Solid forms of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-n-benzylacetamide

Abstract

To provide solid forms of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide (Compound A), and methods of preparing and using the same.SOLUTION: A Form B polymorph of Compound A is provided which has X-ray powder diffraction peaks at approximately 6.4, 19.3 and 19.9° 2θ using Cu Kα radiation, where the term "approximately" represents ±0.2° 2θ of the described value.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 555,390, filed September 7, 2017, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Background Signal transduction is any process by which a cell converts one type of signal or stimulus into another. Protein kinases are involved in signal transduction. Tyrosine kinases are enzymes that can transfer a phosphate group from ATP to a tyrosine residue in a protein through a process called phosphorylation, which is an important mechanism in signal transduction for the regulation of enzyme activity. Because kinases are involved in the regulation of a wide variety 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 cause cellular transformation. Therefore, modulation of kinase signaling cascades may be an important means for treating or preventing diseases and disorders.

[0003] Various known inhibitors of protein kinases have various therapeutic uses. One promising therapeutic use of protein kinase inhibitors is as an anti-cancer agent. 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide is a tyrosine kinase inhibitor that can modulate kinase cascades. The free base compound is disclosed in U.S. Pat. No. 7,300,931.

[0004] Polymorphism of a compound affects many of the compound's properties, such as solubility, hygroscopicity, chemical reactivity, and stability. Many of the inconsistencies encountered in drug performance can be attributed to polymorphism. Despite the importance of polymorphism, methods for predicting the possible existence of polymorphs of a compound and the conditions under which polymorphs may form are unreliable, and methods for creating polymorphs often fail to consistently and reliably produce polymorphs.

[0005] Therefore, there is a pressing need to discover solid forms of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide that exhibit desirable physicochemical properties. The present application addresses this need. [Prior art documents] [Patent documents]

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

[0007] Overview The present application provides a compound having the following structure: [ka]

[0013] A solid form of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide (Compound A) is provided.

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

[0009] In one aspect, the present application provides a Form A polymorph of Compound A, characterized by an X-ray powder diffraction ("XRPD") pattern comprising peaks at approximately 4.3, 17.0, and 21.1 degrees 2θ using Cu Kα radiation. In one aspect, Form A is characterized by an XRPD pattern substantially similar to that set forth in Figures 1, 5, 7, 9, 11, 13, or 18. In one aspect, Form A is evident by PLM, appearing as birefringent particles as shown in Figure 23.

[0010] In one embodiment, the Form A polymorph is characterized by a single endothermic event with onset at about 124° C. to about 135° C. or about 135° C. to about 139° C., as measured by DSC. In one embodiment, the Form A polymorph is characterized by multiple endothermic events with onsets at about 124° C. to about 135° C. and about 135° C. to about 139° C., as measured by DSC. In one embodiment, the Form A polymorph is characterized by a TGA or DSC thermogram substantially similar to those depicted in Figures 12 or 14.

[0011] In one embodiment, the present application provides the Form B polymorph of Compound A, characterized by an XRPD pattern comprising peaks at approximately 6.4, 19.3, and 19.9 degrees 2θ using Cu Kα radiation. In one embodiment, the Form B polymorph is characterized by an XRPD pattern substantially similar to that set forth in Figures 1, 6, 8, 10, 15, or 20. In one embodiment, Form B appears as birefringent particles, as evident by PLM, as shown in Figure 24.

[0012] In one embodiment, the Form B polymorph is characterized by an endothermic event with an onset at about 133° C. to about 138° C. as measured by DSC. In one embodiment, the Form B polymorph is characterized by a TGA or DSC thermogram substantially similar to that depicted in FIG.

[0013] In one embodiment, the present application provides the Form C polymorph of Compound A, characterized by an XRPD pattern comprising peaks at approximately 7.9, 17.2, 17.6, and 20.3 degrees 2θ using Cu Kα radiation. In one embodiment, the Form C polymorph is characterized by an XRPD pattern substantially similar to that depicted in Figures 1 or 2. In one embodiment, Form C is evident by PLM and appears as birefringent particles, as shown in Figure 25.

[0014] In one embodiment, the Form C polymorph is characterized by an endothermic event with an onset at about 136° C. to about 140° C. as measured by DSC. In one embodiment, the Form C polymorph is characterized by a TGA or DSC thermogram substantially similar to that depicted in FIG.

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

[0016] The present application also provides a pharmaceutical composition comprising any one of the solid forms of Compound A described herein (e.g., any of Forms A, B, C, and the amorphous form) 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 proliferative disorder) in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role, the method comprising administering to a subject in need of treatment or prevention of the disease or condition (e.g., a cell proliferative disorder) in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role a therapeutically effective amount of a composition comprising any one of the solid forms of Compound A described herein.

[0018] The present application also provides a solid form of Compound A described herein for use in treating or preventing a disease or condition (e.g., a cell proliferative disorder) in which tyrosine kinases (e.g., Src tyrosine kinase) play a role in a subject in need thereof.

[0019] The present application also provides a solid form of Compound A described herein for use in the manufacture of a medicament for the treatment or prevention of a disease or condition (e.g., a cell proliferative disorder) in which tyrosine kinases (e.g., Src tyrosine kinase) play a role in a subject in need of such treatment or prevention.

[0020] The present application also provides the use of a solid form of Compound A described herein in the manufacture of a medicament for the treatment or prevention of a disease or condition (e.g., a cell proliferative disorder) in which tyrosine kinases (e.g., Src tyrosine kinase) play a role in a subject in need of such treatment or prevention.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to this application. In case of conflict, the present specification, including definitions, will control. Furthermore, 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 claims. [The present invention 1001] A polymorph of Compound A selected from Form A, Form B, and Form C: [ka] 1. A polymorph of Compound A, wherein Form A is characterized by having X-ray powder diffraction peaks at approximately 4.3, 17.0, and 21.1 degrees two-theta using Cu Kα radiation; Form B is characterized by having X-ray powder diffraction peaks at approximately 6.4, 19.3, and 19.9 degrees two-theta using Cu Kα radiation; and Form C is characterized by having X-ray powder diffraction peaks at approximately 7.9, 17.2, and 17.6 degrees two-theta using Cu Kα radiation.

[0023] [Invention 1002] The Form A polymorph of 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 degrees 2θ using Cu Kα radiation.

[0024] [Invention 1003] The Form A polymorph of Invention 1001, characterized by having an X-ray powder diffraction pattern substantially similar to that depicted in Figure 1, 5, 7, 9, 11, 13 or 18.

[0025] [Invention 1004] The Form A polymorph of Invention 1001, characterized by an endothermic event with an onset at about 124°C to about 135°C as measured by DSC.

[0026] [Invention 1005] The Form A polymorph of Invention 1001, characterized by an endothermic event with an onset at about 135°C to about 139°C as measured by DSC.

[0027] [Invention 1006] The Form A polymorph of Invention 1001, characterized by endothermic events with onsets at about 124°C to about 135°C and about 135°C to about 139°C as measured by DSC.

[0028] [Invention 1007] The Form A polymorph of Invention 1001, characterized by a DSC thermogram substantially similar to that depicted in Figure 12 or 14.

[0029] [Invention 1008] The Form A polymorph of Invention 1001, characterized by a weight loss of approximately 0.36% from about 33°C to about 150°C as measured by TGA.

[0030] [Invention 1009] The Form B polymorph of 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 degrees 2θ using Cu Kα radiation.

[0031] [Invention 1010] The Form B polymorph of Invention 1001, characterized by having an X-ray powder diffraction pattern substantially similar to that depicted in Figure 1, 6, 8, 10, 15 or 20.

[0032] [Invention 1011] The Form B polymorph of invention 1001, characterized by an endothermic event with an onset at about 133°C to about 138°C as measured by DSC.

[0033] [Invention 1012] The Form B polymorph of Invention 1001, characterized by a DSC thermogram substantially similar to that depicted in Figure 16.

[0034] [Invention 1013] The Form B polymorph of Invention 1001, characterized by a weight loss of approximately 0.20% from about 33°C to about 150°C as measured by TGA.

[0035] [Invention 1014] The Form C polymorph of Invention 1001, characterized by having X-ray powder diffraction peaks at approximately 5.8, 7.9, 8.7, 17.2, and 17.6 degrees 2θ using Cu Kα radiation.

[0036] [Invention 1015] The Form C polymorph of Invention 1001, characterized by having an X-ray powder diffraction pattern substantially similar to that depicted in Figure 1 or 2.

[0037] [Invention 1016] The Form C polymorph of Invention 1001, characterized by an endothermic event with an onset at about 136°C to about 140°C as measured by DSC.

[0038] [Invention 1017] The Form C polymorph of Invention 1001, characterized by a DSC thermogram substantially similar to that depicted in Figure 3.

[0039] [Invention 1018] The Form C polymorph of Invention 1001, characterized by a weight loss of approximately 0.18% from about 33°C to about 150°C as measured by TGA.

[0040] [Invention 1019] Invention 1 A pharmaceutical composition comprising the 001 polymorph and a pharmaceutically acceptable carrier or excipient.

[0041] [Invention 1020] A method for preparing Form A polymorph of Invention 1001, comprising sparging vapors of an anti-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 an anti-solvent to a solution of Compound A in chloroform, methanol, acetone, tetrahydrofuran, dioxane, ethanol, 2-Me-THF, ethyl acetate, or dichloromethane.

[0042] [Invention 1021] A process for preparing the Form B polymorph of Invention 1001, comprising: slurried Compound A in chloroform; diffusing vapors of an anti-solvent into a concentrated solution of Compound A in methanol or chloroform; slowly cooling a solution of Compound A in acetone, isopropyl acetate, 2-Me-THF, ethyl acetate, acetonitrile, or a mixture of chloroform and heptane; or adding an anti-solvent to a solution of Compound A in chloroform, methanol, acetone, or acetonitrile.

[0043] [Invention 1022] A method for preparing the Form C polymorph of Invention 1001, comprising: slurrying 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; allowing vapors of the solvent to interact with the solid form of Compound A; diffusing vapors of an anti-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 crystallizing a solution of Compound A in a solvent in the presence of a polymer.

[0044] [Present Invention 1023] A method for treating or preventing a disease or condition in which Src tyrosine kinase plays a role, comprising administering to a subject in need thereof a polymorph of Present Invention 1001.

[0045] [Present Invention 1024] A polymorph of Present Invention 1001 for treating or preventing a disease or condition in which Src tyrosine kinase plays a role in a subject in need thereof.

[0046] [Invention 1025] A polymorph of Invention 1001 for use in the manufacture of a medicament for the treatment or prevention of a disease or condition in which Src tyrosine kinase plays a role in a subject in need thereof.

[0047] [Invention 1026] Use of a polymorph of Invention 1001 in the manufacture of a medicament for the treatment or prevention of a disease or condition in which Src tyrosine kinase plays a role in a subject in need thereof. [Brief explanation of the drawings]

[0048] [Figure 1] XRPD overlays of Forms A, B and C as described above and generated from screening are provided. [Figure 2] The XRPD of Form C is provided below. [Figure 3] A DSC / TGA overlay of Form C is provided. [Figure 4] An XRPD overlay of a mixture of Forms C and B obtained from a solvent slurry experiment is provided. [Figure 5] An XRPD overlay of Form A obtained from a liquid vapor diffusion experiment is provided. [Figure 6] An XRPD overlay of Form B obtained from a liquid vapor diffusion experiment is provided. [Figure 7]An XRPD overlay of Form A obtained from the slow cooling experiment is provided. [Figure 8] An XRPD overlay of Form B obtained from the slow cooling experiment is provided. [Figure 9] 1 shows an XRPD overlay of Form A obtained from an anti-solvent addition experiment. [Figure 10] XRPD overlays of a mixture of Forms A and B (CHCl3 / IPA) and of Form B obtained from anti-solvent addition experiments are shown. [Figure 11] The XRPD of Form A after air drying is given below. [Figure 12] A DSC / TGA overlay of Form A after air drying is shown. [Figure 13] The XRPD of Form A is given (wet cake, air dried and vacuum dried). [Figure 14] The DSC thermogram of Form A after vacuum drying is shown. [Figure 15] The XRPD of Form B is provided below. [Figure 16] A DSC / TGA overlay of Form B is provided. [Figure 17] The DVS of Form A at 25° C. and up to 95% relative humidity (RH) is given. [Figure 18] XRPD overlays of Form A before DVS and after DVS experiments at 25° C. and up to 95% RH are provided. [Figure 19] The DVS of Form B at 25° C. and up to 95% RH is given. [Figure 20] XRPD overlays of Form B before DVS and after DVS experiments at 25° C. and up to 95% RH are provided. [Figure 21] The DVS of Form C at 25° C. and up to 95% RH is given. [Figure 22] XRPD overlays of Form C before DVS and Form B after DVS experiments at 25° C. and up to 95% RH are provided. [Figure 23] PLM images of Form A are shown below. [Figure 24]PLM images of Form B are shown below. [Figure 25] PLM images of Form C are shown. [Figure 26] The XRPD of Form A at ambient storage conditions is provided. [Figure 27] The XRPD of Form A at 25° C. / 60% RH storage conditions is provided. [Figure 28] The XRPD of Form A at 40° C. / 75% RH storage conditions is provided. [Figure 29] The XRPD of Form A at 55°C / 75% RH storage conditions is provided. [Figure 30] The XRPD of Form B at ambient storage conditions is provided. [Figure 31] The XRPD of Form B at 25° C. / 60% RH storage conditions is given below. [Figure 32] The XRPD of Form B at 40° C. / 75% RH storage conditions is provided. [Figure 33] The XRPD of Form B at 55°C / 75% RH storage conditions is given below. [Figure 34] The XRPD of Form C at ambient storage conditions is provided. [Figure 35] The XRPD of Form C at 25° C. / 60% RH storage conditions is provided. [Figure 36] The XRPD of Form C at 40° C. / 75% RH storage conditions is provided. [Figure 37] The XRPD of Form C at 55°C / 75%RH storage conditions is provided. DETAILED DESCRIPTION OF THE INVENTION

[0049] Detailed Description solid form The present application provides a compound having the following structure: [ka]

[0013] A solid form of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide (Compound A) is provided.

[0050] 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 an anhydrous form of Compound A. In one embodiment, the present application provides a polymorph of an anhydrous form of Compound A.

[0051] Form A In one embodiment, the present application provides a Form A polymorph of Compound A ("Form A") characterized by an X-ray powder diffraction ("XRPD") pattern comprising peaks at approximately 4.3, 17.0, and 21.1 degrees 2θ using Cu Kα radiation. In one embodiment, Form A is characterized by an XRPD pattern comprising peaks at approximately 4.3, 6.4, 8.6, 12.7, 17.0, and 21.1 degrees 2θ using Cu Kα radiation. In one embodiment, Form A is characterized by an XRPD pattern comprising peaks at approximately the positions indicated in the table below.

[0052] Table 1. XRPD Peak List for Form A [Table 1]

[0053] In one embodiment, Form A is characterized by an XRPD pattern substantially similar to that set forth in Figure 1, 5, 7, 9, 11, 13, or 18. In one embodiment, Form A is characterized by an XRPD pattern substantially similar to that set forth in Figure 11.

[0054] In one embodiment, Form A appears as birefringent particles that are evident by PLM. In one embodiment, Form A appears as depicted in FIG.

[0055] In one embodiment, Form A is characterized by one endothermic event with an onset between about 124°C and about 135°C or between about 135°C and about 139°C, as measured by DSC. In one embodiment, Form A is characterized by multiple endothermic events with onsets between about 124°C and about 135°C and between about 135°C and about 139°C, as measured by DSC. In one embodiment, Form A is characterized by an endothermic event with an onset between about 124°C and about 135°C, as measured by DSC. In one embodiment, Form A is characterized by an endothermic event with an onset at about 128°C, as measured by DSC. In one embodiment, Form A is characterized by an endothermic event with an onset at about 135°C and about 139°C, as measured by DSC. In one embodiment, Form A is characterized by an endothermic event with an onset at about 138°C, as measured by DSC. In one embodiment, Form A is characterized by multiple endothermic events with onsets at approximately 128° C. and approximately 138° C., as measured by DSC. In one embodiment, Form A is characterized by a DSC thermogram substantially similar to that depicted in Figures 12 or 14.

[0056] In one embodiment, Form A exhibits a weight loss of approximately 0.36% from about 33° C. to about 150° C. as measured by TGA.

[0057] In one embodiment, Form A is non-hygroscopic. In one embodiment, Form A exhibits non-hygroscopicity (e.g., less than 0.2% w / w water uptake) at 25°C to 45°C and 0-80% RH. In one embodiment, Form A exhibits a DVS isotherm substantially similar to that set forth in Figure 17 at 25°C and up to 95% RH. In one embodiment, the XRPD pattern of Form 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 Form A after DVS at 25°C and up to 95% RH is substantially similar to that set forth in Figure 18.

[0058] In one embodiment, Form A is stable under various storage conditions. In one embodiment, Form A is stable at about 20°C to about 250°C, about 20°C to about 200°C, about 20°C to about 180°C, about 20°C to about 160°C, about 20°C to about 140°C, about 20°C to about 120°C, about 20°C to about 100°C, about 20°C to about 80°C, about 20°C to about 60°C, or about 20°C to about 40°C 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 about 60% RH to about 98% RH (e.g., 75% RH or 96% 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 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 percent purity (LCAP) results show no significant decrease in area percent purity for Form A at selected conditions at predetermined time points over the 8-week study, as shown in the table below.

[0059] Table 2. HPLC results for Form A [Table 2]

[0060] In one embodiment, Form A exhibits no change in physical form under ambient conditions for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 26. In one embodiment, Form A exhibits no change in physical form under 25°C / 60% RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 27. In one embodiment, Form A exhibits no change in physical form under 40°C / 75% RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 28. In one embodiment, Form A exhibits no change in physical form under 55°C / 75% RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 29.

[0061] In one embodiment, Form A is soluble in aqueous solution. In one embodiment, Form A is completely soluble (>20 mg / ml) in aqueous solution (e.g., water) at room temperature. 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 being dissolved.

[0062] In one embodiment, Form A is anhydrous.

[0063] In one embodiment, Form A is prepared via liquid vapor diffusion. In one embodiment, Form A is prepared by diffusing the vapor of an anti-solvent into a concentrated solution of Compound A in a solvent. In one embodiment, the solvent is methanol or ethanol and the anti-solvent is hexane.

[0064] In one embodiment, Form A is prepared by slow cooling of a solution of Compound A.

[0065] 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.

[0066] In one embodiment, Form A is prepared via anti-solvent addition. In one embodiment, Form A is formed when an anti-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 anti-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 antisolvent, when methanol is the solvent and water is the antisolvent, when acetone is the solvent and heptane is the antisolvent, when tetrahydrofuran is the solvent and MTBE is the antisolvent, when dioxane is the solvent and water is the antisolvent, when dioxane is the solvent and MIBK is the antisolvent, when ethanol is the solvent and isopropyl acetate is the antisolvent, when 2-Me-THF is the solvent and toluene is the antisolvent, when ethyl acetate is the solvent and MIBK is the antisolvent, or when dichloromethane is the solvent and MIBK is the antisolvent. In one embodiment, a mixture of Form A and Form B is formed when chloroform is the solvent and isopropanol is the antisolvent.

[0067] Form B In one embodiment, the present application provides the Form B polymorph of Compound A ("Form B"), characterized by an XRPD pattern comprising peaks at approximately 6.4, 19.3, and 19.9 degrees 2θ using Cu Kα radiation. In one embodiment, Form B is characterized by an XRPD pattern comprising peaks at approximately 6.4, 7.2, 19.3, 19.9, 21.6, 22.1, and 22.6 degrees 2θ using Cu Kα radiation. In one embodiment, Form B is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below.

[0068] Table 3: XRPD Peak List for Form B [Table 3]

[0069] In one embodiment, Form B is characterized by an XRPD pattern substantially similar to that set forth in Figure 1, 6, 8, 10, 15, or 20. In one embodiment, Form B is characterized by an XRPD pattern substantially similar to that set forth in Figure 15.

[0070] In one embodiment, Form B appears as birefringent particles evident by PLM. In one embodiment, Form A appears as depicted in FIG.

[0071] In one embodiment, form B is characterized by an endothermic event with an onset of approximately 133° C. to approximately 138° C. as measured by DSC. In one embodiment, form B is characterized by an endothermic event with an onset of approximately 136° C. as measured by DSC. In one embodiment, form B is characterized by a DSC thermogram substantially similar to that depicted in FIG.

[0072] In one embodiment, Form B exhibits a weight loss of approximately 0.20% from about 33° C. to about 150° C. as measured by TGA.

[0073] In one embodiment, Form B is non-hygroscopic. In one embodiment, Form B exhibits non-hygroscopicity (e.g., less than 0.2% w / w water uptake) at 25°C to 45°C at 0-80% RH. In one embodiment, Form B exhibits a DVS isotherm at 25°C and up to 95% RH substantially similar to that set forth in Figure 19. 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 set forth in Figure 20.

[0074] In one embodiment, Form B is stable under various storage conditions. In one embodiment, Form B is stable at about 20°C to about 250°C, about 20°C to about 200°C, about 20°C to about 180°C, about 20°C to about 160°C, about 20°C to about 140°C, about 20°C to about 120°C, about 20°C to about 100°C, about 20°C to about 80°C, about 20°C to about 60°C, or about 20°C to about 40°C 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 about 60% RH to about 98% RH (e.g., 75% RH or 96% 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 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 percent purity (LCAP) results show no significant decrease in area percent purity for Form B at selected conditions at predetermined time points over the 8-week study, as shown in the table below.

[0075] Table 4. HPLC results for Form B [Table 4]

[0076] In one embodiment, Form B exhibits no change in physical form under ambient conditions for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 30. In one embodiment, Form B exhibits no change in physical form under 25°C / 60% RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 31. In one embodiment, Form B exhibits no change in physical form under 40°C / 75% RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 32. In one embodiment, Form B exhibits no change in physical form under 55°C / 75% RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 33.

[0077] In one embodiment, Form B is soluble in aqueous solutions. In one embodiment, Form B is completely soluble (>20 mg / ml) in aqueous solutions (e.g., water) at room temperature. 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 being dissolved.

[0078] In one embodiment, Form B is anhydrous.

[0079] In one embodiment, Form B is prepared by slurrying Compound A in a solvent. In one embodiment, Form B is prepared by slurrying Compound A in chloroform. In one embodiment, the slurrying is carried out at room temperature. In one embodiment, the slurrying is carried out with continuous stirring. In one embodiment, slurrying Compound A in chloroform produces a mixture of Form B and Form C.

[0080] In one embodiment, Form B is prepared via liquid vapor diffusion. In one embodiment, Form B is prepared by diffusing the vapor of an anti-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 anti-solvent is MTBE. In one embodiment, the solvent is chloroform and the anti-solvent is MTBE.

[0081] In one embodiment, Form B is prepared by slow cooling of a solution of Compound A.

[0082] 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.

[0083] In one embodiment, Form B is prepared via anti-solvent addition. In one embodiment, Form B is formed when an anti-solvent is added to a solution of Compound A in chloroform, methanol, acetone, or acetonitrile. In one embodiment, the anti-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 anti-solvent, when acetone is the solvent and toluene is the anti-solvent, or when acetonitrile is the solvent and isopropanol is the anti-solvent. In one embodiment, a mixture of Form A and Form B is formed when chloroform is the solvent and isopropanol is the anti-solvent.

[0084] Form C In one embodiment, the present application provides the Form C polymorph of Compound A ("Form C"), characterized by an XRPD pattern comprising peaks at approximately 7.9, 17.2, and 17.6 degrees 2θ using Cu Kα radiation. In one embodiment, Form C is characterized by an XRPD pattern comprising peaks at approximately 5.8, 7.9, 8.7, 17.2, and 17.6 degrees 2θ using Cu Kα radiation. In one embodiment, Form C is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below.

[0085] Table 5. XRPD Peak List for Form C [Table 5]

[0086] In one embodiment, Form C is characterized by an XRPD pattern substantially similar to that depicted in Figure 1, 6, 8, 10, or 15. In one embodiment, Form C is characterized by an XRPD pattern substantially similar to that depicted in Figure 1 or Figure 2.

[0087] In one embodiment, Form C appears as birefringent particles that are evident by PLM. In one embodiment, Form A appears as depicted in FIG.

[0088] In one embodiment, Form C is characterized by an endothermic event with an onset of approximately 136° C. to approximately 140° C. as measured by DSC. In one embodiment, Form C is characterized by an endothermic event with an onset of approximately 136° C. as measured by DSC. In one embodiment, Form C is characterized by a DSC thermogram substantially similar to that depicted in FIG.

[0089] In one embodiment, Form C exhibits a weight loss of approximately 0.18% from about 33° C. to about 150° C. as measured by TGA.

[0090] In one embodiment, Form C is non-hygroscopic. In one embodiment, Form C exhibits non-hygroscopicity (e.g., less than 0.2% w / w water uptake) at 25°C to 45°C at 0-80% RH. In one embodiment, Form C exhibits a DVS isotherm substantially similar to that set forth in Figure 21 at 25°C and up to 95% RH. In one embodiment, the XRPD pattern of Form 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 Form C after DVS at 25°C and up to 95% RH is substantially similar to that set forth in Figure 22.

[0091] In one embodiment, Form C is stable under various storage conditions. In one embodiment, Form C is stable at about 20°C to about 250°C, about 20°C to about 200°C, about 20°C to about 180°C, about 20°C to about 160°C, about 20°C to about 140°C, about 20°C to about 120°C, about 20°C to about 100°C, about 20°C to about 80°C, about 20°C to about 60°C, or about 20°C to about 40°C 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 about 20°C to about 250°C, about 20°C to about 200°C, about 20°C to about 180°C, about 20°C to about 160°C, about 20°C to about 140°C, about 20°C to about 120°C, about 20°C to about 100°C, about 20°C to about 80°C, about 20°C to about 60°C, or about 20°C to about 40°C. Form C is stable at approximately 60% RH to approximately 98% RH (e.g., 75% RH or 96% RH) for 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 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 Percent Purity (LCAP) results show no significant decrease in area percent purity for Form C at selected conditions at given time points over the 8-week study, as shown in the table below.

[0092] Table 6. HPLC results for Form C [Table 6]

[0093] In one embodiment, Form C exhibits no change in physical form under ambient conditions for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 34. In one embodiment, Form C exhibits no change in physical form under 25°C / 60% RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 35. In one embodiment, Form C exhibits no change in physical form under 40°C / 75% RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 36. In one embodiment, Form C exhibits no change in physical form under 55°C / 75% RH for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks, as depicted in Figure 37.

[0094] In one embodiment, Form C is insoluble in aqueous solutions. In one embodiment, Form C is insoluble (e.g., <1 mg / mL) in aqueous solutions (e.g., water) at room temperature and when heated to 50°C. In one embodiment, Form C is soluble (e.g., >1 mg / mL) 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. In one embodiment, Form C is insoluble (e.g., <1 mg / mL) in n-heptane and water at room temperature and when heated to 50°C. In one embodiment, Form C is insoluble in MTBE solution at room temperature but soluble when heated to 50°C.

[0095] In one embodiment, Form C is anhydrous.

[0096] In one embodiment, Form C is prepared by slurrying Compound A in a solvent. In one embodiment, Form C is prepared by slurrying 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 slurrying Compound A in a 1:3 mixture of chloroform / MTBE. In one embodiment, Form C is prepared from slurrying Compound A in a 1:3 mixture of methanol / water. In one embodiment, Form C is prepared from slurrying Compound A in a 1:3 mixture of acetone / heptane. In one embodiment, Form C is prepared from slurrying Compound A in a 1:3 mixture of tetrahydrofuran / toluene. In one embodiment, Form C is prepared by slurrying Compound A in a mixture of dioxane / isopropanol (1:3). In one embodiment, Form C is prepared by slurrying Compound A in a mixture of ethanol / dichloromethane (1:1). In one embodiment, Form C is prepared by slurrying Compound A in a mixture of acetonitrile / ethyl acetate (1:1). In one embodiment, Form C is prepared by slurrying Compound A in a mixture of ethyl acetate / heptane (1:1). In one embodiment, Form C is prepared by slurrying Compound A in a mixture of acetonitrile / water (1:1). In one embodiment, Form C is prepared by slurrying Compound A in a mixture of dichloromethane / MTBE (1:1). In one embodiment, Form C is prepared by slurrying Compound A in a mixture of MIBK / toluene (1:1). In one embodiment, Form C is prepared by slurrying Compound A in a mixture of 2-Me-THF / isopropyl acetate (1:1). In one embodiment, Form C is prepared by slurrying Compound A in a mixture of acetonitrile / isopropanol (1:1). In one embodiment, Form C is prepared by slurrying Compound A in a mixture of ethyl acetate / toluene (1:1).In one embodiment, Form C is prepared by slurrying Compound A in a 1:1 mixture of methanol / heptane. In one embodiment, Form C is prepared by slurrying Compound A in a 1:1 mixture of acetone / water. In one embodiment, Form C is prepared by slurrying Compound A in a 1:1 mixture of tetrahydrofuran / MTBE. In one embodiment, slurrying is carried out at room temperature. In one embodiment, slurrying is carried out with continuous stirring. In one embodiment, slurrying Compound A in chloroform produces a mixture of Form B and Form C. In one embodiment, Form C is slurried in acetonitrile, ethyl acetate, MIBK, dichloromethane, isopropanol, toluene, isopropyl acetate, or heptane at 50° C. In one embodiment, seeds of Form C are added prior to slurrying.

[0097] In one embodiment, Form C is prepared via solid vapor diffusion. In one embodiment, Form C is prepared by interacting solvent vapor with a solid form of Compound A. In one embodiment, Form C is prepared by interacting solvent vapor with Compound A for a specific period of time. In one embodiment, Form C is prepared by interacting solvent vapor with a solid form of Compound A for one day. In one embodiment, Form C is prepared by interacting solvent vapor with a solid form of Compound A for two days. In one embodiment, Form C is prepared by interacting solvent vapor with a solid form of Compound A for three days. In one embodiment, Form C is prepared by interacting solvent vapor with a solid form of Compound A for four days. In one embodiment, Form C is prepared by interacting solvent vapor with a solid form of Compound A for five days. In one embodiment, Form C is prepared by interacting solvent vapor with a solid form of Compound A for six days. In one embodiment, Form C is prepared by interacting solvent vapor with a solid form of Compound A for seven days. In one embodiment, Form C is prepared by allowing a solvent vapor to interact at room temperature with a solid form of Compound A. In one embodiment, Form C is prepared from solid vapor evaporation, and the solvent is dichloromethane, ethyl acetate, MTBE, acetonitrile, or DMF.

[0098] In one embodiment, Form C is prepared via liquid vapor diffusion. In one embodiment, Form C is prepared by diffusing the vapor of an anti-solvent into a concentrated solution of Compound A in a solvent. In one embodiment, the solvent is dichloromethane and the anti-solvent is acetone.

[0099] In one embodiment, Form C is prepared by slow cooling of a solution of Compound A.

[0100] 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.

[0101] 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.

[0102] The terms "crystalline polymorph," "crystalline polymorph," "crystalline form," "polymorph," or "polymorphic form" refer to crystalline structures in which a compound (e.g., its free base, salt, or solvate) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, crystalline shapes, optical and electrical properties, stability, and solubility. The crystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystalline form to dominate. Crystalline polymorphs 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 a single or mixture of crystalline forms, or anhydrous or hydrated crystalline forms.

[0103] The differences in physical properties exhibited by polymorphs are the result of the arrangement or conformation 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 dissolution rate (an important factor in bioavailability). Differences in stability can also be due to changes in chemical reactivity (e.g., differential oxidation, such that a dosage form fades more rapidly when composed of one polymorph than when composed of another), mechanical properties (e.g., tablets crumble on storage as a kinetically favored polymorph converts to a thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are more susceptible to disintegration at high humidity). In extreme cases, as a result of solubility / dissolution differences, some polymorphic transitions can result in a lack of efficacy or, at the other extreme, toxicity. Additionally, the physical properties of the crystals may be important in processing; for example, one polymorph may be more prone to forming solvates, or may be difficult to filter and wash away impurities (e.g., particle shape and size distribution may differ between polymorphs). do.

[0104] The term "amorphous form" refers to a non-crystalline solid form of a substance.

[0105] Furthermore, the compounds of the present application (e.g., free bases and salts, as well as amorphous forms, crystalline forms, and polymorphs thereof) can exist in either hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules or in unsolvated form. Non-limiting examples of hydrates include hemihydrates, monohydrates, dihydrates, etc. Non-limiting examples of solvates include DMSO solvates, DMSO hemisolvates, etc.

[0106] All forms of the compounds of the present application are contemplated, either in admixture or in pure or substantially pure form, including crystalline forms of racemic mixtures and crystalline forms of individual isomers.

[0107] Polymorphs of a molecule can be obtained by a number of methods known in the art, including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation.

[0108] Techniques for characterizing solid forms of a compound, such as polymorphs, include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, 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.

[0109] As used herein, the term "solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvate is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one substance with one or more water molecules, where water retains its molecular state as HO, and such combinations can form one or more hydrates. For example, the solvate may be a DMSO solvate, a dichloromethane (DCM) solvate, a methyl ethyl ketone (MEK) solvate, or a tetrahydrofuran (THF) solvate.

[0110] As used herein, the terms "unsolvated" or "desolvated" refer to solid state forms of a substance that do not contain a solvent (e.g., crystalline forms, amorphous forms, and polymorphs).

[0111] As used herein, the term "pure" refers to a compound that is about 90-100%, preferably 95-100%, and more preferably 98-100% (wt / wt) or 99-100% (wt / wt) pure, e.g., having less than about 10%, less than about 5%, less than about 2%, or less than about 1% of impurities present. Such impurities include, for example, decomposition products, oxidation products, solvents, and / or other undesirable impurities.

[0112] As used herein, a compound is "stable" if 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) over a period of time (e.g., 1 week, 2 weeks, 3 weeks, and 4 weeks). A compound is not considered stable under certain conditions when degradation impurities appear or 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, a compound is less stable if it exhibits high hygroscopicity (i.e., a tendency to absorb water under high humidity conditions). Thus, in some embodiments, the stability of a compound can be measured by assessing 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).

[0113] As used herein, the term "mixing" means combining, blending, stirring, shaking, rolling or agitating. The term "agitating" means mixing, shaking, agitating or rotating. The term "agitating" means mixing, shaking, agitating or rotating.

[0114] Unless expressly stated otherwise, the terms "approximately" and "about" are synonymous. In one embodiment, "approximately" and "about" represent the stated amount, value, or time period ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5%. In another embodiment, "approximately" and "about" represent the recited amount, value, or time period ±10%, ±8%, ±6%, ±5%, ±4%, or ±2%. In yet another embodiment, "approximately" and "about" represent the recited amount, value, or time period ±5%. In yet another embodiment, "approximately" and "about" represent the recited amount, value, or time period ±2% or ±1%.

[0115] When the terms "approximately" and "about" are used when describing XRPD peaks, these terms refer to the listed X-ray powder diffraction peak ±0.3°2θ, ±0.2°2θ, or ±0.1°2θ. In another embodiment, the terms "approximately" and "about" refer to the listed X-ray powder diffraction peak ±0.2°2θ. In another embodiment, the terms "approximately" and "about" refer to the listed X-ray powder diffraction peak ±0.1°2θ.

[0116] When used when describing a temperature or temperature range, the terms "approximately" and "about" refer to the represented temperature or temperature range ±5° C., ±2° C., or ±1° C. In another embodiment, the terms "approximately" and "about" refer to the represented temperature or temperature range ±2° C.

[0117] Methods and Assays Synthesis of Compound A Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protecting groups, can be obtained from the relevant scientific literature or from standard reference textbooks in the field. While not limited to any one or a few 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, PGM Protective Groups in Organic Synthesis, 3 rd ; John Wiley & Sons: New York, 1999.

[0118] Methods for preparing the free base of Compound A are described in U.S. Pat. Nos. 7,300,931, 7,851,470, and 7,939,529, the entire contents of each of which are incorporated herein by reference.

[0119] X-ray Powder Diffraction (XRPD) XRPD analysis is performed using a diffractometer operating in reflector mode. The 2-theta position is calibrated against standards before running the experiment.

[0120] 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 while the change in sample weight is recorded.

[0121] Differential Scanning Calorimetry (DSC) Differential scanning calorimetry (DSC) is performed in sealed plates using a differential scanning calorimeter. Samples and references are heated from room temperature to 300°C and the resulting heat flow response is monitored.

[0122] Dynamic Vapor Sorption (DVS) was measured using a Surface Measurement Systems (SMS) DVS Intrinsic. Tests were performed at 25°C while the RH was varied from 0% to 95%, in 10% increments from 0% to 90% RH, and in 5% increments 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.

[0123] 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 Forms A, B, and C after storage under various conditions. Chemical stability was estimated by measuring and comparing the area percent of the material peaks at various time points.

[0124] Solubility Estimation The solubility of the present solid forms in various solvents is measured. Solvent is added to the sample in 100 μL steps until a total volume of 100 μL is reached, followed by the addition of solvent until the sample dissolves or the concentration is less than 1.0 mg / mL. The approximate solubility is then calculated.

[0125] Polymorph Screening Method Slurry Compound A is suspended in a solvent and stirred. The solid prepared by slurry is then isolated and analyzed by various methods for characterization of solids, such as XRPD.

[0126] Anti-solvent addition: Concentrated stock solutions of Compound A in various solvents are prepared. The solutions are stirred and the anti-solvent is added quickly to induce precipitation. The solids are then isolated and analyzed by various methods for characterizing solids, such as XRPD.

[0127] Concentrated stock solutions of Compound A in various solvents are prepared, heated, and slowly cooled to induce precipitation. The solids are then isolated and analyzed by various methods for characterizing solids, such as XRPD.

[0128] Liquid Vapor Diffusion: Concentrated stock solutions of Compound A in various solvents are prepared in inner vials and placed inside larger sealed vials containing anti-solvents. The solids are then isolated and analyzed by various methods for characterizing solids, such as XRPD.

[0129] Solid Vapor Diffusion A sample of Compound A is prepared in an inner vial and placed inside a larger vial containing a volatile solvent and sealed. The 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 characterizing solids, such as XRPD.

[0130] 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 a polymer. The solid is then isolated and analyzed by various methods for characterizing solids, such as XRPD.

[0131] Pharmaceutical Compositions The present application also provides pharmaceutical compositions comprising one or more compounds of the present application (e.g., solid forms, amorphous forms, crystalline forms, and polymorphs of Compound A) in combination with at least one pharmaceutically acceptable excipient or carrier. In one embodiment, the pharmaceutical composition comprises a solid form of Compound A of the present application and a pharmaceutically acceptable excipient, and the pharmaceutical composition is formulated for topical administration.

[0132] A "pharmaceutical composition" is a formulation containing a 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 may be in any of a variety of forms, such as, for example, a capsule, an IV bag, a tablet, a single pump of an aerosol inhaler, or a vial. The amount of active ingredient (e.g., one or more formulations of the disclosed compounds) in a unit dose of the composition is an effective amount and will vary according to the specific treatment involved. Those skilled in the art will recognize that routine modifications to dosages are sometimes necessary depending on the age and condition of the patient. Dosages will also depend on the route of administration. Various routes are contemplated, including topical, oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. 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 aspect, the active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0133] As used herein, the term "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or challenge, commensurate with a reasonable benefit / risk ratio. The term "compounds," "materials," "compositions," "carriers," and / or "dosage forms" refers to compounds, materials, compositions, carriers, and / or dosage forms that

[0134] A "pharmaceutically acceptable excipient" generally refers to an excipient that is safe, non-toxic, and not biologically or otherwise undesirable, and that is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for human pharmaceutical use as well as veterinary use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0135] The pharmaceutical compositions of the present 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 can contain the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate, or phosphate; and an agent for adjusting osmolality such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0136] The compounds or pharmaceutical compositions of the present 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 the present application can be injected directly into a tumor, injected into the bloodstream or a body cavity, taken orally, or applied to the skin using a patch. The selected dose should be sufficient to constitute effective treatment, but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, precancer, etc.) and the patient's health should preferably be closely monitored during and for a reasonable period after treatment.

[0137] The pharmaceutical compositions of the present application may also be formulated for topical administration. Topical compositions may be administered to affected areas of a subject, such as the skin. The affected areas of the skin may be located on one or more areas independently selected from the scalp, forehead, forearm, 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 on one or more areas independently selected from the scalp, forehead, forearm, face, nose, ears, eyelids, lips, neck, arms, hands, torso, legs, and feet.

[0138] As used herein, the term "therapeutically effective amount" refers to an amount of an agent 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 method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician. In a preferred aspect, the disease or condition to be treated is cancer. In another aspect, the disease or condition to be treated is a cell proliferative disorder.

[0139] For any compound, the therapeutically effective amount can be estimated initially in cell culture assays, for example, of neoplastic cells, or in animal models, 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. Therapeutic / prophylactic efficacy and toxicity, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 The LD (the dose lethal to 50% of the population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending upon the dosage form used, sensitivity of the patient, and the route of administration.

[0140] Dosage and administration are adjusted to provide sufficient levels of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's general health, the subject's age, weight, and sex, diet, timing and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3-4 days, weekly, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0141] Pharmaceutical compositions containing the active compounds of the present application can be prepared in a generally known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, powdering, emulsifying, encapsulating, encapsulating, or lyophilizing processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and / or adjuvants that facilitate the processing of the active compounds into pharmaceutically usable preparations. Of course, the appropriate formulation depends on the selected route of administration.

[0142] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. 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 should be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0143] Sterile injectable solution can be prepared by incorporating active compound in the required amount in suitable solvent with one or combination of the above-listed components as needed, then sterilizing by filtration.Generally, dispersion is prepared by incorporating active compound into sterile vehicle that contains basic dispersion medium and other components required from the above-listed components.For the preparation of sterile powder for sterile injectable solution, the method of preparation is vacuum drying and freeze-drying, which produces powder of active ingredient and any other desired component from the solution of active ingredient and any other desired component that has been previously sterilized and filtered.

[0144] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier. Oral compositions can be enclosed 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, troches, 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 swished, expectorated, or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavor.

[0145] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0146] Systemic administration can also be via transmucosal or transdermal routes. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, for transmucosal administration, detergents, bile acids, and fusidic acid derivatives. Transmucosal administration can be achieved through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams, as generally known in the art.

[0147] The active compounds can be prepared with pharmaceutically acceptable carriers that can protect the compound against rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art. Materials can also be obtained commercially. Liposomal suspensions (including liposomes targeted 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. Pat. No. 4,522,811.

[0148] For ease of administration and uniformity of dosage, it is particularly advantageous to prepare oral or parenteral compositions in dosage unit form.Dosage unit form as used herein refers to a physically discrete unit suitable as a unitary dosage for the subject to be treated, and each unit contains a predetermined amount of active compound calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The specification for dosage unit form of the present disclosure is determined and directly depends on the inherent characteristics of active compound and the specific therapeutic effect to be achieved.

[0149] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the patient being treated, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors influencing the selected dosage. Generally, the dose should be sufficient to cause a delay, preferably regression, of tumor growth, 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 amount of an agent is one that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. For example, tumor regression in a patient can be measured with reference to tumor diameter. A decrease in tumor diameter indicates regression. Regression can also be indicated by failure of tumor to recur after treatment has ceased. As used herein, the term "dosage-effective manner" refers to a dose-effective manner in which the tumor is administered. It represents the amount of active compound required to produce a desired biological effect in an animal or cell.

[0150] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0151] The compounds of the present application may be administered topically, orally, nasally, transdermally, pulmonary, inhalationally, bucally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compounds are administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0152] Techniques for formulation and administration of the disclosed compounds of this disclosure are described in Remington: The Science and Practice of Pharmacy, 1999. th, edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0153] Unless otherwise specified, all percentages and ratios used herein are by weight. Other features and advantages of the present application will be apparent from the different examples. The examples provided illustrate different components and methods useful in carrying out the present application. The examples do not limit the present application. Based on the present application, one skilled in the art can identify and utilize other components and methods useful for carrying out the present application.

[0154] Treatment method The present application provides a method for treating a cell proliferative disorder in a subject in need thereof by administering to the subject a therapeutically effective amount of one or more compounds of the present application (e.g., solid, amorphous, crystalline, or polymorphic form). The present application also provides a method of protecting against a cell proliferative disorder in a subject in need thereof by administering to the subject a therapeutically effective amount of one or more compounds of the present application (e.g., solid, amorphous, crystalline, or polymorphic form). The cell proliferative disorder can be cancer or a precancerous condition. The present application further provides the use of one or more compounds of the present application for the preparation of a medicament useful for the treatment or prevention of a cell proliferative disorder.

[0155] As used herein, a "subject in need thereof" is a subject who has a cell proliferative disorder or who is at increased risk of developing a cell proliferative disorder compared to the population as a whole. A subject in need thereof can have a precancerous condition. A "subject" includes a mammal. The mammal can be any mammal, for example, a human, a primate, a bird, a mouse, a rat, a fowl, a dog, a cat, a cow, a horse, a goat, a camel, a sheep, or a pig. Preferably, the mammal is a human.

[0156] As used herein, the term "cell proliferative disorder" refers to a condition in which uncontrolled or abnormal proliferation of cells, or both, can lead to the development of an undesirable condition or disease, which may be cancerous or non-cancerous, e.g., a psoriatic condition. As used herein, the term "psoriatic condition" or "psoriasis" refers to a disorder involving keratinocyte hyperproliferation, inflammatory cell infiltration, and cytokine alterations. Cell proliferative disorders include precancerous or precancerous conditions. Cell proliferative disorders include cancer. Exemplary cell proliferative disorders encompass a variety of conditions in which cell division is deregulated. Exemplary cell proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, precancerous conditions, intraepithelial neoplasia, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immune system tumors, blood system 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 greater than or exceeding that expected or observed among adjacent or juxtaposed cells within the same tissue.

[0157] The term "cancer" includes solid tumors as well as hematologic tumors and / or malignancies. A "precancerous cell" or "precancerous cell" is a cell that exhibits a cell proliferative disorder that is a precancer or precancerous condition. A "cancer cell" or "cancerous cell" is a cell that exhibits a cell proliferative disorder that is cancer.

[0158] Exemplary non-cancerous conditions or disorders include rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout and other joint conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; actinic keratosis; actinic keratosis (solar keratosis); ichthyosis; atopic dermatitis; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic kidney disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neurotrauma; Alzheimer's disease; Huntington's disease. These include, but are not limited to, Tony'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; tendonitis; tenosynovitis; herniated, herniated or prolapsed disc syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcosis; bone resorption diseases such as osteoporosis; graft versus host reaction; multiple sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as shingles, herpes simplex type I or II, influenza virus and cytomegalovirus; and diabetes.

[0159] Exemplary cancers include adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodeimal tumor, visual pathway and and hypothalamic glioma, breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Sézary 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 tumor, ovarian germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, pancreatic islet cell tumor (endocrine pancreas), Kaposi's sarcoma, kidney cancer, renal cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, hairy cell leukemia, lip and oral cavity cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, Malignant mesothelioma, mesothelioma, metastatic squamous cell neck cancer, 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 cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, prostate cancer,These include, but are not limited to, rectal cancer, renal pelvis and ureter, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family of sarcoma tumors, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (stomach) cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary tract, gestational trophoblastic neoplasia, urethral cancer, endometrial cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0160] "Actinic keratosis," or "AK," is a common precancerous skin condition caused by excessive exposure to ultraviolet light. AK is a rough, dry, brown, pink, or red spot (lesion) that often appears 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 are exposed to prolonged, intense sunlight, such as the hands, back, and other areas on the trunk and legs. AK is most common in fair-skinned, middle-aged or elderly individuals. Subjects with AK may have a single lesion or multiple lesions. AK can lead to squamous cell carcinoma.

[0161] As used herein, the term "torso" refers to any part of a subject that is not an arm, leg, or head.

[0162] Clinical variants of AK include classic (or common), hypertrophic (or hyperkeratotic), atrophic, keratotic AK, pigmented AK, actinic cheilitis, and Bowen-like AK. Unless expressly stated otherwise, the methods described herein can be applied to all clinical variants, including those listed herein.

[0163] Treatments for AK include cryosurgery, surgical excision and / or debridement of the affected area, photodynamic therapy, and topical preparations (e.g., creams, gels, patches, etc.) containing steroids, fluorouracil, diclofenac, imiquimod, and 5-aminolevulinic acid (Ameluz®). An approved treatment for AK is Picato (Ingenol Mebutate)®, a gel containing ingenol mebutate (0.015% or 0.05%). This gel is applied to the affected area once daily for three consecutive days on the face or scalp (0.015%) or once daily for two consecutive days on the trunk or limbs (0.05%).

[0164] Skin toxicity associated with the use of other AK treatments, such as Picato (Ingenol Mebutate)®, is known to result in unwanted side effects or adverse reactions, namely local skin reactions (LSRs), including vesiculation, pustulation, erosion, ulceration, redness, swelling, peeling, scaling, hard lumps, dryness, pus, and blistering. Other side effects include application site pain, application site pruritus, application site irritation, application site swelling, application site burning, application site infection, periorbital edema, nasopharyngitis, chills, sore throat, ptosis, swollen eyes, hypopigmentation, hyperpigmentation, and headache.

[0165] The present application provides a method for treating or preventing a disease or condition (e.g., a cell proliferative disorder) in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role, the method comprising administering to a subject in need of treatment or prevention of the disease or condition (e.g., a cell proliferative disorder) in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role a therapeutically effective amount of a composition comprising any one of the solid forms of Compound A described herein.

[0166] The present application also provides a solid form of Compound A described herein for use in treating or preventing a disease or condition (e.g., a cell proliferative disorder) in which tyrosine kinases (e.g., Src tyrosine kinase) play a role in a subject in need thereof.

[0167] The present application provides a method for treating or preventing a disease or condition (e.g., a cell proliferative disorder) in which a tyrosine kinase (e.g., Src tyrosine kinase) plays a role, in a subject in need of such treatment or prevention. Also provided is a solid form of Compound A described herein for use in the manufacture of a medicament for the treatment or prevention of a sexual disorder.

[0168] The present application also provides the use of a solid form of Compound A described herein in the manufacture of a medicament for the treatment or prevention of a disease or condition (e.g., a cell proliferative disorder) in which tyrosine kinases (e.g., Src tyrosine kinase) play a role in a subject in need of such treatment or prevention.

[0169] In one embodiment, the disease or condition is precancer (e.g., a precancerous condition described herein). In one embodiment, the disease or condition is cancer (e.g., a cancerous condition described herein). In one embodiment, the disease or condition is AK.

[0170] In one aspect, the solid forms of the present application are administered or are for administration or are for the manufacture of a medicament for topical administration to a subject in need thereof.

[0171] In one aspect, the present application provides a method for treating or preventing actinic keratosis or psoriasis, comprising administering to a subject in need thereof a therapeutically effective amount of a solid form of the present application.

[0172] In one embodiment, for any of the methods disclosed herein, a solid form of Compound A is administered to the affected area of ​​the subject, and the affected area is the skin.

[0173] In one embodiment, for any of the methods disclosed herein, administration of a solid form of Compound A reduces the number and / or severity of local skin reactions or other adverse side effects in the subject compared to other treatments for actinic keratosis or psoriasis. In one embodiment, the other treatment for actinic keratosis or psoriasis comprises topical administration of ingenol mebutate.

[0174] In one aspect, for any of the methods disclosed herein, administration of a solid form of Compound A reduces the number of subjects with local skin reactions or other adverse side effects compared to other treatments for actinic keratosis or psoriasis.

[0175] In one aspect, for any of the methods disclosed herein, the local skin reaction is selected from the group selected from vesiculation, pustulation, sores, ulcers, redness, swelling, peeling, scaling, hard lumps, dryness, pus, and blistering.

[0176] In one aspect, for any of the methods disclosed herein, other side effects are selected from the group consisting of application site pain, application site pruritus, application site irritation, application site swelling, application site burning, application site infection, periorbital edema, nasopharyngitis, chills, sore throat, ptosis, puffy eyes, hypopigmentation, hyperpigmentation, and headache.

[0177] In one aspect, this application relates to treating a disease or condition (e.g., AK) described herein or the treatment of a disease or condition (e.g., AK) described herein. In one aspect, this application relates to preventing a disease or condition (e.g., AK) described herein or the prevention of a disease or condition (e.g., AK) described herein.

[0178] definition As used herein, "treating" or "treat" describes the management and care of a patient to combat a disease, condition, or disorder, and includes the administration of a compound of the present application to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder.

[0179] As used herein, "preventing" or "prevent" describes inhibiting the onset or eliminating the symptoms or complications of a disease, condition or disorder.

[0180] As used herein, the term "alleviating" describes a process by which the severity of a sign or symptom of a disorder is reduced. Importantly, a sign or symptom may be alleviated without being eliminated. In preferred embodiments, administration of a compound of the present application results in the elimination of a sign or symptom, although elimination is not required. An effective dosage is expected to reduce the severity of a sign or symptom. For example, a sign or symptom of a disorder, such as cancer, that can occur in multiple sites is alleviated if the severity of cancer is reduced in at least one of multiple sites.

[0181] The term "symptom" as used herein is defined as a disease, illness, injury, or a manifestation that something is not right in the body. A symptom is felt or noticed by the individual experiencing the symptom, but may not be easily noticed by others.

[0182] The term "sign" as used herein is also defined as an indication that something is not right in the body. However, a sign is defined as something that can be seen by a doctor, nurse, or other medical professional. [Example]

[0183] Example 1 X-ray Powder Diffraction (XRPD) XRPD analysis was performed using a Panalytical X'Pert on a Si zero background holder, scanning the sample between 3 and 40° 2-theta. 3 The measurements were performed on a Powder XRPD. The 2-theta position was calibrated against a Panalytical 640 Si powder standard. The test material was gently compressed onto a glass disk inserted into the sample holder. The XRPD was then run on a Panalytical X'Pert operating in reflectance mode. 3 The sample was loaded into a Powder XRPD diffractometer and analyzed using the following experimental conditions: [Table 7]

[0184] Example 2 Thermogravimetry / Differential Thermal Analysis (TGA) Test materials were weighed into open platinum plates and placed in a TA Instruments TA Q500 Thermogravimetry / Analyzer (TGA). The samples were then heated from room temperature to 300°C at a rate of 10°C / min, during which the change in sample weight was recorded. 3 / min sample purge flow rate and 25 cm 3 Nitrogen was used as the purge gas with a balance purge flow rate of 1000 psi / min.

[0185] Example 3 Differential Scanning Calorimetry (DSC) Test materials were weighed into aluminum DSC pans and sealed by crimping. The sample pans were then loaded into 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 scan rate of 10°C / min, and the resulting heat flow response was monitored. Nitrogen was used as the purge gas.

[0186] Example 4 Dynamic Vapor Sorption (DVS) Dynamic vapor sorption (DVS) was measured using SMS (Surface Measurement Systems) DVS Intrinsic with the following parameters: [Table 8]

[0187] 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.

[0188] Table 7. HPLC method parameters [Table 9]

[0189] Example 6: Estimation of Solubility The solubility of the present solid form in various solvents was measured according to the following procedure. Sample (approximately 2 mg) was weighed into a 4 mL glass vial. Solvent was added to the vial in steps of 50 μL per step until a total volume of 100 μL was reached, followed by 100 μL per step until the concentration was less than 1.0 mg / mL. The solution was thoroughly mixed after each addition by sonication for 2 minutes and vortexing for 1 minute. Solvent addition was terminated when the sample was dissolved or the concentration was less than 1.0 mg / mL. The volumes of solvent (V1 and V2) were recorded, and the approximate solubility was calculated.

[0190] Example 7 Polymorph Screening Method—Slurry 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). Centrifugation at 14,000 rpm for 5 minutes at room temperature was used to isolate solids for XRPD analysis. If no solid or gel was obtained, the slurry was transferred to a fume hood for evaporation.

[0191] Anti-solvent addition: A concentrated stock solution of compound A in a solvent was prepared. The solution was stirred, and the anti-solvent was quickly added to induce precipitation. The solid was isolated for XRPD analysis by filtration or centrifugation. If no solid was obtained, the solution was transferred to a fume hood for evaporation.

[0192] Slow Cooling: A concentrated stock solution of Compound A in a solvent was prepared. The suspension was heated to 50°C and held 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. To induce precipitation, the solution was cooled to 5°C. Solids were isolated for XRPD analysis by filtration or centrifugation. Unprecipitated samples were cooled to -20°C to induce precipitation.

[0193] 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 antisolvent. The solid was isolated for XRPD analysis by filtration or centrifugation.

[0194] Solid Vapor Diffusion: A 5-15 mg sample of Compound A 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 a volatile solvent. The outer vial was then sealed. The system was kept at room temperature for 7 days to allow the solvent vapor to interact with the solid. The resulting solid was isolated and analyzed by XRPD.

[0195] Polymer-induced crystallization: 5–15 mg of compound A sample was weighed into a glass vial. A predetermined amount of 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.

[0196] Example 8 Characterization of Form C Form C was characterized by XRPD, TGA, and DSC (as described above). The XRPD analysis of Form C is shown in FIG.

[0197] Form C exhibited an endotherm at 136°C as measured by DSC (Figure 3). Form C exhibited a 0.18% weight loss before 150°C as measured by TGA, consistent with an anhydrous state (Figure 3).

[0198] Example 9 Solubility of Form C The solubility of Form C was estimated in solvents according to the above method and the results are listed in Table 8.

[0199] Table 8. Solubility of Form C in selected solvents [Table 10] *Dissolved after heating to 50°C for 2 hours.

[0200] Example 10 Mud-Based Polymorph Screening Compound A was slurried according to the method described above. The resulting solid was analyzed by XRPD and identified with respect to its physical state. The results are listed in Table 9.

[0201] The slurry was screened at room temperature and at 50° C. and showed similar XRPD patterns corresponding to Form C. A slurry in chloroform at room temperature gave Form C+B (FIG. 4).

[0202] Table 9. Summary of Mud-Based Polymorph Screening Experiments [Table 11] [Table 12] *Solution observed for 7 days before evaporation

[0203] Example 11 Vapor Diffusion Compound A was prepared for liquid and solid vapor diffusion experiments according to the methods described above. The resulting solids were analyzed by XRPD and identified with respect to their physical state (Tables 10 and 11).

[0204] Solid vapor diffusion experiments gave Form C. Liquid vapor diffusion experiments gave Form A with EtOH / hexane and MeOH / hexane (Figure 5) and Form B with MeOH / MTBE and CHCl3 / MTBE (Figure 6).

[0205] Table 10. Summary of solid vapor diffusion experiments [Table 13]

[0206] Table 11. Summary of liquid vapor diffusion experiments [Table 14]

[0207] Example 12 Slow Cooling Compound A was prepared for slow cooling experiments according to the method described above. The resulting solid was analyzed by XRPD and identified with respect to its physical state (Table 12). The slow cooling experiment yielded Form A (Figure 7) and Form B (Figure 8).

[0208] Table 12. Summary of cooling experiments [Table 15]

[0209] Example 13 Polymer-Induced Crystallization Compound A was prepared for polymer-induced crystallization experiments according to the method described above. The resulting solid was analyzed by XRPD and identified with respect to its physical state (Table 13).

[0210] Table 13. Summary of Polymer Experiments [Table 16]

[0211] Example 14 Antisolvent Crystallization Compound A was prepared for antisolvent addition experiments according to the method described above. The resulting solid was analyzed by XRPD and identified with respect to its physical state (Table 14). Most of the antisolvent addition experiments gave Form A (Figure 9), Form A+B, and Form B (Figure 10).

[0212] Table 14. Summary of antisolvent experiments [Table 17]

[0213] Example 15 Characterization of Form A Multiple screening methods yielded Form A. A sample of Form A was obtained via anti-solvent addition (solvent: EtOH, anti-solvent: IPAc) at room temperature and analyzed by XRPD (Example 12 and Figure 11).

[0214] DSC analysis showed that Form A exhibited endotherms at 128.5° C. and 137.5° C. (FIG. 12). As measured by TGA, Form A exhibited a weight loss of 0.36% before 150° C.

[0215] Form A showed no decrease in crystallinity after air-drying or vacuum-drying as measured by XRPD (Figure 13). DSC analysis showed that Form A (vacuum-dried) showed no change from the air-dried sample (Figure 14).

[0216] Example 16 Characterization of Form B Multiple screening methods yielded Form B. An example from anti-solvent addition (solvent: MeOH, anti-solvent: IPAC) is shown in Figure 15.

[0217] DSC analysis showed that Form B exhibited an endotherm at 136°C (Figure 16). TGA analysis showed a 0.20% weight loss before 150°C.

[0218] Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein, which equivalents are intended to be encompassed by the claims appended hereto.

Claims

1. A polymorph of Compound A selected from Form A, Form B, and Form C: 【Chemical 1】 1. A polymorph of Compound A, wherein Form A is characterized by having X-ray powder diffraction peaks at approximately 4.3, 17.0, and 21.1 degrees two-theta using Cu Kα radiation; Form B is characterized by having X-ray powder diffraction peaks at approximately 6.4, 19.3, and 19.9 degrees two-theta using Cu Kα radiation; and Form C is characterized by having X-ray powder diffraction peaks at approximately 7.9, 17.2, and 17.6 degrees two-theta using Cu Kα radiation.

2. 10. The Form A polymorph of claim 1, characterized by having X-ray powder diffraction peaks at approximately 4.3, 6.4, 8.6, 12.7, 17.0, and 21.1 degrees 2θ using Cu Kα radiation.

3. 10. The Form A polymorph of claim 1, characterized by having an X-ray powder diffraction pattern substantially similar to that set forth in Figure 1, 5, 7, 9, 11, 13 or 18.

4. 10. The Form A polymorph of claim 1, characterized by an endothermic event with an onset at about 124°C to about 135°C as measured by DSC.

5. 10. The Form A polymorph of claim 1, characterized by an endothermic event with an onset at about 135°C to about 139°C as measured by DSC.

6. 10. The Form A polymorph of claim 1, characterized by endothermic events with onsets between about 124°C and about 135°C and between about 135°C and about 139°C as measured by DSC.

7. 12. The Form A polymorph of claim 1, characterized by a DSC thermogram substantially similar to that depicted in Figure 12 or 14.

8. 10. The Form A polymorph of claim 1, characterized by a weight loss of approximately 0.36% from about 33°C to about 150°C as measured by TGA.

9. 2. The Form B polymorph of claim 1, 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 degrees 2θ using Cu Kα radiation.

10. 2. The Form B polymorph of claim 1, characterized by having an X-ray powder diffraction pattern substantially similar to that set forth in Figure 1, 6, 8, 10, 15 or 20.

11. 10. The Form B polymorph of claim 1, characterized by an endothermic event with an onset at about 133°C to about 138°C as measured by DSC.

12. 17. The Form B polymorph of claim 1, characterized by a DSC thermogram substantially similar to that depicted in Figure 16.

13. 10. The Form B polymorph of claim 1, characterized by a weight loss of approximately 0.20% from about 33°C to about 150°C as measured by TGA.

14. 10. The Form C polymorph of claim 1, characterized by having X-ray powder diffraction peaks at approximately 5.8, 7.9, 8.7, 17.2, and 17.6 degrees 2θ using Cu Kα radiation.

15. 2. The Form C polymorph of claim 1, characterized by having an X-ray powder diffraction pattern substantially similar to that set forth in Figures 1 or 2.

16. 10. The Form C polymorph of claim 1, characterized by an endothermic event with an onset at about 136°C to about 140°C as measured by DSC.

17. 10. The Form C polymorph of claim 1, characterized by a DSC thermogram substantially similar to that set forth in Figure 3.

18. 10. The Form C polymorph of claim 1, characterized by a weight loss of approximately 0.18% from about 33°C to about 150°C as measured by TGA.

19. 10. A pharmaceutical composition comprising the polymorph of claim 1 and a pharmaceutically acceptable carrier or excipient.

20. 10. A process for preparing the Form A polymorph of claim 1, comprising: sparging vapors of an anti-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 an anti-solvent to a solution of Compound A in chloroform, methanol, acetone, tetrahydrofuran, dioxane, ethanol, 2-Me-THF, ethyl acetate, or dichloromethane.

21. 10. A process for preparing the Form B polymorph of claim 1, comprising: slurried Compound A in chloroform; diffusing vapors of an anti-solvent into a concentrated solution of Compound A in methanol or chloroform; slowly cooling a solution of Compound A in acetone, isopropyl acetate, 2-Me-THF, ethyl acetate, acetonitrile, or a mixture of chloroform and heptane; or adding an anti-solvent to a solution of Compound A in chloroform, methanol, acetone, or acetonitrile.

22. 10. A method for preparing the Form C polymorph of claim 1, comprising: slurrying 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; allowing vapors of the solvent to interact with the solid form of Compound A; diffusing vapors of an anti-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 crystallizing a solution of Compound A in a solvent in the presence of a polymer.

23. 10. A method for treating or preventing a disease or condition in which Src tyrosine kinase plays a role, comprising administering the polymorph of claim 1 to a subject in need of treatment or prevention of the disease or condition in which Src tyrosine kinase plays a role.

24. 10. The polymorph of claim 1 for treating or preventing a disease or condition in which Src tyrosine kinase plays a role in a subject in need thereof.

25. 10. The polymorph of claim 1 for use in the manufacture of a medicament for the treatment or prevention of a disease or condition in which Src tyrosine kinase plays a role in a subject in need thereof.

26. 10. Use of the polymorph of claim 1 in the manufacture of a medicament for the treatment or prevention of a disease or condition in which Src tyrosine kinase plays a role in a subject in need thereof.

Images