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

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 preparing the disclosed crystalline forms, pharmaceutical compositions and kits comprising the forms, and methods of treatment and uses comprising administration thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a continuation of U.S. patent application serial number 62 / 913,606 filed on October 10, 2019, the entire disclosure of which is incorporated herein by reference in its entirety.

[0003] 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, also referred to herein as Compound 1. The present disclosure also relates to methods of preparing the disclosed crystalline forms, pharmaceutical compositions and kits comprising the forms, and methods of treatment and uses comprising administration thereof. Background Art

[0004] 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 that is being developed as a new agent for the treatment of various conditions, including heavy menstrual bleeding and other symptoms associated with uterine leiomyoma, pain and other symptoms associated with endometriosis, and prostate cancer. Compound 1 may also be used to treat other diseases or conditions. See, for example, 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, WO2018060501, and WO2018060463.

[0005] Compound 1 and methods of making Compound 1 are described in US Pat. No. 7,300,935, US Pat. No. 8,058,280, US Pat. No. 8,735,401, US Pat. No. 9,346,822, and US Pat. No. 9,758,528.

[0006] U.S. Pat. No. 9,758,528, which is incorporated herein by reference in its entirety, describes methods of producing Compound 1 and certain synthetic intermediates, as well as two crystalline forms of Compound 1: crystals of a tetrahydrofuran (THF) solvate of Compound 1 and crystals of an anhydrous form of Compound 1 (referred to herein as Form I of Compound 1). For reference, as described in detail in U.S. Pat. No. 9,758,528, Form I of Compound 1 can be characterized by an XRPD pattern having peaks at approximately 7.4°, 8.9°, 9.9°, 12.1°, 16.6°, 17.3°, 22.2°, 22.8°, and 27.4° 2θ.

[0007] Form I of Compound 1 may also be characterized by Figure 4 XRPD pattern depicted in . Form I of Compound 1 begins to melt at about 189° C. and begins to degrade at about 197° C. Form I of Compound 1 shows an exothermic peak at about 237° C. according to DSC and shows degradation at about 245° C. according to TG. Figure 5 and 6 Thermogravimetric analysis (TG) and differential scanning calorimetry (DSC) thermograms of Form I of Compound 1 are shown, respectively. Summary of the invention

[0008] One aspect of the present disclosure is directed to 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, referred to as Form XIII of Compound 1. In some embodiments, Form XIII of Compound 1 is characterized in that an X-ray powder diffraction pattern comprises at least three peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, Form XIII of Compound 1 is characterized in that an X-ray powder diffraction pattern comprises at least five peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, 14.1°, 18.0°, 19.1°, and 21.5° 2θ ± 0.2° 2θ. In some embodiments, Form XIII of Compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at 5.6°, 5.9°, 9.1°, 11.4°, and 14.1° 2θ ± 0.2° 2θ. In certain such embodiments, the X-ray powder diffraction pattern comprises one or more peaks selected from 18.0°, 19.1°, and 21.5° ± 0.2° 2θ. In some embodiments, the XRPD pattern of Form XIII of Compound 1 is similar to Figure 1 The patterns shown in are basically the same.

[0009] In some embodiments, Form XIII of Compound 1 is characterized by a thermogravimetric analysis thermogram indicating a continuous weight loss of about 8.6% between about 32°C and about 120°C. In some embodiments, Form XIII of Compound 1 is characterized by a TG thermogram indicating a continuous weight loss of about 8.6% between about 32°C and about 120°C. Figure 2 The patterns shown in are basically the same.

[0010] In some embodiments, Form XIII of Compound 1 is characterized by an onset of melting between about 99°C and about 101°C. In some embodiments, Form XIII of Compound 1 is characterized by an onset of melting at about 100°C. In some embodiments, Form XIII of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 105°C and about 107°C. In some embodiments, Form XIII of Compound 1 is characterized by a DSC thermogram comprising an endothermic peak at about 106°C. In some embodiments, Form XIII of Compound 1 is characterized by a DSC thermogram with a peak of about 107°C. Figure 3 The patterns shown in are basically the same.

[0011] In some embodiments, Form XIII of Compound 1 is characterized by having at least two of the following:

[0012] a) an XRPD pattern comprising at least three peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, and 14.1° 2θ ± 0.2° 2θ;

[0013] b) has an onset of melting at about 100° C. as measured by DSC; and

[0014] c) has an endothermic peak at about 106° C. as measured by DSC.

[0015] One aspect of the present disclosure relates to a pharmaceutical composition comprising a crystalline form of the present disclosure and a pharmaceutically acceptable carrier.

[0016] Another aspect of the present disclosure relates to a method for preparing Form XIII of Compound 1, the method comprising:

[0017] a) suspending 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, designated Form I of Compound 1, in DMSO at room temperature;

[0018] b) separating the white suspension produced by step a); and

[0019] c) isolating the precipitated solid from the white suspension to obtain Compound 1 Form XIII.

[0020] Another aspect of the present disclosure relates to a method for preparing Form XIII of Compound 1, the method comprising:

[0021] a) suspending 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, designated Form I of Compound 1, in DMSO at room temperature;

[0022] b) separating the white suspension produced in step a);

[0023] c) subjecting the white suspension to a series of temperature cycles from about 15°C to about 30°C to about 15°C, from about 10°C to about 30°C to about 10°C, and from about 5°C to about 35°C to about 5°C; and

[0024] d) isolating the precipitated solid from the white suspension to obtain Compound 1 Form XIII.

[0025] In some embodiments, there are six temperature cycles from about 15° C. to about 30° C. and then to about 15° C. In some embodiments, there are six temperature cycles from about 10° C. to about 30° C. and then to about 10° C. In some embodiments, there are eight temperature cycles from about 5° C. to about 35° C. and then to about 5° C. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Depicted is the powder X-ray diffraction pattern of Form XIII of Compound 1.

[0027] Figure 2 Depicted is a thermogravimetric analysis (TG) thermogram of Form XIII of Compound 1.

[0028] Figure 3 Depicted is a differential scanning calorimetry (DSC) thermogram of Form XIII of Compound 1.

[0029] Figure 4 Depicted is a powder X-ray diffraction pattern of Form I of Compound 1. Figure 2 Modified.

[0030] Figure 5 Depicted is the TG thermogram of Form I of Compound 1.

[0031] Figure 6Depicted is the DSC thermogram of Form I of Compound 1.

[0032] Figure 7 Depicted is Form XIII of Compound 1 1 H NMR spectrum (400 MHz). 1 The solvent for H NMR acquisition was DMSO. DETAILED DESCRIPTION

[0033] 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 preparing the forms, pharmaceutical compositions and kits comprising the forms, and methods of treatment and uses comprising administration thereof. The chemical structure of Compound 1 is as follows:

[0034]

[0035] General information

[0036] The articles "a" and "an" are used in this disclosure to refer to one or more than one (ie, to at least one) of the grammatical object of the article. For example, "an element" refers to one element or more than one element.

[0037] Unless stated otherwise, in this disclosure, the term "and / or" is used to mean "and" or "or".

[0038] Crystalline forms of the present disclosure

[0039] Form XIII is a crystalline dimethyl sulfoxide (DMSO) solvate of Compound 1. As used herein, the term "solvate" includes stoichiometric solvates and non-stoichiometric solvates, such as channel-type solvates, formed by Compound 1 and a solvent. Examples of suitable solvents may include, but are not limited to, DMSO.

[0040] Compound 1 Form XIII

[0041] The present disclosure provides a crystalline form of compound 1 referred to as Form XIII of compound 1. In some embodiments, Form XIII of compound 1 is a DMSO solvate. In some embodiments, Form XIII of compound 1 is characterized in that the XRPD pattern comprises at least three peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, Form XIII of compound 1 is characterized in that the XRPD pattern comprises at least five peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, 14.1°, 18.0°, 19.1°, and 21.5° 2θ ± 0.2° 2θ. In some embodiments, Form XIII of compound 1 is characterized in that the XRPD pattern has peaks at 5.6°, 5.9°, 9.1°, 11.4°, and 14.1° 2θ ± 0.2° 2θ. In certain such embodiments, the XRPD pattern has one or more peaks selected from 18.0°, 19.1°, and 21.5°±0.2° 2θ. In some embodiments, Form XIII of Compound 1 is characterized by an XRPD pattern that is Figure 1 The patterns shown in are basically the same.

[0042] Compound 1 Form XIII can also be characterized using thermogravimetric analysis (TG). In some embodiments, Compound 1 Form XIII is characterized by a TG thermogram indicating a continuous weight loss of about 8.6% between about 32°C and about 120°C. In some embodiments, Compound 1 Form XIII is characterized by a TG thermogram indicating a continuous weight loss of about 8.6% between about 32°C and about 120°C. Figure 2 The patterns shown in are basically the same.

[0043] Form XIII of Compound 1 can also be characterized using differential scanning calorimetry (DSC). In some embodiments, Form XIII of Compound 1 is characterized by an onset of melting between about 99°C and about 101°C. In some embodiments, Form XIII of Compound 1 is characterized by an onset of melting at about 100°C. In some embodiments, Form XIII of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 105°C and about 107°C. In some embodiments, Form XIII of Compound 1 is characterized by a DSC thermogram comprising an endothermic peak at about 106°C. In some embodiments, Form XIII of Compound 1 is characterized by a DSC thermogram with a peak of about 107°C. Figure 3 The patterns shown in are basically the same.

[0044] In some embodiments, Form XIII of Compound 1 is characterized by having at least two of the following:

[0045] a) an XRPD pattern comprising at least three peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, and 14.1° 2θ ± 0.2° 2θ;

[0046] b) has an onset of melting at about 100° C. as measured by DSC; and

[0047] c) has an endothermic peak at about 106° C. as measured by DSC.

[0048] In some embodiments, the XRPD pattern comprises peaks at 5.6°, 5.9°, 9.1°, 11.4°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 5.6°, 5.9°, and 9.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 5.6°, 5.9°, and 11.4° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 5.6°, 5.9°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 9.1°, 11.4°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 5.9°, 11.4°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 5.6°, 11.4°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 5.9°, 9.1°, and 11.4° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 5.6°, 9.1°, and 11.4° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 5.6°, 9.1°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises peaks at 5.9°, 9.1°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern comprises one or more peaks selected from 18.0°, 19.1°, and 21.5° ± 0.2° 2θ.

[0049] In some embodiments, a single crystal structure of Form XIII of Compound 1 has 1-5 molecules of DMSO and one molecule of Compound 1. In some embodiments, a single crystal structure of Form XIII of Compound 1 has one molecule of DMSO and one molecule of Compound 1. In some embodiments, a single crystal structure of Form XIII of Compound 1 has two molecules of DMSO and one molecule of Compound 1. In some embodiments, a single crystal structure of Form XIII of Compound 1 has 2.5 molecules of DMSO and one molecule of Compound 1. In some embodiments, a single crystal structure of Form XIII of Compound 1 has three molecules of DMSO and one molecule of Compound 1. In some embodiments, a single crystal structure of Form XIII of Compound 1 has four molecules of DMSO and one molecule of Compound 1. In some embodiments, a single crystal structure of Form XIII of Compound 1 has five molecules of DMSO and one molecule of Compound 1. In some embodiments, a single crystal structure of Form XIII of Compound 1 has five molecules of DMSO and two molecules of Compound 1.

[0050] In some embodiments, Form XIII of Compound 1 has about 1 wt % to about 10 wt % DMSO relative to the total weight of Compound 1 as Form XIII of Compound 1. In some embodiments, Form XIII of Compound 1 has about 7 wt % to about 9 wt % DMSO relative to the total weight of Compound 1 as Form XIII of Compound 1. In some embodiments, Form XIII of Compound 1 has about 8 wt % to about 9 wt % DMSO relative to the total weight of Compound 1 as Form XIII of Compound 1. In some embodiments, Form XIII of Compound 1 has about 8.6 wt % DMSO relative to the total weight of Compound 1 as Form XIII of Compound 1.

[0051] In some embodiments, Form XIII of Compound 1 disclosed herein can be characterized by an XRPD pattern having the peaks listed in Table 1. All peaks are listed at angles 2θ ± 0.2° 2θ.

[0052]

[0053] Impurity profile of crystalline Form XIII of Compound 1

[0054] By producing Form XIII of Compound 1, the purity of the crystalline form of Compound 1 can be improved. Accordingly, Form XIII and Form I of Compound 1 having high purity can be obtained. In the desired crystalline form of Compound 1 (e.g., Form I and Form XIII), impurities such as U-1, U-2, and U-3 can be minimized.

[0055] The water purity of Form XIII of Compound 1 is summarized in Table 2:

[0056]

[0057] As shown in Table 2, Form XIII of Compound 1 shows high purity and low levels of impurities U-1, U-2, and U-3. When preparing pharmaceutical grade compounds, it is desirable and in some aspects necessary to minimize or control the amount of impurities to below certain limits because they may be inactive, toxic, or have other undesirable effects. In U.S. Pat. No. 9,758,528, a tetrahydrofuran (THF) solvate form of Compound 1 is disclosed as an intermediate in the production of Form I of Compound 1. The higher purity of Form XIII of Compound 1 can enable the production of Form I of Compound 1 of higher purity compared to the THF solvate of Form I.

[0058] Preparation of the Crystalline Forms of the Disclosure

[0059] Form XIII of Compound 1 may be used during the synthesis or production of Form I of Compound 1. Form I of Compound 1 and methods of 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 synthesis and crystallization methods. The XRPD pattern of Form I of Compound 1 is depicted at Figure 4 Methods for preparing Compound 1 prior to crystallization are described in U.S. Patent No. 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 8,735,401, and U.S. Patent No. 9,346,822, which are incorporated herein by reference in their entirety.

[0060] In some embodiments, Form I of Compound 1 can be prepared by using Form XIII of Compound 1. For example, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:1.2) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about four days. The precipitated solid from the resulting suspension is recovered to obtain Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0061] In some embodiments, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:5.5) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about six days. The precipitated solid from the resulting suspension is recovered to provide Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0062] In some embodiments, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:5.5) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 11 days. The precipitated solid from the resulting suspension is recovered to provide Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0063] In some embodiments, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:8.6) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 17 days. The precipitated solid from the resulting suspension is recovered to provide Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0064] For example, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:1.2) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about four days. The precipitated solid from the resulting suspension is recovered to provide Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0065] In some embodiments, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:5.5) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about six days. The precipitated solid from the resulting suspension is recovered to provide Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0066] In some embodiments, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:5.5) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 11 days. The precipitated solid from the resulting suspension is recovered to provide Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0067] In some embodiments, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:8.6) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 17 days. The precipitated solid from the resulting suspension is recovered to provide Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0068] The present disclosure provides a method for preparing Form XIII of Compound 1. In some embodiments, a THF solvate form of Compound 1 (see U.S. Patent No. 9,758,528) is added to a container containing DMSO and the solid fails to dissolve. Solid-solid form conversion is known in the art. Without being bound by any particular theory, the THF solvate form of Compound 1 can be converted to Form XIII of Compound 1 described herein via, for example, solid-solid conversion. The solid is recovered from the container to obtain Form XIII of Compound 1.

[0069] In some embodiments, Form XIII of compound 1 can be prepared by using Form I of compound 1. In certain such embodiments, Form I of compound 1 is suspended in DMSO at room temperature and the precipitated solid is recovered from the resulting suspension to obtain Form XIII of compound 1. In some embodiments, a mixture of Form I of compound 1 in DMSO is seeded with a small amount of Form XIII of compound 1.

[0070] In some embodiments, the method for preparing Form XIII of Compound 1 comprises suspending Form I of Compound 1 in DMSO at room temperature; isolating a white suspension resulting from the suspension of Form I of Compound 1 in DMSO; subjecting the white suspension to a series of temperature cycles from about 15°C to about 30°C, then to about 15°C, from about 10°C to about 30°C, then to about 10°C, and from about 5°C to about 35°C, then to about 5°C; and isolating the precipitated solid from the white suspension to obtain Form XIII of Compound 1. In some embodiments, there are six temperature cycles from about 15°C to about 30°C, then to about 15°C. In some embodiments, there are six temperature cycles from about 10°C to about 30°C, then to about 10°C. In some embodiments, there are eight temperature cycles from about 5°C to about 35°C, then to about 5°C. In some embodiments, the mixture of Form I of Compound 1 in DMSO is inoculated with a small amount of Form XIII of Compound 1.

[0071] Pharmaceutical composition

[0072] The disclosed crystalline Form XIII of Compound 1 can be used alone, but if administered to a subject, it will generally be administered in the form of a pharmaceutical composition in which Form XIII of Compound 1 is combined with a pharmaceutically acceptable carrier. Conventional procedures for selecting and preparing suitable pharmaceutical compositions are described, for example, in "Pharmaceuticals-The Science of Dosage Form Designs," ME Aulton, Churchill Livingstone, 1988, which is incorporated herein by reference in its entirety.

[0073] As used in the present disclosure, the term "carrier" may encompass carriers, excipients, and diluents and may refer to materials, compositions, or vehicles involved in carrying a medicament (such as the crystalline form of the present disclosure) or transporting a medicament (such as the crystalline form of the present disclosure) from one organ or part of the body of a subject to another organ or part of the body. Such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. The carrier should be selected based on the release distribution properties of the compatibility and desired dosage form. Exemplary carrier materials may include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, etc. See, for example, Oover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975.

[0074] 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 XIII 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 XIII of Compound 1.

[0075] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Form XIII of Compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Form I and Form XIII of Compound 1 and a pharmaceutically acceptable carrier.

[0076] Depending on the mode of administration, the pharmaceutical composition will contain about 0.05% to about 99% by weight (percentage by weight), more particularly about 0.05% to about 80% by weight, still more particularly about 0.10% to about 70% by weight, even more particularly about 0.10% to about 50% by weight of one or more disclosed crystalline forms, all weight percentages being based on the total composition. In some embodiments, the pharmaceutical composition is administered transdermally, transmucosally, or topically (e.g., applied to the skin or mucous membrane). In some embodiments, the pharmaceutical composition is administered as a vaginal suppository.

[0077] The pharmaceutical compositions of the present disclosure may comprise a therapeutically effective amount of one or more disclosed crystalline forms formulated together with one or more pharmaceutically acceptable carriers. Examples of pharmaceutically acceptable carriers include sugars such as lactose, dextrose, mannitol, glucose and sucrose; starches such as those 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; tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; 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; ethanol; phosphate buffered solution; lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents; coating agents; sweeteners, flavoring agents and aroma enhancers; preservatives and antioxidants.

[0078] Treatments and uses

[0079] The present disclosure provides a method of treating a disorder comprising administering an effective amount of one or more crystalline forms described herein, or one or more pharmaceutical compositions described herein comprising the one or more crystalline forms, thereby treating the disorder in a subject in need thereof.

[0080] In some embodiments of the methods and purposes disclosed herein, the disease 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 hypertrophy, uterine fibroids (uterine leiomyoma), adenomyoma, uterine fibroids, precocious puberty, menopause, premenstrual syndrome, dysmenorrhea, multifocal ovarian syndrome, polycystic ovary syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, menstrual bleeding and symptoms related to these conditions. Such symptoms may include anemia, irregular menstrual cycle, spotting, inflammation, pain, fatigue, urinary tract obstruction, frequent urination, incontinence, constipation, anxiety, sleep disorders, quality of life decline, daily activities difficulties, female sexual dysfunction and depression. In some embodiments of the methods and purposes disclosed herein, the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer or ovarian cancer. Other conditions that Compound 1 can be used to treat are described in U.S. Pat. No. 7,300,935, U.S. Pat. No. 8,058,280, U.S. Pat. No. 8,735,401, U.S. Pat. No. 9,346,822, WO2018060501, and WO2018060463, which are incorporated herein by reference in their entireties.

[0081] In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is prostate cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is uterine cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is breast cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is ovarian cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is uterine leiomyoma. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is heavy menstrual bleeding associated with uterine leiomyoma. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is endometriosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is pain associated with endometriosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is adenomyosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is heavy menstrual bleeding.

[0082] 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; cattle, 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.

[0083] When used in conjunction with one or more crystalline forms or pharmaceutical compositions of the present disclosure, the term "effective amount" or "therapeutically effective amount" may refer to an amount of the 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 alteration of a biological system. For example, an "effective amount" for therapeutic use may be the amount of the one or more pharmaceutical compositions comprising one or more crystalline forms as disclosed herein required to provide a clinically significant reduction in a disorder. An appropriate "effective amount" in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0084] As used herein, the terms "treat" or "treatment" or their cognates are intended to indicate a delay in the development of a condition; and / or a reduction in the severity of such symptoms that will or are expected to occur. Thus, these terms can include improving existing symptoms of a condition; preventing other symptoms; improving or preventing the underlying cause of a symptom; inhibiting a condition, e.g., arresting the development of a condition; alleviating a condition; causing regression of a condition; relieving symptoms caused by a condition; or stopping or alleviating symptoms of a condition.

[0085] As used in the present disclosure, the terms "administered / administration / administering" may refer to directly administering one or more crystalline forms or pharmaceutical compositions of the present disclosure to a subject.

[0086] The present disclosure provides a method of treating a condition, comprising administering an effective amount of Form XIII of Compound 1, thereby treating the condition in a subject in need thereof. The present disclosure provides a method of treating a condition, comprising administering an effective amount of a mixture of Form I and Form XIII of Compound 1, thereby treating the condition in a subject in need thereof. In some embodiments, the condition is a hormone-dependent condition.

[0087] The present disclosure provides a method for treating a condition, comprising administering an effective amount of one or more pharmaceutical compositions of the present disclosure, thereby treating the condition in a subject in need thereof. In some embodiments, the present disclosure provides a method for treating a condition, comprising administering an effective amount of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein, thereby treating the condition in a subject in need thereof. In some embodiments, the present disclosure provides a method for treating a condition, comprising administering an effective amount of one or more pharmaceutical compositions comprising Form XIII of Compound 1, thereby treating the condition in a subject in need thereof. In some embodiments, the present disclosure provides a method for treating a condition, comprising administering an effective amount of one or more pharmaceutical compositions comprising a mixture of Form I and Form XIII of Compound 1, thereby treating the condition in a subject in need thereof. In some embodiments, the condition is a hormone-dependent condition.

[0088] The present disclosure provides one or more crystalline forms of the present disclosure or one or more pharmaceutical compositions of the present disclosure for treating a condition in a subject in need thereof. In some embodiments, the one or more crystalline forms comprise Form XIII of Compound 1. In some embodiments, the one or more crystalline forms are a mixture of Form I and Form XII of Compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise one or more crystalline forms disclosed herein. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise Form XIII of Compound 1. In some embodiments, one or more pharmaceutical compositions of the present disclosure comprise a mixture of Form I and Form XIII of Compound 1. In some embodiments, the condition is a hormone-dependent condition.

[0089] The present disclosure provides the use of one or more crystalline forms of the present disclosure for treating a condition in a subject in need thereof. In some embodiments, the present disclosure provides the use of Form XIII of Compound 1 for treating a condition in a subject in need thereof. In some embodiments, the present disclosure provides the use of a mixture of Form I and Form XIII of Compound 1 for treating a condition in a subject in need thereof. In some embodiments, the condition is a hormone-dependent condition.

[0090] The present disclosure provides one or more pharmaceutical compositions of the present disclosure for use in treating a condition in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein for use in treating a condition in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising Form XIII of Compound 1 for use in treating a condition in a subject in need thereof. In some embodiments, the present disclosure provides one or more pharmaceutical compositions comprising a mixture of Form I and Form XIII of Compound 1 for use in treating a condition in a subject in need thereof. In some embodiments, the condition is a hormone-dependent condition.

[0091] The present disclosure provides the use of one or more crystalline forms of the present disclosure in the manufacture of a medicine for treating a condition. In some embodiments, the present disclosure provides the use of Form XIII of Compound 1 in the manufacture of a medicine for treating a condition. In some embodiments, the present disclosure provides the use of a mixture of Form I and Form XII of Compound 1 in the manufacture of a medicine for treating a condition. In some embodiments, the condition is a hormone-dependent condition.

[0092] The present disclosure provides the use of one or more pharmaceutical compositions of the present disclosure in the manufacture of medicines for treating conditions. 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 medicines for treating conditions. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising Form XIII of Compound 1 in the manufacture of medicines for treating conditions. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising a mixture of Form I and Form XIII of Compound 1 in the manufacture of medicines for treating conditions. In some embodiments, the condition is a hormone-dependent condition.

[0093] The present disclosure provides the use of one or more crystalline forms of the present disclosure as a medicine for treating a condition. In some embodiments, the present disclosure provides the use of Form XIII of Compound 1 as a medicine for treating a condition. In some embodiments, the present disclosure provides the use of a mixture of Form I and Form XIII of Compound 1 as a medicine for treating a condition. In some embodiments, the condition is a hormone-dependent condition.

[0094] The present disclosure provides the use of one or more pharmaceutical compositions of the present disclosure as medicines for treating conditions. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein as medicines for treating conditions. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising Form XIII of Compound 1 as medicines for treating conditions. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising a mixture of Form I and Form XIII of Compound 1 as medicines for treating conditions. In some embodiments, the condition is a hormone-dependent condition.

[0095] In some embodiments of the methods and uses of the present disclosure, only one pharmaceutical composition of the present disclosure is used in the methods or uses. In some embodiments of the methods and uses of the present disclosure, only one crystalline form of the present disclosure is used in the methods or uses.

[0096] For the therapeutic uses mentioned herein, the dosage applied will of course vary with the one or more crystalline forms or pharmaceutical compositions employed, the mode of administration, the desired treatment, and the indicated condition. For example, if inhaled, the daily dose of one or more crystalline forms of the present disclosure may be in the range of about 0.05 micrograms per kilogram of body weight (μg / kg) to about 100 micrograms per kilogram of body weight (μg / kg). Alternatively, if the one or more crystalline forms or pharmaceutical compositions are administered orally, the daily dose of one or more crystalline forms of the present disclosure may be in the range of about 0.01 micrograms per kilogram of body weight (μg / kg) to about 100 milligrams per kilogram of body weight (mg / kg).

[0097] However, it should be understood that the total daily dosage of one or more crystalline forms or pharmaceutical compositions disclosed herein will be determined by the attending physician within the scope of reasonable medical judgment. The specific therapeutically effective dosage level for any particular patient will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific crystalline form employed; the specific pharmaceutical composition employed; the patient's age, weight, general health, sex and diet; the administration time, route of administration and excretion rate of the specific crystalline form employed; the duration of treatment; drugs used in combination or concomitantly with the specific crystalline form employed; and similar factors well known in the medical field. A physician or veterinarian of ordinary skill in the art can easily determine and prescribe a therapeutically effective amount of one or more crystalline forms or pharmaceutical compositions disclosed herein required to treat, counteract or prevent the progression of the condition.

[0098] Combination therapy

[0099] In some embodiments, one or more crystalline forms or pharmaceutical compositions described herein may be used alone or together or in combination, or in combination with one or more other therapeutic agents or pharmaceutical compositions. Co-administration or combined use may refer to the administration of any form of two or more different compounds, crystalline forms or pharmaceutical compositions, so that the second compound, crystalline form or pharmaceutical composition is administered when the previously administered compound, crystalline form or pharmaceutical composition is still effective in vivo. For example, different compounds, crystalline forms or pharmaceutical compositions may be administered in the same preparation or in separate preparations or simultaneously or sequentially, or by separate administration of a single therapeutic component. In some embodiments, different compounds, crystalline forms or pharmaceutical compositions may be administered within about one hour, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, or about one week apart from each other. Therefore, individuals receiving such treatment may benefit from the combined effects of different compounds, crystalline forms or pharmaceutical compositions.

[0100] 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, the combination with 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.

[0101] 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 an estradiol equivalent. In some embodiments, one or more crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with progesterone. 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 an estradiol equivalent and progesterone. In some embodiments, the progesterone is norethindrone acetate.

[0102] In some embodiments, a combination of one or more crystalline forms or pharmaceutical compositions provided herein or a combination of other known pharmaceutical agents or pharmaceutical compositions with one or more crystalline forms or pharmaceutical compositions provided herein are formulated into pharmaceutical compositions and medicines that can be used 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.

[0103] In some embodiments of the present disclosure, one or more crystalline forms or pharmaceutical compositions of the present disclosure are administered in a subtherapeutic dose, wherein a subtherapeutic dose is a dose that would be insufficient to treat one of the conditions listed herein if administered alone.

[0104] Reagent test kit

[0105] In some embodiments, the disclosure also provides a pharmaceutical package or kit comprising one or more containers filled with at least one crystalline form or pharmaceutical composition of the disclosure. Optionally, such containers may be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use or sale of drugs or biological products, which notice reflects (a) agency approval of its manufacture, use or sale for human administration, (b) instructions for use, or both.

[0106] The foregoing applies to any crystalline form, pharmaceutical composition, method and use described herein. In particular, the present disclosure encompasses any combination of the features of such crystalline forms, pharmaceutical compositions, methods and uses (alone or in combination) with the features described for the various kits described in this section.

[0107] Although methods and materials similar to or equivalent to those described herein can be used in the implementation or testing of the present disclosure, illustrative methods and materials are described herein. Other features, objects and advantages of the present disclosure will be apparent from the description and claims. In the specification and the accompanying claims, singular forms also include plural forms, unless the context clearly provides otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entirety.

[0108] Each embodiment described herein may be used alone or in combination with any one or more of the other embodiments.

[0109] Implementation plan list

[0110] Some embodiments of the present disclosure include those of Embodiment 1:

[0111] Embodiment I-1. 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, which is referred to as Form XIII of Compound 1.

[0112] Embodiment I-2. The crystalline form of Embodiment I-1, characterized in that the X-ray powder diffraction pattern comprises at least three peaks selected from 5.6°, 5.9°, 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ.

[0113] Embodiment I-3. A crystalline form of Embodiment I-1, characterized in that the X-ray powder diffraction pattern comprises at least five peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, 14.1°, 18.0°, 19.1° and 21.5° 2θ ± 0.2° 2θ.

[0114] Embodiment I-4. The crystalline form of Embodiment I-1, characterized in that the X-ray powder diffraction pattern comprises peaks at 5.6°, 5.9°, 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ.

[0115] Embodiment I-5. The crystalline form of Embodiment I-4, wherein the X-ray powder diffraction pattern comprises one or more peaks selected from 18.0°, 19.1°, and 21.5°±0.2° 2θ.

[0116] Embodiment I-6. A crystalline form of any one of Embodiments I-1 to I-5, characterized in that the XRPD pattern is Figure 1 The patterns shown in are basically the same.

[0117] Embodiment I-7. The crystalline form of any one of Embodiments I-1 to I-6, characterized by a thermogravimetric (TG) thermogram indicating a continuous weight loss of about 8.6% between about 32°C and about 120°C.

[0118] Embodiment I-8. A crystalline form of any one of Embodiments I-1 to I-7, characterized in that the TG thermogram is Figure 2 The patterns shown in are basically the same.

[0119] Embodiment I-9. The crystalline form of any one of Embodiments I-1 to I-8, characterized by an onset of melting between about 99°C and about 101°C.

[0120] Embodiment I-10. The crystalline form of any one of Embodiments I-1 to I-9, characterized in that it begins to melt at about 100°C.

[0121] Embodiment I-11. The crystalline form of any one of Embodiments I-1 to I-10, characterized in that the differential scanning calorimetry (DSC) thermogram comprises an endothermic peak between about 105°C and about 107°C.

[0122] Embodiment I-12. The crystalline form of any one of Embodiments I-1 to I-11, characterized in that the DSC thermogram comprises an endothermic peak at about 106°C.

[0123] Embodiment I-13. A crystalline form of any one of Embodiments I-1 to I-12, characterized in that the DSC thermogram is Figure 3The patterns shown in are basically the same.

[0124] Embodiment I-14. The crystalline form of Embodiment I-1, characterized by having at least two of the following:

[0125] a) an XRPD pattern comprising at least three peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, and 14.1° 2θ ± 0.2° 2θ;

[0126] b) has an onset of melting at about 100° C. as measured by DSC; and

[0127] c) has an endothermic peak at about 106° C. as measured by DSC.

[0128] Embodiment I-15. A pharmaceutical composition comprising one or more crystalline forms of any one of Embodiments I-1 to I-14 and a pharmaceutically acceptable carrier.

[0129] Embodiment I-16. A pharmaceutical composition of Embodiment I-15, comprising 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 known as Form I of Compound 1.

[0130] Embodiment I-17. A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of one or more crystalline forms of any one of Embodiments I-1 to I-14.

[0131] Embodiment I-18. The method of Embodiment I-17, comprising administering to a subject an effective amount of 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, known as Form I of Compound 1.

[0132] Embodiment I-19. 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-15 or I-16.

[0133] Embodiment 1-20. The method of any one of Embodiments 1-17 to 1-19, wherein the disorder is a hormone-dependent condition.

[0134] Embodiment I-21. The method of embodiment I-20, wherein the hormone-dependent condition is sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of sex hormone-dependent cancer, prostate hypertrophy, uterine fibroids, adenomyoma, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multifocal ovary syndrome, polycystic ovary syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis or heavy menstrual bleeding.

[0135] Embodiment 1-22. The method of Embodiment 1-20 or 1-21, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer.

[0136] Embodiment 1-23. The method of any one of Embodiments 1-20 to 1-22, wherein the hormone-dependent condition is prostate cancer.

[0137] Embodiment 1-24. The method of any one of Embodiments 1-20 to 1-22, wherein the hormone-dependent condition is uterine cancer.

[0138] Embodiment 1-25. The method of any one of Embodiments 1-20 to 1-22, wherein the hormone-dependent condition is breast cancer.

[0139] Embodiment 1-26. The method of any one of Embodiments 1-20 to 1-22, wherein the hormone-dependent condition is ovarian cancer.

[0140] Embodiment 1-27. The method of Embodiment 1-20 or 1-21, wherein the hormone-dependent condition is uterine leiomyoma.

[0141] Embodiment 1-28. The method of embodiment 1-20, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine leiomyoma.

[0142] Embodiment 1-29. The method of embodiment 1-20, wherein the hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma.

[0143] Embodiment 1-30. The method of Embodiment 1-20 or 1-21, wherein the hormone-dependent condition is endometriosis.

[0144] Embodiment 1-31. The method of Embodiment 1-20 or 1-21, wherein the hormone-dependent condition is adenomyosis.

[0145] Embodiment 1-32. The method of Embodiment 1-20 or 1-21, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0146] Embodiment 1-33. The method of any one of Embodiments 1-17 to 1-33, comprising administering estradiol or a corresponding amount of an estradiol equivalent to the subject.

[0147] Embodiment 1-34. The method of any one of Embodiments 1-17 to 1-33, comprising administering progesterone to the subject.

[0148] Embodiment 1-35. The method of any one of Embodiments 1-17 to 1-33, comprising administering to the subject estradiol or a corresponding amount of an estradiol equivalent and a progesterone.

[0149] Embodiment 1-36. The method of Embodiment 1-34 or 1-35, wherein the progesterone is norethindrone acetate.

[0150] Embodiment I-37. One or more crystalline forms of any one of Embodiments I-1 to I-14 for use in treating a disorder in a subject in need thereof.

[0151] Embodiment I-38. One or more crystalline forms for use of Embodiment I-37, said one or more crystalline forms for use comprising 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 known as Form I of Compound 1, for treating a condition in a subject in need thereof.

[0152] Embodiment 1-39. One or more crystalline forms for use according to Embodiment 1-37 or 1-96, wherein the disorder is a hormone-dependent condition.

[0153] Embodiment I-40. One or more crystalline forms for use according to Embodiment I-39, wherein the hormone-dependent condition is sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of sex hormone-dependent cancer, prostate hypertrophy, uterine fibroids, adenomyoma, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multifocal ovary syndrome, polycystic ovary syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis or heavy menstrual bleeding.

[0154] Embodiment 1-41. One or more crystalline forms for use according to Embodiment 1-39 or 1-40, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer or ovarian cancer.

[0155] Embodiment 1-42. One or more crystalline forms for use according to any one of Embodiments 1-39 to 1-41, wherein the hormone-dependent condition is prostate cancer.

[0156] Embodiment 1-43. One or more crystalline forms for use according to any one of Embodiments 1-39 to 1-41, wherein the hormone-dependent condition is uterine cancer.

[0157] Embodiment 1-44. One or more crystalline forms for use according to any one of Embodiments 1-39 to 1-41, wherein the hormone-dependent condition is breast cancer.

[0158] Embodiment 1-45. One or more crystalline forms for use according to any one of Embodiments 1-39 to 1-41, wherein the hormone-dependent condition is ovarian cancer.

[0159] Embodiment 1-46. One or more crystalline forms for use according to Embodiment 1-39 or 1-40, wherein the hormone-dependent condition is uterine leiomyoma.

[0160] Embodiment 1-47. One or more crystalline forms for use according to Embodiment 1-39, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine leiomyoma.

[0161] Embodiment 1-48. One or more crystalline forms for use according to Embodiment 1-39, wherein the hormone-dependent condition is pain or other symptoms associated with uterine leiomyomata.

[0162] Embodiment 1-49. One or more crystalline forms for use according to Embodiment 1-39 or 1-40, wherein the hormone-dependent condition is endometriosis.

[0163] Embodiment I-50. One or more crystalline forms for use according to Embodiments I-39 or I-40, wherein the hormone-dependent condition is adenomyosis.

[0164] Embodiment I-51. One or more crystalline forms for use according to Embodiments I-39 or I-40, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0165] Embodiment I-52. One or more crystalline forms for use according to any one of Embodiments I-37 to I-51, wherein the one or more crystalline forms for use are used in combination with estradiol or a corresponding amount of an estradiol equivalent.

[0166] Embodiment I-53. One or more crystalline forms for use of any one of Embodiments I-37 to I-51, wherein the one or more crystalline forms for use are used in combination with a progesterone.

[0167] Embodiment I-54. One or more crystalline forms for use according to any one of Embodiments I-37 to I-51, wherein the one or more crystalline forms for use are used in combination with estradiol or a corresponding amount of an estradiol equivalent or a progesterone.

[0168] Embodiment I-55. One or more crystalline forms for use according to Embodiments I-53 or I-54, wherein the progesterone is norethindrone acetate.

[0169] Embodiment 1-56. The pharmaceutical composition of Embodiment 1-15 or 1-16 for use in treating a disorder in a subject in need thereof.

[0170] Embodiment 1-57. The pharmaceutical composition for use according to Embodiment 1-56, wherein the disorder is a hormone-dependent condition.

[0171] Embodiment I-58. The pharmaceutical composition for use of embodiment I-57, wherein the hormone-dependent condition is sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of sex hormone-dependent cancer, prostate hypertrophy, uterine fibroids, adenomyoma, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multifocal ovary syndrome, polycystic ovary syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis or heavy menstrual bleeding.

[0172] Embodiment I-59. The pharmaceutical composition for use according to Embodiment I-57 or I-58, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer or ovarian cancer.

[0173] Embodiment I-60. The pharmaceutical composition for use according to any one of Embodiments I-57 to I-59, wherein the hormone-dependent condition is prostate cancer.

[0174] Embodiment I-61. The pharmaceutical composition for use according to any one of Embodiments I-57 to I-59, wherein the hormone-dependent condition is uterine cancer.

[0175] Embodiment I-62. The pharmaceutical composition for use according to any one of Embodiments I-57 to I-59, wherein the hormone-dependent condition is breast cancer.

[0176] Embodiment I-63. The pharmaceutical composition for use according to any one of Embodiments I-57 to I-59, wherein the hormone-dependent condition is ovarian cancer.

[0177] Embodiment 1-64. The pharmaceutical composition for use according to Embodiment 1-57 or 1-58, wherein the hormone-dependent condition is uterine leiomyoma.

[0178] Embodiment 1-65. The pharmaceutical composition for use according to embodiment 1-57, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine leiomyoma.

[0179] Embodiment 1-66. The pharmaceutical composition for use according to embodiment 1-57, wherein the hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma.

[0180] Embodiment I-67. The pharmaceutical composition for use according to Embodiment I-57 or I-58, wherein the hormone-dependent condition is endometriosis.

[0181] Embodiment 1-68. The pharmaceutical composition for use according to Embodiment 1-57 or 1-58, wherein the hormone-dependent condition is adenomyosis.

[0182] Embodiment 1-69. The pharmaceutical composition for use according to embodiment 1-57 or 1-58, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0183] Embodiment I-70. The pharmaceutical composition for use according to any one of embodiments I-56 to I-69, wherein the pharmaceutical composition for use is used in combination with estradiol or a corresponding amount of an estradiol equivalent.

[0184] Embodiment I-71. The pharmaceutical composition for use of any one of Embodiments I-56 to I-69, wherein the pharmaceutical composition for use is used in combination with a progesterone.

[0185] Embodiment I-72. The pharmaceutical composition for use according to any one of embodiments I-56 to I-69, wherein the pharmaceutical composition for use is used in combination with estradiol or a corresponding amount of an estradiol equivalent and a progesterone.

[0186] Embodiment I-73. The pharmaceutical composition for use of Embodiment I-71 or I-72, wherein the progesterone is norethindrone acetate.

[0187] Embodiment I-74. Use of one or more crystalline forms of any one of Embodiments I-1 to I-14 for treating a disorder in a subject in need thereof.

[0188] Embodiment I-75. The use of Embodiment I-74, comprising using 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, referred to as Form I of Compound 1, to treat a condition in a subject in need thereof.

[0189] Embodiment 1-76. Use of the pharmaceutical composition of Embodiment 1-15 or 1-16 for treating a disorder in a subject in need thereof.

[0190] Embodiment I-77. Use of the crystalline form of any one or more embodiments I-1 to I-14 for the manufacture of a medicament for treating a disorder.

[0191] Embodiment 1-78. The use of Embodiment 1-77, comprising using 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, referred to as Form I of Compound 1, in the manufacture of a medicament for treating a condition.

[0192] Embodiment I-79. Use of the pharmaceutical composition of Embodiment I-15 or I-16 in the manufacture of a medicament for treating a disorder.

[0193] Embodiment I-80. Use of one or more crystalline forms of any one of Embodiments I-1 to I-14 as a medicament for treating a disorder.

[0194] Embodiment I-81. The use of Embodiment I-80, comprising the use of 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, referred to as Form I of Compound 1, as a medicine for treating a disorder.

[0195] Embodiment I-82. Use of the pharmaceutical composition of Embodiment I-15 or I-16 as a medicament for treating a disorder.

[0196] Embodiment 1-83. The use of any one of Embodiments 1-74 to 1-82, wherein the disorder is a hormone-dependent condition.

[0197] Embodiment I-84. The use of embodiment I-83, wherein the hormone-dependent condition is sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of sex hormone-dependent cancer, prostate hypertrophy, uterine fibroids, adenomyoma, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multifocal ovary syndrome, polycystic ovary syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis or heavy menstrual bleeding.

[0198] Embodiment 1-85. The use of Embodiment 1-83 or 1-84, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer or ovarian cancer.

[0199] Embodiment 1-86. The use of any one of Embodiments 1-83 to 1-85, wherein the hormone-dependent condition is prostate cancer.

[0200] Embodiment 1-87. The use of any one of Embodiments 1-83 to 1-85, wherein the hormone-dependent condition is uterine cancer.

[0201] Embodiment 1-88. The use of any one of Embodiments 1-83 to 1-85, wherein the hormone-dependent condition is breast cancer.

[0202] Embodiment 1-89. The use of any one of Embodiments 1-83 to 1-85, wherein the hormone-dependent condition is ovarian cancer.

[0203] Embodiment 1-90. The use of Embodiment 1-83 or 1-84, wherein the hormone-dependent condition is uterine leiomyoma.

[0204] Embodiment 1-91. The use of embodiment 1-83, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine leiomyoma.

[0205] Embodiment 1-92. The use of embodiment 1-83, wherein the hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma.

[0206] Embodiment 1-93. The use of Embodiment 1-83 or 1-84, wherein the hormone-dependent condition is endometriosis.

[0207] Embodiment 1-94. The use of Embodiment 1-83 or 1-84, wherein the hormone-dependent condition is adenomyosis.

[0208] Embodiment 1-95. The use of embodiment 1-83 or 1-84, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0209] Embodiment 1-96. The use according to any one of embodiments 1-74 to 1-95, which comprises using estradiol or a corresponding amount of an estradiol equivalent to treat a disorder.

[0210] Embodiment 1-97. The use of any one of Embodiments 1-74 to 1-95, comprising using progesterone to treat a condition.

[0211] Embodiment 1-98. The use according to any one of embodiments 1-74 to 1-95, which comprises using estradiol or corresponding amounts of an estradiol equivalent and progesterone to treat a disorder.

[0212] Embodiment I-99. The use of Embodiment I-97 or I-98, wherein the progesterone is norethindrone acetate.

[0213] Embodiment I-100. A method for preparing a crystalline form of any one of Embodiments I-1 to I-14, the method comprising:

[0214] a) suspending 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, designated Form I of Compound 1, in DMSO at room temperature;

[0215] b) separating the white suspension produced by step a); and

[0216] c) isolating the precipitated solid from the white suspension to obtain Compound 1 Form XIII.

[0217] Embodiment I-101. A method for preparing a crystalline form of any one of Embodiments I-1 to I-14, the method comprising:

[0218] a) suspending 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, designated Form I of Compound 1, in DMSO at room temperature;

[0219] b) separating the white suspension produced in step a);

[0220] c) subjecting the white suspension to a series of temperature cycles from about 15°C to about 30°C to about 15°C, from about 10°C to about 30°C to about 10°C, and from about 5°C to about 35°C to about 5°C; and

[0221] d) isolating the precipitated solid from the white suspension to obtain Compound 1 Form XIII.

[0222] Example

[0223] General Methods of Embodiment

[0224] X-ray powder diffraction (XRPD)

[0225] X-ray powder diffraction patterns were collected using a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation generated using an Optix long fine focus source. An elliptical gradient multilayer reflector was used to focus the Cu Kα X-rays through the sample and onto the detector. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to verify the position of the Si 111 peak. The sample was sandwiched between 3 μm thick films and analyzed in transmission geometry. The background generated by air was minimized using beam stops, short anti-scatter extensions, and anti-scatter knife edges. Soller slits for the incident beam and diffracted beams were used to minimize the broadening from axial divergence. A scanning position sensitive detector (X'Celerator) and Data Collector software version 2.2b located 240 mm from the sample were used to collect diffraction patterns. Proprietary software (TRIADS TM v2.1) to determine the position (° 2θ) of the peaks along the x-axis in the figures and tables. Based on the USP discussion of the variability of X-ray powder diffraction (United States Pharmacopeia, USP 42-NF 37 to S1, <941> , Characterization of Crystalline and Partially Crystalline Solids by X-Ray Powder Diffraction (XRPD), officially released on 8 / 1 / 2019), gives a peak position variability of ±0.2° 2θ. For the d-space table, the wavelength used to calculate the d-spacing is Cu-Kα1 wavelength (Phys. Rev. A 56 (6) 4554-4568 (1997)).

[0226] Differential Scanning Calorimetry (DSC)

[0227] Differential scanning calorimetry was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Tau hysteresis adjustment was performed with indium, tin, and zinc. Temperature and enthalpy were adjusted with octane, phenyl salicylate, indium, tin, and zinc. The adjustment was then verified with octane, phenyl salicylate, indium, tin, and zinc. The sample was placed in a sealed aluminum DSC pan and the weight was accurately recorded. The lid of the pan was pierced and then inserted into the DSC cell. A weighed aluminum pan configured as a sample pan was placed on the reference side of the cell. Data was collected from -30°C to 350°C at 10°C / min.

[0228] Thermogravimetric analysis (TG)

[0229] TG analysis was performed using a TA Instrument Q5000 thermogravimetric analyzer. Nickel and Alumel TM Temperature calibration was performed. The sample was placed in a platinum pan and inserted into the TG furnace. The furnace was heated to 350°C at a rate of 10°C / min under nitrogen purge.

[0230] Preparation and characterization of Form XIII of Compound 1

[0231] Form I of Compound 1

[0232] The present disclosure provides methods for preparing Form I of Compound 1.

[0233] Method 1: Form I of Compound 1 can be prepared by using Form XIII of Compound 1. For example, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:1.2) at a temperature of about 35°C + / - 5°C. The mixture is kept at about 35°C + / - 5°C for about four days. The precipitated solid from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, the mixture is inoculated with a small amount of Form I of Compound 1.

[0234] Method 2: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:5.5) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about six days. The precipitated solid from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, the mixture was seeded with a small amount of Form I of Compound 1.

[0235] Method 3: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:5.5) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 11 days. The precipitated solid from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, the mixture was inoculated with a small amount of Form I of Compound 1.

[0236] Method 4: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:8.6) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 17 days. The precipitated solid from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, the mixture was inoculated with a small amount of Form I of Compound 1.

[0237] Method 5: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:1.2) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about four days. The precipitated solid from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, the mixture was seeded with a small amount of Form I of Compound 1.

[0238] Method 6: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:5.5) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about six days. The precipitated solid from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, the mixture was seeded with a small amount of Form I of Compound 1.

[0239] Method 7: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:5.5) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 11 days. The precipitated solid from the resulting suspension is recovered to give Form I of Compound 1. In some experiments, the mixture was seeded with a small amount of Form I of Compound 1.

[0240] Method 8: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:8.6) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 17 days. The precipitated solid from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, the mixture was seeded with a small amount of Form I of Compound 1.

[0241] Compound 1 Form XIII

[0242] The present disclosure provides methods for preparing Form XIII of Compound 1.

[0243] Method 1: Charge DMSO (1.4 V) to a container. Then add the THF solvate form of Compound 1 (see US Pat. No. 9,758,528) (1.0 equiv.). The solid fails to dissolve in the solution. Recover the solid to obtain Compound 1 Form XIII.

[0244] Method 2: When spontaneous precipitation occurred, a clear solution of Compound 1 Form I was prepared in DMSO at ambient temperature. A portion of the resulting white thick suspension was subjected to a series of temperature cycling experiments, including 6 cycles from 15°C to about 30°C and then to about 15°C, 6 cycles from about 10°C to about 30°C and then to about 10°C, and 8 cycles from 5°C to about 35°C and then to about 5°C. A few of the needle-like particles produced were of single crystal quality and size. Crystal 16 TM Temperature cycling experiments were performed. In some experiments, the suspension was inoculated with a small amount of Compound 1 Form XIII.

[0245] Method 3: Compound 1 Form I was suspended in DMSO at room temperature and the precipitated solid from the resulting suspension was recovered after 6-17 days to give Compound 1 Form XIII. In some experiments, the suspension was inoculated with a small amount of Compound 1 Form XIII.

[0246] XRPD Characterization of Form XIII of Compound 1

[0247] XRPD data for crystalline Form XIII of Compound 1 disclosed herein were collected as detailed above. The XRPD pattern of Form XIII of Compound 1 is Figure 1 The peaks present in this XRPD pattern are listed in Table 1 above. All peak lists are at angles 2θ±0.2°2θ. The single crystal structure of Form XIII of Compound 1 was found to have one molecule of Compound 1 and 2.5 molecules associated with DMSO (or two molecules of Compound 1 and 5 molecules of DMSO).

[0248] Thermal Analysis (DSC and TG) of Form XIII of Compound 1

[0249] DSC and TG data for Form XIII of Compound 1 disclosed herein were collected as detailed above. The TG thermogram of Form XIII of Compound 1 is Figure 2 The DSC thermogram of Form XIII of Compound 1 is Figure 3 The following table details the thermal events in DSC and TG of Form XIII of Compound 1.

[0250] Thermal events in DSC and TG of Form XIII

[0251]

[0252] Characterization of Impurities Present in Form XIII of Compound 1

[0253] The amounts of impurities U-1, U-2, and U-3 present in Form XIII of Compound 1 were determined by HPLC. The water purity of Form XIII of Compound 1 is summarized in the table below:

[0254]

[0255] Use of Alliance TM HPLC data were collected using a Waters system with HPLC system and Empower software. The column used was Inertsil ODS-4, 4.6 mm x 150 mm, 3 μm (GL Sciences Corp.). The HPLC method was as follows:

[0256]

[0257]

[0258] Compound Retention time (minutes) U-1 13.62 U-2 16.10 Compound 1 24.97 U-3* 42.16

[0259] *Due to chromatographic effects, the retention time of U-3 may vary.

Claims

1. A crystalline form of a dimethyl sulfoxide 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 in that the X-ray powder diffraction pattern is substantially the same as the pattern shown in Figure 1.

2. The crystalline form according to claim 1, characterized by a thermogravimetric (TG) thermogram indicating a continuous weight loss of 8.6% between 32°C and 120°C.

3. The crystalline form of claim 1, characterized by a TG thermogram substantially the same as the pattern shown in Figure 2.

4. The crystalline form of claim 1, characterized by an onset of melting between 99°C and 101°C.

5. The crystalline form of claim 1, characterized by an onset of melting at 100°C.

6. The crystalline form of claim 1, characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between 105°C and 107°C.

7. The crystalline form of claim 1, characterized in that the DSC thermogram comprises an endothermic peak at 106°C.

8. The crystalline form of claim 1, characterized by a DSC thermogram substantially identical to the pattern shown in FIG3.

9. The crystalline form of claim 1, characterized by having at least one of the following: a) has an onset of melting at 100°C as measured by DSC; and b) has an endothermic peak at 106°C as measured by DSC.

10. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

11. A method for preparing a crystalline form according to any one of claims 1 to 9, the method comprising: a) suspending an anhydrous 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 DMSO at room temperature; b) separating the white suspension produced by step a); and c) separating the precipitated solid from the white suspension to obtain the crystalline form according to any one of claims 1 to 9.

12. A method for preparing a crystalline form according to any one of claims 1 to 9, the method comprising: a) suspending an anhydrous 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 DMSO at room temperature; b) separating the white suspension produced in step a); c) subjecting the white suspension to a series of temperature cycles from 15°C to 30°C to 15°C, 10°C to 30°C to 10°C, and 5°C to 35°C to 5°C; and d) separating the precipitated solid from the white suspension to obtain the crystalline form according to any one of claims 1 to 9.

13. The crystalline form of any one of claims 1-9, wherein a single crystal structure of the crystalline form comprises 1-5 DMSO molecules and one 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 molecule.

14. The method of claim 11, wherein the anhydrous 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 characterized by an X-ray powder diffraction pattern comprising 2θ peaks at 7.4°, 8.9°, 9.9°, 12.1°, 16.6°, 17.3°, 22.2°, 22.8°, and 27.4°.

15. The method of claim 12, wherein the anhydrous 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 characterized by an X-ray powder diffraction pattern comprising 2θ peaks at 7.4°, 8.9°, 9.9°, 12.1°, 16.6°, 17.3°, 22.2°, 22.8°, and 27.4°.

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