Crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea ethanol solvate

Abstract

The present disclosure relates to crystalline solvated forms of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea. The present disclosure also relates to methods of making the disclosed crystalline forms, pharmaceutical compositions and kits containing the crystalline forms, and therapeutic methods including their administration and uses.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 257,073, filed October 18, 2021, the disclosure of which is incorporated by reference herein in its entirety. [Background technology]

[0002] background Compound 1, N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, is a gonadotropin releasing hormone (GnRH) antagonist approved for pharmaceutical use to treat a variety of conditions, including prostate cancer and heavy menstrual bleeding, as well as other symptoms associated with uterine fibroids, and is in development for the treatment of pain and other symptoms associated with endometriosis. Compound 1 may also be useful in the treatment of other diseases or disorders. See, e.g., U.S. Patent No. 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 8,735,401, U.S. Patent No. 9,346,822, U.S. Patent No. 10,449,191, U.S. Patent No. 10,786,501, and U.S. Patent No. 11,033,551.

[0003] Compound 1 and methods for preparing Compound 1 are described in U.S. Patent No. 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 8,735,401, U.S. Patent No. 9,346,822, U.S. Patent No. 9,758,528, U.S. Patent No. 10,150,778, U.S. Patent No. 10,464,945, U.S. Patent No. 10,544,160, U.S. Patent No. 11,053,257, U.S. Patent Application No. 17 / 349,584, U.S. Patent No. 10,350,170, International Patent Application No. PCT / EP2021 / 064280, International Patent Publication No. WO2021 / 069711, and International Patent Publication No. WO2021 / 069700.

[0004] U.S. Patent No. 9,758,528, the entirety of which is incorporated herein by reference, describes methods for preparing Compound 1 and certain synthetic intermediates, as well as two crystalline forms of Compound 1: a crystalline tetrahydrofuran (THF) solvate of Compound 1 and a crystalline anhydrous form of Compound 1 (referred to herein as Compound 1 Form I). For reference, as detailed in U.S. Patent No. 9,758,528, Compound 1 Form I can be characterized by a powder X-ray diffraction (XRPD) pattern with peaks at approximately 7.4°, 8.9°, 9.9°, 12.1°, 16.6°, 17.3°, 22.2°, 22.8°, and 27.4° 2θ. Compound 1 Form I begins to melt at about 189°C and decompose at about 197°C. Compound 1 Form I exhibits an exothermic peak at about 237°C by DSC and decomposition at about 245°C by TG.

[0005] International Patent Publication No. WO2021 / 069711, the entirety of which is incorporated herein by reference, describes methods of preparing several crystalline forms of Compound 1, including a second anhydrous form (referred to as Form II); a hemihydrate form (referred to as Form III); a toluene solvate (referred to as Form V); an anisole solvate (referred to as Form VI); an isopropanol solvate (referred to as Form VII); a dioxane solvate (referred to as Form VIII); an α,α,α-trifluorotoluene solvate (referred to as Form IX); a trifluoroethanol solvate (referred to as Form X); a DMF solvate (referred to as Form XI); and an acetone solvate (referred to as Form XII).

[0006] International Patent Publication No. WO2021 / 069700, the entirety of which is incorporated herein by reference, describes a method for preparing a DMSO solvate crystal form of Compound 1 (referred to as Form XIII). Summary of the Invention

[0007] overview Disclosed herein is a crystalline form of an ethanol solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form XIV of Compound 1. In some embodiments, Form XIV of Compound 1 is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ. In some embodiments, Compound 1, Form XIV, is characterized by an X-ray powder diffraction pattern including at least five peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, is characterized by an X-ray powder diffraction pattern including at 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ.

[0008] Also disclosed herein is a method for preparing a crystalline form of the ethanol solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea. In some embodiments, the method for preparing such a crystalline form may include dissolving a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea in dimethylformamide (DMF) to form a solution. The method may also include adding the solution to ethanol to form a second solution. The method may further include agitating the second solution to produce a suspension. The method may also include isolating a solid from the suspension to obtain Form XIV of compound 1.

[0009] Also disclosed herein is a pharmaceutical composition of the crystalline form of the ethanol solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows the powder X-ray diffraction pattern of Compound 1, Form XIV. [Diagram 2] FIG. 2 shows the overlay of powder X-ray diffraction patterns of Compound 1 in Form XIV, Compound 1 in Form XI, the THF solvate of Compound 1, and Compound 1 in Form II. [Diagram 3] 3A-C show overlaid powder X-ray diffraction patterns of Compound 1 in Form XIV and the THF solvate of Compound 1. [Figure 4]FIG. 4 shows the thermogravimetric analysis of Form XIV of compound 1, showing a step of approximately −6.036%. [Diagram 5] FIG. 5 shows a differential scanning calorimetry analysis of Compound 1, Form XIV, showing an onset temperature of approximately 142.33° C. and a peak temperature of approximately 149.24° C. [Figure 6] Figures 6A-D show the H NMR spectrum (600 MHz) of Form XIV of compound 1 in dimethylsulfoxide-d6. Figure 6A shows the full NMR spectrum indicating the presence of ethanol in the crystalline form. Figures 6B-6D are expanded regions of the full NMR spectrum. [Figure 7] 7A and 7B show XRPD, TG, and DSC analyses of a sample preparation of Compound 1 in Form XIV. [Figure 8] 8A and 8B show XRPD, TG, and DSC analyses of a sample preparation of Compound 1 in Form XIV. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Detailed Description

[0012] Described herein are crystalline solvate forms of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea (Compound 1), methods of making the crystalline forms, pharmaceutical compositions and kits containing the crystalline forms, and methods of treatment and uses including their administration. The chemical structure of Compound 1 is as follows:

[0013] [ka]

[0014] General information The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0015] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0016] Crystalline forms of the present disclosure Form XIV is a crystalline ethanol solvate of Compound 1. As used herein, the term "solvate" includes stoichiometric solvates and non-stoichiometric solvates, such as channel solvates, formed by Compound 1 and a solvent. In some embodiments, suitable solvents can include, but are not limited to, ethanol.

[0017] Compound 1 Form XIV

[0018] The present disclosure provides a crystalline form of Compound 1 characterized as Compound 1 Form XIV. In some embodiments, Compound 1 Form XIV is an ethanol solvate. In some embodiments, Compound 1 Form XIV is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one peak selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ. In some embodiments, Compound 1 Form XIV is characterized by an XRPD pattern comprising at least two peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, is characterized by an XRPD pattern comprising at least three peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV is characterized by an XRPD pattern comprising at least six peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ. In some embodiments, compound 1, Form XIV, is characterized by an XRPD pattern comprising peaks at 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ±0.2° 2θ.In some embodiments, compound 1, Form XIV, is characterized by an XRPD pattern substantially the same as that shown in FIG.

[0019] In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern including peaks at 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern including peaks at 7.31°, 10.69°, and 15.43°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern including peaks at 7.31°, 8.38°, 10.69°, and 15.43°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern including peaks at 7.31°, 9.96°, 10.69°, and 15.43°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern including peaks at 7.31°, 10.69°, 15.43°, and 19.02°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern including peaks at 7.31°, 10.69°, 15.43°, and 23.36°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern including peaks at 7.31°, 8.38°, 9.96°, 10.69°, and 15.43°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern including peaks at 7.31°, 8.38°, 10.69°, 15.43°, and 19.02°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern including peaks at 7.31°, 8.38°, 10.69°, 15.43°, and 23.36°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern including peaks at 7.31°, 9.96°, 10.69°, 15.43°, and 19.02°2θ±0.2°2θ. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern including peaks at 7.31°, 9.96°, 10.69°, 15.43°, and 23.36°2θ±0.2°2θ.In some embodiments, compound 1, Form XIV, exhibits an XRPD pattern comprising peaks at 7.31°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ±0.2° 2θ.

[0020] In some embodiments, Compound 1, Form XIV is characterized by an XRPD pattern comprising peaks having approximate d-spacing values ​​selected from the group consisting of 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, and 12.083 Å. In some embodiments, Compound 1, Form XIV is characterized by an XRPD pattern comprising at least two peaks having approximate d-spacing values ​​selected from the group consisting of 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å. In some embodiments, Compound 1, Form XIV is characterized by an XRPD pattern comprising at least three peaks having approximate d-spacing values ​​selected from the group consisting of 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å. In some embodiments, Compound 1, Form XIV, is characterized by an XRPD pattern comprising at least four peaks having approximate d-spacing values ​​selected from the group consisting of 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å. In some embodiments, Compound 1, Form XIV, is characterized by an XRPD pattern comprising at least five peaks having approximate d-spacing values ​​selected from the group consisting of 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å. In some embodiments, Compound 1, Form XIV, is characterized by an XRPD pattern comprising at least six peaks having approximate d-spacing values ​​selected from the group consisting of 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å. In some embodiments, Compound 1, Form XIV, is characterized by an XRPD pattern comprising peaks having approximate d-spacing values ​​of 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å.

[0021] In some embodiments, Compound 1 Form XIV exhibits an XRPD pattern comprising peaks with approximate d-spacing values ​​of 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å. In some embodiments, Compound 1 Form XIV exhibits an XRPD pattern comprising peaks with approximate d-spacing values ​​of 5.738 Å, 8.269 Å, and 12.083 Å. In some embodiments, Compound 1 Form XIV exhibits an XRPD pattern comprising peaks with approximate d-spacing values ​​of 5.738 Å, 8.269 Å, 8.874 Å, and 12.083 Å. In some embodiments, Compound 1 Form XIV exhibits an XRPD pattern comprising peaks with approximate d-spacing values ​​of 5.738 Å, 8.269 Å, 10.543 Å, and 12.083 Å. In some embodiments, Compound 1 Form XIV exhibits an XRPD pattern comprising peaks with approximate d-spacing values ​​of 3.805 Å, 5.738 Å, 8.269 Å, and 12.083 Å. In some embodiments, Compound 1 Form XIV exhibits an XRPD pattern comprising peaks with approximate d-spacing values ​​of 4.662 Å, 5.738 Å, 8.269 Å, and 12.083 Å. In some embodiments, Compound 1 Form XIV exhibits an XRPD pattern comprising peaks with approximate d-spacing values ​​of 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, and 12.083 Å. In some embodiments, Compound 1 Form XIV exhibits an XRPD pattern comprising peaks with approximate d-spacing values ​​of 3.805 Å, 5.738 Å, 8.269 Å, 8.874 Å, and 12.083 Å. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern that includes peaks with approximate d-spacing values ​​of 3.805 Å, 5.738 Å, 8.269 Å, 10.543 Å, and 12.083 Å. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern that includes peaks with approximate d-spacing values ​​of 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, and 12.083 Å.In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern comprising peaks with approximate d-spacing values ​​of 4.662 Å, 5.738 Å, 8.269 Å, 10.543 Å, and 12.083 Å. In some embodiments, Compound 1, Form XIV, exhibits an XRPD pattern comprising peaks with approximate d-spacing values ​​of 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å. In some embodiments, Compound 1, Form XIV, is isostructural with the tetrahydrofuran (THF) solvate of Compound 1 disclosed in U.S. Patent No. 9,758,528.

[0022] Compound 1 Form XIV may also be characterized by thermogravimetry (TG). In some embodiments, compound 1 Form XIV is characterized by a TG thermogram that exhibits a continuous weight loss between about 2.0% and about 10.0% between about 49°C and about 172°C. In some embodiments, compound 1 Form XIV is characterized by a TG thermogram that exhibits a continuous weight loss between about 3.0% and about 9.0% between about 49°C and about 172°C. In some embodiments, compound 1 Form XIV is characterized by a TG thermogram that exhibits a continuous weight loss between about 4.0% and about 8.0% between about 49°C and about 172°C. In some embodiments, compound 1 Form XIV is characterized by a TG thermogram that exhibits a continuous weight loss between about 5.0% and about 7.0% between about 49°C and about 172°C. In some embodiments, Compound 1, Form XIV is characterized by a TG thermogram that exhibits a continuous weight loss of between about 5.5% and about 6.5% between about 49° C. and about 172° C. In some embodiments, Compound 1, Form XIV is characterized by a TG thermogram that exhibits a continuous weight loss of about 6.0% between about 49° C. and about 172° C. In some embodiments, Compound 1, Form XIV is characterized by a TG thermogram substantially similar to the pattern depicted in FIG.

[0023] Form XIV of compound 1 may also be characterized by differential scanning calorimetry (DSC). In some embodiments, Form XIV of compound 1 is characterized by an onset of melting between about 140°C and about 145°C. In some embodiments, Form XIV of compound 1 is characterized by an onset of melting between about 141°C and about 143°C. In some embodiments, Form XIV of compound 1 is characterized by an onset of melting between about 141.5°C and about 142.5°C. In some embodiments, Form XIV of compound 1 is characterized by an onset of melting at about 142°C. In some embodiments, Form XIV of compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 145°C and about 155°C. In some embodiments, Form XIV of compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 147°C and about 151°C. In some embodiments, Compound 1, Form XIV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 148° C. and about 150° C. In some embodiments, Compound 1, Form XIV is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 148.5° C. and about 149.5° C. In some embodiments, Compound 1, Form XIV is characterized by a DSC thermogram comprising an endothermic peak at about 149° C. In some embodiments, Compound 1, Form XIV is characterized by a DSC thermogram substantially similar to the pattern depicted in FIG.

[0024] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least two peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; c) an onset of melting between about 141° C. and about 143° C. as measured by DSC; and d) An endothermic peak between about 148°C and about 150°C as measured by DSC The present invention is characterized by having at least two of the following:

[0025] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least three peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; c) an onset of melting between about 141° C. and about 143° C. as measured by DSC; and d) An endothermic peak between about 148°C and about 150°C as measured by DSC The present invention is characterized by having at least two of the following:

[0026] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least two peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; c) an onset of melting at about 142° C. as measured by DSC; and d) An endothermic peak between about 148°C and about 150°C as measured by DSC The present invention is characterized by having at least two of the following:

[0027] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least two peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; c) an onset of melting between about 141° C. and about 143° C. as measured by DSC; and d) An endothermic peak at approximately 149°C as measured by DSC The present invention is characterized by having at least two of the following:

[0028] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least three peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; c) an onset of melting at about 142° C. as measured by DSC; and d) An endothermic peak at about 149°C as measured by DSC The present invention is characterized by having at least two of the following:

[0029] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least two peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; c) an onset of melting between about 141° C. and about 143° C. as measured by DSC; and d) An endothermic peak between about 148°C and about 150°C as measured by DSC The present invention is characterized by having each of the following:

[0030] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least two peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; and c) An endothermic peak between about 148°C and about 150°C as measured by DSC The present invention is characterized by having each of the following:

[0031] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least three peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; c) an onset of melting between about 141° C. and about 143° C. as measured by DSC; and d) An endothermic peak between about 148°C and about 150°C as measured by DSC The present invention is characterized by having each of the following:

[0032] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least three peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; and c) An endothermic peak between about 148°C and about 150°C as measured by DSC The present invention is characterized by having each of the following:

[0033] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least two peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; c) an onset of melting at about 142° C. as measured by DSC; and d) An endothermic peak between about 148°C and about 150°C as measured by DSC The present invention is characterized by having each of the following:

[0034] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least two peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; and c) An endothermic peak between about 148°C and about 150°C as measured by DSC The present invention is characterized by having each of the following:

[0035] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least two peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; c) an onset of melting between about 141° C. and about 143° C. as measured by DSC; and d) An endothermic peak at approximately 149°C as measured by DSC The present invention is characterized by having each of the following:

[0036] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least two peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; and c) An endothermic peak at approximately 149°C as measured by DSC The present invention is characterized by having each of the following:

[0037] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least three peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; c) an onset of melting at about 142° C. as measured by DSC; and d) An endothermic peak at about 149°C as measured by DSC The present invention is characterized by having each of the following:

[0038] In some embodiments, Compound 1, Form XIV, is: a) an XRPD pattern comprising at least three peaks selected from the group consisting of 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; and c) An endothermic peak at about 149°C as measured by DSC The present invention is characterized by having each of the following:

[0039] In some embodiments, compound 1, Form XIV, has a single crystal structure.

[0040] In some embodiments, Compound 1, Form XIV, comprises ethanol in an amount of about 1% to about 10% by weight, based on the total weight of compound 1 present in Compound 1, Form XIV. In some embodiments, Compound 1, Form XIV, comprises ethanol in an amount of about 5% to about 7% by weight, based on the total weight of compound 1 present in Compound 1, Form XIV. In some embodiments, Compound 1, Form XIV, comprises ethanol in an amount of about 5.5% to about 6.5% by weight, based on the total weight of compound 1 present in Compound 1, Form XIV. In some embodiments, Compound 1, Form XIV, comprises ethanol in an amount of about 6.0% by weight, based on the total weight of compound 1 present in Compound 1, Form XIV.

[0041] In some embodiments, Compound 1 FormXIV contains ethanol in an amount of about 0.1 mol to about 1.5 mol per mole of compound 1 present in Compound 1 FormXIV. In some embodiments, Compound 1 FormXIV contains ethanol in an amount of about 0.5 mol to about 1.3 mol per mole of compound 1 present in Compound 1 FormXIV. In some embodiments, Compound 1 FormXIV contains ethanol in an amount of about 0.7 mol to about 1.1 mol per mole of compound 1 present in Compound 1 FormXIV. In some embodiments, Compound 1 FormXIV contains ethanol in an amount of about 0.8 mol to about 1.0 mol per mole of compound 1 present in Compound 1 FormXIV. In some embodiments, Compound 1 FormXIV contains ethanol in an amount of about 0.9 mol per mole of compound 1 present in Compound 1 FormXIV. In some embodiments, Compound 1 FormXIV contains ethanol in an amount of about 0.9 mol per mole of compound 1 present in Compound 1 FormXIV. In some embodiments, Compound 1 FormXIV contains ethanol in an amount of about 0.9 mol per mole of compound 1 present in Compound 1 FormXIV in DMSO-d6 that is substantially the same as the pattern shown in FIG. 6A. 1 Characterized by H NMR spectrum.

[0042] In some embodiments, compound 1 Form XIV is substantially free of THF. As used herein, "substantially free of THF" refers to an amount of THF that is not detectable using routine characterization techniques well known to those skilled in the art. In some embodiments, compound 1 Form XIV has less than about 720 ppm, less than about 500 ppm, less than about 300 ppm, less than about 250 ppm, or less than about 50 ppm THF.

[0043] In some embodiments, Compound I Form XIV disclosed herein may be characterized by an XRPD pattern having prominent peaks as listed in Table 1. All peaks listed are in degrees 2θ±0.2 degrees 2θ.

[0044] [Table 1]

[0045] In some embodiments, Compound I Form XIV disclosed herein can be characterized by an XRPD pattern having observed peaks listed in Table 2. All peaks listed are in °2θ±0.2°2θ. It should be understood that not all peaks are observed due to low relative intensity. In some embodiments of Compound I Form XIV disclosed herein, Compound 1 Form XIV has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks listed in Table 2. In some embodiments, Compound 1 Form XIV has more than 15 peaks listed in Table 2.

[0046] [Table 2-1]

[0047] [Table 2-2]

[0048] Preparation of the Crystalline Forms of the Disclosure Form XIV of Compound 1 may be used during the synthesis or preparation of Form I of Compound 1. Form I of Compound 1 and methods for preparing Form I of Compound 1 are described in U.S. Patent No. 9,758,528, which is incorporated herein by reference in its entirety, particularly with respect to synthetic and crystallization methods. Methods for preparing pre-crystallized Compound 1 are described in U.S. Patent No. 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 8,735,401, U.S. Patent No. 9,346,822, U.S. Patent No. 9,758,528, U.S. Patent No. 10,150,778, U.S. Patent No. 10,464,945, U.S. Patent No. 10,544,160, U.S. Patent No. 11,053,257, U.S. Patent Application No. 17 / 349,584, U.S. Patent No. 10,350,170, International Patent Application No. PCT / EP2021 / 064280, International Patent Publication No. WO2021 / 069711, and International Patent Publication No. WO2021 / 069700, which are incorporated by reference in their entireties.

[0049] In some embodiments, compound 1, Form I, can be made by using compound 1, Form XIV.

[0050] The present disclosure provides a method for preparing Form XIV of compound 1. In some embodiments, Form XIV of compound 1 can be prepared from other forms of compound 1. In some embodiments, Form XIV of compound 1 can be prepared from a crystalline form of compound 1. In some embodiments, Form XIV of compound 1 can be prepared from one or more of Form I of compound 1, a THF solvate form of compound 1, Form II of compound 1, Form III of compound 1, Form V of compound 1, Form VI of compound 1, Form VII of compound 1, Form VIII of compound 1, Form IX of compound 1, Form X of compound 1, Form XI of compound 1, Form XII of compound 1, and Form XIII of compound 1. In some embodiments, Form XIV of compound 1 can be prepared from one or more of Form I of compound 1 and a THF solvate form of compound 1.

[0051] In some embodiments, Compound 1, Form XIV, is prepared from Compound 1, Form I. In some embodiments, the method for preparing Compound 1, Form XIV, comprises dissolving Compound 1, Form I, in a polar solvent that is miscible with ethanol to obtain a solution. In some embodiments, the polar solvent is dimethylformamide (DMF). In some embodiments, dissolving Compound 1, Form I, in DMF is performed at room temperature.

[0052] In some embodiments, the method of preparing Compound 1, Form XIV, comprises adding a solution of Compound 1, Form I, to ethanol to form a second solution. In some embodiments, the second solution has an ethanol / polar solvent volume ratio between about 85 / 15 v / v and about 99 / 1 v / v. In some embodiments, the second solution has an ethanol / polar solvent volume ratio between about 88 / 12 v / v and about 98 / 2 v / v. In some embodiments, the second solution has an ethanol / polar solvent volume ratio between about 90 / 10 v / v and about 96 / 4 v / v. In some embodiments, the second solution has an ethanol / polar solvent volume ratio between about 92 / 8 v / v and about 94 / 6 v / v. In some embodiments, the second solution has an ethanol / polar solvent volume ratio of about 93 / 7 v / v.

[0053] In some embodiments, the method of preparing Form XIV of compound I comprises stirring the second solution to form a suspension. In some embodiments, the method of preparing Form XIV of compound I comprises isolating the solid from the suspension to obtain Form XIV of compound I. In some embodiments, the second solution is cooled before and / or during stirring.

[0054] In some embodiments, the second solution is held at room temperature before stirring. In some embodiments, the second solution is cooled before stirring. In some embodiments, the second solution is cooled to between about 0° C. and −25° C. before stirring. In some embodiments, the second solution is cooled to between about 0° C. and −25° C.; 0° C. and −20° C.; 0° C. and −15° C.; 0° C. and −10° C.; 0° C. and −5° C.; −5° C. and −25° C.; −5° C. and −20° C.; −5° C. and −15° C.; −5° C. and −10° C.; −10° C. and −25° C.; −10° C. and −20° C.; −10° C. and −15° C.; −15° C. and −25° C.; −15° C. and −20° C.; or −20° C. and −25° C. before stirring. In some embodiments, the second solution is cooled to between about -10°C and -25°C for about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, or about 3 days before stirring. In some embodiments, the second solution is cooled to between about -10°C and -25°C for about 1 day before stirring.

[0055] In some embodiments, the second solution is stirred for about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, or about 3 days before stirring. In some embodiments, the second solution is stirred at room temperature. In some embodiments, the second solution is cooled while stirring. In some embodiments, the second solution is cooled to between about -10°C and -25°C while stirring. In some embodiments, the second solution is cooled to between about 0°C and -25°C; 0°C and -20°C; 0°C and -15°C; 0°C and -10°C; 0°C and -5°C; -5°C and -25°C; -5°C and -20°C; -5°C and -15°C; -5°C and -10°C; -10°C and -25°C; -10°C and -20°C; -10°C and -15°C; -15°C and -25°C; -15°C and -20°C; or -20°C and -25°C while stirring. In some embodiments, the second solution is cooled to a temperature between about -10°C and -25°C for about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, or about 3 days before stirring, and then stirred at a temperature between about -10°C and -25°C for about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, or about 3 days. In some embodiments, the second solution is cooled to a temperature between about -10°C and -25°C for about 1 day before stirring, and then stirred at a temperature between about -10°C and -25°C for about 1 day.

[0056] In some embodiments, the solids may be isolated by filtration. In some embodiments, the solids may be isolated by syringe filtration or vacuum filtration. In some embodiments, the solids may be isolated by syringe filtration. In some embodiments, the solids may be isolated by cold syringe filtration. In some embodiments, the filtration is performed at a temperature between about 0° C. and −25° C.

[0057] In some embodiments, the method of preparing compound 1, Form XIV, comprises dissolving a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea in ethanol (EtOH) to form a solution. In some embodiments, the crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea is dissolved in EtOH at room temperature. In some embodiments, the crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea is dissolved in EtOH at reflux temperature. In some embodiments, the crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea is dissolved in EtOH at a temperature between about 0°C and reflux temperature or between about 25°C and reflux temperature. In some embodiments, the EtOH does not include other solvents.

[0058] In some embodiments, the EtOH solution of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea is cooled. In some embodiments, the solution is cooled to between about 5°C and -10°C. In some embodiments, the solution is cooled to between about 5°C and -5°C; 5°C and 0°C; 0°C and -10°C; 0°C and -5°C; or -5°C and -10°C. In some embodiments, the solution is cooled to about 5°C, 4°C, 3°C, 2°C, 1°C, 0°C, -1°C, -2°C, -3°C, -4°C, -5°C, -6°C, -7°C, -8°C, -9°C, and -10°C. In some embodiments, the solution is cooled for about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, or more than about 1 hour.

[0059] In some embodiments, the cooled solution of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea in EtOH is stirred to form a suspension. In some embodiments, the cooled solution is stirred for about 1, about 2, about 3, about 4, about 5, about 6, or more than about 6 hours.

[0060] In some embodiments, the solid from the suspension is isolated to obtain Form XIV of Compound 1. In some embodiments, the solid from the suspension is isolated by filtration (e.g., vacuum filtration). In some embodiments, the solid from the suspension is further dried. In some embodiments, the solid is dried at about 40° C. In some embodiments, the solid is dried under vacuum at about 40° C. In some embodiments, the solid is dried under a stream of inert gas (e.g., nitrogen). In some embodiments, Compound 1, Form XIV, is free of other solvents.

[0061] Pharmaceutical Compositions Although the disclosed crystalline Form XIV of Compound 1 may be used per se, when administered to a subject, it will generally be administered in the form of a pharmaceutical composition in which Form XIV of Compound 1 is combined with a pharma- ceutically acceptable carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described, for example, in "Pharmaceuticals-The Science of Dosage Form Designs," MEAulton, Churchill Livingstone, 1988, which is incorporated herein by reference in its entirety.

[0062] The term "carrier" as used in this disclosure can include carriers, excipients, and diluents, and can refer to materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that are involved in carrying or transporting pharmaceuticals, such as the crystalline forms of the present disclosure, from one organ or part of the body of a subject to another organ or part of the body. Carriers should be selected based on the compatibility and release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, and the like. See, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975.

[0063] In some embodiments, the present disclosure provides a pharmaceutical composition comprising one or more crystalline forms disclosed herein. In some embodiments, the present disclosure provides a pharmaceutical composition comprising only one crystalline form disclosed herein. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Form XIV of compound 1. In other embodiments, the present disclosure provides a pharmaceutical composition comprising two crystalline forms disclosed herein. For example, a pharmaceutical composition comprising compound 1 may comprise Form I of compound 1 and Form XIV of compound 1.

[0064] In some embodiments, the disclosure provides a pharmaceutical composition comprising Form XIV of Compound 1 and a pharma- ceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising Forms I and XIV of Compound 1 and a pharma- ceutically acceptable carrier.

[0065] Depending on the mode of administration, the pharmaceutical composition will contain from about 0.05 to about 99% by weight (weight percent), more specifically from about 0.05 to about 80% by weight, even more specifically from about 0.10 to about 70% by weight, and even more specifically from about 0.10 to about 50% by weight of one or more of the disclosed crystalline forms, all weight percents being based on the total composition. In some embodiments, the pharmaceutical composition is administered transdermally, transmucosally, or topically (e.g., to the skin or mucosa). In some embodiments, the pharmaceutical composition is administered as a vaginal suppository.

[0066] The pharmaceutical compositions of the present disclosure may comprise one or more of the disclosed crystalline forms in a therapeutically effective amount, formulated together with one or more pharma- ceutically acceptable carriers. Examples of pharma-ceutically acceptable carriers include sugars such as lactose, dextrose, mannitol, glucose and sucrose; starches such as starch derived from corn, wheat or potato and other pharmaceutical grade starches such as sodium starch glycolate; cellulose and its derivatives such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, cellulose acetate and microcrystalline cellulose; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes. excipients; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; releasing agents; coating agents; sweeteners, flavorings and fragrances; preservatives and antioxidants.

[0067] Provided herein are pharmaceutical compositions that are substantially free of THF.

[0068] Treatment Methods and Uses The present disclosure provides methods of treating a disorder comprising administering an effective amount of one or more of the crystalline forms, or one or more pharmaceutical compositions comprising said one or more crystalline forms, described herein, thereby treating the disorder in a subject in need thereof.

[0069] In some embodiments of the method and use of the present disclosure, the disorder is a hormone-dependent condition.The hormone-dependent condition may include sex hormone-dependent cancer (e.g., prostate cancer, uterine cancer, breast cancer, and ovarian cancer), bone metastasis of sex hormone-dependent cancer, prostatic hyperplasia, uterine fibroids, adenomyoma, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovarian syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, heavy menstrual bleeding, and symptoms associated with these conditions.Such symptoms may include anemia, irregular periods, spotting, inflammation, pain, fatigue, urinary obstruction, frequent urination, incontinence, constipation, anxiety, sleep disorder, reduced quality of life, difficulty with activities of daily living, female sexual dysfunction, and depression.In some embodiments of the method and use of the present disclosure, the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer. Additional disorders for which Compound 1 is useful for treating are described in U.S. Patent No. 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 8,735,401, U.S. Patent No. 9,346,822, U.S. Patent No. 10,449,191, U.S. Patent No. 10,786,501, and U.S. Patent No. 11,033,551, which are incorporated by reference in their entireties.

[0070] In some embodiments of the disclosed methods and uses, the hormone-dependent condition is prostate cancer. In some embodiments of the disclosed methods and uses, the hormone-dependent condition is uterine cancer. In some embodiments of the disclosed methods and uses, the hormone-dependent condition is breast cancer. In some embodiments of the disclosed methods and uses, the hormone-dependent condition is ovarian cancer. In some embodiments of the disclosed methods and uses, the hormone-dependent condition is uterine fibroids. In some embodiments of the disclosed methods and uses, the hormone-dependent condition is heavy menstrual bleeding associated with uterine fibroids. In some embodiments of the disclosed methods and uses, the hormone-dependent condition is pain or other symptoms associated with uterine fibroids. In some embodiments of the disclosed methods and uses, the hormone-dependent condition is endometriosis. In some embodiments of the disclosed methods and uses, the hormone-dependent condition is pain associated with endometriosis. In some embodiments of the disclosed methods and uses, the hormone-dependent condition is adenomyosis. In some embodiments of the disclosed methods and uses, the hormone-dependent condition is heavy menstrual bleeding.

[0071] A "patient" or "subject" is a mammal. Examples of mammals may include, but are not limited to, any member of the class Mammalia, including humans; non-human primates, such as chimpanzees, monkeys, baboons, and rhesus monkeys; cows, horses, sheep, goats, and pigs; rabbits, dogs, and cats; and rodents, such as rats, mice, and guinea pigs. In some embodiments, the patient or subject is a human.

[0072] The term "effective amount" or "therapeutically effective amount" when used in connection with one or more crystalline forms or pharmaceutical compositions of the present disclosure may refer to an amount of one or more crystalline forms or pharmaceutical compositions sufficient to provide a desired biological result. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disorder, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use may be the amount of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein that is required to provide a clinically significant reduction in the disorder. The appropriate "effective amount" in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0073] As used herein, the terms "treat" or "treatment" or their cognates are meant to refer to the postponement of the onset of a disorder; and / or the reduction in the severity of such symptoms that will or are expected to develop. That is, these terms can include ameliorating existing symptoms of a disorder; preventing additional symptoms; ameliorating or preventing the underlying cause of a symptom; inhibiting a disorder, e.g., arresting the onset of a disorder; alleviating a disorder; causing regression of a disorder; alleviating symptoms caused by a disorder; or arresting or alleviating symptoms of a disorder.

[0074] As used in this disclosure, the terms "administered," "administration," or "administering" may refer to the direct administration of any of one or more crystalline forms or pharmaceutical compositions of the present disclosure to a subject.

[0075] The present disclosure provides a method of treating a disorder in a subject in need thereof, comprising administering an effective amount of Form XIV of Compound 1, thereby treating the disorder in the subject in need thereof. The present disclosure provides a method of treating a disorder in a subject in need thereof, comprising administering an effective amount of a mixture of Form I and Form XIV of Compound 1, thereby treating the disorder in the subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.

[0076] The present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions of the present disclosure, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising Form XIV of compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more pharmaceutical compositions comprising a mixture of Form I and Form XIV of compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.

[0077] The present disclosure provides one or more crystalline forms of the present disclosure or one or more pharmaceutical compositions of the present disclosure for use in treating a disorder in a subject in need thereof. In some embodiments, the one or more crystalline forms comprise Form XIV of compound 1. In some embodiments, the one or more crystalline forms are a mixture of Form I and Form XIV of compound 1. In some embodiments, the one or more pharmaceutical compositions of the present disclosure comprise one or more crystalline forms disclosed herein. In some embodiments, the one or more pharmaceutical compositions of the present disclosure comprise Form XIV of compound 1. In some embodiments, the one or more pharmaceutical compositions of the present disclosure comprise a mixture of Form I and Form XIV of compound 1. In some embodiments, the disorder is a hormone-dependent condition.

[0078] The present disclosure provides the use of one or more crystalline forms of the present disclosure for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of Form XIV of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of a mixture of Forms I and XIV of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.

[0079] The present disclosure provides the use of one or more pharmaceutical compositions of the present disclosure for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising Form XIV of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising a mixture of Form I and Form XIV of compound 1 for treating a disorder in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.

[0080] The present disclosure provides the use of one or more crystalline forms of the present disclosure in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of Form XIV of compound 1 in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of a mixture of Forms I and XIV of compound 1 in the manufacture of a medicament for treating a disorder. In some embodiments, the disorder is a hormone-dependent condition.

[0081] The present disclosure provides the use of one or more pharmaceutical compositions of the present disclosure in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising Form XIV of Compound 1 in the manufacture of a medicament for treating a disorder. The present disclosure provides the use of one or more pharmaceutical compositions comprising a mixture of Form I and Form XIV of Compound 1 in the manufacture of a medicament for treating a disorder. In some embodiments, the disorder is a hormone-dependent condition.

[0082] The present disclosure provides the use of one or more crystalline forms of the present disclosure as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of Form XIV of the compound as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of a mixture of Form I and Form XIV of compound 1 as a medicament for treating a disorder. In some embodiments, the disorder is a hormone-dependent condition.

[0083] The present disclosure provides the use of one or more pharmaceutical compositions of the present disclosure as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising Form XIV of compound 1 as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising a mixture of Form I and Form XIV of compound 1 as a medicament for treating a disorder. In some embodiments, the disorder is a hormone-dependent condition.

[0084] In some embodiments of the methods and uses of the present disclosure, only one pharmaceutical composition of the present disclosure is used in the method or use.In some embodiments of the methods and uses of the present disclosure, only one crystalline form of the present disclosure is used in the method or use.

[0085] For therapeutic use as described herein, the dosage administered will of course vary depending on the crystalline form(s) or pharmaceutical composition used, the mode of administration, the desired treatment and the indication.For example, the daily dosage of the crystalline form(s) of the present disclosure can range from about 0.05 micrograms per kilogram of body weight (μg / kg) to about 100 micrograms per kilogram of body weight (μg / kg) when inhaled.Alternatively, the daily dosage of the crystalline form(s) of the present disclosure can range from about 0.01 micrograms per kilogram of body weight (μg / kg) to about 100 milligrams per kilogram of body weight (mg / kg) when the crystalline form(s) or pharmaceutical composition is orally administered.

[0086] However, it will be understood that the total daily use of one or more crystalline forms or pharmaceutical compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any particular patient will depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the specific crystalline form used; the specific pharmaceutical composition used; the age, weight, general health, sex and diet of the patient; the time of administration, the route of administration and the rate of excretion of the specific crystalline form used; the duration of treatment; the drugs used in combination with or simultaneously with the specific crystalline form used; and similar factors well known in the medical field.A physician or veterinarian who is skilled in the art can easily determine and prescribe the therapeutically effective amount of one or more crystalline forms or pharmaceutical compositions disclosed herein required to treat, combat or prevent the progression of the disorder.

[0087] Combination therapy In some embodiments, one or more of the crystal forms or pharmaceutical compositions described herein may be used alone, or may be administered together or in conjunction with one or more other therapeutic agents or pharmaceutical compositions, or may be used in combination. Concurrent administration or combined use may refer to any form of administration of two or more different compounds, crystal forms or pharmaceutical compositions, such that a second compound, crystal form or pharmaceutical composition is administered while the previously administered compound, crystal form or pharmaceutical composition is still effective in the body. For example, different compounds, crystal forms or pharmaceutical compositions may be administered either in the same formulation or in separate formulations, either simultaneously, sequentially, or with separate administration of individual components of the treatment. In some embodiments, different compounds, crystal forms or pharmaceutical compositions may be administered within about 1 hour, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, or about 1 week of each other. That is, an individual undergoing such treatment may benefit from the combined effect of different compounds, crystal forms or pharmaceutical compositions.

[0088] In some embodiments, one or more crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with one or more other crystalline forms or pharmaceutical compositions of the present disclosure in the methods or uses of the present disclosure.In certain such embodiments, a combination of one or more other crystalline forms or pharmaceutical compositions of the present disclosure is used in a method of treating one or more of the disorders listed herein.

[0089] In some embodiments, one or more crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with estradiol or a corresponding amount of estradiol equivalents.In some embodiments, one or more crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with progestin.In some embodiments, one or more crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with estradiol or a corresponding amount of estradiol equivalents and progestin.In some embodiments, the progestin is norethindrone acetate.

[0090] In some embodiments, a combination of one or more of the crystalline forms or pharmaceutical compositions provided herein, or a combination of other known drugs or pharmaceutical compositions and one or more of the crystalline forms or pharmaceutical compositions provided herein, are formulated into pharmaceutical compositions and medicaments that are useful in the methods and uses of the present disclosure.The present disclosure also provides the use of such combinations in the treatment of one or more of the disorders listed herein.

[0091] In some embodiments of the present disclosure, one or more crystalline forms or pharmaceutical compositions of the present disclosure are administered at a sub-therapeutic dose, where a sub-therapeutic dose is a dose that, if administered alone, would be insufficient to treat one of the disorders listed herein.

[0092] kit In some embodiments, the disclosure also provides pharmaceutical packages or kits comprising one or more containers filled with at least one crystalline form or pharmaceutical composition of the disclosure, optionally bearing a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceutical or biological products, the notice reflecting (a) approval by the governmental agency of the manufacture, use, or sale for human administration, (b) instructions for use, or both.

[0093] The above applies to any of the crystal forms, pharmaceutical compositions, methods, and uses described herein. The present disclosure specifically contemplates any combination of the features of such crystal forms, pharmaceutical compositions, methods, and uses (alone or in combination) with the features described for the various kits described in this section.

[0094] Although similar or equivalent methods and materials to those described herein can be used in the practice or testing of this disclosure, exemplary methods and materials are described herein.Other features, objects, and advantages of this disclosure will be apparent from the description and claims.In the specification and the appended claims, the singular form also includes the plural form, unless the context clearly dictates otherwise.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.All patents and publications cited herein are incorporated herein in their entirety by reference.

[0095] Each embodiment described herein may be used alone or in combination with any one or more of the other embodiments.

[0096] Enumerated embodiments Embodiment I-1. A crystalline form of the ethanol solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form XIV of compound 1.

[0097] Embodiment I-2. The crystalline form of embodiment I-1, characterized by a powder X-ray diffraction pattern including at least three peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ.

[0098] Embodiment I-3. The crystalline form of embodiment I-1 or I-2, characterized by a powder X-ray diffraction pattern including at least five peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ.

[0099] Embodiment I-4. The crystalline form of any one of embodiments I-1 to I-3, characterized by a powder X-ray diffraction pattern comprising peaks at 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ ± 0.2° 2θ.

[0100] Embodiment I-5. The crystalline form of any one of embodiments I-1 to I-4, characterized by a powder X-ray diffraction pattern substantially the same as the pattern shown in FIG.

[0101] Embodiment I-6. The crystalline form of any one of embodiments I-1 to I-5, characterized by a thermogravimetry (TG) thermogram exhibiting a continuous weight loss of about 6.0% between about 49°C and about 172°C.

[0102] Embodiment I-7. The crystalline form of any one of embodiments I-1 to I-6, characterized by a TG thermogram substantially the same as the pattern depicted in FIG.

[0103] Embodiment I-8. The crystalline form of any one of embodiments I-1 to I-7, characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 147° C. and about 150° C.

[0104] Embodiment I-9. The crystalline form of any one of embodiments I-1 to I-8, characterized by a DSC thermogram comprising an endothermic peak at about 149° C.

[0105] Embodiment I-10. The crystalline form of any one of embodiments I-1 to I-19, characterized by a DSC thermogram substantially the same as the pattern depicted in FIG.

[0106] Embodiment I-11. The crystalline form of any one of embodiments I-1 to I-10, characterized by a powder X-ray diffraction pattern including at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å.

[0107] Embodiment I-12. A powder X-ray diffraction pattern comprising: (a) at least three peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ; (b) at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; and (c) an endothermic peak at about 149° C. as measured by DSC. The crystalline form of embodiment I-1, characterized by having at least two of:

[0108] Embodiment I-13. The crystalline form of any one of embodiments I-1 through I-12, wherein the crystalline form is substantially free of tetrahydrofuran (THF).

[0109] Embodiment I-14. A pharmaceutical composition comprising the crystalline form of any one of embodiments I-1 to I-13.

[0110] Embodiment I-15. The pharmaceutical composition of embodiment I-14, wherein the composition is substantially free of (THF).

[0111] Embodiment I-16. A method for preparing a crystalline form of any one of embodiments I-1 to I-13, the method comprising: (a) dissolving a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea in dimethylformamide (DMF) to form a solution; (b) adding the solution of step a) to ethanol to form a second solution; (c) stirring the second solution to form a suspension; and (d) isolating the solid from the suspension to obtain Form XIV of compound 1. A method comprising:

[0112] Embodiment I-17. The method of embodiment I-16, wherein the second solution is cooled to between about -10°C and -25°C.

[0113] Embodiment I-18. The method of embodiment I-16 or I-17, wherein the second solution of step b) is cooled to between about -10°C and -25°C for 1 day.

[0114] Embodiment I-19. The method of any one of embodiments I-16 to I-18, wherein the stirring in step c) is carried out at between about -10°C and -25°C.

[0115] Embodiment I-20. The method of any one of embodiments I-16 to I-19, wherein the isolation of step d) is accomplished using syringe filtration.

[0116] Embodiment I-21. A method for preparing any one of the crystalline forms of embodiment I-1 I-14, the method comprising: (a) dissolving a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea in ethanol (EtOH) to form a solution; (b) cooling the solution of step a); (c) stirring the cooled solution to form a suspension; and (d) isolating a solid from the suspension to obtain Form XIV of compound 1. A method comprising:

[0117] Embodiment I-22. The method of embodiment I-21, wherein the solution of step a) is cooled to between about 5° C. and −10° C.

[0118] Embodiment I-23. The method of embodiment I-21 or I-22, wherein the stirring in step c) is carried out at between about 5° C. and −10° C.

[0119] Embodiment I-24. The method of any one of embodiments I-21 to I-23, wherein the isolation of step d) is accomplished using filtration.

[0120] Embodiment II-22. A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline form of any one of embodiments I-1 to I-13.

[0121] Embodiment II-23. A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment I-14 or I-15.

[0122] Embodiment II-24. The method of any one of embodiments II-22 to II-23, wherein the disorder is a hormone-dependent condition.

[0123] Embodiment II-25. The method of embodiment II-24, wherein the hormone-dependent condition is a sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of a sex hormone-dependent cancer, prostatic hyperplasia, uterine myoma, adenomyoma, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, or heavy menstrual bleeding.

[0124] Embodiment II-26. The method of Embodiment II-24 or II-25, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer.

[0125] Embodiment II-27. The method of any one of embodiments II-24 to II-26, wherein the hormone-dependent condition is prostate cancer.

[0126] Embodiment II-28. The method of any one of embodiments II-24 to II-26, wherein the hormone-dependent condition is uterine cancer.

[0127] Embodiment II-29 The method of any one of embodiments II-24 to II-26, wherein the hormone-dependent condition is breast cancer.

[0128] Embodiment II-30. The method of any one of embodiments II-24 to II-26, wherein the hormone-dependent condition is ovarian cancer.

[0129] Embodiment II-31. The method of embodiment II-24, wherein the hormone-dependent condition is uterine fibroids.

[0130] Embodiment II-32. The method of Embodiment II-24, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine fibroids.

[0131] Embodiment II-33. The method of embodiment II-24, wherein the hormone-dependent condition is pain or other symptoms associated with uterine fibroids.

[0132] Embodiment II-35. The method of embodiment II-24 or II-25, wherein the hormone-dependent condition is endometriosis.

[0133] Embodiment II-36. The method of embodiment II-24 or II-25, wherein the hormone-dependent condition is adenomyosis.

[0134] Embodiment II-37. The method of embodiment II-24 or II-25, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0135] Embodiment II-38. The method of any one of embodiments II-22 to II-37, wherein the method comprises administering estradiol or a corresponding amount of estradiol equivalents to the subject.

[0136] Embodiment II-39. The method of any one of embodiments II-22 to II-38, wherein the method comprises administering a progestin to the subject.

[0137] Embodiment II-40. The method of any one of embodiments II-22 to II-37, wherein the method comprises administering to the subject estradiol or a corresponding amount of an estradiol equivalent, and a progestin.

[0138] Embodiment II-41. The method of Embodiment II-39 or II-40, wherein the progestin is norethindrone acetate.

[0139] Embodiment II-42. The crystalline form of any one of embodiments I-1 to I-13 for use in treating a disorder in a subject in need thereof.

[0140] Embodiment II-43. The crystalline form for use according to embodiment II-42, wherein the disorder is a hormone-dependent condition.

[0141] Embodiment II-44. The crystalline form for use in embodiment II-43, wherein the hormone-dependent condition is a sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of a sex hormone-dependent cancer, prostatic hyperplasia, uterine fibroids, adenomyoma, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovarian syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, or heavy menstrual bleeding.

[0142] Embodiment II-45. The crystalline form for use according to any one of embodiments II-42 to II-44, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer.

[0143] Embodiment II-46. The crystalline form for use according to any one of embodiments II-43 to II-45, wherein the hormone-dependent condition is prostate cancer.

[0144] Embodiment II-47. The crystalline form for use according to any one of embodiments II-43 to II-45, wherein the hormone-dependent condition is uterine cancer.

[0145] Embodiment II-48. The crystalline form for use according to any one of embodiments II-43 to II-45, wherein the hormone-dependent condition is breast cancer.

[0146] Embodiment II-49. The crystalline form for use according to any one of embodiments II-43 to II-45, wherein the hormone-dependent condition is ovarian cancer.

[0147] Embodiment II-50. The crystalline form for use in embodiment II-43, wherein the hormone-dependent condition is uterine fibroids.

[0148] Embodiment II-51. The crystalline form for use in embodiment II-43, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine fibroids.

[0149] Embodiment II-52. The crystalline form for use in embodiment II-43, wherein the hormone-dependent condition is pain or other symptoms associated with uterine fibroids.

[0150] Embodiment II-53. The crystalline form for use according to embodiment II-43 or II-44, wherein the hormone-dependent condition is endometriosis.

[0151] Embodiment II-54. The crystalline form for use in embodiment II-43 or II-44, wherein the hormone-dependent condition is adenomyosis.

[0152] Embodiment II-55. The crystalline form for use in embodiment II-43 or II-44, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0153] Embodiment II-56. The crystalline form for use of any one of the embodiments II-42 to II-55, wherein the crystalline form for use is used in combination with estradiol or a corresponding amount of estradiol equivalents.

[0154] Embodiment II-57. The crystalline form for use of any one of embodiments II-42 to II-55, wherein one or more of the crystalline forms for use are used in combination with a progestin.

[0155] Embodiment II-58. The crystalline form of any one of embodiments II-42 to II-55, wherein the one or more crystalline forms for use are used in combination with estradiol or a corresponding amount of estradiol equivalents, and a progestin.

[0156] Embodiment II-59. The crystalline form for use in embodiment II-57 or II-58, wherein the progestin is norethindrone acetate.

[0157] Embodiment II-60. The pharmaceutical composition of embodiment II-15 or II-16 for use in treating a disorder in a subject in need thereof.

[0158] Embodiment II-61. The pharmaceutical composition for use of embodiment II-60, wherein the disorder is a hormone-dependent condition.

[0159] Embodiment II-62. A pharmaceutical composition for use according to embodiment II-61, wherein the hormone-dependent condition is a sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of a sex hormone-dependent cancer, prostatic hyperplasia, uterine myoma, adenomyoma, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovarian syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, or heavy menstrual bleeding.

[0160] Embodiment II-63. The pharmaceutical composition for use according to embodiment II-61 or II-62, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer.

[0161] Embodiment II-64. The pharmaceutical composition for use of any one of embodiments II-61 to II-63, wherein the hormone-dependent condition is prostate cancer.

[0162] Embodiment II-65. The pharmaceutical composition for use of any one of embodiments II-61 to II-63, wherein the hormone-dependent condition is uterine cancer.

[0163] Embodiment II-66. The pharmaceutical composition for use of any one of embodiments II-61 to II-63, wherein the hormone-dependent condition is breast cancer.

[0164] Embodiment II-67. The pharmaceutical composition for use of any one of embodiments II-61 to II-63, wherein the hormone-dependent condition is ovarian cancer.

[0165] Embodiment II-68. The pharmaceutical composition for use of embodiment II-61, wherein the hormone-dependent condition is uterine fibroids.

[0166] Embodiment II-69. The pharmaceutical composition for use according to embodiment II-61, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine fibroids.

[0167] Embodiment II-70. The pharmaceutical composition for use of embodiment II-61, wherein the hormone-dependent condition is pain or other symptoms associated with uterine fibroids.

[0168] Embodiment II-71. The pharmaceutical composition for use according to embodiment II-61 or II-62, wherein the hormone-dependent condition is endometriosis.

[0169] Embodiment II-72. The pharmaceutical composition for use according to embodiment II-61 or II-62, wherein the hormone-dependent condition is adenomyosis.

[0170] Embodiment II-73. The pharmaceutical composition for use according to embodiment II-61 or II-62, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0171] Embodiment II-74. The pharmaceutical composition for use according to any one of embodiments II-60 to II-73, wherein the pharmaceutical composition for use is used in combination with estradiol or a corresponding amount of estradiol equivalents.

[0172] Embodiment II-75. The pharmaceutical composition for use of any one of embodiments II-60 to II-73, wherein the pharmaceutical composition for use is used in combination with a progestin.

[0173] Embodiment II-76. The pharmaceutical composition for use of any one of embodiments II-60 to II-73, wherein the pharmaceutical composition for use is used in combination with estradiol or a corresponding amount of estradiol equivalents, and a progestin.

[0174] Embodiment II-77. The pharmaceutical composition for use according to embodiment II-75 or II-76, wherein the progestin is norethindrone acetate.

[0175] Embodiment II-78. Use of a crystalline form of any one of embodiments I-1 to I-13 in the manufacture of a medicament for treating a disorder.

[0176] Embodiment II-79. Use of the pharmaceutical composition of embodiment I-14 or I-15 in the manufacture of a medicament for treating a disorder.

[0177] Embodiment II-80. Use of the crystalline form of any one of embodiments II-1 to II-13 as a medicament for treating a disorder.

[0178] Embodiment II-81. Use of the pharmaceutical composition of embodiment II-14 or I-15 as a medicament for treating a disorder.

[0179] Embodiment II-82. The use of any one of embodiments II-78 to II-81, wherein the disorder is a hormone-dependent condition.

[0180] Embodiment II-83. The use of embodiment II-82, wherein the hormone-dependent condition is a sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of a sex hormone-dependent cancer, prostatic hyperplasia, uterine fibroids, adenomyomas, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovarian syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, or heavy menstrual bleeding.

[0181] Embodiment II-84. The use of embodiment II-82 or II-83, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer.

[0182] Embodiment II-85. The use of any one of embodiments II-82 to II-84, wherein the hormone-dependent condition is prostate cancer.

[0183] Embodiment II-86. The use of any one of embodiments II-82 to II-84, wherein the hormone-dependent condition is uterine cancer.

[0184] Embodiment II-87. The use of any one of embodiments II-82 to II-84, wherein the hormone-dependent condition is breast cancer.

[0185] Embodiment II-88. The use of any one of embodiments II-82 to II-84, wherein the hormone-dependent condition is ovarian cancer.

[0186] Embodiment II-89. The use of any one of embodiments II-82 to II-83, wherein the hormone-dependent condition is uterine fibroids.

[0187] Embodiment II-90. The use of embodiment II-82, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine fibroids.

[0188] Embodiment II-91. The use of embodiment II-82, wherein the hormone-dependent condition is pain or other symptoms associated with uterine fibroids.

[0189] Embodiment II-92. The use of embodiment II-82 or II-83, wherein the hormone-dependent condition is endometriosis.

[0190] Embodiment II-93. The use of embodiment II-82 or II-83, wherein the hormone-dependent condition is adenomyosis.

[0191] Embodiment II-94. The use of embodiment II-82 or II-83, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0192] Embodiment II-95. The use of any one of embodiments II-81 to II-94, wherein the use comprises the use of estradiol or a corresponding amount of an estradiol equivalent for treating a disorder.

[0193] Embodiment II-96. The use of any one of embodiments II-81 to II-94, wherein the use comprises the use of a progestin to treat the disorder.

[0194] Embodiment II-97. The use of any one of embodiments II-81 to II-94, wherein the use comprises the use of estradiol or a corresponding amount of an estradiol equivalent, and a progestin, to treat a disorder.

[0195] Embodiment II-98. The use of embodiment II-96 or II-97, wherein the progestin is norethindrone acetate. EXAMPLES

[0196] General Methods of the Examples X-ray Powder Diffraction (XRPD) Powder X-ray diffractograms were performed using a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation generated using an Optix long precision focus source. An elliptically graded multilayer mirror was used to focus the Cu Kα X-rays through the specimen onto the detector. Prior to analysis, a silicon specimen (NIST SRM 640f) was analyzed to confirm that the Si 111 peak position matched the NIST certified position. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, short anti-scatter extensions, and an anti-scatter knife edge were used to minimize background generated by air. Soller slits for the incident and diffracted beams were used to minimize spread from axial divergence. Diffraction patterns were collected using a scanning position detector (X'Celerator) located 240 mm from the specimen and Data Collector software v.5.5. Depending on the instrument used to collect the data and / or the inherent peak resolution, a rounding algorithm was used to round each peak to the nearest 0.1° or 0.01°2θ. The positions of the peaks along the x-axis (°2θ) in both figures and tables were calculated using proprietary software (TRIADS TM Peak position variability was determined using the FTIR (v2.1) method. Peak position variability was determined according to the USP discussion of variability in powder X-ray diffraction (United States Pharmacopeia, USP42-NF 37 to S1, <941> , Characterization of Crystalline and Partially Crystalline Solids by X-ray Powder Diffraction (XRPD), official since August 1, 2019, to within ±0.2°2θ. For the d-space list, the wavelength used for d-space calculations was 1.5405929 Å, the Cu-Kα1 wavelength (Phys. Rev. A56(6)4554-4568(1997)).

[0197] XRPD analysis of Example 2 was performed using a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation generated using an Empyrean Cu LFF HR long fine focus source. Sample specimens were sandwiched between 6 μm thick Mylar® films and analyzed in transmission geometry. For the d-space listing, the wavelength used for d-space calculations was the Cu-Kα1 wavelength of 1.5405980 Å.

[0198] Differential Scanning Calorimetry (DSC) DSC analysis was performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature and enthalpy were adjusted with indium, tin, and zinc. Adjustments were then verified with indium and balance verified with calcium oxalate. Samples were placed in an open aluminum pan that was tared. The sample was weighed, then the pan was sealed, the lid pierced, and inserted into the furnace. The furnace was heated under nitrogen and data was collected from 25°C to 350°C at 10°C / min.

[0199] DSC analysis of Example 2 was performed using a TA Instruments Discovery DSC 2500 instrument. Temperature and enthalpy calibration was performed using indium and tin standards. Samples were placed in open aluminum pans and the weights were accurately recorded. The pans were then inserted into the autosampler tray of the DSC instrument and from there placed on the sample platform. A weighed empty aluminum sample pan was placed on the reference platform. The DSC cell was heated under a nitrogen flow of 50 ml / min and data was collected from 30°C to 260°C at 10°C / min.

[0200] Thermogravimetry (TG) TG analysis was performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature and enthalpy were adjusted with indium, tin, and zinc. Adjustment was then verified with indium and balance verified with calcium oxalate. Samples were placed in an open aluminum pan that was tared. The sample was weighed, then the pan was sealed, the lid was pierced, and inserted into the furnace. The furnace was heated under nitrogen and data was collected from 25°C to 350°C at 10°C / min.

[0201] The TG analysis of Example 2 was carried out using a TA Instruments Discovery TGA 5500 instrument. Temperature calibration was performed using alumel and nickel Curie temperature standards. Samples were placed in open platinum sample pans. The pans were then inserted into the autosampler tray of the TG instrument and placed from there onto the sample hanging wire of the balance. An empty platinum sample pan was placed onto the reference platinum hanging wire of the balance. The furnace was heated under a nitrogen flow of 25 ml / min and data was collected from ambient temperature to 260°C at 10°C / min.

[0202] Proton nuclear magnetic resonance ( 1 H NMR) 1 H NMR spectra were obtained using an Avance 600 MHz NMR spectrometer. Samples were prepared by dissolving approximately 5-10 mg of the material to be characterized in dimethylsulfoxide-d6 (DMSO-d6). Spectra were calibrated to an internal tetramethylsilane (TMS) standard.

[0203] Preparation and characterization of compound 1 Form XIV Compound 1 Form XIV The present disclosure provides a method for preparing Compound 1, Form XIV.

[0204] Example 1:Compound 1, Form I (118.6 mg) was dissolved in DMF (0.4 mL) at ambient temperature. The solution was filtered through a 0.2 μm nylon filter into a vial containing EtOH (5 mL). The resulting solution was left unstirred and placed in a freezer for 1 day. The resulting clear solution was then stirred between −10° C. and −25° C. for 1 day to give a slurry. The solid was isolated at low temperature by syringe filtration using a cold syringe and filter to give compound 1, Form XIV. These conditions are summarized in Table 3 below.

[0205] Comparative Example 1-4: Some comparative example conditions under which Form XIV of compound 1 was not obtained are summarized in Table 3 below.

[0206] [Table 3]

[0207] XRPD characteristics of compound 1 in Form XIV XRPD data for crystalline Form XIV of compound 1 disclosed herein was collected as detailed above. The XRPD pattern of Form XIV of compound 1 is detailed in FIG. 1. Prominent peaks present in this XRPD pattern are shown in Table 1, and observed peaks present in this XRPD pattern are shown in Table 2. All peaks are listed in °2θ±0.2°2θ. The XRPD pattern was successfully indexed, and tentative unit cell parameters are provided below in Table 4. Indexing of the XRPD pattern indicates that the material exists primarily or exclusively as a single crystalline phase. The XRPD pattern indicates that Form XIV of compound 1 is isostructural to the tetrahydrofuran (THF) solvate of compound 1 disclosed in U.S. Patent No. 9,758,528. The XRPD patterns of Form XIV of compound 1, Form XI of compound 1, THF solvate of compound 1, and Form II of compound 1 are shown and compared in FIG. 2. The XRPD patterns of Compound 1 in Form XIV and the tetrahydrofuran (THF) solvate of Compound 1 are shown and compared in Figures 3A-C.

[0208] [Table 4]

[0209] Thermal analysis (DSC and TG) of compound 1 in Form XIV DSC and TG data for Compound 1, Form XIV disclosed herein were collected as detailed above. The TG thermogram for Compound 1, Form XIV is shown in FIG. 4. The DSC thermogram for Compound 1, Form XIV is shown in FIG. 5. The thermal events in the DSC and TG for Compound 1, Form XIV are summarized in Table 5 below. The TG thermogram showed a weight loss of 6.0% from 49 to 171° C., which corresponds to 0.9 moles of ethanol. In the DSC thermogram, an endotherm was observed with an onset temperature of 142° C.

[0210] [Table 5]

[0211] Compound 1 Form XIV 1 H NMR characteristics Compound 1 Form XIV 1 The H NMR spectrum is shown in Figure 6A-D. The spectrum is consistent with the structure of compound 1 and indicates the presence of traces of DMF and 1.15 moles of EtOH (relative to 1 mole of compound 1).

[0212] Example 2: Further preparation and characterization of Form XIV of compound 1

[0213] Example 2:Compound 1, Form XIV was additionally prepared by dissolving compound 1, Form I (1.0 g) in abs. ethanol (78 ml) at reflux temperature. The solution was filtered through a 0.1 μm nylon filter into a 100 ml EasyMax reactor, and the clear solution was cooled to 0° C. over approximately 30 min. The resulting slurry was stirred for 3 h, and the solid was filtered. The resulting wet crystals were dried under nitrogen flow in vacuum (500 mbar) at 40° C. for 30 min to obtain 0.325 g of compound 1, Form XIV. The sample was characterized by XRPD (FIG. 7A), TG-MS (FIG. 7B), DSC (FIG. 7C), and NMR. The XRPD analysis is shown in Table 6.

[0214] [Table 6-1]

[0215] [Table 6-2]

[0216] Compound 1, Form XIV was additionally prepared by dissolving compound 1, Form I (1.0 g) in abs. ethanol (130 ml) at reflux temperature. The clear solution was cooled to 0° C. over about 30 min. The resulting slurry was stirred for 3 h and the solid was filtered. The resulting wet crystals were dried at 40° C. in vacuum (500 mbar) under a nitrogen stream for 30 min to obtain 0.533 g of compound 1, Form XIV. The sample was characterized by XRPD ( FIG. 8A ), TG and DSC ( FIG. 8B , TG thermogram shows about 6.5% weight loss from 60 to 155° C., corresponding to 0.94 moles of ethanol, and an endothermic peak on DSC was observed at 147.2° C.) and NMR (the spectrum is consistent with the structure of compound 1 and indicates the presence of 0.98 moles of EtOH for 1 mole of compound 1.). The XRPD analysis is shown in Table 7.

[0217] [Table 7-1]

[0218]

Table 7-2

Claims

1. A crystal of an ethanol solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form XIV of Compound 1.

2. 2. The crystal of claim 1, characterized by a powder X-ray diffraction pattern including at least three peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ.

3. 2. The crystal of claim 1, characterized by a powder X-ray diffraction pattern including at least five peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ.

4. 2. The crystal of claim 1, characterized by a powder X-ray diffraction pattern including peaks at 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ.

5. 2. The crystal of claim 1, characterized by a powder X-ray diffraction pattern substantially the same as the pattern shown in FIG.

6. 2. The crystal of claim 1, characterized by a thermogravimetry (TG) thermogram showing a continuous weight loss of about 6.0% between about 49°C and about 172°C.

7. 10. The crystal of claim 1, characterized by a TG thermogram substantially similar to the pattern shown in FIG.

8. 2. The crystal of claim 1, characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 147°C and about 150°C.

9. 2. The crystal of claim 1, characterized by a DSC thermogram including an endothermic peak at about 149°C.

10. 10. The crystal of claim 1, characterized by a DSC thermogram substantially the same as the pattern shown in FIG.

11. 2. The crystal of claim 1, characterized by a powder X-ray diffraction pattern including at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å.

12. below: a) a powder X-ray diffraction pattern comprising at least three peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36°2θ±0.2°2θ; b) a powder X-ray diffraction pattern comprising at least three peaks having approximate d-spacing values ​​selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; and c) an endothermic peak at about 149°C as measured by DSC The crystal of claim 1, characterized by having at least two of the following:

13. 2. The crystal of claim 1, wherein the crystal is substantially free of tetrahydrofuran (THF).

14. A pharmaceutical composition comprising the crystal of any one of claims 1 to 13.

15. 15. The pharmaceutical composition of claim 14, wherein the composition is substantially free of THF.

16. A method for preparing the crystal of any one of claims 1 to 13, the method comprising: a) dissolving crystals of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea in dimethylformamide (DMF) to form a solution; b) adding the solution of step a) to ethanol to form a second solution; c) stirring the second solution to form a suspension; and d) Isolating the solid from the suspension to obtain Form XIV of Compound 1. A method comprising:

17. 17. The method of claim 16, wherein the second solution is cooled to between about -10°C and -25°C.

18. 17. The method of claim 16, wherein the second solution of step b) is cooled to between about -10°C and -25°C for 1 day.

19. 17. The method of claim 16, wherein the stirring in step c) is carried out at between about -10°C and -25°C.

20. 17. The method of claim 16, wherein the isolation of step d) is accomplished using syringe filtration.

21. A method for preparing the crystal of any one of claims 1 to 13, the method comprising: a) dissolving crystals of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea in ethanol (EtOH) to form a solution; b) cooling the solution of step a); c) stirring the cooled solution to form a suspension; and d) Isolating the solid from the suspension to obtain Form XIV of Compound 1. A method comprising:

22. 22. The method of claim 21, wherein the solution of step a) is cooled to between about 5°C and -10°C.

23. 22. The method of claim 21, wherein the stirring in step c) is carried out at between about 5°C and -10°C.

24. 22. The method of claim 21, wherein the isolation in step d) is achieved using filtration.

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