TGA or DSC thermogram substantially similar to that shown in Figure 16.

[0013] In one embodiment, the present application provides a morphology C polymorph of compound A, characterized by an XRPD pattern containing peaks at approximately 7.9, 17.2, 17.6, and 20.3°2θ using Cu Kα irradiation. In one embodiment, the morphology C polymorph is characterized by an XRPD pattern substantially similar to that described in Figure 1 or 2. In one embodiment, morphology C is evident by PLM and appears as a birefringent particle shown in Figure 25.

[0014] In one embodiment, the morphology C polymorph is characterized by an endothermic event that begins at approximately 136°C to approximately 140°C when measured by DSC. In one embodiment, the morphology C polymorph is characterized by a TGA or DSC thermogram substantially similar to that shown in Figure 3.

[0015] In one embodiment, the present application provides an amorphous form of compound A.

[0016] The present application also provides a pharmaceutical composition comprising one of the solid forms of compound A described herein (e.g., any of forms A, B, C, and amorphous forms) and a pharmaceutically acceptable carrier or excipient.

[0017] The present application also provides a method for treating or preventing a disease or condition (e.g., a cell proliferation disorder) in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role, comprising administering a therapeutically effective amount of a composition comprising any one of the solid forms of compound A described herein to a subject who needs to be treated or prevented from having a disease or condition (e.g., a cell proliferation disorder) in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role.

[0018] This application also provides a solid form of compound A described herein for treating or preventing diseases or conditions in which tyrosine kinases (e.g., Src tyrosine kinases) play a role (e.g., cell proliferation disorders) in subjects where treatment or prevention of such diseases or conditions is required.

[0019] The present application also provides a solid form of compound A described herein for use in the manufacture of a pharmaceutical for the treatment or prevention of a disease or condition in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role (e.g., a cell proliferation disorder) in a subject requiring treatment or prevention of such a disease or condition in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role (e.g., a cell proliferation disorder).

[0020] This application also provides for the use of compound A described herein in solid form in the manufacture of a pharmaceutical for the treatment or prevention of a disease or condition in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role (e.g., a cell proliferation disorder) in a subject requiring treatment or prevention of such a disease or condition in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role (e.g., a cell proliferation disorder).

[0021] Unless otherwise defined, all technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification, unless the context clearly dictates otherwise, the singular form also includes the plural form. In the practice or testing of the present application, methods and materials similar or equivalent to those described herein may be used, but suitable methods and materials are described below. All publications, patent applications, patents, and other references cited herein are incorporated by reference. The references cited herein do not admit that they are prior art to the present application. In case of conflict, the specification including the definitions shall prevail. Further, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0022] Other features and advantages of the present disclosure will become apparent from the following detailed description and the claims. [Invention 1001] ]> A polymorph of compound A, selected from form A, form B, and form C: TIFF0007843116000002.tif29128 The aforementioned form A is characterized by having X-ray powder diffraction peaks at approximately 4.3, 17.0, and 21.1°2θ when irradiated with Cu Kα, The aforementioned form B is characterized by having X-ray powder diffraction peaks at approximately 6.4, 19.3 and 19.9°2θ using Cu Kα irradiation, and The aforementioned form C is characterized by having X-ray powder diffraction peaks at approximately 7.9, 17.2, and 17.6°2θ when irradiated with Cu Kα. A polymorph of compound A. [Invention 1002] A polymorph of the present invention 1001, characterized by having X-ray powder diffraction peaks at approximately 4.3, 6.4, 8.6, 12.7, 17.0 and 21.1°2θ using Cu Kα irradiation. [Invention 1003] A polymorph of the 1001 of the present invention characterized by having an X-ray powder diffraction pattern substantially similar to that described in Figures 1, 5, 7, 9, 11, 13, or 18. [Invention 1004] A polymorph of morphology A of the present invention, characterized by an endothermic event that begins at approximately 124°C to approximately 135°C when measured by DSC. [Invention 1005] A polymorph of morphology A of the present invention, characterized by an endothermic event that begins at approximately 135°C to approximately 139°C when measured by DSC. <0><000122> A polymorph of the 1001 of the present invention, characterized by endothermic events that begin at approximately 124°C to approximately 135°C and approximately 135°C to approximately 139°C, as measured by DSC. [Invention 1007] A polymorph of morphology A of the present invention, characterized by a DSC thermogram substantially similar to that described in Figure 12 or 14. [Invention 1008] A polymorph of the present invention 1001, characterized by a weight loss of approximately 0.36% between approximately 33°C and approximately 150°C, as measured by TGA. [Invention 1009] A polymorph B of the present invention 1001, characterized by having X-ray powder diffraction peaks at approximately 6.4, 7.2, 19.3, 19.9, 21.6, 22.1, and 22.6°2θ using Cu Kα irradiation. [Invention 1010] A polymorph B of the present invention 1001, characterized by having an X-ray powder diffraction pattern substantially similar to that described in Figures 1, 6, 8, 10, 15, or 20. [Invention 1011] A polymorph B of the present invention 1001, characterized by an endothermic event that begins at approximately 133°C to approximately 138°C, as measured by DSC. [Invention 1012] A morphological B polymorph of the present invention 1001, characterized by a DSC thermogram substantially similar to that shown in Figure 16. [Invention 1013] The morph B polymorph of the present invention 1001 is characterized by a weight loss of approximately 0.20% between approximately 33°C and approximately 150°C, as measured by TGA. [Invention 1014] Morphological C polymorph of the present invention 1001, characterized by having X-ray powder diffraction peaks at approximately 5.8, 7.9, 8.7, 17.2, and 17.6°2θ using Cu Kα irradiation. [Invention 1015] A polymorph C of the present invention 1001 characterized by having an X-ray powder diffraction pattern substantially similar to that described in Figure 1 or 2. [Invention 1016] The morphological C polymorph of the present invention 1001 is characterized by an endothermic event that begins at approximately 136°C to approximately 140°C, as measured by DSC. [Invention 1017] Morphological C polymorph of the present invention 1001, characterized by a DSC thermogram substantially similar to that shown in Figure 3. [Invention 1018] The morphological C polymorph of the present invention 1001 is characterized by a weight loss of approximately 0.18% between approximately 33°C and approximately 150°C, as measured by TGA. [Invention 1019] A pharmaceutical composition comprising a polymorph of the present invention 1001 and a pharmaceutically acceptable carrier or excipient. [Invention 1020] A method for preparing the morphological A polymorph of the present invention 1001, Diffusing the vapor of the reverse solvent into a concentrated solution of compound A in methanol or ethanol, Slowly cooling a solution of compound A in isopropanol, a mixture of THF and water, or a mixture of acetone and MTBE, or Adding a reverse solvent to a solution of compound A in chloroform, methanol, acetone, tetrahydrofuran, dioxane, ethanol, 2-Me-THF, ethyl acetate, or dichloromethane. Methods that include... [Invention 1021] A method for preparing the morph B polymorph of the present invention 1001, To turn compound A into a slurry in chloroform, Diffusing the vapor of the reverse solvent into a concentrated solution of compound A in methanol or chloroform, Slowly cool a solution of compound A in acetone, isopropyl acetate, 2-Me-THF, ethyl acetate, acetonitrile, or a mixture of chloroform and heptane, or Adding a reverse solvent to a solution of compound A in chloroform, methanol, acetone, or acetonitrile. Methods that include... [Invention 1022] A method for preparing the morphological C polymorph of the present invention 1001, Compound A is turned into a muddy substance in methanol, ethanol, isopropanol, acetone, MIBK, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-Me-THF, dioxane, MTBE, acetonitrile, dichloromethane, chloroform, toluene, heptane, water, or a mixture thereof. Interacting the solvent vapor with the solid form of compound A, Diffusing the vapor of the reverse solvent into a concentrated solution of compound A in dichloromethane, Slowly cooling a solution of compound A in toluene, MIBK, or a mixture of methanol and toluene, or Crystallization of a solution of compound A in a solvent in the presence of a polymer. Methods that include... [Invention 1023] A method for treating or preventing a disease or condition in which Src tyrosine kinase plays a role, comprising administering a polymorph of the present invention 1001 to a subject who requires treatment or prevention of a disease or condition in which Src tyrosine kinase plays a role. [Invention 1024] A polymorph of the present invention 1001 for treating or preventing diseases or conditions in which Src tyrosine kinase plays a role in subjects requiring treatment or prevention of diseases or conditions in which Src tyrosine kinase plays a role. [Invention 1025] A polymorph of Invention 1001 for use in the manufacture of a pharmaceutical for the treatment or prevention of a disease or condition in which Src tyrosine kinase plays a role in a subject requiring treatment or prevention of a disease or condition in which Src tyrosine kinase plays a role. [Invention 1026] Use of polymorph of Invention 1001 in the manufacture of a pharmaceutical for the treatment or prevention of a disease or condition in which Src tyrosine kinase plays a role in a subject requiring treatment or prevention of a disease or condition in which Src tyrosine kinase plays a role. [Brief explanation of the drawing]

[0023] [Figure 1] The XRPD overlays of morphologies A, B, and C, generated from the aforementioned screening, are described below. [Figure 2] The XRPD for form C is described. [Figure 3] This document describes the DSC / TGA overlay for form C. [Figure 4] This section describes the XRPD overlay of a mixture of morphologies C and B obtained from solvent-based sludge experiments. [Figure 5] This section describes the XRPD overlay of morphology A obtained from liquid vapor diffusion experiments. [Figure 6] This section describes the XRPD overlay of form B obtained from liquid vapor diffusion experiments. [Figure 7] The XRPD overlay of morphology A obtained from the slow cooling experiment is described below. [Figure 8] The XRPD overlay of morphology B obtained from the slow cooling experiment is described below. [Figure 9] The XRPD overlay of morphology A obtained from the reverse solvent addition experiment is described below. [Figure 10] This document describes the mixture of form A and form B (CHCl3 / IPA) obtained from the reverse solvent addition experiment, as well as the XRPD overlay of form B. [Figure 11] The XRPD image of morphology A after air drying is described. [Figure 12] The DSC / TGA overlay of morphology A after air drying is described. [Figure 13] Describe the XRPD for form A (wet cake, air-dried, and vacuum-dried). [Figure 14] The DSC thermogram of morphology A after vacuum drying is described. [Figure 15] The XRPD for form B is described. [Figure 16] The DSC / TGA overlay for form B is described below. [Figure 17] The DVS values ​​for Form A at 25°C and a maximum relative humidity (RH) of 95% are listed. [Figure 18] XRPD overlays of morphology A before DVS and morphology A after DVS experiments at 25°C and up to 95% RH are described. [Figure 19] The DVS values ​​for morphology B at 25°C and a maximum RH of 95% are described. [Figure 20] XRPD overlays of morphology B before DVS and morphology B after DVS experiments at 25°C and up to 95% RH are described. [Figure 21] The DVS values ​​for morphology C at 25°C and a maximum RH of 95% are described. [Figure 22] XRPD overlays of morphology C before DVS and morphology B after DVS experiments at 25°C and up to 95% RH are described. [Figure 23] The PLM image for form A is described. [Figure 24] The PLM image for form B is described. [Figure 25] The PLM image for form C is described. [Figure 26] The XRPD of morphology A under ambient preservation conditions is described. [Figure 27] The XRPD of form A under storage conditions of 25°C / 60%RH is described. [Figure 28] The XRPD of form A under storage conditions of 40°C / 75%RH is described. [Figure 29]The XRPD of form A under storage conditions of 55°C / 75%RH is described. [Figure 30] The XRPD of morphology B under ambient preservation conditions is described. [Figure 31] The XRPD of form B under storage conditions of 25°C / 60%RH is described. [Figure 32] The XRPD of form B under storage conditions of 40°C / 75%RH is described. [Figure 33] The XRPD for form B under storage conditions of 55°C / 75%RH is described. [Figure 34] The XRPD of morphology C under ambient preservation conditions is described. [Figure 35] The XRPD for morphology C under storage conditions of 25°C / 60%RH is described. [Figure 36] The XRPD of morphology C under storage conditions of 40°C / 75%RH is described. [Figure 37] The XRPD of morphology C under storage conditions of 55°C / 75%RH is described. [Modes for carrying out the invention]

[0024] Detailed explanation solid form This application has the following structure: The solid form of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-benzylacetamide (compound A) is provided at TIFF0007843116000003.tif28128.

[0025] In one embodiment, the present application provides a crystalline form of compound A. In one embodiment, the present application provides a polymorph of compound A. In one embodiment, the present application provides a crystalline form of the anhydrous compound A. In one embodiment, the present application provides a polymorph of the anhydrous compound A.

[0026] Form A In one embodiment, the present invention provides a morphology A polymorph ("morphology A") of compound A, characterized by an X-ray powder diffraction ("XRPD") pattern containing peaks at approximately 4.3, 17.0, and 21.1°2θ using Cu Kα irradiation. In one embodiment, morphology A is characterized by an XRPD pattern containing peaks at approximately 4.3, 6.4, 8.6, 12.7, 17.0, and 21.1°2θ using Cu Kα irradiation. In one embodiment, morphology A is characterized by an XRPD pattern containing peaks at roughly the positions shown in the table below.

[0027] (Table 1) XRPD peak list for morphology A TIFF0007843116000004.tif114148

[0028] In one embodiment, morphology A is characterized by an XRPD pattern substantially similar to that described in Figures 1, 5, 7, 9, 11, 13, or 18. In one embodiment, morphology A is characterized by an XRPD pattern substantially similar to that described in Figure 11.

[0029] In one embodiment, morphology A appears as a birefringent particle that is clearly visible by PLM. In one embodiment, morphology A appears as shown in Figure 23.

[0030] In one embodiment, morphology A is characterized by a single endothermic event that begins at approximately 124°C to approximately 135°C or approximately 135°C to approximately 139°C when measured by DSC. In one embodiment, morphology A is characterized by multiple endothermic events that begin at approximately 124°C to approximately 135°C and approximately 135°C to approximately 139°C when measured by DSC. In one embodiment, morphology A is characterized by an endothermic event that begins at approximately 124°C to approximately 135°C when measured by DSC. In one embodiment, morphology A is characterized by an endothermic event that begins at approximately 128°C when measured by DSC. In one embodiment, morphology A is characterized by an endothermic event that begins at approximately 135°C to approximately 139°C when measured by DSC. In one embodiment, morphology A is characterized by an endothermic event that begins at approximately 138°C when measured by DSC. In one embodiment, morphology A is characterized by a series of endothermic events that begin at approximately 128°C and approximately 138°C, as measured by DSC. In one embodiment, morphology A is characterized by a DSC thermogram substantially similar to that shown in Figure 12 or 14.

[0031] In one embodiment, form A exhibits a weight loss of approximately 0.36% at temperatures ranging from approximately 33°C to approximately 150°C, as measured by TGA.

[0032] In one embodiment, morphology A is non-hygroscopic. In one embodiment, morphology A exhibits non-hygroscopicity at 25°C to 45°C in 0 to 80% RH (e.g., less than 0.2% w / w water uptake). In one embodiment, morphology A exhibits DVS isotherms substantially similar to those shown in Figure 17 at 25°C and up to 95% RH. In one embodiment, the XRPD pattern of morphology A does not change after exposure to a DVS experiment at 25°C and up to 95% RH. In one embodiment, the XRPD pattern of morphology A after DVS at 25°C and up to 95% RH is substantially similar to that shown in Figure 18.

[0033] In one embodiment, form A is stable under various storage conditions. In one embodiment, form A is stable at approximately 20°C to approximately 250°C, approximately 20°C to approximately 200°C, approximately 20°C to approximately 180°C, approximately 20°C to approximately 160°C, approximately 20°C to approximately 140°C, approximately 20°C to approximately 120°C, approximately 20°C to approximately 100°C, approximately 20°C to approximately 80°C, approximately 20°C to approximately 60°C, or approximately 20°C to approximately 40°C for at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, or 1 year at approximately 60%RH to approximately 98%RH (e.g., 75%RH or 96%RH). In one embodiment, form A is stable under ambient conditions for at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, or 1 year. In one embodiment, form A is stable at 20-90°C / 60-98%RH for at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, or 1 year. In one embodiment, form A is stable at 25°C / 60%RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks. In one embodiment, form A is stable at 40°C / 75%RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks. In one embodiment, form A is stable at 55°C / 75%RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks. In one embodiment, HPLC area percentage purity (LCAP) results, as shown in the table below, do not show a significant decrease in area percentage purity for form A at specified time points over an 8-week study under selected conditions.

[0034] (Table 2) HPLC results for morphology A TIFF0007843116000005.tif45170

[0035] In one embodiment, form A shows no change in physical form under ambient conditions for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 26. In one embodiment, form A shows no change in physical form under 25°C / 60%RH for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 27. In one embodiment, form A shows no change in physical form under 40°C / 75%RH for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 28. In one embodiment, form A shows no change in physical form under 55°C / 75%RH for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 29.

[0036] In one embodiment, form A is soluble in aqueous solution. In one embodiment, form A dissolves completely in aqueous solution (e.g., water) at room temperature (>20 mg / ml). In one embodiment, form A has low thermodynamic water solubility (e.g., less than 1.5 mg / ml). In one embodiment, form A forms a gel after dissolution.

[0037] In one embodiment, form A is an anhydrous substance.

[0038] In one embodiment, form A is prepared by liquid vapor diffusion. In one embodiment, form A is prepared by diffusing the vapor of the reverse solvent into a concentrated solution of compound A in a solvent. In one embodiment, the solvent is methanol or ethanol, and the reverse solvent is hexane.

[0039] In one embodiment, form A is prepared by slowly cooling a solution of compound A.

[0040] In one embodiment, form A is formed by cooling a solution of compound A in isopropanol. In one embodiment, form A is formed by slowly cooling a solution of compound A in a mixture of solvents. In one embodiment, form A is formed by slowly cooling a solution of compound A in a mixture of THF and water. In one embodiment, THF and water are mixed in a ratio of about 1:3. In one embodiment, form A is formed by slowly cooling a solution of compound A in a mixture of acetone and MTBE. In one embodiment, acetone and MTBE are mixed in a ratio of about 1:3.

[0041] In one embodiment, form A is prepared by reverse solvent addition. In one embodiment, form A is formed when a reverse solvent is added to a solution of compound A in chloroform, methanol, acetone, tetrahydrofuran, dioxane, ethanol, 2-Me-THF, ethyl acetate, or dichloromethane. In one embodiment, the reverse solvent is selected from the group consisting of MTBE, water, heptane, isopropanol, MIBK, isopropyl acetate, and toluene. In one embodiment, form A is formed when chloroform is the solvent and MTBE is the reverse solvent; when methanol is the solvent and water is the reverse solvent; when acetone is the solvent and heptane is the reverse solvent; when tetrahydrofuran is the solvent and MTBE is the reverse solvent; when dioxane is the solvent and water is the reverse solvent; when dioxane is the solvent and MIBK is the reverse solvent; when ethanol is the solvent and isopropyl acetate is the reverse solvent; when 2-Me-THF is the solvent and toluene is the reverse solvent; when ethyl acetate is the solvent and MIBK is the reverse solvent; or when dichloromethane is the solvent and MIBK is the reverse solvent. In one embodiment, a mixture of form A and form B is formed when chloroform is the solvent and isopropanol is the reverse solvent.

[0042] Form B In one embodiment, the present application provides a morphology B polymorph ("morphology B") of compound A characterized by an XRPD pattern containing peaks at approximately 6.4, 19.3, and 19.9°2θ using Cu Kα irradiation. In one embodiment, morphology B is characterized by an XRPD pattern containing peaks at approximately 6.4, 7.2, 19.3, 19.9, 21.6, 22.1, and 22.6°2θ using Cu Kα irradiation. In one embodiment, morphology B is characterized by an XRPD pattern containing peaks at roughly the positions shown in the table below.

[0043] (Table 3) XRPD peak list for morphology B TIFF0007843116000006.tif95148

[0044] In one embodiment, form B is characterized by an XRPD pattern substantially similar to that described in Figures 1, 6, 8, 10, 15, or 20. In one embodiment, form B is characterized by an XRPD pattern substantially similar to that described in Figure 15.

[0045] In one embodiment, morphology B appears as a birefringent particle that is clearly visible by PLM. In one embodiment, morphology A appears as shown in Figure 24.

[0046] In one embodiment, morphology B is characterized by an endothermic event that begins at approximately 133°C to approximately 138°C when measured by DSC. In one embodiment, morphology B is characterized by an endothermic event that begins at approximately 136°C when measured by DSC. In one embodiment, morphology B is characterized by a DSC thermogram substantially similar to that shown in Figure 16.

[0047] In one embodiment, form B exhibits a weight loss of approximately 0.20% at temperatures ranging from approximately 33°C to approximately 150°C, as measured by TGA.

[0048] In one embodiment, form B is nonhygroscopic. In one embodiment, form B exhibits nonhygroscopicity at 0–80% RH and 25°C–45°C (e.g., water uptake less than 0.2% w / w). In one embodiment, form B exhibits DVS isotherms substantially similar to those shown in Figure 19 at 25°C and up to 95% RH. In one embodiment, the XRPD pattern of form B does not change after exposure to a DVS experiment at 25°C and up to 95% RH. In one embodiment, the XRPD pattern of form B after DVS at 25°C and up to 95% RH is substantially similar to that shown in Figure 20.

[0049] In one embodiment, form B is stable under various storage conditions. In one embodiment, form B is stable at approximately 20°C to approximately 250°C, approximately 20°C to approximately 200°C, approximately 20°C to approximately 180°C, approximately 20°C to approximately 160°C, approximately 20°C to approximately 140°C, approximately 20°C to approximately 120°C, approximately 20°C to approximately 100°C, approximately 20°C to approximately 80°C, approximately 20°C to approximately 60°C, or approximately 20°C to approximately 40°C for at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, or 1 year at approximately 60%RH to approximately 98%RH (e.g., 75%RH or 96%RH). In one embodiment, form B is stable under ambient conditions for at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, or 1 year. In one embodiment, form B is stable at 20-90°C / 60-98%RH for at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, or 1 year. In one embodiment, form B is stable at 25°C / 60%RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks. In one embodiment, form B is stable at 40°C / 75%RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks. In one embodiment, form B is stable at 55°C / 75%RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks. In one embodiment, HPLC area percentage purity (LCAP) results, as shown in the table below, do not show a significant decrease in area percentage purity for form B at specified time points over an 8-week study under selected conditions.

[0050] (Table 4) HPLC results for morphology B TIFF0007843116000007.tif44170

[0051] In one embodiment, form B shows no change in physical form under ambient conditions for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 30. In one embodiment, form B shows no change in physical form under 25°C / 60%RH for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 31. In one embodiment, form B shows no change in physical form under 40°C / 75%RH for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 32. In one embodiment, form B shows no change in physical form under 55°C / 75%RH for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 33.

[0052] In one embodiment, form B is soluble in aqueous solution. In one embodiment, form B dissolves completely in aqueous solution (e.g., water) at room temperature (>20 mg / ml). In one embodiment, form B has low thermodynamic water solubility (e.g., less than 1.5 mg / ml). In one embodiment, form B forms a gel after dissolution.

[0053] In one embodiment, form B is an anhydrous substance.

[0054] In one embodiment, form B is prepared by molten compound A in a solvent. In one embodiment, form B is prepared by molten compound A in chloroform. In one embodiment, molten compounding is carried out at room temperature. In one embodiment, molten compounding is carried out using continuous stirring. In one embodiment, molten compound A in chloroform produces a mixture of form B and form C.

[0055] In one embodiment, form B is prepared by liquid vapor diffusion. In one embodiment, form B is prepared by diffusing the vapor of the reverse solvent into a concentrated solution of compound A in a solvent. In one embodiment, a solution of compound A is converted to form B when the solvent is methanol and the reverse solvent is MTBE. In one embodiment, the solvent is chloroform and the reverse solvent is MTBE.

[0056] In one embodiment, form B is prepared by slowly cooling a solution of compound A.

[0057] In one embodiment, form B is formed by cooling a solution of compound A in acetone, isopropyl acetate, 2-Me-THF, ethyl acetate, or acetonitrile. In one embodiment, form B is formed by slowly cooling a solution of compound A in a mixture of solvents. In one embodiment, form B is formed by slowly cooling a solution of compound A in a mixture of chloroform and heptane. In one embodiment, chloroform and heptane are mixed in a ratio of about 1:3. In one embodiment, form B is formed by slowly cooling a solution of compound A in a mixture of dioxane and isopropyl acetate. In one embodiment, dioxane and isopropyl acetate are mixed in a ratio of about 1:3.

[0058] In one embodiment, form B is prepared by reverse solvent addition. In one embodiment, form B is formed when the reverse solvent is added to a solution of compound A in chloroform, methanol, acetone, or acetonitrile. In one embodiment, the reverse solvent is selected from the group consisting of isopropyl acetate, toluene, and isopropanol. In one embodiment, form B is formed when methanol is the solvent and isopropyl acetate is the reverse solvent, when acetone is the solvent and toluene is the reverse solvent, or when acetonitrile is the solvent and isopropanol is the reverse solvent. In one embodiment, a mixture of form A and form B is formed when chloroform is the solvent and isopropanol is the reverse solvent.

[0059] Form C In one embodiment, the present application provides a morphology C polymorph ("morphology C") of compound A characterized by an XRPD pattern containing peaks at approximately 7.9, 17.2, and 17.6°2θ using Cu Kα irradiation. In one embodiment, morphology C is characterized by an XRPD pattern containing peaks at approximately 5.8, 7.9, 8.7, 17.2, and 17.6°2θ using Cu Kα irradiation. In one embodiment, morphology C is characterized by an XRPD pattern containing peaks at roughly the positions shown in the table below.

[0060] (Table 5) XRPD peak list for morphology C TIFF0007843116000008.tif163148

[0061] In one embodiment, form C is characterized by an XRPD pattern substantially similar to that described in Figures 1, 6, 8, 10, or 15. In one embodiment, form C is characterized by an XRPD pattern substantially similar to that described in Figure 1 or Figure 2.

[0062] In one embodiment, morphology C appears as a birefringent particle that is clearly visible in PLM. In one embodiment, morphology A appears as shown in Figure 25.

[0063] In one embodiment, morphology C is characterized by an endothermic event that begins at approximately 136°C to approximately 140°C when measured by DSC. In one embodiment, morphology C is characterized by an endothermic event that begins at approximately 136°C when measured by DSC. In one embodiment, morphology C is characterized by a DSC thermogram substantially similar to that shown in Figure 3.

[0064] In one embodiment, form C exhibits a weight loss of approximately 0.18% at temperatures ranging from approximately 33°C to approximately 150°C, as measured by TGA.

[0065] In one embodiment, morphology C is nonhygroscopic. In one embodiment, morphology C exhibits nonhygroscopicity at 0–80% RH and 25°C–45°C (e.g., water uptake less than 0.2% w / w). In one embodiment, morphology C exhibits DVS isotherms substantially similar to those shown in Figure 21 at 25°C and up to 95% RH. In one embodiment, the XRPD pattern of morphology C does not change after exposure to a DVS experiment at 25°C and up to 95% RH. In one embodiment, the XRPD pattern of morphology C after DVS at 25°C and up to 95% RH is substantially similar to that shown in Figure 22.

[0066] In one embodiment, form C is stable under various storage conditions. In one embodiment, form C is stable at approximately 20°C to approximately 250°C, approximately 20°C to approximately 200°C, approximately 20°C to approximately 180°C, approximately 20°C to approximately 160°C, approximately 20°C to approximately 140°C, approximately 20°C to approximately 120°C, approximately 20°C to approximately 100°C, approximately 20°C to approximately 80°C, approximately 20°C to approximately 60°C, or approximately 20°C to approximately 40°C for at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, or 1 year at approximately 60%RH to approximately 98%RH (e.g., 75%RH or 96%RH). In one embodiment, form C is stable under ambient conditions for at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, or 1 year. In one embodiment, form C is stable at 20-90°C / 60-98%RH for at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, or 1 year. In one embodiment, form C is stable at 25°C / 60%RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks. In one embodiment, form C is stable at 40°C / 75%RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks. In one embodiment, form C is stable at 55°C / 75%RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks. In one embodiment, HPLC area percentage purity (LCAP) results, as shown in the table below, do not show a significant decrease in area percentage purity for form C at specified time points over an 8-week study under selected conditions.

[0067] (Table 6) HPLC results for morphology C TIFF0007843116000009.tif44170

[0068] In one embodiment, morphology C does not show any change in physical form under ambient conditions for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 34. In one embodiment, morphology C does not show any change in physical form under 25°C / 60%RH for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 35. In one embodiment, morphology C does not show any change in physical form under 40°C / 75%RH for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 36. In one embodiment, morphology C does not show any change in physical form under 55°C / 75%RH for at least 1, 2, 3, 4, or 8 weeks, as shown in Figure 37.

[0069] In one embodiment, form C is insoluble in aqueous solution. In one embodiment, form C is insoluble in aqueous solution (e.g., water) at room temperature and when heated to 50°C (e.g., <1 mg / mL). In one embodiment, form C is soluble in methanol, ethanol, isopropanol, acetone, MIBK, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-Me-THF, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, and toluene, and mixtures thereof, at room temperature and when heated to 50°C (e.g., >1 mg / mL). In one embodiment, form C is insoluble in n-heptane and water at room temperature and when heated to 50°C (e.g., <1 mg / mL). In one embodiment, form C is insoluble in MTBE solution at room temperature but soluble when heated to 50°C.

[0070] In one embodiment, form C is an anhydrous substance.

[0071] In one embodiment, form C is prepared by molten compound A in a solvent. In one embodiment, form C is prepared by molten compound A in methanol, ethanol, isopropanol, acetone, MIBK, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-Me-THF, dioxane, MTBE, acetonitrile, dichloromethane, chloroform, toluene, heptane, water, or a mixture thereof. In one embodiment, form C is prepared by molten compound A in a chloroform / MTBE mixture (1:3). In one embodiment, form C is prepared by molten compound A in a methanol / water mixture (1:3). In one embodiment, form C is prepared by molten compound A in an acetone / heptane mixture (1:3). In one embodiment, form C is prepared by molten compound A in a tetrahydrofuran / toluene mixture (1:3). In one embodiment, form C is prepared by molten compound A in a mixture of dioxane / isopropanol (1:3). In one embodiment, form C is prepared by molten compound A in a mixture of ethanol / dichloromethane (1:1). In one embodiment, form C is prepared by molten compound A in a mixture of acetonitrile / ethyl acetate (1:1). In one embodiment, form C is prepared by molten compound A in a mixture of ethyl acetate / heptane (1:1). In one embodiment, form C is prepared by molten compound A in a mixture of acetonitrile / water (1:1). In one embodiment, form C is prepared by molten compound A in a mixture of dichloromethane / MTBE (1:1). In one embodiment, form C is prepared by molten compound A in a mixture of MIBK / toluene (1:1). In one embodiment, form C is prepared by molten compound A in a 2-Me-THF / isopropyl acetate mixture (1:1). In one embodiment, form C is prepared by molten compound A in an acetonitrile / isopropanol mixture (1:1). In one embodiment, form C is prepared by molten compound A in an ethyl acetate / toluene mixture (1:1).In one embodiment, form C is prepared by molten compound A in a methanol / heptane mixture (1:1). In one embodiment, form C is prepared by molten compound A in an acetone / water mixture (1:1). In one embodiment, form C is prepared by molten compound A in a tetrahydrofuran / MTBE mixture (1:1). In one embodiment, molten compounding is carried out at room temperature. In one embodiment, molten compounding is carried out using continuous stirring. In one embodiment, molten compound A in chloroform produces a mixture of form B and form C. In one embodiment, form C is molten in acetonitrile, ethyl acetate, MIBK, dichloromethane, isopropanol, toluene, isopropyl acetate, or heptane at 50°C. In one embodiment, a seed of form C is added before molten compounding.

[0072] In one embodiment, form C is prepared by solid vapor diffusion. In one embodiment, form C is prepared by interacting the vapor of a solvent with the solid form of compound A. In one embodiment, form C is prepared by interacting the vapor of a solvent with compound A for a specific period of time. In one embodiment, form C is prepared by interacting the vapor of a solvent with the solid form of compound A for one day. In one embodiment, form C is prepared by interacting the vapor of a solvent with the solid form of compound A for two days. In one embodiment, form C is prepared by interacting the vapor of a solvent with the solid form of compound A for three days. In one embodiment, form C is prepared by interacting the vapor of a solvent with the solid form of compound A for four days. In one embodiment, form C is prepared by interacting the vapor of a solvent with the solid form of compound A for five days. In one embodiment, form C is prepared by interacting the vapor of a solvent with the solid form of compound A for six days. In one embodiment, form C is prepared by interacting the vapor of a solvent with the solid form of compound A for seven days. In one embodiment, form C is prepared by interacting the vapor of a solvent with the solid form of compound A at room temperature. In one embodiment, form C is prepared from solid vapor evaporation, the solvent being dichloromethane, ethyl acetate, MTBE, acetonitrile, or DMF.

[0073] In one embodiment, form C is prepared by liquid vapor diffusion. In one embodiment, form C is prepared by diffusing the vapor of the reverse solvent into a concentrated solution of compound A in a solvent. In one embodiment, the solvent is dichloromethane and the reverse solvent is acetone.

[0074] In one embodiment, form C is prepared by slowly cooling a solution of compound A.

[0075] In one embodiment, form C is formed by cooling a solution of compound A in toluene or MIBK. In one embodiment, form C is formed by slowly cooling a solution of compound A in a mixture of solvents. In one embodiment, form C is formed by slowly cooling a solution of compound A in a mixture of methanol and toluene. In one embodiment, methanol and toluene are mixed in a ratio of about 1:3.

[0076] In one embodiment, form C is prepared from compound A through polymer-induced crystallization. In one embodiment, form C is formed by crystallizing a solution of compound A in a solvent in the presence of a polymer. In one embodiment, form C is formed by crystallizing a solution of compound A in a solvent selected from the group consisting of methanol, ethanol, acetone, acetonitrile, chloroform, ethyl acetate, MIBK, isopropanol, and toluene, in the presence of a polymer. In one embodiment, form C is formed by crystallizing a solution of compound A in the presence of a polymer selected from the group consisting of hypromellose acetate succinate (HPMC-AS), methylcellulose (MC), polyvinylpyrrolidone / vinyl acetate (PVP-VA), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP). In one embodiment, form C is formed by crystallizing a solution of compound A in methanol in the presence of HPMC-AS. In one embodiment, form C is formed by crystallizing a solution of compound A in acetonitrile in the presence of HPMC-AS. In one embodiment, form C is formed by crystallizing a solution of compound A in ethyl acetate in the presence of PVA. In one embodiment, a mixture of the form C polymorph and amorphous compound A is formed by crystallizing a solution of compound A in ethanol in the presence of MC. In one embodiment, a mixture of the form C polymorph and amorphous compound A is formed by crystallizing a solution of compound A in acetone in the presence of PVP-VA. In one embodiment, a mixture of the form C polymorph and amorphous compound A is formed by crystallizing a solution of compound A in chloroform in the presence of PVP-VA. In one embodiment, a mixture of the form C polymorph and amorphous compound A is formed by crystallizing a solution of compound A in MIBK in the presence of PVP. In one embodiment, a mixture of the form C polymorph and amorphous compound A is formed by crystallizing a solution of compound A in isopropanol in the presence of HPMC-AS. In one embodiment, a mixture of the form C polymorph and amorphous compound A is formed by crystallizing a solution of compound A in toluene in the presence of MC.

[0077] The terms "crystalline polymorphism," "crystalline polymorphism," "crystalline form," "polymorph," or "polymorphic form" refer to a crystalline structure in which a compound (e.g., its free base, salt, or solvate) can crystallize in different crystalline packing configurations, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, crystalline forms, optical and electrical properties, stability, and solubility. Crystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to dominate. Crystallographic polymorphisms of a compound can be prepared by crystallization under different conditions. Furthermore, crystalline polymorphism may exist but is not limited to it, and any crystalline form may be single, a mixture of crystalline forms, or anhydrous or hydrated crystalline forms.

[0078] Differences in physical properties exhibited by polymorphisms are a result of the arrangement or three-dimensional structure of molecules in the crystal lattice and can affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and solubility (an important factor in bioavailability). Differences in stability can also result from changes in chemical reactivity (e.g., differential oxidation, where the dosage form fades more rapidly when composed of one polymorph than when composed of another), mechanical properties (e.g., tablets crumble during storage as a kinetically preferred polymorph transforms into a thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are more prone to disintegration at high humidity). In extreme cases, as a result of solubility / solubility differences, the transition of some polymorphs may lead to a lack of potency, or conversely, toxicity. Furthermore, the physical properties of the crystals can be important in processing; for example, one polymorph may be more likely to form solvates, or impurities may be difficult to filter and wash away (e.g., particle shape and size distribution may differ between polymorphs).

[0079] The term "amorphous form" refers to the non-crystalline solid form of a substance.

[0080] Furthermore, the compounds of this application (e.g., free bases and salts, and amorphous, crystalline, and polymorphic forms thereof) may exist in hydrated or unhydrated (anhydrous) forms, as solvates with other solvent molecules, or in unsolvated forms. Non-limiting examples of hydrates include hemihydrates, monohydrates, dihydrates, etc. Non-limiting examples of solvates include DMSO solvate, DMSO hemisolvate, etc.

[0081] All forms of the compound of this application are envisioned, either as a mixture or in a pure or substantially pure form, such as the crystalline form of a racemic mixture and the crystalline forms of individual isomers.

[0082] Molecular polymorphisms can be obtained by numerous methods known in this art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation.

[0083] Techniques for determining the properties of the solid forms of polymorphs and other compounds include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy (e.g., infrared (IR) and Raman spectroscopy), TGA, DTA, DVS, solid-state NMR, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies and dissolution studies.

[0084] As used herein, the term “solvate” means a solvation form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to capture solvent molecules in a molar ratio fixed in the crystalline solid state, and for this reason, form solvates. When the solvate is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one substance and one or more water molecules, where water retains its molecular state as H2O, and such combinations can form one or more hydrates. For example, solvates may be DMSO solvate, dichloromethane (DCM) solvate, methyl ethyl ketone (MEK) solvate, or tetrahydrofuran (THF) solvate.

[0085] As used herein, the terms “unsolvated” or “desolvated” refer to the solid state form of a substance that does not contain a solvent (e.g., crystalline form, amorphous form, and polymorphic form).

[0086] As used herein, the term “pure” means a compound that is about 90–100%, preferably 95–100%, more preferably 98–100% (weight / weight) or 99–100% (weight / weight) pure, and which may contain, for example, less than about 10%, less than about 5%, less than about 2%, or less than 1% impurities. Such impurities include, for example, decomposition products, oxidation products, solvents, and / or other undesirable impurities.

[0087] When used herein, a compound is considered "stable" if, over a period of time (e.g., one, two, three, and four weeks), no significant amount of degradation products are observed under constant conditions of humidity (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, and 95% RH), light exposure, and temperature (e.g., above 0°C, e.g., 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, and 70°C). A compound is not considered stable under certain conditions if degradation impurities appear, or if the area percentage of existing impurities (e.g., AUC as determined by HPLC) begins to increase. The amount of degradation increase as a function of time is important in determining the stability of a compound. In some embodiments, if a compound exhibits high hygroscopicity (i.e., a tendency to absorb water under high humidity conditions), the compound is less stable. Therefore, in some embodiments, the stability of a compound can be measured by evaluating its hygroscopicity. A compound is more hygroscopic if it absorbs more water than another compound under the same storage conditions (e.g., the same humidity and / or temperature).

[0088] As used herein, the term “mixing” means combining, blending, stirring, shaking, rotating, or churning. The term “stirring” means mixing, shaking, churning, or rotating. The term “churning” means mixing, shaking, churning, or rotating.

[0089] Unless explicitly stated otherwise, the terms “approximately” and “about” are synonymous. In one aspect, “approximately” and “about” represent ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5% of the stated quantity, value, or period. In another aspect, “approximately” and “about” represent ±10%, ±8%, ±6%, ±5%, ±4%, or ±2% of the listed quantity, value, or period. In yet another aspect, “approximately” and “about” represent ±5% of the listed quantity, value, or period. In yet another aspect, “approximately” and “about” represent ±2% or ±1% of the listed quantity, value, or period.

[0090] When the terms “approximately” and “about” are used to describe XRPD peaks, these terms represent the described X-ray powder diffraction peaks ±0.3°²θ, ±0.2°²θ, or ±0.1°²θ. In another embodiment, the terms “approximately” and “about” represent the listed X-ray powder diffraction peaks ±0.2°²θ. In another embodiment, the terms “approximately” and “about” represent the listed X-ray powder diffraction peaks ±0.1°²θ.

[0091] When the terms “approximately” and “about” are used to express temperature or a temperature range, these terms represent the expressed temperature or temperature range ±5°C, ±2°C, or ±1°C. In another embodiment, the terms “approximately” and “about” represent the expressed temperature or temperature range ±2°C.

[0092] Methods and assays Synthesis of compound A Standard synthetic methods, including the use of protecting groups, as well as techniques for preparing organic molecules and modifying and handling functional groups, can be obtained from relevant scientific literature or standard reference textbooks in this field. While not limited to one or more sources, well-established reference textbooks on organic synthesis include Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 thed.; John Wiley & Sons: New York, 2001; and Greene, TW; Wuts, PGMProtective Groups in Organic Synthesis, 3 rd Includes John Wiley & Sons: New York, 1999.

[0093] Methods for preparing the free base of compound A are described in U.S. Patents 7,300,931, 7,851,470 and 7,939,529, the entire contents of each of these patents being incorporated herein by reference.

[0094] X-ray powder diffraction (XRPD) XRPD analysis is performed using a diffractometer operating in reflection mode. The 2-theta position is calibrated against a standard before performing the experiment.

[0095] Thermogravimetric / differential thermal analysis (TGA) Thermogravimetric analysis (TGA) is performed in an open plate using a thermogravimetric analyzer. The sample is heated from room temperature to 300°C, and the change in sample weight is recorded during this process.

[0096] Differential Scanning Calorimetry (DSC) Differential scanning calorimetry (DSC) is performed using a differential scanning calorimeter in a sealed plate. The sample and reference are heated from room temperature to 300°C, and the resulting heat flow response is monitored.

[0097] Dynamic water vapor adsorption (DVS) Dynamic water vapor adsorption (DVS) was measured using SMS (Surface Measurement Systems) DVS Intrinsic. The tests were conducted at 25°C, with RH varying from 0% to 95%, in increments of 10% within the 0%RH to 90%RH range and in increments of 5% up to 95%RH. The change in mass after each increase or decrease in RH was recorded as a percentage of the original mass of the starting material.

[0098] High-performance liquid chromatography (HPLC) analysis High-performance liquid chromatography (HPLC) analysis was performed using an Agilent 1100 system with DAD to determine the chemical stability of compound A in forms A, B, and C after storage under various conditions. Chemical stability was estimated by measuring and comparing the area percentage of material peaks at various time points.

[0099] Estimation of solubility The solubility of the solid form of the present invention in various solvents is measured. Solvent is added to the sample in 100 μL steps until the total volume reaches 100 μL, and then until the sample dissolves or the concentration is less than 1.0 mg / mL. The approximate solubility is then calculated.

[0100] Polymorphic screening method muddy substance Compound A is suspended in a solvent and stirred. The solid prepared from the slurry is then isolated and analyzed by various methods for determining the properties of the solid, such as XRPD.

[0101] Back solvent addition Concentrated stock solutions of compound A are prepared in various solvents. The solutions are stirred, and a reverse solvent is rapidly added to induce precipitation. The solid is then isolated and analyzed by various methods for determining the properties of the solid, such as XRPD.

[0102] Slow cooling Concentrated stock solutions of compound A are prepared in various solvents, heated, and slowly cooled to induce precipitation. The solid is then isolated and analyzed by various methods for determining the properties of the solid, such as XRPD.

[0103] Liquid vapor diffusion Concentrated stock solutions of compound A in various solvents are prepared in an inner vial and placed inside a larger, sealed vial containing the reverse solvent. The solid is then isolated and analyzed by various methods for determining the properties of the solid, such as XRPD.

[0104] Solid vapor diffusion A sample of compound A is prepared in an inner vial, placed inside a larger vial containing a volatile solvent, and sealed. This system is maintained at room temperature, allowing the solvent vapor to interact with the solid. The solid is then isolated and analyzed by various methods for determining the properties of the solid, such as XRPD.

[0105] Polymer-induced crystallization A sample of compound A is prepared in a glass vial. A predetermined amount of a selected solvent is then added to dissolve the sample, followed by the addition of the polymer. The solid is then isolated and analyzed by various methods for determining the properties of the solid, such as XRPD.

[0106] Pharmaceutical composition The present application also provides a pharmaceutical composition comprising one or more of the compounds of the present application (e.g., in solid, amorphous, crystalline, and polymorphic forms of compound A) in combination with at least one pharmaceutically acceptable excipient or carrier. In one embodiment, the pharmaceutical composition comprises the solid form of compound A of the present application and a pharmaceutically acceptable excipient, and the pharmaceutical composition is formulated for topical administration.

[0107] A "pharmaceutical composition" is a preparation containing the compound of the present application in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any form in various forms, such as capsules, IV bags, tablets, single pumps or vials of aerosol inhalers. The amount of the active ingredient (e.g., preparation of one or more of the disclosed compounds) in a unit dose of the composition is an effective amount and will vary depending on the specific treatment involved. Those skilled in the art will understand that it may sometimes be necessary to make standard adjustments to the dosage depending on the patient's age and symptoms. The dosage will also depend on the route of administration. Various routes are envisioned, including topical, oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, subarachnoid, and intranasal. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or sprays.

[0108] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, carrier and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problems or challenges, in proportion to a reasonable benefit / risk ratio.

[0109] "Pharmacologically acceptable excipients" generally means excipients that are safe, non-toxic, and free from biological or other undesirable hazards, and are useful in preparing pharmaceutical compositions, and include excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used herein and in the claims, "pharmaceutically acceptable excipients" includes both one and more such excipients.

[0110] The pharmaceutical compositions of this application are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous), intradermal, subcutaneous, oral (e.g., inhalation), transdermal, topical, and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents such as water for injection, physiological saline solution, non-volatile oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffering agents such as acetate, citrate, or phosphate; and osmotic regulators such as sodium chloride or dextrose. pH can be adjusted using an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be sealed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0111] The compounds or pharmaceutical compositions of this application can be administered to a subject by many of the well-known methods currently used for treatment. For example, for the treatment of cancer, the compounds of this application may be injected directly into the tumor, injected into the bloodstream or body cavity, taken orally, or applied to the skin using a patch. The selected dose should be sufficient to constitute an effective treatment, but should not be so high as to cause unacceptable side effects. The state of the disease symptoms (e.g., cancer, precancerous disease) and the patient's health should preferably be closely monitored for a reasonable period during and after the treatment.

[0112] The pharmaceutical compositions of this application may also be formulated for topical administration. Topical compositions may be administered to the affected area, such as the skin. The affected area of ​​the skin may be located in one or more sites independently selected from the scalp, forehead, forearms, face, nose, ears, eyelids, lips, neck, arms, hands, torso, legs, and feet. In one embodiment, there may be more than one affected area. In one embodiment, there may be more than one affected area located in one or more sites independently selected from the scalp, forehead, forearms, face, nose, ears, eyelids, lips, neck, arms, hands, torso, legs, and feet.

[0113] As used herein, the term “therapeutically effective dose” refers to the amount of an agent used to treat, alleviate, or prevent a specified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. The exact effective dose for a subject will depend on the subject’s weight, body size, and health; the nature and severity of the symptoms; and the therapeutic agent or combination of therapeutic agents selected for administration. A therapeutically effective dose for a given situation can be determined by routine experimental methods within the scope of the clinician’s skill and judgment. In a preferred context, the disease or condition to be treated is cancer. In another context, the disease or condition to be treated is a cytoproliferative disorder.

[0114] For any compound, the therapeutically effective dose can first be estimated, for example, in a cell culture assay of neoplastic cells, or in an animal model, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans, including therapeutic / preventive effects and toxicity, e.g., ED. 50 (Therapeutic dose effective in 50% of the population) and LD 50 The dose (lethal to 50% of the population) can be determined by standard pharmaceutical methods in cell cultures or experimental animals. The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, and the LD50. 50 / ED 50 It can be expressed as a ratio. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dosage may vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0115] Dosage and administration are adjusted to deliver a sufficient level of activator or to maintain the desired effect. Factors to consider include the severity of the disease state, the subject's overall health, age, weight and sex, diet, timing and frequency of administration, drug combinations, sensitivity to response, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3-4 days, weekly, or bi-weekly, depending on the half-life and clearance rate of the specific formulation.

[0116] Pharmaceutical compositions containing the active compound of this application may be produced in a generally known manner, for example, by conventional mixing, dissolution, granulation, sugar-coating, powdering, emulsification, encapsulation, or freeze-drying processes. The pharmaceutical compositions may be prepared in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and / or auxiliaries that facilitate the processing of the active compound into a pharmaceutically usable preparation. Of course, the appropriate preparation depends on the chosen route of administration.

[0117] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (if water-soluble) or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid enough to allow easy passage through an injection needle. The composition must be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi. Carriers may be solvents or dispersion media containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol) and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Inhibition of microbial activity can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride. Long-term absorption of the injectable composition can be achieved by including absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0118] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount into a suitable solvent, along with one or a combination of the components listed above, as needed, and then sterilizing by filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other required components obtained from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation method is vacuum drying and freeze-drying, which yield a powder of the active component and any further desired components from a pre-sterilized filtered solution of the active component and any further desired components.

[0119] Oral compositions generally comprise an inert diluent or an edible, pharmaceutically acceptable carrier. Oral compositions can be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a liquid carrier for use as a mouthwash, where the compound in the liquid carrier is applied orally and either rinsed, spat out, or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; flow promoters such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0120] For administration by inhalation, the compound is delivered in the form of an aerosol spray from a suitable nebulizer, such as a pressurized container or dispenser containing a gas like carbon dioxide, or from a sprayer.

[0121] Systemic administration may also be by mucosal or transdermal means. For mucosal or transdermal administration, a penetrating agent suitable for the barrier to be penetrated is used in the formulation. Such penetrating agents are commonly known in the art and, for example, for mucosal administration, include surfactants, bile acids, and fusidic acid derivatives. Mucosal administration can be achieved through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated in ointments, plasters, gels, or creams, as are commonly known in the art.

[0122] The active compound can be prepared with a pharmaceutically acceptable carrier that can protect the compound from rapid removal from the body, such as a controlled-release formulation including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyacid anhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be obvious to those skilled in the art. The materials can also be commercially available. Liposome suspensions (containing liposomes directed to infected cells using monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0123] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions in drug unit form. The drug unit form used herein represents a physically separated unit suitable as a unit dose for the target to be treated, and each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect in cooperation with the required pharmaceutical carrier. The specifications for the drug unit form in this disclosure depend directly on the inherent characteristics of the active compound and the specific therapeutic effect to be achieved.

[0124] In therapeutic applications, the dosage of a pharmaceutical composition used in accordance with this disclosure will vary depending on factors influencing the selected dosage, particularly the agonist, the age, weight, and clinical condition of the patient being treated, and the experience and judgment of the clinician or practitioner administering the treatment. Generally, the dosage should be sufficient to result in delayed tumor growth, preferably regression, and preferably complete regression of the cancer. Dosages can range from about 0.01 mg / kg / day to about 5,000 mg / kg / day. An effective dose of the drug is one that provides an objectively identifiable improvement that is noticeable to a clinician or other qualified observer. For example, tumor regression in a patient may be measured by reference to the diameter of the tumor. A decrease in tumor diameter indicates regression. Regression is also indicated by the absence of tumor recurrence after discontinuation of treatment. As used herein, the term “effective dosage” refers to the amount of the active compound required to produce the desired biological effect in a subject or cell.

[0125] Pharmaceutical compositions may be included in containers, packs, or dispensers along with instructions for administration.

[0126] The compound of this application may be administered topically, orally, nasally, percutaneously, into the lungs, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, subarachnoidally, or parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0127] The techniques for compounding and administering the compounds disclosed in this disclosure are described in Remington: The Science and Practice of Pharmacy, 19 thThis can be found in edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid extenders or diluents and sterile aqueous or organic solutions. The compounds will be present in such a pharmaceutical composition in an amount sufficient to give the desired dosage within the range described herein.

[0128] Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of this application are evident from different examples. The examples provided illustrate different components and methods useful for carrying out this application. The examples are not limiting to this application. Based on this application, those skilled in the art can identify and utilize other components and methods useful for carrying out this application.

[0129] Treatment method The present application provides a method for treating cytoproliferative disorders in subjects requiring treatment of said cytoproliferative disorders by administering one or more of the compounds of the present application (e.g., in solid form, amorphous form, crystalline form, or polymorph) in a therapeutically effective amount to said subjects. The present application also provides a method for protecting subjects requiring protection against cytoproliferative disorders by administering one or more of the compounds of the present application (e.g., in solid form, amorphous form, crystalline form, or polymorph) in a therapeutically effective amount to said subjects. The cytoproliferative disorders may be cancer or precancerous conditions. The present application further provides the use of one or more of the compounds of the present application for the preparation of pharmaceuticals useful for the treatment or prevention of cytoproliferative disorders.

[0130] As used herein, “subjects requiring it” refers to subjects with cytoproliferative disorders, or subjects whose risk of developing cytoproliferative disorders is increased compared to the general population. Subjects requiring it may have precancerous conditions. “Subjects” include mammals. Mammals may be any mammal, for example, humans, primates, birds, mice, rats, poultry, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. Preferably, the mammal is a human.

[0131] As used herein, the term “proliferative disorder” refers to a condition in which uncontrolled or abnormal proliferation of cells, or both, can lead to the development of undesirable symptoms or diseases, which may be cancerous or non-cancerous, such as psoriatic symptoms. As used herein, the terms “psoriatic symptoms” or “psoriasis” refer to a disorder involving excessive keratinocyte proliferation, inflammatory cell infiltration, and cytokine changes. Proliferative disorders include precancerous or precancerous symptoms. Proliferative disorders include cancer. Exemplary proliferative disorders encompass a variety of conditions in which cell division is deregulated. Exemplary proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, precancerous symptoms, carcinomas in situ, encapsulated tumors, metastatic tumors, humoral tumors, solid tumors, immune system tumors, hematological tumors, cancer, carcinoma, leukemia, lymphoma, sarcoma, and rapidly dividing cells. As used herein, the term “rapidly dividing cells” is defined as any cell that divides at a rate exceeding or greater than that expected or observed among adjacent or juxtaposed cells within the same tissue.

[0132] The term "cancer" includes solid tumors, as well as hematological malignancies and / or malignant lesions. "Precancerous cells" are cells that exhibit cytoproliferative disorders that are precancerous or precancerous. "Cancer cells" are cells that exhibit cytoproliferative disorders that are cancerous.

[0133] Exemplary non-cancerous conditions or disorders include: rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative disorders; acromegaly; rheumatoid spondylitis; osteoarthritis; gout and other joint conditions; sepsis; septic shock; endotoxin shock; Gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pneumonia; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; actinic keratosis; ichthyosis; atopic dermatitis; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic kidney disease; irritable bowel syndrome; fever (pyresis); restenosis; cerebral malaria; stroke and ischemic injury; neurological trauma; Alzheimer's disease; Huntington's disease This includes, but is not limited to, Ton's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendinitis; tenosynovitis; herniated, herniated or prolapsed disc syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcosis; bone resorption disorders such as osteoporosis; graft-versus-host reaction; multiple sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as herpes zoster, herpes simplex type 1 or 2, influenza virus and cytomegalovirus; and diabetes mellitus.

[0134] Exemplary cancers include adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendiceal cancer, pediatric cerebellar astrocytoma, pediatric cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, bladder cancer, uringary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumors, brainstem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectoderm tumor, visual pathway Hypothalamic glioma, breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal cancer, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Seziary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor ( GIST), germ cell tumors, ovarian germ cell tumors, gestational trophoblastic tumors, gliomas, head and neck cancers, hepatocellular carcinoma (liver cancer), Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancers, islet cell tumors (pancreatic endocrine tumors), Kaposi's sarcoma, kidney cancer, renal cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, hairy cell leukemia, lip and oral cancers, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-associated lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenström macroglobulinemia, medulloblastoma, melanoma, intraocular melanoma, Merkel cell carcinoma, Malignant mesothelioma, mesothelioma, metastatic squamous cell carcinoma of the neck, oral cancer, tongue cancer, multiple endocrine neoplasia syndrome, myelodysplastic syndrome, myelodysplastic / myeloproliferative disorders, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial carcinoma, low-grade ovarian tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal blastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuroblastoma, prostate cancer,This includes, but is not limited to, rectal cancer, renal pelvis and ureteral cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family of sarcomas, soft tissue sarcomas, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, pharyngeal cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other parts of the urinary tract, gestational trophoblastic neoplasm, urethral cancer, endometrial uterine cancer, uterine body cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0135] Actinic keratosis, or AK, is a common precancerous skin condition caused by excessive exposure to ultraviolet (UV) light. AK is characterized by rough, dry, brown, pink, or red spots (lesions) that often appear on parts of the head, including the face, throat, neck, nose, forehead, ears, or lips. AK can also appear on other parts of the body that receive prolonged, intense sunlight, such as the hands, back, and other areas of the torso and legs. AK is most common in fair-skinned middle-aged or elderly individuals. Subjects affected by AK may have a single lesion or multiple lesions. AK can lead to squamous cell carcinoma.

[0136] As used herein, the term "torso" refers to the part of the subject other than the arms, legs, or head.

[0137] Clinical variants of AK include classical (or common), hypertrophic (or hyperkeratotic), atrophic, keratotic AK, pigmented AK, actinic cheilitis, and Bowen-like AK. Unless otherwise expressly stated, the methods described herein may be applied to all clinical variants, including those listed herein.

[0138] Treatments for AK include cryosurgery, surgical excision and / or curettage of the affected area, photodynamic therapy, and topical formulations (e.g., creams, gels, patches) containing steroids, fluorouracil, diclofenac, imiquimod, and 5-aminolevulinic acid (Ameluz®). The approved treatment for AK is Picato (Ingenol Mebutate)®, a gel containing ingenol mebutate (0.015% or 0.05%). This gel is applied once daily for three consecutive days to the affected area on the face or scalp (0.015%) or once daily for two consecutive days to the torso or limbs (0.05%).

[0139] Skin toxicity associated with the use of other AK treatments, such as Picato (Ingenol Mebutate) (registered trademark), is known to result in undesirable side effects or adverse reactions, namely local skin reactions (LSRs) including vesicle formation, pustule formation, erosion, ulceration, redness, swelling, peeling, scaling, hard nodules, dryness, pus, and blister formation. Other side effects include application site pain, application site itching, application site irritation, application site swelling, application site burning, application site infection, periorbital edema, nasopharyngitis, chills, sore throat, ptosis, swollen eyes, depigmentation, hyperpigmentation, and headache.

[0140] The present invention provides a method for treating or preventing a disease or condition (e.g., a cell proliferation disorder) in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role, comprising administering a therapeutically effective amount of a composition comprising any one of the solid forms of compound A described herein to a subject who is in need of treatment or prevention of a disease or condition (e.g., a cell proliferation disorder) in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role.

[0141] This application also provides a solid form of compound A described herein for treating or preventing diseases or conditions in which tyrosine kinases (e.g., Src tyrosine kinases) play a role (e.g., cell proliferation disorders) in subjects where treatment or prevention of such diseases or conditions is required.

[0142] The present application also provides a solid form of compound A described herein for use in the manufacture of a pharmaceutical for the treatment or prevention of a disease or condition in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role (e.g., a cell proliferation disorder) in a subject requiring treatment or prevention of such a disease or condition in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role (e.g., a cell proliferation disorder).

[0143] This application also provides for the use of compound A described herein in solid form in the manufacture of a pharmaceutical for the treatment or prevention of a disease or condition in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role (e.g., a cell proliferation disorder) in a subject requiring treatment or prevention of such a disease or condition in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role (e.g., a cell proliferation disorder).

[0144] In one embodiment, the disease or symptom is precancerous (e.g., precancerous symptoms as described herein). In one embodiment, the disease or symptom is cancerous (e.g., cancerous symptoms as described herein). In one embodiment, the disease or symptom is AK.

[0145] In one embodiment, the solid form of the present invention is for the manufacture of a pharmaceutical product to be administered, for administration, or for topical administration to a subject requiring such administration.

[0146] In one embodiment, the present application provides a method for treating or preventing actinic keratosis or psoriasis, comprising administering a therapeutically effective amount of the solid form of the present application to a subject in need of treatment or prevention of actinic keratosis or psoriasis.

[0147] In one embodiment, in any of the methods disclosed herein, the solid form of compound A is administered to the affected area, which is the skin.

[0148] In one embodiment, with respect to any of the methods disclosed herein, administration of compound A in solid form reduces the number and / or severity of topical skin reactions or other adverse side effects in the subject compared to other treatments for actinic keratosis or psoriasis. In one embodiment, other treatments for actinic keratosis or psoriasis include topical administration of ingenol mebutate.

[0149] In one embodiment, with respect to any of the methods disclosed herein, administration of compound A in solid form reduces the number of subjects experiencing topical skin reactions or other adverse side effects compared to other treatments for actinic keratosis or psoriasis.

[0150] In one embodiment, with respect to any of the methods disclosed herein, the local skin reaction is selected from the group consisting of vesicle formation, pustule formation, erosion, ulceration, redness, swelling, peeling, scaling, hard nodule, dryness, pus and blister formation.

[0151] In one embodiment, with respect to any of the methods disclosed herein, other adverse reactions are selected from the group consisting of application site pain, application site itching, application site irritation, application site swelling, application site burning, application site infection, periorbital edema, nasopharyngitis, chills, sore throat, ptosis, swollen eye, depigmentation, hyperpigmentation, and headache.

[0152] In one embodiment, the present application relates to treating or treating a disease or symptom described herein (e.g., AK). In one embodiment, the present application relates to preventing or preventing a disease or symptom described herein (e.g., AK).

[0153] definition As used herein, “to treat” or “to treat” describes the management and treatment of a patient to combat a disease, symptom, or disorder, and includes the administration of the compounds of this application to alleviate the symptoms or complications of a disease, symptom, or disorder, or to eliminate the disease, symptom, or disorder.

[0154] As used herein, “prevention” or “prevention” means suppressing or eliminating the onset of symptoms or complications of a disease, symptom, or disorder.

[0155] As used herein, the term “alleviate” describes a process by which the severity of a sign or symptom of a disorder is reduced. Importantly, the sign or symptom may be alleviated without being eliminated. In a preferred embodiment, administration of the compound of the application results in the elimination of the sign or symptom, but elimination is not essential. An effective dose is expected to reduce the severity of the sign or symptom. For example, if the severity of cancer is reduced in at least one of several sites, the signs or symptoms of a disorder such as cancer, which may occur in multiple sites, will be alleviated.

[0156] As used herein, the term “symptom” is defined as a disease, illness, injury, or any manifestation of something being inappropriate within the body. A symptom is felt or noticed by the individual experiencing it, but may not be readily noticeable to others.

[0157] As used herein, the term "symptom" is also defined as an indication that something is not appropriate within the body. However, a symptom is defined as something that can be observed by a physician, nurse, or other healthcare provider.

Example

[0158] Example 1 X-ray powder diffraction (XRPD) The XRPD analysis scanned the sample between 3 and 40° 2-theta on a Panalytical X’Pert 3 on a Powder XRPD. The 2-theta positions were calibrated against a Panalytical 640 Si powder standard. The test material was gently compressed onto a glass disk inserted into the sample holder. Then, the sample was placed in a Panalytical X’Pert 3 Powder XRPD diffractometer operating in reflection mode and analyzed using the following experimental conditions. TIFF0007843116000010.tif58128

[0159] Example 2 Thermogravimetric / differential thermal analysis (TGA) The test material was weighed into an open platinum plate and placed in a TA Instruments TA Q500 thermogravimetric / analyzer (TGA). Then, the sample was heated from room temperature to 300 °C at a rate of 10 °C / min, during which the change in sample weight was recorded. 15 cm 3 / min sample purge flow rate and 25 cm 3 / min balance purge flow rate, using nitrogen as the purge gas.

[0160] Example 3 Differential scanning calorimetry (DSC) The sample material was weighed into an aluminum DSC pan and sealed by compression. The sample pan was then placed in a TA Instruments TA Q2000 DSC. Once a stable heat flow response was obtained, the sample and reference were heated from room temperature to 300°C at a scanning rate of 10°C / min, and the resulting heat flow response was monitored. Nitrogen was used as the purge gas.

[0161] Example 4 Dynamic water vapor adsorption (DVS) Dynamic water vapor adsorption (DVS) was measured using the SMS (Surface Measurement Systems) DVS Intrinsic with the following parameters. TIFF0007843116000011.tif39154

[0162] Example 5 High-performance liquid chromatography (HPLC) analysis For high-performance liquid chromatography (HPLC) analysis, an Agilent 1100 system with DAD was used. The method parameters used are listed in the table below.

[0163] (Table 7) HPLC method parameters TIFF0007843116000012.tif116166

[0164] Example 6 Estimation of solubility The solubility of the solid form of the present invention in various solvents was measured according to the following procedure. A sample (approximately 2 mg) was weighed into a 4 mL glass vial. The solvent was added to the vial in steps of 50 μL until the total volume reached 100 μL, and then in steps of 100 μL until the concentration was less than 1.0 mg / mL. The solution was thoroughly mixed after each addition by sonication for 2 minutes and vortex stirring for 1 minute. The addition of the solvent was stopped when the sample was dissolved or the concentration was less than 1.0 mg / mL. The amounts of solvent (V1 and V2) were recorded, and the approximate solubility was calculated.

[0165] Example 7 Polymorphic screening method ·Sludge Approximately 5–20 mg of compound A was suspended in 0.1–0.5 mL of solvent in a 1.5 or 3.0 mL glass vial. The suspension was stirred at 200 rpm at the target temperature (room temperature or 50°C). The solid for XRPD analysis was isolated by centrifugation at 14,000 rpm for 5 minutes at room temperature. If no solid or gel was obtained, the muddy substance was transferred to a fume hood for evaporation.

[0166] • Addition of reverse solvent A concentrated stock solution of compound A in a solvent was prepared. The solution was stirred, and the reverse solvent was rapidly added to induce precipitation. The solid for XRPD analysis was isolated by filtration or centrifugation. If no solid was obtained, the solution was transferred to a fume hood for evaporation.

[0167] Slow cooling A concentrated stock solution of compound A in a solvent was prepared. The suspension was heated to 50°C and maintained at 50°C for at least 30 minutes. The solution or suspension was then filtered at 50°C using a 0.45 micron PTFE filter, and the filtrate was collected in a clean vial. The solution was cooled to 5°C to induce precipitation. The solid for XRPD analysis was isolated by filtration or centrifugation. Samples that did not precipitate were cooled to -20°C to induce precipitation.

[0168] • Liquid vapor diffusion A concentrated stock solution of compound A in a solvent was prepared in a vial. This inner vial was placed inside a larger, sealed vial containing the reverse solvent. The solid for XRPD analysis was isolated by filtration or centrifugation.

[0169] • Solid vapor diffusion A sample of compound A (5–15 mg) was weighed into a small vial (e.g., 3 mL). This inner vial was placed inside a larger vial (e.g., 20 mL) containing 3–4 mL of volatile solvent. The outer vial was then sealed. This system was maintained at room temperature for 7 days, allowing the solvent vapor to interact with the solid. The resulting solid was isolated and analyzed by XRPD.

[0170] • Polymer-induced crystallization A sample of compound A (5–15 mg) was weighed into a glass vial. A predetermined amount of the selected solvent was then added to dissolve the sample. The corresponding polymer was then added to the vial, and the sample was stirred at room temperature for 7 days. The resulting solid was isolated and analyzed by XRPD.

[0171] Example 8 Determination of the properties of morphology C As described above, morphology C was characterized by XRPD, TGA, and DSC. The XRPD analysis of morphology C is shown in Figure 2.

[0172] Form C showed endothermic activity at 136°C when measured by DSC (Figure 3). Form C showed a 0.18% weight loss before 150°C when measured by TGA, which is consistent with the anhydrous state (Figure 3).

[0173] Example 9 Solubility of form C The solubility of form C was estimated in the solvent according to the method described above, and the results are listed in Table 8.

[0174] (Table 8) Solubility of morph C in selected solvents TIFF0007843116000013.tif95128* was melted after being heated to 50°C for 2 hours.

[0175] Example 10 Polymorphic screening based on muddy material Compound A was converted into a slurry according to the method described above. The resulting solid was analyzed by XRPD and identified in terms of its physical state. The results are listed in Table 9.

[0176] The muddy material was screened at room temperature and 50°C and showed similar XRPD patterns corresponding to morphology C. The muddy material in chloroform at room temperature gave morphology C+B (Figure 4).

[0177] (Table 9) Summary of polymorphic screening experiments using muddy material TIFF0007843116000014.tif93128TIFF0007843116000015.tif219116*Solution observed for 7 days before evaporation

[0178] Example 11 vapor diffusion Compound A was prepared for liquid and solid vapor diffusion experiments according to the method described above. The resulting solid was analyzed by XRPD and identified in terms of its physical state (Tables 10 and 11).

[0179] The solid vapor diffusion experiment yielded morphology C. The liquid vapor diffusion method yielded morphology A (Figure 5) with EtOH / hexane and MeOH / hexane, and morphology B (Figure 6) with MeOH / MTBE and CHCl3 / MTBE.

[0180] (Table 10) Summary of solid vapor diffusion experiments TIFF0007843116000016.tif42133

[0181] (Table 11) Summary of Liquid Vapor Diffusion Experiments TIFF0007843116000017.tif42139

[0182] Example 12 Slow cooling Compound A was prepared for the slow cooling experiment according to the method described above. The resulting solid was analyzed by XRPD and identified in terms of its physical state (Table 12). The slow cooling experiment yielded morphology A (Figure 7) and morphology B (Figure 8).

[0183] (Table 12) Summary of Cooling Experiment TIFF0007843116000018.tif167130

[0184] Example 13 Polymer-Induced Crystallization According to the method described above, Compound A was prepared for the polymer-induced crystallization experiment. The resulting solid was analyzed by XRPD and identified with respect to its physical state (Table 13).

[0185] (Table 13) Summary of Polymer Experiment TIFF0007843116000019.tif107136

[0186] Example 14 Anti-Solvent Crystallization According to the method described above, Compound A was prepared for the anti-solvent addition experiment. The resulting solid was analyzed by XRPD and identified with respect to its physical state (Table 14). Many of the anti-solvent addition experiments gave Form A (Figure 9), Form A + B, and Form B (Figure 10).

[0187] (Table 14) Summary of Anti-Solvent Experiment TIFF0007843116000020.tif93128

[0188] Example 15 Characterization of Form A Form A was obtained from multiple screening methods. Samples of Form A were obtained through anti-solvent addition at room temperature (solvent: EtOH, anti-solvent: IPAc) and analyzed by XRPD (Example 12 and Figure 11).

[0189] DSC analysis showed that Form A exhibited endotherms at 128.5 °C and 137.5 °C (Figure 12). When measured by TGA, Form A showed a 0.36% weight loss before 150 °C.

[0190] Form A did not show a decrease in crystallinity after air drying or vacuum drying when measured by XRPD (Figure 13). DSC analysis showed that Form A (vacuum dried) did not show a change from the air dried sample (Figure 14).

[0191] Example 16 Characterization of Form B Form B was obtained from multiple screening methods. An example from anti-solvent addition (solvent: MeOH, anti-solvent: IPAC) is shown in Figure 15.

[0192] DSC analysis showed that Form B exhibits an endotherm at 136 °C (Figure 16). TGA analysis showed a 0.20% weight loss before 150 °C.

[0193] Equivalents One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments specifically described herein. Such equivalents are intended to be encompassed by the appended claims.

Claims

1. A polymorph of compound A in form B: 【Chemistry 1】 It is characterized by having X-ray powder diffraction peaks at approximately 6.4, 7.2, 19.3, 19.9, 21.6, 22.1, and 22.6°2θ using Cu Kα irradiation. Here, the term "approximately" represents ±0.2°²θ of the stated value. A polymorph of compound A in form B.

2. It is characterized by having X-ray powder diffraction peaks at approximately 6.4, 7.2, 19.3, 19.9, 21.6, 22.1, 22.6, and 24.2°2θ using Cu Kα irradiation. Here, the term "approximately" represents ±0.2°²θ of the stated value. A polymorph of form B as described in claim 1.

3. When measured by DSC, it is characterized by an endothermic event that begins at approximately 133°C to approximately 138°C. Here, the term "approximately" refers to ±2°C of the stated value. A polymorph of form B as described in claim 1.

4. When measured by DSC, it is characterized by an endothermic event that begins at approximately 136°C. Here, the term "approximately" refers to ±2°C of the stated value. A polymorph of form B as described in claim 1.

5. When measured by TGA, it is characterized by a weight loss of approximately 0.20% between approximately 33°C and approximately 150°C. Here, the term "approximately" represents ±0.5% of the stated value, and the term "about" represents ±2°C of the stated value. A polymorph of form B as described in claim 1.

6. A pharmaceutical composition comprising a polymorph of form B according to any one of claims 1 to 5, and a pharmaceutically acceptable carrier or excipient.

7. A method for preparing a polymorph of form B as described in claim 1, Diffusing the vapor of the reverse solvent into a concentrated solution of compound A in methanol or chloroform, Slowly cool a solution of compound A in acetone, isopropyl acetate, 2-Me-THF, ethyl acetate, acetonitrile, or a mixture of chloroform and heptane, or Adding a reverse solvent to a solution of compound A in methanol, acetone, or acetonitrile. Methods that include...

8. A pharmaceutical composition for treating or preventing a disease or symptom in which Src tyrosine kinase plays a role, comprising a polymorph of form B as described in any one of claims 1 to 5.

9. Use of polymorph of form B according to any one of claims 1 to 5 in the manufacture of a pharmaceutical for the treatment or prevention of a disease or symptom in which Src tyrosine kinase plays a role in a subject requiring treatment or prevention of a disease or symptom in which Src tyrosine kinase plays a role.

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