Salt of a SOS-1 inhibitor

Abstract

The present invention relates to the besylate salt of 1-{4-[2-methyl-4-({1-[2-methyl-3-(trifluorome-thyl)phenyl]ethyl}amino) pyrido[3,4-d]pyrimidin-6-yl]-4-oxido-1,4-azaphosphinan-1-yl}ethanone, in any of its anhydrous forms or any hydrate(s), or mixtures thereof, its use for the treatment of disorders, and the use of the besylate salt for the preparation of a medicament.

Description

[0001] BHC243029

[0002] Salt of a SOS-1 Inhibitor

[0003] The present invention relates to a novel salt of the SOS-1 inhibitor l-{4-[2-methyl-4-({ l-[2-methyl-3- (trifluoromethyl)phenyl] ethyl } amino)pyrido [3 ,4-d]pyrimidin-6-yl] -4-oxido- 1 ,4-azaphosphinan- 1 -yl } ethanone, pharmaceutical compositions comprising said SOS-1 inhibitor salt and the use of said SOS-1 inhibitor salt as a medicament.

[0004] BACKGROUND

[0005] The compound l-{4-[2-methyl-4-({ l-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]py- rimidin-6-yl]-4-oxido-l,4-azaphosphinan-l-yl}ethanone is known from WO2022 / 219035 and corresponds to the compound of formula (I): compound of formula (I).

[0006] WO2022 / 219035 describes the compound of formula (I) as an inhibitor of the enzyme SOS-1 which may be used for the treatment of disorders in which hyperproliferation plays an important role, for example in tumor growth and cancer. In particular, the compound of formula (I) modulates the SOS-l / KRAS interaction and is especially relevant for patients that suffer from dysfunctional RAS activation.

[0007] RAS proteins play an important role in human cancer. Mutations in RAS proteins can be found in 20-30% of all human tumors and are recognized as tumorigenic drivers especially in lung, colorectal and pancreatic cancers (Malumbres & Barbacid 2002 Nature Reviews Cancer, Pylayeva-Gupta et al. 2011 Nature Reviews Cancer). Three human Ras genes are known to encode four different RAS proteins of 21 kDa size: H-RAS, N-RAS, and two splice variants ofK-RAS, namely K-RAS 4A and K-RAS-4B. All RAS isoforms are highly conserved within the GTP-binding domain and differ mainly in the hypervariable C-terminal region. The C-termini of the different RAS-isoforms are post-translationally modified by lipidation (far- nesylation, palmitoylation) to facilitate membrane anchorage. The localization of RAS-proteins at the cytoplasmic membrane provides vicinity to transmembrane growth receptors and has been shown to be essential for transmitting growth signals from extracellular growth factor binding to intracellular downstream pathways. A variety of upstream signals may activate RAS proteins depending on the cellular context, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), nerve growth factor receptor (NGFR) and others. Activated RAS can signal through various downstream pathways, e g. the RAF-MEK-ERK or the PI3K-PDK1-AKT pathways. BHC243029

[0008] On the molecular level, RAS proteins function as molecular switches. By binding GTP and GDP they exist in an active (GTP-bound) and inactive (GDP-bound) state in the cell respectively. Active GTP -loaded RAS recruits' other proteins by binding to their cognate RAS-binding domains (RBDs) resulting in activation of the effector protein followed by downstream signaling events of diverse functions, e.g. cytoskel- etal rearrangements, cell proliferation and differentiation. The activity status of RAS is tightly regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GEFs function as activators of RAS by promoting the nucleotide exchange from GDP to GTP. GAPs deactivate RAS- GTP by catalyzing the hydrolysis of the bound GTP to GDP. In a cancer cell, point mutations, typically within the GTP-binding region at codon 12, eliminate the ability of RAS to efficiently hydrolyze bound GTP, even in the presence of a GAP. Therefore, cancer cells comprise increased levels of active mutated RAS-GTP, which is thought to be a key factor for driving cancer cell proliferation.

[0009] Three main families of RAS-specific GEFs have been identified so far (reviewed in Vigil 2010 Nature Reviews Cancer; Rojas et al 2011, Genes & Cancer 2(3) 298-305). There are two son of sevenless (SOS) proteins, SOS1 and SOS2, 4 different isoforms of RAS guanine nucleotide releasing proteins (RAS-GRP1- 4) and two RAS guanine nucleotide releasing factors (RAS-GRF1 and 2). The SOS proteins are ubiquitously expressed and are recruited to sites of activated growth factors. RAS-GRFs are expressed mainly in the nervous system, where they are involved in calcium-dependent activation of RAS. In contrast, RAS GRP proteins are expressed in hematopoietic cells and act in combination with non-receptor tyrosine kinases. In the context of cancer, mainly SOS proteins have been found to be involved. Targeting RAS for cancer therapy has been a dream since the 1990s (Downward 2002 Nature Reviews Cancer, Krens et al. 2010 Drug Discovery Today). Due to the compact nature, the high affinity towards GDP and GTP in combination with high intracellular GTP concentrations, the RAS protein itself has always been considered undruggable, i.e. the chance to identify small chemical molecules that would bind to and inhibit active RAS was rated extremely low. Alternative approaches have been undertaken to reduce RAS signaling, e.g. by addressing more promising drug targets such as enzymes involved in the posttranslational modification of RAS proteins, especially famesyltransferase and geranylgeranyltransferase (Berndt 2011 Nature Reviews Cancer). Inhibitors of famesyltransferase (FTIs) were identified and developed with promising antitumor effects in preclinical models. Unexpectedly, in clinical trials these inhibitors have been of limited efficacy. Targeting upstream and downstream kinases involved in RAS signaling pathways has been more successful. Several drugs are and have been in clinical trials that inhibit different kinases, e.g. EGFR, RAF, MEK, AKT, PI3K (Takashima & Faller 2013 Expert Opin. Ther. Targets). Marketed cancer drugs are available that inhibit RAF, EGFR or MEK.

[0010] Nevertheless, there is still a large unmet need for the treatment of RAS -dependent tumors that are resistant against current therapies. Many research groups have been active to identify small molecules that target RAS directly (RAS small molecules have been reviewed in: Cox et al. 2014 Nature Reviews Drug Discovery, Spiegel et al. 2014 Nature Chemical Biology, Cromm 2015 Angewandte Chemie, Marin-Ramos et al Seminars in Cancer Biology). One group of inhibitors comprises small molecules that inhibit the BHC243029 interaction of RAS with its effectors RAF or PI3K. Another group of compounds acts as covalent inhibitors of a specific cysteine mutant form of K-RAS (glycine to cysteine point mutation G12C). The specific targeting of the K-RAS-G12C mutant might have the benefit of reduced side effects, as the wildtype K- RAS proteins are not affected. Furthermore, several reports show small molecules and peptides that interrupt the GEF assisted activation of RAS (Hillig et al 2019 PNAS; Gray et al 2019 Angewandte Chemie). There seem to be several possible different binding sites that result in this mode of action. Inhibitors may bind to RAS or to the GEF in an allosteric or orthosteric fashion. All these approaches of direct RAS- targeting are in preclinical research or an early development stage. Stabilized peptides have been shown to be active in the nanomolar range . (Leshchiner et al. 2015 PNAS) . Their usefulness as drugs in a clinical setting must be awaited.

[0011] A method to manufacture the compound of formula (I) is also described in WO2022 / 219035 in example 7, in which the compound according to formula (I) was obtained in a solid form and characterized by proton NMR, mass spectrometry and liquid chromatography mass spectrometry.

[0012] In drug development, compounds must selectively and potently modulate their respective target molecule as the compound of formula (I) does, without being limited to the interaction of SOS-1 with KRAS G12C as described in WO2022 / 219035 wherein Biological Assays with an IC50 value of 6.2 nM have been described. However, for a superior efficacy in mammals a lot of other properties become equally important - including among others - solubility, relative bioavailability, distribution or dose linearity. One of the big challenges in drug development is to bring all these different requirements into one dosage form that can be utilized in the final drug product, if at all possible.

[0013] This becomes even more challenging in cases as for the compound according to formula (I) that, for example, showed a particularly unexpected inverse dose dependent nonlinearity for the free base for the relative bioavailability of the compound in a preclinical rodent study.

[0014] The aim of this development was, therefore, to provide a solid form of l-{4-[2-methyl-4-({ l-[2-methyl-3- (trifluoromethyl)phenyl] ethyl } amino)pyrido [3 ,4-d]pyrimidin-6-yl] -4-oxido- 1 ,4-azaphosphinan- 1 -yl (ethanone, that satisfies at least some or even all requirements as set out above.

[0015] DESCRIPTION of the INVENTION

[0016] Surprisingly, it now has been found that in accordance with a first aspect of the invention the besylate salt of l-{4-[2-methyl-4-({l-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidin-6-yl]- 4-oxido-l,4-azaphosphinan-l-yl}ethanone, in any of its anhydrate forms, or any hydrate(s) or mixtures thereof does show that the salt can be obtained in crystalline form and exhibits a near constant relative bioavailability over a therapeutically relevant dosage range and a higher bioavailability compared to the free base and other crystalline available salt(s) at the lower dose. Considering the physico-chemical BHC243029 characteristics of the besylate salt in comparison with the free base and the other crystalline available salt(s), this is even more surprising. The besylate and other crystalline available salt(s) show an increased dissolution rate compared to the free base and all tested compounds show a comparable pH dependent solubility profile, yet only the besylate shows a near constant relative bioavailability and a high relative bioavailability at low dose.

[0017] The besylate salt of the compound of formula (I) can be prepared in the manner described in the experimental section below and corresponds to an anhydrous form which in the following is referred to as An- hydrate I and is characterized by an XRPD according to the reflections presented in Figure 8 in the experimental section.

[0018] Anhydrate I may be converted into one of several hydrated forms of the besylate salt of l-{4-[2-methyl- 4-({l-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidin-6-yl]-4-oxido-l,4-aza- phosphinan-l-yl}ethanone by, for example without being limited to, exposing Anhydrate I to a relative humidity of at least 70%. This hydrated form is in the following referred to as Hydrate I. Hydrate I is characterized by XRPD (Figure 9), TGA-DSC (Figure 2), IR and Raman (Figure 7 and Figure 5) with the data presented in the experimental section.

[0019] Hydrate I may be converted into a second anhydrous form by, for example without being limited to, drying by reducing the relative humidity or by applying temperature. This second anhydrous form is in the following referred to as Anhydrate II, which is also characterized by an XRPD as can be seen in the experimental section (Figure 10).

[0020] Hydrate I and Anhydrate II can be repeatedly converted into each other by the methods described above. Anhydrate I was used as the input material for the relative pre-clinical bioavailability study. Owing to the known interconversion (see e.g. Figure 13), it is assumed that any residual solid transforms to the Hydrate I form for all experiments performed in solution and therefore bioavailability is independent of the input solid state form.

[0021] During salt formation the free base according to formula (I) may be protonated at various positions. According to pKa predictions there are at least three basic positions within the free base according to formula (I) and therefore, in one embodiment of the first aspect of the invention the besylate salt of the compound of formula (I) is according to formula (II) to (IV). formula (II) BHC243029 formula (IV), preferred according to formula (II).

[0022] In different crystallization experiments it was found that only very few salts of l-{4-[2-methyl-4-({l-[2- methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidin-6-yl]-4-oxido-l,4-azaphos- phinan-l-yl} ethanone can be obtained in one or more crystalline forms. Therefore, in another embodiment of the first aspect of the invention, the besylate salt of the compound of formula (I) may be in a crystalline form. Additionally, the besylate salt of any of formulae (II) to (IV) may be in a crystalline form as could be shown for example for the compound of formula (II) for which a crystal structure is provided in the experimental part.

[0023] In accordance with a second aspect of the invention the besylate salt of the compound of formula (I) is used in the treatment or prophylaxis of a disease.

[0024] In one embodiment of the second aspect of the invention the disease is a hyperproliferative disorder, such as cancer, for example.

[0025] The salt of the present invention can be utilized to inhibit, block, reduce, decrease, etc. , cell proliferation and / or cell division, and / or produce apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of the besylate salt of the compound of general formula (I) in any of its anhydrate forms, or any hydrate(s) or mixtures thereof, which is effective to treat the disorder. Hyperproliferative or genetic disorders include, but are not limited to, for example: solid and liquid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include sarcomas, lymphomas, leukaemia's and multiple myeloma. BHC243029

[0026] Examples of breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0027] Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

[0028] Examples of brain cancers include, but are not limited to, brain stem and hypothalamic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor. Tumors of the male reproductive organs include, but are not limited to, prostate and testicular cancer.

[0029] Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.

[0030] Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.

[0031] Tumors of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.

[0032] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0033] Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

[0034] Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0035] Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.

[0036] Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.

[0037] Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0038] Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0039] Multiple myeloma include, but are not limited to, IgG myeloma, IgA myeloma, IgM myeloma, IgD myeloma, IgE myeloma, Bence Jones myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary myeloma and asymptomatic myeloma.

[0040] The term “treating or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma. BHC243029

[0041] The besylate salt of the compound according to formula (I) of the present invention can be used in particular in therapy and prevention, i. e. prophylaxis, of tumor growth and metastases, especially in solid tumors of all indications and stages with or without pre-treatment of the tumor growth.

[0042] The aforementioned disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering the besylate salt of the compound according to formula (I). Therefore, in accordance with a third aspect of the invention the besylate salt of the compound of formula (I) is used for the preparation of a medicament.

[0043] In accordance with a fourth aspect of the invention the besylate salt of the compound of formula (I) is comprised in a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier. These compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof. In accordance with a fifth aspect of the invention the besylate salt of the compound of formula (I) is used for the manufacture of a pharmaceutical composition for the treatment or prevention of a hyperproliferative disorder, such as cancer and tumor diseases.

[0044] A pharmaceutically acceptable diluent or carrier is any diluent or carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of the besylate salt of the compound of formula (I) is that amount which produces a result or exerts an influence on the particular condition being treated. The besylate salt of the compound according to formula (I) of the present invention can be administered with pharmaceutically acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed-release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.

[0045] For oral administration, the besylate salt of the compound according to formula (I) can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatine type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and com starch.

[0046] In a sixth aspect of the invention the besylate salt of the compound of formula (I) is used for the manufacture of a tablet or a capsule which is physically and chemically stable.

[0047] In another embodiment, the besylate salt of the compound according to formula (I) may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, com starch or gelatine, disintegrating agents intended to assist the break-up and dissolution of the BHC243029 tablet following administration such as potato starch, alginic acid, com starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both.

[0048] Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents described above, may also be present.

[0049] The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils . Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soybean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[0050] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or w-propyl p- hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

[0051] The besylate salt of the compound according to formula (I) of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or in- terperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-l,l-dioxolane-4-methanol, ethers such as polyethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or BHC243029 an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methylcellulose, hydroxypropyl methylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.

[0052] Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, com oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulphates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric deteigents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quaternary ammonium salts, as well as mixtures.

[0053] The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. To minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

[0054] Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

[0055] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

[0056] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic BHC243029 parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer’s solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

[0057] A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such material is, for example, cocoa butter and polyethylene glycol.

[0058] Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations which are known in the art.

[0059] The pharmaceutical compositions of this invention may also be in the form of a solid dispersion. The solid dispersion may be a solid solution, glass solution, glass suspension, amorphous precipitation in a crystalline carrier, eutectic or monotectic, compound or complex formation and combinations thereof.

[0060] An aspect of the invention of particular interest is a pharmaceutical composition comprising a solid dispersion, wherein the matrix comprises a pharmaceutically acceptable polymer, such as polyvinylpyrrolidone, vinylpyrrolidone / vinylacetate copolymer, polyalkylene glycol (i.e. polyethylene glycol), hydroxyalkyl cellulose (i.e. hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (i.e. hydroxypropyl methyl cellulose), carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polymethacrylates, polyvinyl alcohol, polyvinyl acetate, vinyl alcohol / vinyl acetate copolymer, polyglycolized glycerides, xanthan gum, carrageenan, chitosan, chitin, polydextrin, dextrin, starch and proteins.

[0061] Another aspect of the invention is a pharmaceutical composition comprising a solid dispersion, wherein the matrix comprises a sugar and / or sugar alcohol and / or cyclodextrin, for example sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, inositol, trehalose, isomalt, inulin, maltodextrin, b-cyclodextrin, hydroxypropyl-b-cyclodextrin or sulfobutyl ether cyclodextrin.

[0062] Additional suitable carriers that are useful in the formation of the matrix of the solid dispersion include, but are not limited to alcohols, organic acids, organic bases, amino acids, phospholipids, waxes, salts, fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and urea.

[0063] The solid dispersion of the compound of formula (II) in the matrix may contain certain additional pharmaceutically acceptable ingredients, such as surfactants, fillers, disintegrants, recrystallization inhibitors, plasticizers, defoamers, antioxidants, detackifier, pH-modifiers, glidants and lubricants. BHC243029

[0064] The solid dispersion of the invention is prepared according to methods known to the art for the manufacture of solid dispersions, such as fusion / melt technology, hot melt extrusion, solvent evaporation (i.e. freeze drying, spray drying or layering of powders of granules), co-precipitation, supercritical fluid technology and electrostatic spinning method.

[0065] The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations " PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al, "Excipients and Their Use in Injectable Products " PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

[0066] Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) BHC243029 carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, com oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); plasticizers (examples include but are not limited to diethyl phthalate and glycerol); solvents (examples include but are not limited to ethanol, com oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, ox- toxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); BHC243029 tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, com starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet / capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnauba wax and white wax); thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

[0067] It is believed that one skilled in the art, using the preceding information and information available in the art, can utilize the present invention to its fullest extent.

[0068] It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein.

[0069] All publications, applications and patents cited above and below are incorporated herein by reference.

[0070] The weight data in the tests and examples which follow are, unless stated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on each case on the volume. BHC243029

[0071] EXPERIMENTAL SECTION

[0072] Preparation of salt compounds

[0073] A salt screening of the crystalline free base was performed using evaporative crystallization by combining 20 mg of the compound according to formula (I) in 300 pL of either ethanol or acetone, 44 pL of salt former (namely hydrochloric acid, sulfuric acid, maleic acid, benzene sulfonic acid, toluene sulfonic acid or fumaric acid), c = 1 mol / L (1.1 eq.) was then added dropwise, and the solutions were stirred until the solvent had completely evaporated. After subsequent drying over P2O5 in a desiccator, all residues were solid. A crystalline salt was only obtained from both benzene sulfonic acid and fumaric acid. All other samples were amorphous. The benzene sulfonic acid salt exists in at least two anhydrous and at least two hydrated forms while the fumarate salt has at least one known crystalline form. In the following, only the salts that were obtained in a crystalline form were further characterized.

[0074] Proton NMR data of the fumarate salt

[0075] ’HNMR (400 MHz, DMSO-t / ,.) 5 ppm 13.15 (br s, 2 H), 9.38 (br d, 1 H), 9.10 (s, 1 H), 9.02 (d, 1 H), 7.80 (d, 1 H), 7.55 (d, 1 H), 7.37 (t, 1 H), 6.62 (s, 2 H), 5.69-5.76 (m, 1 H), 3.99-4.11 (m, 1 H), 3.79-3.97 (m, 2 H), 3.65-3.77 (m, 1 H), 2.62 (s, 3 H), 2.33-2.44 (m, 4 H), 2.22-2.31 (m, 1 H), 2.12 (s, 3 H), 1.86-2.09 (m, 2 H), 1.58 (d, 3 H).

[0076] Instrumental set-up for the XRPD measurements

[0077] Besylate (Anhydrate I, II and Hydrate I)

[0078] X-ray powder diffractograms (XRPDs) were collected on a PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA) in transmission geometry. A 0.5° slit, 4 mm mask and 0.04 rad Seller slits with a focusing mirror were used on the incident beam. A PIXcel3D detector, placed on the diffracted beam, was fitted with a receiving slit and 0.04 rad Seller slits. The software used for data collection was X’Pert Data Collector using X’Pert Operator Interface. The scanning range was between 2° and 42° 2 theta with a 0.013° step at 36.72 sec / step.

[0079] Besylate (Hydrate II)

[0080] An X-ray powder diflfractogram (XRPD) was collected on a Malvern Panalytical Empyrean equipped PiXcel 3D detector with Anton Paar TTK600 and vacuum pump. The scanning range was between 2.5° and 40° 2 theta with a 0.0263° step at 36.47 sec / step. BHC243029

[0081] Fumarate

[0082] An X-ray powder diffractogram (XRPD) was collected on a PANalytical X’Pert PRO diffractometer using Cu-K alpha radiation, a position sensitive detector, at generator settings of 40 kV and 40 mA. The samples were collected in transition mode, prepared as a thin layer between two foils. The seaming range was between 2° and 40° 2 theta with a 0.013° step at 25 sec / step.

[0083] Table 1: X-ray diffractometry of Besylate Salt Anhydrate I (Figure 8), II (Figure 10) and Hydrate I, II (Figure 9 and Figure 11) BHC243029

[0084] Table 2: X-ray diffractometry of Fumarate Salt Anhydrate I (Figure 12) BHC243029 BHC243029

[0085] Single crystal X-ray diffraction analysis of the Besylate Anhydrate I

[0086] Experimental Diffractometer: Bruker AXS X8 Prospector, QS-Nr. 02506

[0087] Detector: Photon II-CCD area detector

[0088] Radiation: Cu Ka (1,54056 A)

[0089] Tube: IpS-microsource

[0090] Monochromator: mirror

[0091] Low temperature device: Cryostream 700

[0092] Measurement temperature : 11 OK

[0093] Measurement method: omega and phi scans

[0094] Data collection and reduction software: APEX 3, v2019.1.0 (Bruker AXS, 2019)

[0095] Absorption correction: Multi-scan (SADABS)

[0096] Structure solution and refinement software: SHELXT-2018 / 3 (Bruker AXS, 2018)

[0097] Visualization software: XP (Bruker AXS, 2018).

[0098] The corresponding X-ray structure can be found in Figure 14

[0099] BHC243029 l.inpn inti ivimtikt C3(i 1133 F3 N5 O5 P S

[0100] Formula weight 663.64

[0101] Temperature 1 10(2) K

[0102] Wavelength 1.54178 A

[0103] Cnsuil bVsktti Orthorhombic

[0104] Space group P2i2i2i

[0105] Unit cell dimensions a = 7.2943(3) A a= 9(F. b = 14.2896(5) A p= 90°.

[0106] L - 3!l.3Ho(i| 141 A y = 9(F.

[0107] Volume 3167.5(2) A3

[0108] Z 4

[0109] Density (calculated) 1.392 Mf / m3 Absorption coeffieient 1.951 mm'1

[0110] F(OOO) 1384

[0111] Crystal size 0.200 x 0.150^ x 0.050 mm3

[0112] Theta range for data collection 4.247 to 63.821 °.

[0113] Index ranges -K -h -N. -Itv -k'- l ti. -35 -1 -35

[0114] Reflections collected 17799

[0115] Indepetideni reflections 5094 (R(int) = 0.0244]

[0116] CotriplctL’ness to theta - 63.821 * 97.5 %

[0117] Absorption correction Scriii-crupii k ul tti <m equivalents

[0118] Max, and min. tfansmission 0.91 and 0.74

[0119] Refinement method Full-matrix least-squares on

[0120] Data i restraints / parameters 5tN4 0 41(1

[0121] Goodness-oTfit on F® 1.037

[0122] Final R indices p>2sigma(I)] R1 = 0.0307, wR2 = 0.0822

[0123] R indices (all data) R1 = 0.0316, wR2 = 0.0828 Absolute structure putuineler 0.029(5)

[0124] Extinction coefficient n / a

[0125] Largest diffi peak and hole 0.481 and -1121 1 e.A'3

[0126] Instrumental set-up for the TGA-DSC measurements

[0127] Thermogravimetric analysis (TGA-DSC) was performed with a Mettler Toledo TGA / DSC 3+. The instrument was purged with nitrogen gas at a flow rate of 30 ml min1. Approximately 3-10 mg of each sample was placed into an aluminum crucible and heated at a heating rate of 20 °C min1from 25 °C to 300 °C. Thermograms are shown in Figure 1, Figure 2 and Figure 3. BHC243029

[0128] Table 3 Differential Scanning Calorimetry and Thermogravimetry

[0129] Infrared spectroscopy

[0130] IR measurements were performed with a Bruker alpha spectrometer in the attenuated total reflectance (ATR) geometry. No sample preparation was performed, and each individual measurement consisted of 32 scans. IR spectra are shown in figures Figure 6 and Figure 7.

[0131] Table 4 Infrared spectroscopy of the compound of formula (I) BHC243029

[0132] Raman spectroscopy

[0133] Raman measurements were performed with a Bruker MultiRAM spectrometer. No sample preparation was performed, and each individual measurement consisted of 64 scans using a laser power of 300 mW. Raman spectra are shown in Figure 4 and Figure 5.

[0134] Table 5 Raman spectroscopy of the compound of formula (I)

[0135] Dynamic vapor sorption of the compound of the formula (I)

[0136] A water sorption isotherm of Besylate Anhydrate I was determined using a DVS Resolution gravimetric sorption analyzer (Hiden isochema). The sample was dried at 0% rH until the sample mass stabilized. Afterwards the dry weight was recorded. The humidity was increased in steps of 10% to 95% rH and then BHC243029 decreased again to 0% rH. At 80% RH, Anhydrate I converts to Hydrate I. Desorption of Hydrate I shows broad hysteresis with the conversion of Hydrate I to Anhydrate II occurring below 10% RH. The equilibrium criterion for each relative humidity set point was 0.002% per minute relative mass change as a function of time. The dynamic vapor sorption isotherm is shown in Figure 13.

[0137] Stability

[0138] The drug substance stabilities were determined by weighing 10 mg of the respective substance into glass vials and storing at 60 °C for one week, 90 °C for 1 day and 90 °C for one week. Afterwards the samples were solved in organic solvent and analyzed with HPLC-UV.

[0139] All three solid forms (free base, besylate, fumarate) were chemically stable under the tested conditions with < 2% (area%) degradation compared to the initial value.

[0140] Solubility measurements

[0141] Suspensions of the drug substance were stirred at 25 °C for 24 h ± 4 h in the respective aqueous media with nominal pH values of 1 ,2 ,3, 4.5, 7 and 8 (± 0.05) prior to filtration and analysis via HPLC. The pH was not adjusted but measured after stirring with drug substance.

[0142] Solubility measurements show a pH dependent solubility profile, and all compounds show comparable thermodynamic solubility trends with higher solubility at lower pH as can be seen in Figure 15.

[0143] Dissolution rate

[0144] Dissolution rate experiments were performed with the Sotax CE7 smart flow through cell equipment. All drug substances were micronized prior to the experiments to ensure comparable particle sizes. One microgram (of free base, salts with correction factor) was weighed into the cells respectively. The cells were flushed with Fasted State Simulated Intestinal Fluid (FaSSIF) (see Figure 16) or Fed State Simulated Intestinal Fluid (FeSSIF) (see Figure 17) with a flow rate of 2 mL / min. Fractions were collected and concentration determination was performed with HPLC-UV. For each substance and medium a triplicate (n=3) was recorded.

[0145] The results show a full release of roughly one microgram for free base, fumarate and besylate salt in both media. The free base shows a slower release than the fumarate and the besylate, especially in FaSSIF. The besylate and fumarate perform comparably. BHC243029

[0146] Formulation preparation for Frei study

[0147] Solution arm:

[0148] 0.2 and 1.4 mg / mL (free form, fumarate or besylate) in PEG400 / ethanol / water (40 / 10 / 50 v / v / v)

[0149] The required amount of drug substance was weighed into a suitable glass container with a stirring bar. Afterwards, the required volume of PEG400 and ethanol was added, and the mixture was stirred until the drug substance was fully dissolved. In the last step, the water was added under stirring. The resulting solution was kept under room temperature until administration.

[0150] Suspension arm:

[0151] 0.2 and 1.4 mg / mL (free form, fumarate or besylate) in Tylose MH 300 in water (0.5% m / v)

[0152] Tylose MH 300 was suspended in cold water and left to swell under stirring overnight. The required amount of drug substance was weighed into a suitable glass container and slightly covered by the Tylose suspension. The mixture was carefully stirred until a homogenous slurry was formed. Afterwards, the rest of the Tylose suspension was added step by step and the formulation was stirred until a homogenous suspension was formed. The suspension was kept under room temperature until administration. in vivo PK Frei-studies

[0153] Male Wistar rats were given the test substances fasting intragastrally by gavage at doses of 1 or 7 mg / kg as a solution or suspension, as a free base or in salt form. They weighed about 250 to 350 g during the study. Three animals were used for each study arm, and a complete profile was created for each of them. For this purpose, blood samples were taken from the animals 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 7 h and 24 h after administration. To determine the plasma concentration of the test substance, the blood was taken in Minitubes with Ks-EDTA as an anticoagulant, placed on ice and then centrifuged at 3000 g. 100 pL of the plasma obtained in this way was mixed with a cold solvent (acetonitrile and an internal standard), which precipitated the proteins and these samples were frozen overnight at -20 °C.

[0154] After thawing, the samples were analyzed together with previously simultaneously prepared calibration standards (e.g. 0.005, 0.01, 0.05, 0.1, 0.5, 1 and 5 pM) in a sequence on a Sciex mass spectrometer (e.g. API 5500) and a Waters chromatography system (e.g. Acquity) on a standard column (e.g. Waters BEH C18, 2.5 pm, 2.1 mm x 50 mm). The conditions of the chromatography system were oven temperature 60 °C, a flow of 0.6 mL / min with a gradient of the two eluents A: water (incl 0.1% acetic acid) and B: methanol or acetonitrile (incl 0.5% acetic acid), which starts at 95% A, is changed to 5% A within 1.5 min, remains there for one minute and is flushed back to 95% A for a further minute, so that injection was carried out every approximately 3.6 min. The test substance eluted after approximately 1.69 min. The BHC243029 parameters of the mass spectrometer were set by default to positive ionization with an atmospheric pressure ion source. An additional sample of test substance in solvent was prepared as a system suitability test before each sequence start.

[0155] From the concentration results obtained, the usual pharmacokinetic parameters were calculated using the company’s own Excel macro “KinEX 4.1”.

[0156] Calculation of AUCs:

[0157] The Area Under the Curve (AUC) was calculated from 0 to the last time point above the lowest limit of quantification as follows: For increasing concentrations according to the linear trapezoidal rule and for decreasing concentrations according to the logarithmic trapezoidal rule. The extrapolated fraction of AUC from the last time point above the lowest limit of quantification to infinity was then obtained from the concentration at the last time point above the lowest limit of determination and the half-life. For the comparability of the AUCs after administration of different doses, the dose-normalized AUC was used:

[0158] The relative bioavailability (Frei), e.g. after oral administration of a suspension and a solution, was calculated from the quotient of the dose-normalized AUCs, e.g. Frei= AUCnOrm(Tylose suspension) / AUCnOrm(so- lution). The results can be seen in Figure 18, Figure 19 and Figure 20.

[0159] Table 6: Comparison of Frei results. The corresponding plasma concentrations can be found in Figure

[0160] 18. Figure 19 and Figure 20

Claims

BHC243029CLAIMS1 ) Besylate salt of l-{4-[2-methyl-4-({ l-[2-methyl-3-(trifluoromethyl)phenyl] ethyl} amino) pyrido[3,4- d]pyrimidin-6-yl]-4-oxido-l,4-azaphosphinan-l-yl}ethanone, in any of its anhydrous forms or any hydrate(s), or mixtures thereof.2) Besylate salt according to claim 1, wherein the besylate salt is according to formula (II) to (IV)formula (IV), preferred according to formula (II).3) Besylate salt of claims 1 or 2, characterized in that the besylate salt is in a crystalline form.BHC2430294) Besylate salt of any of claims 1 to 3 for use in the treatment or prophylaxis of a disease.5) Besylate salt of claim 4 wherein the disease is a hyperproliferative disorder, such as cancer, for example.6) Besylate salt of any of claims 1 to 3 for the preparation of a medicament.7) A pharmaceutical composition comprising a besylate salt according to any of claims 1 to 3, and a pharmaceutically acceptable diluent or carrier.8) Use of the besylate salt of claims 1 to 3 for the manufacture of a pharmaceutical composition for the treatment or prevention of a hyperproliferative disorder, such as cancer and tumor diseases.9) Use of the besylate salt of claims 1 to 3 for the manufacture of a tablet or a capsule which is physically and chemically stable.

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