Crystalline forms of an ALC1 inhibitor useful in the treatment of cancer

Abstract

The present invention relates to novel crystal forms of sodium 7-(4-bromophenyl)-2-oxo-9- (trifluoromethyl)-1,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate, processes for the manufacture thereof and pharmaceutical compositions comprising them. These compounds are useful in treating proliferative diseases, particularly cancer.

Description

[0001] CRYSTALLINE FORMS OF AN ALC1 INHIBITOR USEFUL IN THE TREATMENT OF CANCER

[0002] The present invention relates to novel crystal forms of sodium 7-(4-bromophenyl)-2-oxo-9- (trifhioromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate, processes for the manufacture thereof and pharmaceutical compositions comprising them. These compounds are useful in treating proliferative diseases, particularly cancer.

[0003] Background of the Invention

[0004] Disruption of the chromatin remodeling forces of ALC1 through active small molecule agents enables safe, highly selective cancer therapy. Inhibition of ALC1 in cells with deficiencies in the homologous recombination repair pathway, including mutations in BRCA1 and BRCA2, leads to cell cycle arrest and cell death. Furthermore, ALC1 inhibitors trap PARP enzymes on DNA, potentiating the efficacy of PARP inhibitors. ALC1 inhibitors provide an alternative approach to the treatment of germline or acquired BRCA1 / BRCA2 deficiency, including tumors defined by “BRCAness” or other changes in DNA repair networks while also providing novel therapeutic approaches where ALC1 is amplified as an oncogene. Small molecule inhibitors of the helicase ALC1 (CHD1L) which are suitable for the use in treating proliferative diseases are known from WO 2022 / 117782 Al. One of the most promising compounds disclosed in WO 2022 / 117782 Al is 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydro-4- hydroxypyrido[3',2':4,5]thieno[3,2-d]pyrimidin. A synthesis scheme to prepare this compound is also disclosed in this document.

[0005] For pharmaceutical purposes, the active ingredient should preferably be used in crystalline form. Following the general disclosure of WO 2022 / 117782 Al, the synthesis of 7-(4-bromophenyl)-2-oxo-9- (trifluoromethyl)-l,2-dihydro-4-hydroxypyrido[3',2':4,5]thieno[3,2-d]pyrimidin results in the sodium salt thereof. Sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2- d]pyrimidin-4-olate hydrate is defined by formula (I) below:

[0006] Sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2- d]pyrimidin-4-olate hydrate is a synthetic, small molecule inhibitor of the helicase ALC1 (CHD1L) and is thus suitable for the use in treating proliferative diseases. However, this synthesis scheme of WO 2022 / 117782 Al has disadvantageous properties including an inefficient purification resulting in final purities as low as 95 %. In particular, crystallization in the aqueous solvent system resulted in a first polymorphic form (Form C), which however was found to be a low purity hydrate with high weight loss upon drying. Thus, several further crystallization processes were developed to improve the purity, reproducibility, and stability of the final product. In total, 17 polymorph forms were identified during this development process, designated polymorphic Forms A-Q. Despite the large number of well-defined different crystal forms, only two specific polymorphic forms termed, Form B and Form E, surprisingly showed various unexpected advantages over the other forms. These forms, B and E, were found to be stable against polymorphic conversion, in particular under conditions needed for preparing pharmaceutical compositions. Furthermore, Forms B and E are readily produced and purified, are highly uniform, reproducible, and have a high level of stability during storage at 30-60 % relative humidity. Further, the processes for production of Forms B and E have the advantages of higher yield and better filtration after rinsing with eluent. Finally, compared to the other forms found, being well-defined monohydrates, Forms B and E are advantageous over the DMSO solvates Form A, Form G, Form J, and Form K; the DMF solvate Form P and Form I; the 1,4-dioxane solvates Form L and Form M, the acetone solvates Form D and Form Q; the partial hydrate Form O; the isostructural solvate Form F; and the hydrate forms Form C and Form N which contain an undefined equivalency of water (5.2 % and 4.5 % weight loss prior to 150 °C as observed by TGA, respectively). Finally, Forms B and E are advantageous over Form H due to the requirement of drying under nitrogen to produce Form H.

[0007] Summary of the Invention

[0008] The polymorph space of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2(lH)-one is broad, with 17 distinct crystal forms identified thus far, as shown in figure 1. The particular crystallographic forms identified herein as “Form B” and "Form E" have been found as being distinctly advantageous over the other crystal forms, in particular due to their high degree of stability, ease of production, and favorable salt and solvate form.

[0009] The first aspect of the present invention relates to a new crystallographic form of the ALC1 inhibitor defined by formula (I), i.e. sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate having an XRPD pattern with significant peaks at about 8.4, 12.6, 20.6, 21.3, 24.6, and 38.5 °20 (± 0.2°), which form is referred to herein as "Form B".

[0010] The second aspect of the present invention relates to a new crystallographic form of the ALC1 inhibitor defined by formula (I), i.e. sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate having an XRPD pattern with significant peaks at about 11.3, 15.3, 17.0, 20.8, and 28.5 °20 (± 0.2°), which form is referred to herein as "Form E". The third aspect of the present invention relates to a process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin- 4-olate hydrate form (Form B) comprising the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2(lH)-one in DMSO at RT, preferably about 20-25 °C, b) adding anti-solvent EtOH or EtOH / FEO having about 1 : 1 ratio (v / v), c) maintaining the solution at the same temperature for about 1-24 hours, and d) filtering.

[0011] The fourth aspect of the present invention relates to a process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin- 4-olate hydrate form (Form E) comprising the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in DMSO at increased temperature, preferably about 55-70 °C, or at a temperature below 50 °C, followed by heating the mixture to about 60-70 °C, b) cooling to about 45-65 °C, preferably at a rate of about 5-10 °C / h, c) adding anti -solvent EtOH / FEO having about 1 : 1 to 9: 1 ratio (v / v) of EtOH / FEO into the solution, optionally maintaining the solution at the same temperature for about 1-4 hours, d) cooling the solution to about 0-10 °C, preferably at a rate of about 5-10 °C / hour, and preferably maintaining the solution at the same temperature for about 1 - 24 hours, e) filtering and drying the wet filter cake, preferably at < 40 °C and at 30-60 % relative humidity.

[0012] The fifth aspect of the present invention relates to a pharmaceutical composition comprising a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate according to the present invention or as obtainable by a process of the present invention.

[0013] The sixth aspect of the present invention relates to the crystalline forms or the pharmaceutical compositions according to the present invention for use in the treatment of a proliferative disease, in particular cancer.

[0014] Description of the Figures

[0015] In the following, the content of the Figures comprised in this specification is described. In this context please also refer to the detailed description of the invention above and / or below.

[0016] Figure 1: Overlay of the various XRPD patterns observed for different crystal Forms A to Q of 7-(4- bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4- olate.

[0017] Figure 2: XRPD pattern of the "Form E" crystal of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)- l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate. Figure 3: XRPD patern of the "Form B" crystal of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)- l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate.

[0018] Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0019] In the following, the elements of the present invention will be described. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

[0020] Definitions

[0021] In the following, some definitions of terms frequently used in this specification are provided. These terms will, in each instance of its use, in the remainder of the specification have the respectively defined meaning and preferred meanings.

[0022] As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents, unless the content clearly dictates otherwise.

[0023] "Pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia (United States Pharmacopeia-33 / National Formulary-28 Reissue, published by the United States Pharmacopeia Convention, Inc., Rockville Md., publication date: April 2010) or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0024] A “pharmaceutical composition” according to the invention may be present in the form of a composition, wherein the different active ingredients and diluents and / or carriers are admixed with each other, or may take the form of a combined preparation, where the active ingredients are present in partially or totally distinct form. An example for such a combination or combined preparation is a kit-of-parts.

[0025] The term “carrier”, as used herein, refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatine, malt, rice flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. The compounds of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

[0026] The term “XRPD” used herein, refers to an x-ray powder diffraction pattern defined by 2 0 (2 theta) reflection positions, obtained by using Cu-Ka radiation. The 20 values given here are indicated as degree (°20) with a margin of error of ± 0.2°.

[0027] The term "polymorph" refers to a specific crystal form of the compound (i.e., the structure of the lattice) that can exist in a solid state and in more than one crystal form.

[0028] Embodiments of the Invention

[0029] The present invention relates to novel crystal forms of 7-(4 -bromophenyl) -2 -oxo -9- (trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2(lH)-one referred to as “Form B” and "Form E" with an XRPD pattern consisting of most significant peaks as specified below and as shown in figures 2 and 3, respectively.

[0030] The first aspect of the present invention relates to a new crystallographic form of sodium 7-(4- bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate having an XRPD pattern with significant peaks at about 8.4, 12.6, 20.6, 21.3, 24.6, and 38.5 °20 (± 0.2°), which form is referred to herein as "Form B".

[0031] In a preferred embodiment of the first aspect, the crystal form of sodium 7-(4-bromophenyl)-2- oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate has a XRPD pattern with significant peaks at about 8.4, 12.6, 18.7, 20.6, 21.3, 24.6, 26.9, 28.7, 30.8, 33.1 and 38.5 °20 (± 0.2°). In a further preferred embodiment of the first aspect, the crystal form of sodium 7-(4- bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate has a XRPD pattern with significant peaks at about 8.4, 12.6, 16.6, 18.7, 20.6, 21.3, 24.6, 26.9, 28.7, 30.8, 32.6, 33.1 and 38.5 °20 (± 0.2°).

[0032] In a further preferred embodiment of the first aspect, the crystal form of sodium 7-(4- bromophenyl)-2-oxo-9-(trifluoromethyl)-I,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate has a XRPD pattern substantially as shown in figure 3.

[0033] The second aspect of the present invention relates to a new crystallographic form of sodium 7-(4- bromophenyl)-2-oxo-9-(trifluoromethyl)-I,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate having an XRPD pattern with significant peaks at about 11.3, 15.3, 17.0, 20.8, and 28.5 °20 (± 0.2°), which form is referred to herein as "Form E".

[0034] In a preferred embodiment of the second aspect, the crystal form of sodium 7 -(4 -bromophenyl) -2- oxo-9-(trifluoromethyl)-I,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate has a XRPD pattern with significant peaks at about 11.3, 11.8, 15.3, 17.0, 20.8, 24.9, 28.5 and 31.5 °20 (± 0.2°).

[0035] In a further preferred embodiment of the second aspect, the crystal form of sodium 7-(4- bromophenyl)-2-oxo-9-(trifluoromethyl)-I,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate has a XRPD pattern with significant peaks at about 5.6 11.3, 11.8, 15.3, 17.0, 20.8, 22.7, 23.2 24.9, 28.5, 31.5 and 40.7 °20 (± 0.2°).

[0036] In a further preferred embodiment of the second aspect, the crystal form of sodium 7-(4- bromophenyl)-2-oxo-9-(trifluoromethyl)-I,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate has a XRPD pattern substantially as shown in figure 2.

[0037] The third aspect of the present invention relates to a process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin- 4-olate hydrate form (Form B) comprising the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-I,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2(IH)-one in DMSO, preferably at about 20-25 °C, b) adding anti-solvent EtOH or EtOH / FEO having about 1 : 1 ratio (v / v), c) maintaining the solution at the same temperature for about 1-24 hours, and d) filtering.

[0038] Generally for the processes described herein, in particular the processes of the third and fourth aspect, sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2- d]pyrimidin-2(IH)-one, i.e. the sodium salt of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydro- 4-hydroxypyrido[3',2':4,5]thieno[3,2-d]pyrimidin, can be obtained as described in WO 2022 / 117782 Al, the disclosure of which is incorporated by reference herein. According to the third aspect, the API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2(lH)-one) is dissolved in DMSO. The amount of DMSO is typically suitable to substantially dissolve the solid API. Suitable amounts of DMSO are 10 to 30 times the volume of API used. The API is preferably dissolved at RT, i.e. at 20 to 25 °C, in particular at about 25 °C. Preferably, the DMSO is provided at this temperature before the API is added. After addition of the API into the DMSO, preferably the mixture is maintained at this temperature for 10 min to 1 h, e.g. about 30 min, to allow complete dissolution of the API. During that time, the mixture may be stirred. In a preferred embodiment, after dissolution, the solution of API in DMSO is filtered to remove insoluble ingredients and impurities. Suitable filters are known in the art.

[0039] As next step, typically following the dissolution and / or filtration step, at least a first part of antisolvent is added to the solution. As anti-solvent, in the third aspect EtOH or EtOHTEO having about 1: 1 ratio (v / v) of EtOH and H2O is used. The temperature of the anti-solvent used is typically substantially the same as the DMSO solution comprising the dissolved API. The total amount of anti-solvent added is such that the ratio of DMSO: anti -solvent (EtOH or 1: 1 EtOH / FEO) is about 1:2 to 1:3 (v / v). Thus, in one embodiment, the first part of anti-solvent is less than the amount of anti-solvent needed such that the ratio of DMSO: anti -solvent (EtOH or 1: 1 EtOH / FEO) is about 1:2 to 1:3 (v / v), and typically is about ! to ‘A of the amount needed such that the ratio of DMSO:anti-solvent (EtOH or 1: 1 EtOH / FEO) is about 1:2 to 1:3 (v / v). After addition of the first part of the anti-solvent, the solution is maintained at the same temperature for up to 4 h, preferably 30 min to 60 min. Afterwards, if only a first part of anti-solvent has been added, the second part of the anti-solvent is added such that the ratio of DMSO:anti-solvent (EtOH or 1: 1 EtOH / FEO) is about 1:2 to 1:3 (v / v), preferably about 1:2.

[0040] After addition of the anti -solvent, the solution can be maintained at the same temperature for up to 24 h, preferably 1 to 24 h, more preferably 6 to 18 h. This time range is suitable to obtain high crystallization yields.

[0041] After addition of the anti -solvent, and optionally maintaining the solution at the same temperature for up to 24 h, the solution can be cooled to about 0 to 10 °C, preferably at a rate of about 5 to 10 °C / hour, e.g. at 10 °C / hour, and preferably maintaining the cooled solution at the same temperature for about 1 to 24 hours.

[0042] In order to obtain the solid crystal Form B of the API, the solids are filtered from the solution. Optionally, the obtained filter cake is rinsed, e.g. up to 5 volumes of the cake, preferably using anti-solvent. Optionally, the wet filter cake is dried, typically under conditions which do not deteriorate the obtained crystal Form B.

[0043] Thus, in a preferred embodiment of the third aspect, the process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-I,2-dihydropyrido[3',2':4,5]thieno[3,2- d]pyrimidin-4-olate hydrate Form B comprises the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-I,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in DMSO at RT, preferably about 20-25 °C, b) adding a first part of anti-solvent EtOH or EtOH / H2O having about 1 : 1 ratio (v / v) of EtOH / FEO mixture into the solution, preferably until first precipitation occurs, holding the solution at the same temperature for about 30-60 minutes, c) adding a second part of anti-solvent EtOH or EtOH / FEO having about 1 : 1 ratio (v / v) of EtOH / H2O mixture into the solution until the ratio of DMSO:anti-solvent (EtOH or 1: 1 EtOH / H2O) is about 1 :2 to 1:3 (v / v), and maintaining the solution at the same temperature for about 2-3 hours, d) cooling the solution to about 0-10 °C, preferably at a rate of about 10 °C / hour, and preferably maintaining the solution at the same temperature for about 6-24 hours, e) filtering the mixture and optionally rinsing the filter cake, preferably with anti-solvent, and f) optionally drying the wet filter cake.

[0044] In a further preferred embodiment of the third aspect, the process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2- d]pyrimidin-4-olate hydrate Form B comprises the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in DMSO at 25 °C, b) adding a first part of anti-solvent EtOH or EtOH / H2O having about 1 : 1 ratio (v / v) of EtOH / H2O mixture into the solution, preferably until first precipitation occurs, more preferably about ! to i of the amount of anti -solvent needed to obtain a ratio of DMSO: anti-solvent (EtOH or 1: 1 EtOH / H2O) of about 1:2 to 1:3 (v / v), holding the solution at the same temperature for about 30-60 minutes, c) adding a second part of anti-solvent EtOH or EtOH / H2O having about 1 : 1 ratio (v / v) of EtOH / H2O mixture into the solution until the ratio of DMSO: anti-solvent (EtOH or 1: 1 EtOH / H2O) is about 1 :2 to 1:3 (v / v), and maintaining the solution at the same temperature for about 2-3 hours, d) cooling the solution to about 0-10 °C at a rate of about 10 °C / hour, and maintaining the solution at the same temperature for about 6-24 hours, e) filtering the mixture and optionally rinsing the filter cake, preferably with anti-solvent, and f) optionally drying the wet filter cake.

[0045] The fourth aspect of the present invention relates to a process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin- 4-olate hydrate form (Form E) comprising the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in DMSO at increased temperature, preferably about 55-70 °C, or at a temperature below 50 °C, followed by heating the mixture to about 60-70 °C, b) cooling to about 45-65 °C, preferably at a rate of about 5-10 °C / h, c) adding anti -solvent EtOH / H2O having about 1 : 1 to 9: 1 ratio (v / v) of EtOH / H2O into the solution, optionally maintaining the solution at the same temperature for about 1-4 hours, d) cooling the solution to about 0-10 °C, preferably at a rate of about 5-10 °C / hour, and preferably maintaining the solution at the same temperature for about 1 - 24 hours, e) filtering and drying the wet filter cake, preferably at < 40 °C and at 30-60 % relative humidity.

[0046] According to the fourth aspect, the API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2(lH)-one) is dissolved in DMSO at increased temperature, e.g. at least 50 °C, or at a temperature below 50 °C, followed by heating the mixture to about 50-70 °C. The amount of DMSO is typically suitable to substantially dissolve the solid API. Suitable amounts of DMSO are 10 to 30 times the volume of API used. The API is typically dissolved at a temperature in a range of 55 to 70 °C, preferably in a range of 60 to 65 °C. Preferably, the DMSO is provided at this temperature before the API is added. Alternatively, the API is dissolved in DMSO at a temperature below 50 °C, followed by heating the mixture to about 50-70 °C, preferably 60-70 °C. After addition of the API into the DMSO, preferably the mixture is maintained at the increased temperature / heated to the increased temperature for 10 min to 2 h, e.g. about 30 min to 120 min, to allow complete dissolution of the API. During that time, the mixture may be stirred. In a preferred embodiment, after dissolution, the solution of API in DMSO is filtered to remove insoluble ingredients and impurities. The filter cake may be washed with DMSO, e.g. about 2 to 4 volumes. Suitable filters are known in the art.

[0047] As the next step, typically following the dissolution and / or filtration step, the optionally filtered solution may be cooled to about 45-65 °C, preferably about 50-60 °C. The cooling rate is preferably about 5-10 °C / h.

[0048] As next step, typically following the cooling of the solution, at least a first part of anti-solvent is added to the solution. As anti-solvent, in the fourth aspect EtOH / H2O having about 1: 1 to about 9: 1 ratio (v / v) of EtOH and H2O, preferably about 9: 1 (v / v), is used. The temperature of the anti-solvent used is typically the same as the (cooled) DMSO solution comprising the dissolved API. The total amount of antisolvent added is preferably such that the ratio of DMSO: anti -solvent (EtOH / H2O) is about 1:2 to 1:3 (v / v), preferably about 1:2 (v / v). Thus, in one embodiment, the first part of anti-solvent is less than the amount of anti-solvent added such that the ratio of DMSO:anti-solvent (1: 1-9: 1 EtOH / H2O) is about 1:2 to 1:3 (v / v), and typically is about ! to A of the amount needed such that the ratio of DMSO:anti-solvent (1: 1- 9: 1 EtOH / H2O) is about 1:2 to 1:3 (v / v), preferably about 1:2 (v / v). After addition of the first part of the anti-solvent, the solution can be maintained at the same temperature for up to 4 h, typically, 1 to 4 h, preferably 30 min to 120 min. Afterwards, if only a first part of anti-solvent has been added, the second part of the anti-solvent is added such that the ratio of DMSO:anti-solvent (EtOH / H2O) is about 1:2 to 1:3 (v / v), preferably about 1:2.

[0049] In one embodiment, the total amount of anti -solvent is added in three distinct parts. That is, the first part of anti-solvent is less than the amount of anti-solvent added such that the ratio of DMSO: anti-solvent (1: 1-9: 1 EtOH / H2O) is about 1:2 to 1:3 (v / v), and typically is about ! (25 %) to A (50 %) of the amount needed such that the ratio of DMSO:anti-solvent (1: 1-9: 1 EtOH / H2O) is about 1:2 to 1:3 (v / v), preferably about 1:2 (v / v). After addition of the first part of the anti -solvent, the solution can be maintained at the same temperature for up to 4 h, typically, 1 to 4 h, preferably 30 min to 120 min. Afterwards, a second part of anti -solvent is added such that the total amount of anti-solvent added is still below the ratio of DMSO:anti- solvent (1: 1-9: 1 EtOH / H2O) of about 1:2 to 1:3 (v / v), and typically is about 10 % to 30 % of the amount needed such that the ratio of DMSO:anti-solvent (1: 1-9: 1 EtOH / H2O) is about 1:2 to 1:3 (v / v), preferably about 1:2 (v / v). After addition of the second part of the anti-solvent, the solution can be maintained at the same temperature for up to 4 h, typically, 1 to 4 h, preferably 1 to 3h. Finally, the third part of anti-solvent is added such that the ratio of DMSO: anti-solvent (EtOH / H2O) is about 1:2 to 1:3 (v / v), preferably about 1:2. After addition of the third part of the anti-solvent, the solution can be maintained at the same temperature for up to 4 h, typically, 1 to 4 h, preferably 1 to 3 h. The ratio of the relative amounts of the first part:second part:third part of anti -solvent added can be 25-50 %: 10-30 %:20-65 % (the sum has to be 100 %), preferably about 25-35 %: 15-25 %:40-60 %.

[0050] After addition of the anti-solvent, the solution can be maintained at the same temperature for up to 24 h, preferably 1 to 16 h, more preferably 2 to 3 h. This time range is suitable to obtain high crystallization yields.

[0051] After addition of the anti-solvent, and optionally maintaining the solution at the same temperature for up to 24 h, the solution can be cooled to about 0 to 10 °C, preferably at a rate of about 5 to 10 °C / hour, e.g. at 10 °C / h, and preferably maintaining the cooled solution at the same temperature for about 1 to 24 hours. In one embodiment, the cooling step consists of several alternating steps of cooling and maintaining the solution at said lowered temperature for a while, e.g. the following two steps a) and b) could be alternated until the final temperature is reached: a) lowering the temperature for 5 to 10 °C, followed by b) maintaining the cooled solution at the same temperature for about 1 to 24 hours. These extended times are suitable to obtain high crystallization yields and assures consistent production of the desired Form E.

[0052] In order to obtain the solid crystal Form E of the API, the solids are filtered from the solution. Optionally, the obtained filter cake is rinsed, e.g. up to 5 volumes of the cake, preferably using anti-solvent. Optionally, the wet filter cake can be dried, typically under conditions which do not deteriorate the obtained crystal Form E, e.g. at < 40 °C and at 30-60 % relative humidity.

[0053] In a preferred embodiment of the fourth aspect, the process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin- 4-olate hydrate Form E comprises the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in DMSO at increased temperature, preferably about 55-60 °C, or at a temperature below 50 °C, followed by heating the mixture to about 60-70 °C, b) cooling to about 45-65 °C, preferably at a rate of about 5-10 °C / h, c) adding a first part of anti-solvent EtOH / H2O having about 1: 1 to 9: 1 ratio (v / v) of EtOH / H2O mixture into the solution, preferably until first precipitation occurs, typically in an amount of about ! to i of the amount needed such that the ratio of DMSO:anti-solvent (1 : 1 to 9: 1 EtOH / H2O) is about 1 :2 to 1:3 (v / v), preferably about 1:2 (v / v), holding the solution at the same temperature for about 30-60 minutes, d) adding a second part of anti-solvent EtOH / H2O having about 1 : 1 to 9: 1 ratio (v / v) of EtOH / FEO into the solution until the ratio of DMSO:(1: 1 to 9: 1 EtOH / H2O) is about 1:2 (v / v), and maintaining the solution at the same temperature for about 2-3 hours, e) cooling the solution to about 0-10 °C, preferably at a rate of about 5-10 °C / hour, and preferably maintaining the solution at the same temperature for about 6-24 hours, f) filtering the mixture and optionally rinsing the filter cake, preferably with a 1 : 1 to 9: 1 EtOH / H2O solution, and g) drying the wet filter cake, preferably at < 40 °C and at 30-60 % relative humidity.

[0054] In a further preferred embodiment of the fourth aspect, the process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2- d]pyrimidin-4-olate hydrate Form E comprises the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in DMSO at a temperature of preferably about 55- 70 °C, or at a temperature below 50 °C, followed by heating the mixture to about 60-70°C, and maintaining the temperature for about 30-120 minutes, b) cooling to about 50-55 °C at a rate of about 5-10 °C / h, c) adding a first part of anti-solvent EtOH / H2O having about 9: 1 ratio (v / v) of EtOH / H2O mixture into the solution, preferably until first precipitation occurs, typically in an amount of about ! to i of the amount needed such that the ratio of DMSO:anti -solvent (9: 1 EtOH / H2O) is about 1:2 (v / v), holding the solution at the same temperature for about 30-60 minutes, d) adding a second part of anti-solvent EtOH / H2O having about 9: 1 ratio (v / v) of EtOH / H2O mixture into the solution until the ratio of DMSO: (9: 1 EtOH / H2O) is about 1:2 (v / v), and maintaining the solution at the same temperature for about 2-3 hours, e) cooling the solution to about 0-10 °C, preferably at a rate of about 10 °C / hour, and preferably maintaining the solution at the same temperature for about 6-24 hours, f) filtering the mixture and optionally rinsing the filter cake, preferably with a 9: 1 EtOH / H2O solution, and g) drying the wet filter cake, preferably at < 40 °C and at 30-60 % relative humidity.

[0055] In a further preferred embodiment of the fourth aspect, the process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2- d]pyrimidin-4-olate hydrate Form E comprises the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in 15 volumes of DMSO at 15-25 °C b) heating the mixture, preferably to about 60-70 °C, and maintaining the temperature for about 60- 120 minutes, while stirring c) filtering and rinsing the filter cake with about 2 volumes of DMSO d) cooling to about 50-60 °C at a rate of about 5-10 °C / h, e) adding a first part of anti-solvent (about 9 volumes) EtOH / FEO having about 9: 1 ratio (v / v) of EtOH / H2O mixture into the solution, holding the solution at the same temperature for about 1-2 hours while stirring, f) adding a second part of anti-solvent (about 6 volumes) EtOH / H2O having about 9: 1 ratio (v / v) of EtOH / H2O mixture into the solution and maintaining the solution at the same temperature for about 2-3 hours while stirring, g) adding a third part of anti-solvent (about 15 volumes) EtOH / H2O having about 9: 1 ratio (v / v) of EtOH / H2O mixture into the solution and maintaining the solution at the same temperature for about 2-3 hours while stirring, h) cooling the solution to about 0-10 °C at a rate of about 10°C / hour, and maintaining the solution at the same temperature for about 20-24 hours while stirring, i) filtering the mixture and optionally rinsing the filter cake, preferably with about 10 volumes of an about 9: 1 EtOH / H2O solution, and j) drying the wet filter cake, preferably at < 40 °C and at 30-60 % relative humidity.

[0056] In a preferred embodiment, in cooling step (steps b), e) or h) respectively) of the above embodiments, the cooling step comprises several alternating steps of cooling and maintaining the solution at said lowered temperature for a while, e.g. the following two steps a) and b) could be alternated until the final temperature is reached: a) lowering the temperature for 5 to 10 °C, preferably at a cooling rate of 5 to 10 °C / h, followed by b) maintaining the cooled solution at the same temperature for about 1 to 24 hours, preferably 3 to 18 h. These extended times are suitable to obtain high crystallization yields and assures consistent production of the desired Form E.

[0057] Using the processes as described above, Form E is readily produced and purified, is highly uniform, reproducible, and has a high level of stability during drying at 30-60 % relative humidity.

[0058] The present invention also relates to a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9- (trifhioromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate as obtainable by a process described herein.

[0059] The fifth aspect of the present invention relates to a pharmaceutical composition comprising a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate Form E or Form B according to the present invention or a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate as obtainable by a process described herein. Preferably, the composition is in the form of a solution or a solid dosage form. The pharmaceutical composition may additionally comprise a carrier. The pharmaceutical composition may be for oral or intravenous (iv) administration, preferably iv. The sixth aspect of the present invention relates to the crystalline forms or the pharmaceutical compositions according to the present invention for use in the treatment of a proliferative disease, in particular cancer. Accordingly, the present invention relates to a method of treating a proliferative disease, in particular cancer in a subject in need thereof, comprising administering the crystalline forms or the pharmaceutical compositions according to the present invention.

[0060] In some embodiments of the aspects of the invention, the cancer is breast cancer, ovarian cancer, prostate cancer, pancreatic carcinomas, gastric cancer, gastroesophageal cancer, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, uterine cancer, bone cancer (preferably osteosarcoma), gastric cancer, gastroesophageal cancer, non-small cell lung cancer, bladder cancer, endometrial cancer, brain cancer, in particular astrocytoma cancer or glioma cancer, cervix cancer, kidney cancer (in particular RCC), thyroid cancer, fallopian tube cancer, peritoneal cancer, acute myeloid leukemia, or uveal melanoma. In some embodiments, the cancer is basal-like cancer, basal-like breast cancer, triple negative breast cancer, high grade cancer, or high grade serous ovarian cancer cell. In a particularly preferred embodiment in accordance with the various aspects of the invention, the cancer is breast cancer, prostate cancer, pancreatic carcinomas, fallopian tube cancer, colorectal cancer, hepatocellular carcinoma, or bone cancer (preferably osteosarcoma).

[0061] In a preferred embodiment, the cancer to be treated is BRCA1 deficient and / or BRCA2 deficient. A cancer that is BRCA1 deficient or BRCA2 deficient refers to a cancer that has one or more cells having abnormal BRCA1 levels or activities, or abnormal BRCA2 levels or activities. These abnormal levels or activities interfere with the normal function of BRCA1 or BRCA2 and can cause a defect in HR-mediated DNA repair or decrease the stability of replication forks. Preferably, the proliferative disease is selected from a BRCA-1 and / or BRCA -2 -deficient tumor, and / or the proliferative disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, non-small cell lung cancer, or pancreatic cancer.

[0062] Particularly preferred examples of cancers treatable according to the various aspects of the invention are ovarian and fallopian tube cancer, breast cancer, pancreatic cancer, gastric cancer, colorectal cancer, and pulmonary cancer.

[0063] Preferably, the cancer to be treated in accordance with the various aspects of the invention has relapsed or progressed, preferably after a first line chemotherapy. Thus, preferably, the combinations according to the present invention are for use as second line or third line therapy, more preferably for second line or third line therapy for the treatment of a HR deficient cancer.

[0064] Preferably, the cancer to be treated is at stage III (locally advanced) or IV (metastatic).

[0065] Preferably, the cancer to be treated in accordance with the various aspects of the invention has underlying defects in DNA damage repair, like HR repair, i.e. is a HR deficient cancer (HRD cancer), in particular a HR deficient ovarian cancer, HR deficient breast cancer, HR deficient prostate cancer, or HR deficient pancreatic cancer. In one embodiment, the cancer cells have mutations / deletions / insertions in one or more DNA repair genes as listed in Figures 8 and / or 9, in particular ARID 1 A, ATM, ATRX, BAP1, BLM, BRCA1, BRCA2, BARD1, BRIP1, CHEK1, CHEK2, FANCA / C / D2 / E / F / G / L, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD5 ID, RAD51, RAD5 IB and / or WRN. Most preferred are BRCA1 / 2.

[0066] Preferably, the patient to be treated in accordance with the various aspects of the invention is a cancer patient, preferably having breast cancer, ovarian cancer, prostate cancer, pancreatic carcinomas, gastric, gastroesophageal, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, uterine cancer, bone cancer (preferably osteosarcoma), fallopian tube cancer, peritoneal cancer, acute myeloid leukemia, or uveal melanoma, and optionally having mutations / deletions / insertions in one or more of the HR genes, preferably BRCA1 / 2. In a particular preferred embodiment, the cancer patient has a HR deficient cancer, in particular BRCA-1 and / or BRCA -2 -deficient.

[0067] As disclosed in the Examples below, Forms A to Q of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)- l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate can be obtained. Characteristic peaks of Forms A to Q are summarized in the following Table 1 Table 1

[0068] (Bold most preferred, underlined preferred, italics less preferred)

[0069] The galenic properties of Forms A to Q are summarized in the following Table 2 Table 2

[0070] Of the 17 crystal forms obtained, only Forms E and B show suitability for galenic use, namely acceptable solvent content, suitable stability, and reliable processes for their preparation in good yield and purity.

[0071] This invention will be more fully described in conjunction with the following specific example, which should not be construed as limiting the scope of this invention.

[0072] Abbreviations

[0073] Chemical substances

[0074] ACE acetone

[0075] MeOH Methanol

[0076] EtOH Ethanol

[0077] IPA Propan-2-ol

[0078] ACN Acetonitrile

[0079] EA Ethyl acetate MTBE Methyl tert-butyl ether

[0080] DMSO Dimethyl sulfoxide

[0081] Other abbreviations (in alphabetical order):

[0082] DSC Differential Scanning Calorimetry

[0083] DVS Dynamic Vapor Sorption h Hour

[0084] GC Gas Chromatography

[0085] HPLC High Performance Liquid Chromatography mg Milligram min Minute mb Milliliter

[0086] N / A Not Applicable

[0087] PLM Polarized Light Microscopy

[0088] RT Room Temperature (20-25 °C)

[0089] SEM Scanning Electron Microscope

[0090] TGA Thermogravimetric Analysis

[0091] XRPD X-ray Powder Diffraction

[0092] Apparatus:

[0093] XRPDs have been determined using a Brucker D8 Advance, X-Ray Generator Cu Ka (X = 1.5406 A), tube voltage 40 kV, tube current 40 mA, scan type 20 / 0, scan mode continuous, scan range 3° to 42°, step time 0.25, scan step 0.02°, sample stage rotating

[0094] EXAMPLE 1 - Form A

[0095] Preparation of Form A (a DMSO solvate) of Sodium 7-(4-bromophenyl)-2-oxo-9- (trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate.

[0096] Form A can be obtained by crystallization in DMSO / EtOH or in DMSO / Aceton using the following process:

[0097] 1) Dissolving 50 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) starting material in 20 volumes of DMSO at RT (20-25 °C).

[0098] 2) Adding anti-solvent until DMSO: anti-solvent=l / l (v:v), the solution gradually became turbid.

[0099] 3) Aging for about 2h.

[0100] 4) Cooling to 10 °C, holding for 24h.

[0101] 5) Filtering and drying at 50 °C under vacuum for about 48h.

[0102] The XRPD of Form A is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above. EXAMPLE 2 - Form B

[0103] A) Preparation of Form B of Sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 Ithieno [3 ,2-dl pyrimidin-4 -plate .

[0104] A. 1) Form B can be obtained by reacting free acid of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydro-4-hydroxypyrido[3',2':4,5]thieno[3,2-d]pyrimidin with 10 equivalents of sodium hydroxide for 4 hours at 65 °C to 75 °C, filtering at 20 °C - 30 °C, rinsing with purified water and anhydrous ethanol, and stirring for 2-4 hours at 15 °C to 30 °C with methyl tert-butyl ether

[0105] The TGA profile of Form B showed there were two steps of weight loss; the first was 1.535 % from RT to 65 °C and the second was 4.678 % weight loss from ~85 °C to 180 °C. The DSC profile of Form B showed that there were two endothermic peaks at 50.68 °C and 134.21 °C.

[0106] A.2) Form B can further be obtained by crystallization in DMSO / EtOH or in DMSO / Aceton using the following process:

[0107] 1) Dissolving 50 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) starting material in 20 volumes of DMSO at RT (20-25 °C).

[0108] 2) Adding anti-solvent until DMSO: anti-solvent=l / l (v:v), the solution gradually became turbid.

[0109] 3) Aging for about 2h.

[0110] 4) Cooling to 10 °C, holding for 24h.

[0111] 5) Filtering and drying at 50 °C under vacuum for about 48h.

[0112] A.3) Form B can further be obtained by crystallization in DMSO using EtOH / fTO (v:v) 1: 1 as antisolvent using the following process:

[0113] 1) Dissolving 50 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) starting material in 20 volumes of DMSO at 25 °C.

[0114] 2) Keeping the solution at the same temperature for 30 min, optionally filtering the impurities.

[0115] 3) Adding first part of anti-solvent, the solution gradually became turbid.

[0116] 4) Adding anti-solvent until DMSO: anti-solvent=l / l (v:v).

[0117] 5) Maintaining at the same temperature for 4 to 24h.

[0118] 6) Filtering and rinsing the filter cake with anti-solvent.

[0119] A.4) Form B can further be obtained by crystallization in DMSO using EtOH / EEO (v:v) 1: 1 as antisolvent using the following process: 1) Dissolving 50 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) starting material in 20 volumes of DMSO at 50 °C.

[0120] 2) Keeping the solution at the same temperature for 30 min, filtering the impurities.

[0121] 3) Cooling to 45 °C at 5 °C / h.

[0122] 4) Keeping the solution at the same temperature for 30 min.

[0123] 5) Adding seed crystals (do not dissolve).

[0124] 6) Keeping the solution at the same temperature (45 °C) for 6h min.

[0125] 7) Cooling to 40 °C at 5 °C / h, maintaining temperature for 6h, Cooling to 35 °C at 5 °C / h, maintaining temperature for 6h, Cooling to 30 °C at 5 °C / h, maintaining temperature for 6h, Cooling to 25 °C at 5 °C / h, and maintaining temperature for 6h.

[0126] 8) Adding a first part of anti-solvent, the solution gradually became turbid.

[0127] 9) Adding a second part of anti-solvent until the ratio of DMSO:anti-solvent=l : 1 (addition time about 90 min).

[0128] 10) Maintaining at the same temperature for 24h.

[0129] 11) Cooling to 0 °C at 5 °C / h, keeping temperature for 2h, filtering and rinsing the filter cake with antisolvent.

[0130] The XRPD of Form B is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0131] B) Stability data of Form B

[0132] Form B shows excellent storage stability.

[0133] EXAMPLE 3 - Form C

[0134] Preparation of Form C of Sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate . Form C can be obtained by reacting free acid of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2-dihydro- 4-hydroxypyrido[3',2':4,5]thieno[3,2-d]pyrimidin with 1 equivalent of sodium hydroxide for 4 hours at 65 °C to 75 °C, filtering at 20 °C - 30 °C, rinsing with purified water and anhydrous ethanol, and stirring for 2-4 hours at 15 °C to 30 °C with methyl tert-butyl ether.

[0135] The TGA profile of Form C showed there was 5.242 % weight loss prior to 150 °C. The DSC profile of Form C showed that there was one broad endothermic peak at 145.52 °C.

[0136] Form C can further be obtained by crystallization in DMSO / EtOH or in DMSO / Aceton using the following process:

[0137] 1) Dissolving 50 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) starting material in 20 volumes of DMSO at RT (20-25 °C).

[0138] 2) Adding anti-solvent until DMSO: anti-solvent=l / l (v:v), the solution gradually became turbid.

[0139] 3) Aging for about 2h.

[0140] 4) Cooling to 10 °C, holding for 24h.

[0141] 5) Filtering and drying at 50 °C under vacuum for about 48h.

[0142] The XRPD of Form C is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0143] EXAMPLE 4 - Form D

[0144] Preparation of Form D of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate .

[0145] Form D can be obtained by dispersing 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in acetone (10 volume, 25 °C), keeping the slurry for 24h at 25 °C, and filtering.

[0146] Form D shows a high content of residual solvent and is thus not suitable for pharmaceutical use.

[0147] The XRPD of Form D is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0148] EXAMPLE 5 - Form E

[0149] A) Preparation of Form E of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate .

[0150] A. l) Form E can be obtained, e.g. from Form C, by crystallization in DMSO / H2O at increased temperature (e.g. above 50 °C) using the following process:

[0151] 1) Dissolving 100 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) starting material in 15 volumes of DMSO at 55 °C.

[0152] 2) Cooling to 50 °C.

[0153] 3) Adding H2O until the solution becomes turbid.

[0154] 4) Aging for about 0.5h.

[0155] 5) Adding anti-solvent (H2O) until DMSO: anti-solvent=l / l (v:v).

[0156] 6) Holding at 25 °C for 24h.

[0157] 7) Filtering and drying at 50 °C under vacuum for about 48h.

[0158] A.2) Form E can further be obtained by crystallization in DMSO using EtOH / FEO (v:v) 1: 1 as antisolvent at about 60 °C using the following process:

[0159] 1) Dissolving 50 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) starting material in 20 volumes of DMSO at 60 °C to 70 °C.

[0160] 2) Keeping the solution at the same temperature for 30 min, filtering the impurities

[0161] 3) Cooling to 50 °C to 60 °C at 5 °C / h

[0162] 4) Keeping the solution at the same temperature for 1-2 h.

[0163] 5) Adding a first part of anti-solvent, the solution gradually becomes turbid.

[0164] 6) Adding a second part of anti-solvent until DMSO: anti-solvent=l / l (v:v).

[0165] 7) Cooling to 0-10 °C at 5 °C / h,

[0166] 8) Maintaining at the same temperature for 10-24h,

[0167] 9) Filtering and rinsing the filter cake with anti-solvent.

[0168] 10) Drying at < 40 °C using nitrogen RH 30 %-60 % for 3-6h.

[0169] The TGA profile of Form E showed a 3.4 % - 3.6 % weight loss from RT to 150 °C, the DSC showed a broad endothermic peak at 81.4 °C due to loss of solvent.

[0170] The XRPD of Form E is shown in Figures 1 and 2. The most characteristic peaks are summarized in Table 1 above.

[0171] The residual solvent of the obtained solid of Form E meets all pharmacological requirements for residual solvent content and is thus suitable for pharmaceutical use. The TGA weight loss of 3.768% indicates that Form E is a monohydrate. B) Stability data of Form E

[0172] Form E shows excellent storage stability.

[0173] EXAMPLE 6 - Form F

[0174] Preparation of Form F of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate .

[0175] A) Form F can be obtained, e.g. from Form C, by crystallization in DMSO / EA (ethyl acetate) at increased temperature (e.g. above 50 °C) using the following process:

[0176] 1) Dissolving 100 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) starting material in 15 volumes of DMSO at 55 °C.

[0177] 2) Adding anti-solvent (EA) until DMSO: anti -solvent= 1:3 (v:v), the solution becomes turbid

[0178] 3) Aging for about 2h.

[0179] 4) Cooling to about 25 °C (at about 10 °C / h), holding at 25 °C for 24h.

[0180] 5) Filtering and drying under nitrogen for about 6h.

[0181] B) Alternatively, Form F can be obtained by crystallization in DMSO / anti-solvent, using EtOH, THF or acetone as anti -solvent, at room temperature using the following process:

[0182] 1) Dissolving 167 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) (e.g. Form C) starting material in 4 ml of DMSO at RT (20-25 °C).

[0183] 2) Adding anti-solvent until the solution becomes turbid.

[0184] 3) Filtering.

[0185] C) Alternatively, Form F can be obtained by crystallization in DMF / anti-solvent, using acetone as anti-solvent, at room temperature using the following process: 1) Dissolving 167 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) (e.g. Form C) starting material in 4 ml of DMF at RT (20-25 °C).

[0186] 2) Adding anti-solvent until the solution becomes turbid.

[0187] 3) Filtering.

[0188] The TGA profde of Form F showed a 5.2 % weight loss from RT to 150 °C.

[0189] The XRPD of Form F is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0190] EXAMPLE 7 - Form G

[0191] Preparation of Form G of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate .

[0192] Form G can be obtained by crystallization in DMSO / EtOH at increased temperature and adding the antisolvent at 50°C using the following process:

[0193] 1) Dissolving 1 g API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) (e.g. Form C) starting material in 15 volumes of DMSO at 55 °C.

[0194] 2) Holding the solution at about 55 °C for 30 min.

[0195] 3) Cooling to about 50 °C at 10 °C / h, and holding the solution at about 50 °C for 30 min

[0196] 4) Adding anti-solvent until DMSO: anti-solvent(EtOH)=l / 3 (v:v), the solution gradually became turbid.

[0197] 5) Aging for about 2h at 50 °C.

[0198] 6) Cooling to 20 °C at about 109 °C / h, holding for 24h at 20 °C.

[0199] 7) Filtering, rinsing the cake with about 5 volumes of EtOH.

[0200] The TGA profde of Form G showed there was about 0.791% weight loss prior to 280 °C, indicating the product is a DMSO solvate combined with residual solvent.

[0201] The XRPD of Form G is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0202] EXAMPLE 8 - Form H

[0203] Preparation of Form H of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate . Form H can be obtained by drying Form E at RT at very low humidity, e.g. below 5 % RH. E.g., Form H was obtained by drying Form E for 15 h under dry nitrogen (below 5 % RH).

[0204] Form H is instable upon storage under normal conditions, and converts, upon storage at 25 °C / 40 % RH to Form E, and upon storage at 40 °C / 25 % RH to a mixture of Forms E and H.

[0205] The XRPD of Form H is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0206] EXAMPLE 9 - Form I

[0207] Preparation of Form I of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate .

[0208] Form I can be obtained by crystallization in DMSO / anti -solvent, using acetone, EA or DCM as anti -solvent, at room temperature using the following process:

[0209] 1) Dissolving 167 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) (e.g. Form C) starting material in 4 ml of DMSO at RT (20-25 °C).

[0210] 2) Adding anti-solvent until the solution becomes turbid.

[0211] 3) Filtering.

[0212] Alternatively, Form I can be obtained by crystallization in DMF / anti-solvent, using MTBE, acetone or toluene as anti-solvent, at room temperature using the following process:

[0213] 1) Dissolving 167 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) (e.g. Form C) starting material in 4 ml of DMF at RT (20-25 °C).

[0214] 2) Adding anti-solvent until the solution becomes turbid.

[0215] 3) Filtering.

[0216] The TGA profile of Form I showed a 4.7 % weight loss from RT to 170 °C, the DSC showed two broad endothermic peaks at 81.8 °C and 125.7 °C, due to loss of solvent. NMR showed a residual solvent content of 1.7 % DMF.

[0217] The XRPD of Form I is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0218] EXAMPLE 10 - Form J Preparation of Form J of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate .

[0219] Form J can be obtained by crystallization in DMSO / H2O at room temperature using the following process:

[0220] 1) Dissolving 167 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) (e.g. Form C) starting material in 4 ml of DMSO at RT (20-25 °C).

[0221] 2) Adding anti-solvent (H2O) until the solution becomes turbid.

[0222] 3) Filtering.

[0223] Alternatively, Form J can be obtained by crystallization in DMF / H2O at room temperature using the following process:

[0224] 1) Dissolving 167 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) (e.g. Form C) starting material in 4 ml of DMF at RT (20-25 °C).

[0225] 2) Adding anti-solvent (H2O) until the solution becomes turbid.

[0226] 3) Filtering.

[0227] The TGA profde of Form J showed a 6.0 % weight loss from RT to 130 °C, the DSC showed a broad endothermic peak at 77 °C due to loss of solvent. NMR showed a residual solvent content of 1.8 % DMSO.

[0228] The XRPD of Form J is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0229] EXAMPLE 11 - Form K

[0230] Preparation of Form K of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate .

[0231] Form K can be obtained by crystallization in DMSO / toluene at room temperature using the following process:

[0232] 1) Dissolving 167 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) (e.g. Form C) starting material in 4 ml of DMSO at RT (20-25 °C).

[0233] 2) Adding anti-solvent (toluene) until the solution becomes turbid.

[0234] 3) Filtering. The TGA profile of Form K showed a 5.0 % weight loss from RT to 150 °C, the DSC showed two broad endothermic peaks at 84 °C and 119.4 °C due to loss of solvent. NMR showed a residual solvent content of 0.7 % DMSO.

[0235] The XRPD of Form K is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0236] EXAMPLE 12 - Form L

[0237] Preparation of Form L of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate .

[0238] Form L can be obtained by crystallization in DMSO / l,4-dioxane at room temperature using the following process:

[0239] 1) Dissolving 167 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) (e.g. Form C) starting material in 4 ml of DMSO at RT (20-25 °C).

[0240] 2) Adding anti -solvent (1,4-dioxane) until the solution becomes turbid.

[0241] 3) Filtering.

[0242] The TGA profile of Form L showed a 25.4 % weight loss from RT to 150 °C, the DSC showed a broad endothermic peak at 183.3 °C due to loss of solvent. NMR showed a residual solvent content of 14 % DMSO and 11.2 % 1,4-dioxane.

[0243] The XRPD of Form L is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0244] EXAMPLE 13 - Form M

[0245] Preparation of Form M of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate.

[0246] Form M can be obtained by crystallization in DMF / 1,4-dioxane at room temperature using the following process:

[0247] 1) Dissolving 167 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) (e.g. Form C) starting material in 4 ml of DMF at RT (20-25 °C).

[0248] 2) Adding anti -solvent (1,4-dioxane) until the solution becomes turbid.

[0249] 3) Filtering. The TGA profile of Form M showed a 16.9 % weight loss from 130 °C to 250 °C, the DSC showed two broad endothermic peaks at 183.6 °C and 201.4 °C due to loss of solvent. NMR showed a residual solvent content of 15.3 % 1,4-dioxane.

[0250] The XRPD of Form M is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0251] EXAMPLE 14 - Form N

[0252] Preparation of Form N of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate .

[0253] Form N can be obtained by slurrying solid API in MeOH at RT or 50 °C using the following process:

[0254] 1) Weighing 15 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) starting material (e.g. Form C) into a vial.

[0255] 2) Adding in 1 ml of acetone and stirring for 3 days at RT(25°C) or at 50 °C.

[0256] 3) Filtering remaining solid.

[0257] The TGA profile of Form N showed a 4.5 % weight loss from RT to 150 °C, the DSC showed a broad endothermic peak at 87.7 °C due to loss of water. NMR showed no organic solvent residue.

[0258] The XRPD of Form N is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0259] EXAMPLE 15 - Form O

[0260] Preparation of Form O of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate .

[0261] Form O can be obtained by slurrying solid API in acetone at 50 °C using the following process:

[0262] 1) Weighing 15 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) starting material (e.g. Form C) into a vial.

[0263] 2) Adding in 1 ml of acetone and stirring for 3 days at 50 °C.

[0264] 3) Filtering remaining solid.

[0265] The TGA profile of Form O showed a 1.2 % weight loss from RT to 120 °C, the DSC showed a broad endothermic peak at 57.5 °C due to loss of water. NMR showed no organic solvent residue. The XRPD of Form O is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0266] EXAMPLE 16 - Form P

[0267] Preparation of Form P of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido [3 ',2 ' : 4, 5 ]thieno [3 ,2-d] pyrimidin-4 -olate .

[0268] Form P can be obtained by vapor-liquid diffusion using dissolved API in an atmosphere of anti-solvent at RT using the following process:

[0269] 1) Dissolving 120 mg API (sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate) starting material (e.g. Form C) in 4 ml DMF, filtering the solution with a 0.22 pm filter.

[0270] 2) Placing 0.3 ml of the filtrate in an 8 ml vial, placing the 8 ml vial into a 30 ml vial containing 6 ml of DCM as volatile antisolvent.

[0271] 3) Filtering solids obtained after about 3 to 7 days.

[0272] The TGA profile of Form P showed a 5.2 % weight loss from RT to 130 °C, the DSC showed two broad endothermic peaks at 85.1 °C and 119.4 °C due to loss of solvent. NMR showed a residual solvent content of 4.3 % DMF. Thus, Form P is a DMF solvate.

[0273] The XRPD of Form P is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

[0274] EXAMPLE 17 - Form Q

[0275] Preparation of Form Q of 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate salt.

[0276] Form Q can be obtained by dispersing sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate (e.g. Form B) in acetone (10 volume, 25°C), keeping the slurry for 24h at 25°C, and filtering.

[0277] The DSC showed two broad endothermic peaks at 35.0 °C and 102.7 °C due to loss of solvent. HPLC showed a residual solvent content of 2.91 % acetone and 0.22 % DMSO.

[0278] The XRPD of Form Q is shown in Figure 1. The most characteristic peaks are summarized in Table 1 above.

Claims

Claims1. A crystal form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate having an XRPD pattern with significant peaks at about 8.4, 12.6, 20.6, 21.3, 24.6, and 38.5 °20 (± 0.2°).

2. The crystal form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate according to claim 1, having an XRPD pattern with significant peaks at about 8.4, 12.6, 18.7, 20.6, 21.3, 24.6, 26.9, 28.7, 30.8, 33.1 and 38.5 °20 (± 0.2°).

3. The crystal form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate according to claim 1 or 2 having an XRPD pattern substantially as shown in figure 3.

4. A crystal form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate having an XRPD pattern with significant peaks at about 11.3, 15.3, 17.0, 20.8, and 28.5 °20 (± 0.2°).

5. The crystal form of sodium-7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate according to claim 4 having an XRPD pattern with significant peaks at about 11.3, 11.8, 15.3, 17.0, 20.8, 24.9, 28.5 and 31.5 °20 (± 0.2°).

6. A crystal form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate according to claim 4 or 5 having an XRPD pattern substantially as shown in figure 2.

7. A process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9- (trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate form (Form B) comprising the steps ofa) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2(lH)-one in DMSO at RT, preferably about 20-25 °C, b) adding anti-solvent EtOH or EtOH / FEO having about 1 : 1 ratio (v / v), c) maintaining the solution at the same temperature for about 1-24 hours, and d) filtering.

8. The process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9- (trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate according to claim 7 comprising the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in DMSO at RT, preferably about 20-25 °C, b) adding a first part of anti-solvent EtOH or EtOH / H2O having about 1 : 1 ratio (v / v) of EtOH / H2O mixture into the solution, preferably until first precipitation, holding the solution at the same temperature for about 30-60 minutes, c) adding a second part of anti-solvent EtOH or EtOH / H2O having about 1 : 1 ratio (v / v) of EtOH / H2O mixture into the solution until the ratio of DMSO:anti-solvent (EtOH or 1 : 1 EtOH / H2O) is about 1 :2 to 1 :3 (v / v), and maintaining the solution at the same temperature for about 2-3 hours, d) cooling the solution to about 0-10 °C, preferably at a rate of about 10 °C / hour, and preferably maintaining the solution at the same temperature for about 6-24 hours, e) filtering the mixture and optionally rinsing the filter cake, preferably with antisolvent, and f) optionally drying the wet filter cake.

9. A process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9- (trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate form (Form E) comprising the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in DMSO at increased temperature, preferably about 55-70 °C, or at a temperature below 50 °C, followed by heating the mixture to about 60-70 °C, b) cooling to about 45-65 °C, preferably at a rate of about 5-10 °C / h,c) adding anti-solvent EtOH / lhO having about 1 : 1 to 9: 1 ratio (v / v) of EtOH / EhO into the solution, optionally maintaining the solution at the same temperature for about 1-4 hours, d) cooling the solution to about 0-10 °C, preferably at a rate of about 5-10 °C / hour, and preferably maintaining the solution at the same temperature for about 1 - 24 hours, e) filtering and drying the wet filter cake, preferably at < 40 °C and at 30-60 % relative humidity.

10. The process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9- (trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate according to claim 8, comprising the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in DMSO at increased temperature, preferably about 55-60 °C, or at a temperature below 50 °C, followed by heating the mixture to about 60-70 °C, b) cooling to about 45-65 °C, preferably at a rate of about 5-10 °C / h, c) adding a first part of anti-solvent EtOH / EEO having about 1 : 1 to 9: 1 ratio (v / v) of EtOH / EEO mixture into the solution, preferably until first precipitation, holding the solution at the same temperature for about 30-60 minutes, d) adding a second part of anti-solvent EtOH / EEO having about 1 : 1 to 9: 1 ratio (v / v) of EtOH / EEO into the solution until the ratio of DMSO:(1 : 1 to 9: 1 EtOH / EEO) is about 1 :2 (v / v), and maintaining the solution at the same temperature for about 2- 3 hours, e) cooling the solution to about 0-10 °C, preferably at a rate of about 5-10 °C / hour, and preferably maintaining the solution at the same temperature for about 6-24 hours, f) filtering the mixture and optionally rinsing the filter cake, preferably with a 1 : 1 to 9: 1 EtOH / EEO solution, and g) drying the wet filter cake, preferably at < 40 °C and at 30-60 % relative humidity.

11. The process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9- (trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate form (Form E) according to claim 9 or 10, comprising the steps ofa) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in DMSO at increased temperature, preferably about 55-70 °C, or at a temperature below 50 °C, followed by heating the mixture to about 60-70 °C, and maintaining the temperature for about 30-120 minutes, b) cooling to about 50-55 °C at a rate of about 5-10 °C / h, c) adding a first part of anti-solvent EtOH / lhO having about 9: 1 ratio (v / v) of EtOH / lhO mixture into the solution, preferably until first precipitation, holding the solution at the same temperature for about 30-60 minutes, d) adding a second part of anti-solvent EtOEI / EhO having about 9: 1 ratio (v / v) of EtOEI / EkO mixture into the solution until the ratio of DMSO:(9: 1 EtOEI / EhO) is about 1 :2 (v / v), and maintaining the solution at the same temperature for about 2- 3 hours, e) cooling the solution to about 0-10 °C at a rate of about 10 °C / hour, and maintaining the solution at the same temperature for about 6-24 hours, f) filtering the mixture and optionally rinsing the filter cake, preferably with a 9: 1 EtOEI / EkO solution, and g) drying the wet filter cake, preferably at < 40 °C and at 30-60 % relative humidity.

12. The process for preparing a crystalline form of sodium 7-(4-bromophenyl)-2-oxo-9- (trifluoromethyl)-l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate form (Form E) according to claim 9, 10, or 11, comprising the steps of a) dissolving sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate in about 15 volumes of DMSO at 15-25 °C b heating the mixture, preferably to about 60-70 °C, and maintaining the temperature for about 60-120 minutes, while stirring c) filtering and rinsing the filter cake with about 2 volumes of DMSO d) cooling to about 50-60 °C at a rate of about 5-10 °C / h, e) adding a first part of anti-solvent (about 9 volumes) EtOH / EEO having about 9: 1 ratio (v / v) of EtOH / EEO mixture into the solution, holding the solution at the same temperature for about 1-2 hours while stirring,f) adding a second part of anti-solvent (about 6 volumes) EtOH / EEO having about 9: 1 ratio (v / v) of EtOH / EEO mixture into the solution and maintaining the solution at the same temperature for about 2-3 hours while stirring, g) adding a third part of anti-solvent (about 15 volumes) EtOH / EEO having about 9: 1 ratio (v / v) of EtOH / EEO mixture into the solution and maintaining the solution at the same temperature for about 2-3 hours while stirring, h) cooling the solution to about 0-10 °C at a rate of about 10 °C / hour, and maintaining the solution at the same temperature for about 20-24 hours while stirring, i) filtering the mixture and optionally rinsing the filter cake, preferably with about 10 volumes of an about 9: 1 EtOH / EEO solution, and j) drying the wet filter cake, preferably at < 40 °C and at 30-60 % relative humidity.

13. Pharmaceutical composition comprising a crystalline form of sodium 7-(4-bromophenyl)- 2-oxo-9-(tri fluoromethyl)- l,2-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate according to any one of claims 1 to 6.

14. The crystal form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 13 for use in treating a proliferative disease.

15. The crystal form of sodium 7-(4-bromophenyl)-2-oxo-9-(trifluoromethyl)-l,2- dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-olate hydrate or the pharmaceutical composition according to claim 14, wherein the proliferative disease is cancer.

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