WO2024088829A2

WO2024088829A2 - Salts and polymorphs of 4-(4-methyl-piperazin-1-yl)-n-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1h-indazol-3-yl}-benzamide

Info

Publication number: WO2024088829A2
Application number: PCT/EP2023/078862
Authority: WO
Inventors: Andrea Lombardi Borgia; Enrico BARLOCCHI; Massimo Zampieri
Original assignee: Nerviano Medical Sciences S.R.L.
Priority date: 2022-10-25
Filing date: 2023-10-17
Publication date: 2024-05-02

Abstract

The present invention relates to novel salts of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]- 1H-indazol-3-yl}-benzamide, their solvates, hydrates and polymorphs, as well as to process for their preparation, pharmaceutical compositions containing them and methods of treatment using them. Such new salts as well as their crystalline forms show good physicochemical properties, thus substantially introducing favorable characteristics in handling, storage and formulations. More importantly these salts have been found to have a surprisingly improved oral bioavailability, with respect to the free base, thus resulting particularly advantageous their use for an oral administration.

Description

NMS-119 SALTS AND POLYMORPHS OF 4-(4-METHYL-PIPERAZIN-1-YL)-N-{6-[2-(4-TRIFLUOROMETHYL-BENZYLOXY)- ETHOXY]-1H-INDAZOL-3-YL}-BENZAMIDE Background of the Invention Field of the Invention This invention relates to novel salts of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide, their solvates, hydrates, and polymorphs, as well as to process for their preparation, pharmaceutical compositions containing them and methods of treatment using them. Related Background Art The compound 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide of formula (I) N (I) is described in

1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide, hydrates, solvates or crystalline forms thereof are disclosed. Valuable pharmacological properties are attributed to this compound; it can be used as a protein kinase inhibitor useful in the therapy of diseases which respond to inhibition of protein kinase activity. In particular, this compound can be used to treat diseases associated with FMS-like tyrosine kinase 3 (FLT3) and/or c-KIT and/or colony stimulating factor 1 receptor (CSF-1R) mutated activity or overexpressed protein kinases. FLT3, c-KIT and CSF-1R are all members of the PDGFR family class III receptor tyrosine kinases. FLT3 mutations can be detected in 30% of acute myeloid leukemia (AML) patients (Nakao M, et al. Leukemia.1996 Dec; 10(12): 1911-8) and also in 5-10% of patients with myelodisplastic syndrome (Horiike S, et al. Leukemia.1997 Sep; 11(9): 1442-6). There are two frequent types of somatic FLT3 genetic mutations: internal tandem duplications (ITDs) in the JM domain and point mutations in the activation loop of the tyrosine kinase domain (TKD). Both types of FLT3 mutation cause ligand-independent activation of the receptor and activation of downstream signaling pathways. Mutant FLT3 provides survival advantage to leukemic cells because it causes activation of three major intracellular signalling pathways: PI3K/AKT; RAS/RAF/MAPK and JAK/STAT (Masson K, Rönnstrand L. Cell Signal.2009 Dec;21(12):1717-26). According to 2017 European Leukemia Net risk stratification, patients with FLT3/ITDhigh-positive AML are classified into adverse risk category. This mutation causes resistance to conventional chemotherapy. Although patients with AML can be cured with hematopoietic stem cell transplantation (HSCT), most of these patients are at high risk for relapse. In conclusion, interfering with the FLT3 signaling likely represents a specific and effective way to block tumor cell proliferation in high-risk AML patients and possibly in patients with other indications (Kennedy VE, Smith CC, Frontiers in Oncology, 2020, 10, 612880). Also c-KIT overexpression or mutations can lead to cancer. About 65-85% of GISTs have c-KIT mutations, divided into two categories: mutations of the receptor regulatory domains (extracellular and juxtamembrane) and mutation in the enzymatic domain (Antonescu CR. J Pathol.2011; 223(2): 251-6). Mutation of c-KIT have been identified also in melanoma (Curtin JA, JCO, 2006, 24 (26): 4340-4346), acute myeloid leukemia (Malaise M, Steinbach D, Corbacioglu S, Curr Hematol Malig Rep.2009, 4(2): 77-82), and primary adenoid cystic carcinoma of the salivary gland (Vila L, Liu H, Al-Quran SZ, Coco DP, Dong HJ, Liu C, Mod Pathol.2009; 22(10): 1296-302). Overexpression is reported also in thymic carcinoma (Ströbel P, Hohenberger P, Marx A, J Thorac Oncol.2010; 5 (10 Suppl 4): S286-90), glioma (Morris PG, Abrey LE.Target Oncol.2010; 5(3):193-200), testicular seminoma (Nikolaou M. et al. Anticancer Res. 2007; 27(3B): 1685-8), and small cell lung cancers (SCLC) (Micke P, et al. Clin Cancer Res.2003; 9(1): 188-94). Based on the collection of data, c-KIT kinase activation appears to be the triggering factor for an important group of malignancies, both hematological and solid cancer diseases, thereby suggesting that it could represent a good therapeutic target for the treatment of these pathologies. CSF-1R (M-CSF receptor, c-FMS kinase or CD115) and its ligands, CSF-1 and interleukin 34 (IL-34), regulate the function and survival of tumor-associated macrophages, which are involved in tumorigenesis and in the suppression of antitumor immunity Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Ruttinger D, J Immunother o Cancer 2017, 5:53). High CSF-1 or CSF-1R expression levels in the tumour or peritumoural tissue have been associated with poor patient survival in different malignancies, such as Hodgkin’s lymphoma, breast cancer, and hepatocellular carcinoma [Mantovani A, et al. Nature Reviews Clin Oncol 2017; 14, 399–416.]. Moreover, the CSF-1R/CSF-1 axis has been implicated in the pathogenesis of pigmented villonodular synovitis (PVNS), a benign tumor of the synovium (Brahmi M, Vinceneux A, Cassier PA. Curr Treat Options Oncol. 2016 Feb;17(2):10). CSF-1R has been recently reported also as a novel therapeutic target of AML acting through a mechanism of paracrine cytokine/growth factor signaling in this disease (Edwards DK, et al. Blood.2019 Feb 7;133(6):588-599). CSF-1R has also been found to be highly expressed in blast samples from chronic myelomonocytic leukemia (CMML), a clonal hematopoietic stem cell disorder with poor survival rates post- blast transformation, with no standard targeted therapy. Based on the collection of data, CSF-1R kinase activity appears to be relevant in supporting the growth of many malignancies, both hematological and solid cancer diseases, thereby suggesting that it could represent a good therapeutic target for the treatment of these pathologies. BRIEF DESCRIPTION OF THE DRAWINGS The invention is also illustrated by reference to the accompanying drawings described below. Fig.1-10 show the X-ray diffractograms of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]- 1H-indazol-3-yl}-benzamide free base and their crystalline salts reporting 2-theta angles (deg) on the x axis while intensity (CPS) is reported on the y axis. In particular: Fig.1 shows the X-ray diffractogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide free base form I. Fig.2 shows the X-ray diffractogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrochloride form I. Fig.3 shows the X-ray diffractogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrobromide form I. Fig.4 shows the X-ray diffractogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide besylate form I. Fig.5 shows the X-ray diffractogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide napsylate form I. Fig.6 shows the X-ray diffractogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide tosylate form I. Fig.7 shows the X-ray diffractogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide L-malate form I. Fig.8 shows the X-ray diffractogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrogensulfate form I. Fig.9 shows the X-ray diffractogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hemioxalate form I (half mole of counterion). Fig.10 shows the X-ray diffractogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hemioxalate form II (half mole of counterion). Fig.11-20 show the DSC thermograms of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide free base and their crystalline salt forms. The thermogram reports temperature (°C) on the x axis while normalized heat flow (W/g) is reported on the y axis. In particular: Fig.11 shows the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide free base form I. Fig.12 shows the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrochloride form I. Fig.13 shows the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrobromide form I. Fig.14 shows the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide besylate form I. Fig.15 shows the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide napsylate form I. Fig.16 shows the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide tosylate form I. Fig.17 shows the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide L-malate form I. Fig.18 shows the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrogensulfate form I. Fig.19 shows the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hemioxalate form I (half mole of counterion). Fig.20 shows the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hemioxalate form II (half mole of counterion). Fig.21 shows the DVS profiles (hygroscopicity test) of the following salts of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide: hydrochloride form I (A), hydrobromide form I (B), besylate form I (C), napsylate form I (D), tosylate form I (E), L-malate form I (F), hydrogensulfate form I (G), hemioxalate form I (H) (half mole of counterion). Fig.22 shows the DVS profile (hygroscopicity test) of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)- ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate form II (half mole of counterion). Summary of the Invention The present invention relates to 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol- 3-yl}-benzamide salts, their solvates, hydrates and polymorphs. In the previous disclosed WO2012/152763 A1 patent application, the 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide free base has been reported to inhibit FLT3 and/or c- KIT kinases, thus to be used in the treatment of cancer and others diseases. Preclinical investigation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide as free base has shown not optimal pharmacokinetic properties for its use for an oral administration. Furthermore, good and reproducible physicochemical and bulk properties, such as adequate solubility, low hygroscopicity, crystallinity, chemical stability at variable storage temperature, humidity are required to ensure proper biopharmaceutical behavior and to allow a safer and efficacious oral administration. We have now surprisingly found that novel salts of the 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide, as well as their crystalline forms, have an unexpected improved pharmacokinetic profile with respect to the free base. The novel salts have good physicochemical properties; in particular, they are crystalline, low or moderately hygroscopic, thus substantially introducing favorable characteristics in handling, storage and formulations; more importantly these salts have been found to have a surprisingly improved oral bioavailability, with respect to the free base, thus resulting particularly advantageous their use for an oral administration. Generally, as used herein, “salts” refers to a compound prepared by a reaction of an organic acid or a base drug with a pharmaceutically acceptable mineral or organic acid or base. The term “salt” includes hydrate and solvates of salts made in accordance with this invention. Example of pharmaceutically acceptable mineral or organic acids or bases are those listed in table 1-8 in Handbook of pharmaceutical salts, P.H. Stahl and C.G. Wermuth (eds.) VHCA, Zurich pp334- 345. In a first object, the present invention relates to new salts of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, hydrobromide, benzene sulphonate (besylate), naphthalene-2-sulphonate (napsylate) p-toluene sulphonate (tosylate), L-malate, hydrogensulfate and hemioxalate (half mole of counterion), their solvates, hydrates and crystalline forms characterized by an X-ray powder diffraction pattern comprising peaks at reflection angle 2-theta, measured with Cu-Kα1 radiation of wavelength λ= 1.54060 Angstrom, of: hydrocloride form I: 6.4, 12.8, 19.2 and 23.4°; hydrobromide form I: 6.4, 13.9, 19.4, 21.1 and 23.4°; besylate form I: 4.2, 16.2, 17.9, 22.3 and 24.3°; napsylate form I: 12.0, 16.4, 20.2, 22.3 and 23.9°; tosylate form I: 4.1, 12.2, 16.3, 22.2 and 24.1°; L-malate form I: 4.9, 18.5, 19.5 and 21.7°; sulfate form I: 5.4, 16.5, 23.7 and 26.9°; hemioxalate form I: 5.5, 18.5, 19.0 and 22.3°; hemioxalate form II: 5.7, 11.5, 18.2, 20.3 and 23.0°. Another object of the present invention relates to new salts of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, hydrobromide, benzene sulphonate (besylate), naphthalene-2-sulphonate (napsylate) p-toluene sulphonate (tosylate), L-malate, hydrogensulfate and hemioxalate, their, solvates, hydrates and crystalline forms characterized by an X-ray powder diffraction pattern comprising peaks at reflection angle 2-theta, measured with Cu-Kα1 radiation of wavelength λ= 1.54060 Angstrom of: hydrocloride form I: 6.4, 12.8, 19.2, 19.7, 22.1, 23.4 and 24.1°; hydrobromide form I: 6.4, 13.9, 17.0, 19.4, 20.4, 20.8, 21.1, 22.0, 23.4 and 24.2°; besylate form I: 4.2, 8.4, 10.8, 16.2, 17.9, 20.6, 21.8, 22.3, 22.7 and 24.3°; napsylate form I: 10.3, 12.0, 16.4, 17.1, 18.0, 18.4, 18.8, 20.2, 22.3 and 23.9°; tosylate form I: 4.1, 8.1, 10.5, 12.2, 16.3, 17.5, 20.4, 22.2, 24.1 and 25.8°; L-malate form I: 4.9, 18.2, 18.5, 19.5, 20.8, 21.7 and 22.9°; hydrogensufate form I: 5.4, 10.9, 16.5, 17.4, 19.4, 21.2, 23.7 and 26.9°; hemioxalate form I: 5.5, 11.1, 15.6, 16.6, 18.5, 19.0, 20.0 and 22.3°; hemioxalate form II: 5.7, 9.6, 11.5, 14.9, 15.6, 16.6, 17.3, 17.9, 18.2, 18.6, 19.0, 19.5, 20.3, 21.7 and 23.0°. In some preferred embodiments, the present invention relates to salts of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, benzene sulphonate (besylate), and hemioxalate, their solvates, hydrates and crystalline forms, as defined above. In more preferred embodiments, the present invention relates to 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate salt, its solvates, hydrates and crystalline forms as defined above. In other more preferred embodiments, the present invention relates to 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate Form I, or hemioxalate Form II, as defined above. A further object of the invention is to provide a process for obtaining a salt or a crystalline form of 4-(4-methyl-piperazin- 1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide by mixing the free base with from 0.5 to 2 equivalents of suitable acid in a polar organic solvent, preferably dichloromethane, THF (tetrahydrofurane), EtOH, MeOH, (1- or 2-) propanol, (1- or 2-) butanol, tert-butanol, 2-methoxyethanol, acetonitrile, acetone and mixtures thereof. If necessary, the precipitation or the crystallization of the obtained salt may be favored by addition or reworking in an anhydrous solvent, for instance diethyl ether, n-hexane or cyclohexane. The precipitation or the crystallization of the obtained salt may also be achieved by addition of a suitable anti-solvent, for instance acetone, acetonitrile, n-butanol, absolute ethanol, methanol, i-propylether, methyl t-butyl ether, dichloromethane, heptane, n-hexane, 2-methoxyethanol, methyl ethyl ketone, methyl isobutyl ketone, 1-propanol, t- butanol, toluene, water, to a solution of the salt in a suitable solvent, for instance N,N-dimethylformamide, dimethylsulfoxide. A crystalline form of a salt of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide may also be obtained by converting another crystalline form or a mixture of crystalline forms of the same salt, for instance by stirring a slurry in a suitable solvent, for instance ethanol, chloroform, dichloromethane, 1,4- dioxane, methanol, at a temperature ranging from 20°C to reflux and for a time ranging from 1 hour to 3 days. In one embodiment the process relates to the preparation of salt or a crystalline form of the salt of 4-(4-methyl-piperazin- 1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, besylate and hemioxalate. In a preferred another embodiment the process for the preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hydrochloride salt as crystal form I, is carried out with from 0.5 to 2 equivalents of hydrochloric acid in an organic solvent, preferably the process is carried out with 1 equivalent of hydrochloric acid in dichloromethane and 2-propanol mixture. In another preferred embodiment the process for the preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide besylate salt as crystal form I, is carried out with from 0.5 to 2 equivalents of benzenesulfonic acid in an organic solvent, preferably the process is carried out with 1 equivalent of benzenesulfonic acid in dichloromethane, 2-propanol and ethanol mixture. In another preferred embodiment the process for the preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate salt as crystal form I, is carried out with from 0.5 to 2 equivalents of oxalic acid in an organic solvent, preferably the process is carried out with 0.5 equivalents of oxalic acid in 2-propanol and ethanol mixture. In another preferred embodiment the process for the preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate salt as crystal form II, is carried out with from 0.5 to 2 equivalents of oxalic acid in an organic solvent, preferably the process is carried out with 0.5 equivalents of oxalic acid in ethanol. According to the present invention, the definition of salts also comprises their crystalline forms, solvates and hydrates thereof. The term “solvates” as used herein, means compounds formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute. Well known solvent molecules include water, alcohols and other polar organic solvents. Alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and t- butanol. Alcohols also include polymerized alcohols such as polyalkylene glycols (e.g. polyethylene glycol, polypropylene glycol). The term “hydrates” as used herein, means compounds formed by solvation, wherein the solvent is water. Unless otherwise specified, when referring to “solvates” and “hydrates” the present invention includes both stoichiometric and non-stoichiometric ones. Stoichiometric solvates have a fixed ratio of solvent molecules to the molecules of the compound. This is typically due to a bonding interaction between the solvent and the compound molecule. In non-stoichiometric solvates, the solvent is not present in a fixed ratio to the molecules of the compound and often can vary. In a non-stoichiometric solvate, the solvent is often present in the void spaces or channels within the crystalline lattice. Stoichiometric hydrates have a fixed ratio of water molecules to the molecules of the compound. This is typically due to a bonding interaction between the water and the compound molecule. In non-stoichiometric hydrates, the water is not present in a fixed ratio to the molecules of the compound and often can vary. In a non-stoichiometric hydrate, the water is often present in the void spaces or channels within the crystalline lattice. The term “polymorph” as used herein, refers to a distinct ”crystal modification” or “polymorphic form” or “crystalline form”, which differs from another with respect to X-ray powder diffraction patterns, physicochemical and/or pharmacokinetic properties and thermodynamic stability. A further object of the invention is to provide a pharmaceutical composition comprising a salt of the 4-(4-methyl- piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, hydrobromide, benzene sulphonate (besylate), naphthalene-2-sulphonate (napsylate) p- toluene sulphonate (tosylate), L-malate, hydrogensulfate and hemioxalate and their solvates, hydrates and crystalline forms as active ingredient and a pharmaceutically acceptable excipient and/or carrier. In a preferred embodiment, the pharmaceutical composition comprises crystalline forms of a salt of 4-(4-methyl- piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, benzene sulphonate (besylate) and hemioxalate and their solvates, hydrates and crystalline forms as active ingredient and a pharmaceutically acceptable excipient and/or carrier. In a most preferred embodiment, the pharmaceutical composition comprises hemioxalate crystalline form (I) or hemioxalate crystalline form (II) of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide as active ingredient and a pharmaceutically acceptable excipient and/or carrier. A further object of the invention is to provide a salt of the 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, hydrobromide, benzene sulphonate (besylate), naphthalene-2-sulphonate (napsylate) p-toluene sulphonate (tosylate), L-malate, hydrogensulfate and hemioxalate and their solvates, hydrates and crystalline forms for use as a medicament. In a preferred embodiment the invention provides salts of the 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from hydrochloride, benzene sulphonate (besylate) and hemioxalate and their solvates, hydrates and crystalline forms for use as a medicament. In most preferred embodiment the invention provides hemioxalate crystalline form (I) or hemioxalate crystalline form (II) of the 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide for the use as a medicament. A further object of the present invention provides a salt of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, hydrobromide, benzene sulphonate (besylate), naphthalene-2-sulphonate (napsylate) p-toluene sulphonate (tosylate), L-malate, sulphate and hemioxalate and their solvates, hydrates and crystalline forms, for use in a method for treating a disease state treatable by FLT3, c-KIT or CSF1R inhibition, which comprises administering to a mammal, preferably a human, in need thereof an effective amount of the pharmaceutical salt as defined above. A further object of the invention is to provide a method for treating disease state in a mammal, preferably a human, in need of FLT3, c-KIT or CSF-1R inhibition comprising administering to said mammal a therapeutically effective amount of a salt of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, hydrobromide, benzene sulphonate (besylate), naphthalene-2- sulphonate (napsylate) p-toluene sulphonate (tosylate), L-malate, hydrogensulfate and hemioxalate and their solvates, hydrates and crystalline forms. A further object of the invention is to provide the use of a salt of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, hydrobromide, benzene sulphonate (besylate), naphthalene-2-sulphonate (napsylate) p-toluene sulphonate (tosylate), L-malate, hydrogensulfate and hemioxalate and their solvates, hydrates and crystalline forms, for the manufacture of a medicament for the treatment of a disease state treatable by c-KIT, FLT3 or CSF-1R inhibition. A further object of the invention is to provide a pharmaceutical composition comprising a salt of 4-(4-methyl-piperazin- 1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, hydrobromide, benzene sulphonate (besylate), naphthalene-2-sulphonate (napsylate) p-toluene sulphonate (tosylate), L-malate, sulphate and hemioxalate and their solvates, hydrates and crystalline forms for treating a mammal, preferably a human, suffering from a disease state treatable by FLT3, KIT or CSF-1R inhibition. Salts of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide may be administered as the sole pharmaceutical agent or in combination with one or more additional therapeutic agents where the combination causes no unacceptable adverse effects. This combination therapy includes administration of a single pharmaceutical dosage formulation which contain the pharmaceutical salt and one or more additional therapeutic agents, as well as administration of the pharmaceutical salt and each additional therapeutic agent in its own separate pharmacological dosage formulation. For example, a pharmaceutical salt and a therapeutic agent may be administered to a patient together in a single oral dosage composition such as tablet or capsule, or each agent may be administered in a separate dosage formulation. Where separate dosage formulations are used, the pharmaceutical salt and one or more additional therapeutic agents may be administered at essentially the same time (e.g., concurrently) or at separately staggered times (e.g., sequentially. In another aspect, the present invention provides a combination of a salt of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide selected from the group consisting of hydrochloride, hydrobromide, benzene sulphonate (besylate), naphthalene-2-sulphonate (napsylate) p-toluene sulphonate (tosylate), L-malate, sulphate and hemioxalate and their solvates, hydrates and crystalline forms, with one or more chemotherapeutic agents. In a preferred embodiment the chemotherapeutic agents are selected from the group consisting of cytostatic, or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, immunotherapy agents, anti-PD-1 monoclonal antibodies, anti-PDL1 monoclonal antibodies, anti-CTLA4 monoclonal antibodies, immunomodulatory agents, interferon-type agents, cyclooxygenase inhibitors, matrixmetalloprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents, farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like. The term "disease state treatable" means that the treatment according to the invention provides remission of the disease state or at least the conditions and quality of life of the mammal under treatment are improved. Example of such disease states are in particular different cancers that may include, carcinoma such as bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), salivary gland, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, thymus, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T- cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, chronic myelomonocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including gastrointestinal stromal tumor, fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma neuroblastoma, glioma and schwannomas; other tumors, including mast cell disease, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer, Kaposi's sarcoma and mesothelioma and others. In one preferred embodiment the cancer is selected from the group consisting of acute myelogenous leukemias (AML) and chronic myelomonocytic leukemia (CMML). Another example of such disease states are specific cellular proliferation disorders such as, for example, pigmented villonodular synovitis, benign prostate hyperplasia, familial adenomatosis polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis. Another example of such disease states are is to treat immune cell-associated diseases and disorders, such as inflammatory and autoimmune diseases, for examples multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases (IBD), Crohn’s disease, irritable bowel syndrome, pancreatitis, ulcerative colitis, diverticulosis, myasthenia gravis, vasculitis, psoriasis, scleroderma, asthma, allergy, systemic sclerosis, vitiligo, arthritis such as osteoarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis. Another example of such disease is to treat FLT3 mutated cancers, such as acute myeloid leukemia, chronic myelomonocytic leukemia, or myelodisplastic syndrome. Another example of such disease is to treat c-KIT mutated cancers, such as gastrointestinal stromal tumors, melanoma, acute myeloid leukemia, primary adenoid cystic carcinoma of the salivary gland, thymic carcinoma, glioma, testicular seminoma, small cell lung cancers, mast cell disease or piebaldism. Another example of such disease is to treat CSF1R pathway depending cancers, such as acute myeloid leukemia, chronic myelomonocytic leukemia, or solid tumors with high presence of tumor associated macrophages. The effective dose of compound of formula (I) salts may vary according to the disease, severity of the disorder and the conditions of the patient to be treated. Therefore, the physician, as always, must set the optimal dose for each patient. Anyway, the effective dosage range may be from about 20 to about 500 mg per dose (calculated as a free base), from 1 to 3 times daily. A salt of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide as above defined, its solvate, hydrate or a crystalline form, is readily orally absorbed, therefore it is preferably orally administered. Needless to say, the compounds of the present invention may be administered also by any administration route, for instance by parenteral, topical, rectal and nasal route. As a further aspect it has been found that 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrochloride salt can be obtained as a crystalline solid in the crystalline form named form I. Hydrochloride salt is characterized by retention of some residual iPrOH and by high-melting point, high crystallinity, slight hygroscopicity, with a water uptakes of about 1.5% at 25°C/90% RH. The hydrochloride salt results chemically and physically stable after 1 month under accelerated conditions showing retention of iPrOH also after stability storage at 40°C/75%RH (PXRD profile Fig.2; DSC profile Fig.12; DVS profile Fig.21A). As a further aspect it has been found that 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrobromide salt can be obtained as a crystalline solid in the crystalline form named form I. Hydrobromide salt is characterized by retention of some residual iPrOH and by high-melting point, high crystallinity, slight hygroscopicity, with a water uptakes of about 1.4% at 25°C/90% RH. The hydrobromide salt results chemically and physically stable after 1 month under accelerated conditions showing retention of iPrOH also after stability storage at 40°C/75%RH (PXRD profile Fig.3; DSC profile Fig.13; DVS profile Fig.21B). As a further aspect it has been found that 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide besylate salt can be obtained as a crystalline solid in the crystalline form named form I. Besylate salt is characterized by retention of some residual iPrOH and by high-melting point, high crystallinity, low hygroscopicity (reversible), with a water uptakes of about 1.6% at 25°C/90% RH. The benzenesulfonate salt results chemically and physically stable after 1 month under accelerated conditions showing loss of iPrOH after stability storage at 40°C/75%RH (PXRD profile Fig.4; DSC profile Fig.14; DVS profile Fig.21C). As a further aspect it has been found that 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide napsylate salt can be obtained as a crystalline solid in the crystalline form named form I. Napsylate salt is characterized by retention of some residual iPrOH and by high-melting point, high crystallinity, low hygroscopicity (reversible), with a water uptakes of about 1.4% at 25°C/90% RH. The naphthalenesulfonate salt results chemically and physically stable after 1 month under accelerated conditions showing loss of iPrOH after stability storage at 40°C/75%RH (PXRD profile Fig.5; DSC profile Fig.15; DVS profile Fig.21D). As a further aspect it has been found that 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide tosylate salt can be obtained as a crystalline solid in the crystalline form named form I. Tosylate salt is characterized by retention of some residual iPrOH and by high-melting point, high crystallinity, low hygroscopicity, with a water uptakes of about 0.5% at 25°C/90% RH. The toluenesulfonate salt results chemically and physically stable after 1 month under accelerated conditions showing loss of iPrOH after stability storage at 40°C/75%RH (PXRD profile Fig.6; DSC profile Fig.16; DVS profile Fig.21E). As a further aspect it has been found that 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide L-malate salt can be obtained as a crystalline solid in the crystalline form named form I. L- malate salt is characterized by a melting point range below 150 °C, high crystallinity, moderate hygroscopicity, with a water uptakes of about 2.8% at 25°C/90% RH. The L-malate salt results chemically and physically stable after 1 month under accelerated conditions (PXRD profile Fig.7; DSC profile Fig.17; DVS profile Fig.21F). As a further aspect it has been found that 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrogensulfate salt can be obtained as a crystalline solid in the crystalline form named form I. Hydrogensulfate salt has been characterized as probable hydrated form showing high-melting point with initial desolvation, high crystallinity, moderate hygroscopicity, with a water uptakes of about 2.4% at 25°C/90% RH. The hydrogensulfate salt results chemically and physically stable after 1 month under accelerated conditions (PXRD profile Fig.8; DSC profile Fig.18; DVS profile Fig.21G). As a further aspect it has been found that 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hemioxalate salt can be obtained as a crystalline solid in stoichiometric ratio 1:0.5 in two crystalline forms named form I and form II, respectively. Form I is a high melting crystalline form of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hemioxalate salt that shows a low hygroscopicity with a water uptake of 0.3% at 25°C/90%RH that is reversible by lowering RH at constant temperature of 25°C and results chemically and physically stable after 1 month under accelerated conditions. Form I undergoes a reversible solid to solid transition at about 130 °C with conversion to form III characterized by a DSC melting endotherm at about 215°-250° C with concurrent decomposition (PXRD profile: Fig.9; DSC profile: Fig. 19; DVS profile: Fig.21H). Form II is a high melting crystalline form of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]- 1H-indazol-3-yl}-benzamide hemioxalate salt that shows a low hygroscopicity with a water uptake of 0.8% at 25°C/90%RH that is reversible by lowering RH at constant temperature of 25°C and results stable after 1 month under accelerated conditions. Form II undergoes a reversible solid to solid transition at about 190 °C with conversion to form III characterized by a DSC melting endotherm at about 205°-255°C with concurrent decomposition (PXRD profile: Fig.10; DSC profile: Fig. 20; DVS profile: Fig.22). High water solubility, high crystallinity and high termal stability of the 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide salts, render these salts particularly suitable for the use in liquid formulations, for oral as well as for intravenous formulations. Furthemore, the hydrochloride, benzene sulphonate and hemioxalate salts are also unexpectedly more orally bioavailable in comparison to the free base, thus particularly suitable for an oral formulation. The description of the solid state properties of the salts of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide together with the complete list of related PXRD and DSC figures are shown in Table 1. Table 1 - Description of the solid state properties and Figures/Tables references of the salts and free base forms of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide 4-(4-methyl-piperazin-1-yl)-N-{6-[2- (4-trifluoromethyl-benzyloxy)- Crystalline PXRD PXRD Significant PXRD peaks (2- DSC F Fi T l h * Fi

Tables 2a and 2b report the pharmacokinetic parameters of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide as free base and some crystalline salts thereof after oral administration in different species. Experimental data were obtained following the procedure reported in the example 15 below. Table 2a- Pharmacokinetic parameters in dog after 10 mg/kg oral administration of 4-(4-methyl-piperazin-1- yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide free base and salts Compound C max (µM) AUC∞ (µM.h) Estimated %F

Table 2b- Pharmacokinetic parameters in monkey after 10 mg/kg oral administration of 4-(4-methyl-piperazin- 1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide free base and salts Compound C max (µM) AUC∞ (µM.h) Estimated %F

, y y pp y yl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hydrochloride, benzene sulphonate and hemioxalate salts show, after oral administration at the same dose of 10 mg/kg, an improved exposure in one or both species with respect to the free base, resulting in an improved oral bioavailability. In particular, this improvement is surprisingly high after the administration of crystalline forms I and II of the hemioxalate salt. Even more surprisingly, the hemioxalate salt form crystalline II, when administered orally in monkey, ensures a significantly higher exposure than the free base but also than the form I of the hemioxalate salt. According to a further aspect of the invention a pharmaceutical composition can be formulated according to known method in the art in any of the pharmaceutical forms known in the art for administration to a mammal, including humans. For instance, a pharmaceutical composition which comprises a salt of a compound of formula (I) defined herein in association with a pharmaceutically acceptable diluent or carrier. The compositions of the invention may be in a form suitable for oral use. Examples of these forms are: tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules. The compositions of the invention may also be in a form suitable for topical use. Examples of these forms are: creams, ointments, gels, or aqueous or oily solutions or suspensions. The compositions of the invention may also be in a form suitable for administration by inhalation such as, for example, finely divided powder or a liquid aerosol. The compositions of the invention may also be in a form suitable for administration by insufflation such as, for example, finely divided powder. The compositions of the invention may also be in a form suitable for parenteral administration (such as, for example, a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular) or as a suppository for rectal dosing. The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain one or more additives such as, for example, colouring, sweetening, flavouring and preservative agents. Suitable pharmaceutically acceptable excipients in the formulation of a tablet include can be, for example, fillers such as lactose, mannitol, microcrystalline cellulose, sodium carbonate, pregelatinized starch, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as sodium croscarmellose, corn starch, crospovidone or sodium starch glycolate; binding agents such as starch, povidone, sucrose; lubricating agents such as magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, polyethylene glycols or talc; glidants, such as colloidal silicon dioxide; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants such as ascorbic acid. Tablet formulations may be uncoated or submitted to a coating process, to modify their disintegration properties and the subsequent absorption of the active ingredient in the gastrointestinal track, to improve stability or appearance. Uncoated and coated tablets require the use of conventional coating agents and/or procedures well known in the art. Compositions for oral use may be formulated as hard gelatin capsules where the filling mixture is prepared with the active ingredient that is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin and including the above mentioned excipients for tablet formulations. Compositions for oral use may also be formulated as soft gelatin capsules where the filling mixture is prepared with the active ingredient that is mixed with water or an oil such as peanut oil, liquid paraffin, soya bean oil, coconut oil, or preferably olive oil, or other acceptable vehicle. Compositions for oral use may also be in the form of hard gelatin capsules in which the active ingredient is formulated as a stable pharmaceutical solid or semisolid dispersion comprising the active ingredient and, for example, a hydrophilic carrier, a water-soluble vitamin E derivative as antioxidant agent and optionally other excipients. Aqueous suspensions are generally prepared with the finely powdered active ingredient in together with the addition of one suspending agents, (such as, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone) dispersing or wetting agents (such as, for example, lecithin, polyoxyethylene stearate, or polyoxyethylene sorbitol monooleate, polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more suitable additives such as preservatives, anti-oxidants, colouring agents, flavouring and/or sweetening agents to provide a palatable oral preparation. Oily suspensions may be obtained by suspending the active ingredient in a suitable vegetable oil (such as, for example, olive oil and sesame oil). Dispersible or lyophilised powders as well as granules suitable for preparation of an aqueous suspension or solution by the addition of water contain the active ingredient and suitable excipients (bulking, dispersing or suspending agents and preservatives). The formulation may also be a sterile injectable suspension, solution, emulsion prepared according to known procedures using appropriate excipients selected, for example, among the above mentioned dispersing, wetting and suspending agents. Topical formulations, such as creams, ointments, gels, solutions or suspensions, may be prepared by formulating an active ingredient with a conventional, vehicle or diluent using conventional procedure well known in the art. Compositions for administration by insufflation may be finely divided powder containing particles of suitable average diameter of, for example, 50 µm or less, the powder itself composed by either active ingredient as is or diluted with suitable carriers such as lactose. The powder for insufflation is formulated in a capsule containing a suitable amount of active to be used with a turbo- inhaler device. Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants and devices may be used to dispense a defined quantity of active ingredient. Examples of compositions for oral use in the form of hard gelatine capsules are described in example 14. EXAMPLES The following Examples illustrate the invention. Temperatures are measured in degrees Celsius (°C). Unless otherwise indicated, the reactions or experiments take place at room temperature. Abbreviations: RT: room temperature RH: relative humidity PXRD: Powder X-Ray diffraction DSC: Differential Scanning Calorimetry DVS: Dynamic Vapor Sorption TGA: Thermogravimetric Analysis Example 1: gram-scale preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrochloride salt (form I) A mixture of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide (1.5 g, 2.71 mmol), dichloromethane (15 mL) and 2-propanol (15 mL) is treated with 2N HCl (1.355 mL, 2.71 mmol). The resulting thick suspension is stirred at room temperature for 3 hours, then cooled to 0-5°C and stirred for additional 30 minutes. The suspension is then filtered over a sintered glass Buchner funnel and the pad washed 2 times with 3 mL of 2-propanol/dichloromethane 1:1. The solid is collected and dried in oven at 45°C under vacuum (10-30 mmHg) until constant weight, affording 1.45 g of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrochloride form I as a white powder. ¹H NMR (401 MHz, DMSO-d6) δ ppm 2.84 (s, 3 H) 3.15 (br. s., 3 H) 3.51 (br. s., 2 H) 3.86 (dd, J=5.19, 3.72 Hz, 2 H) 4.05 (br. s., 2 H) 4.23 (dd, J=5.31, 3.60 Hz, 2 H) 4.70 (s, 2 H) 6.72 (dd, J=8.91, 2.08 Hz, 1 H) 6.87 (d, J=2.07 Hz, 1 H) 7.10 (d, J=9.03 Hz, 2 H) 7.59 (dd, J=8.48, 2.75 Hz, 3 H) 7.72 (d, J=8.06 Hz, 2 H) 8.01 (d, J=8.91 Hz, 2 H) 10.20 (br. s., 1 H) 10.47 (s, 1 H) 12.49 (s, 1 H). Example 2: gram-scale preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrobromide salt (form I) A mixture of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide (1.5 g, 2.71 mmol), dichloromethane (15 mL) and 2-propanol (15 mL) is treated with 48% HBr (0.307 mL, 2.71 mmol). The resulting thick suspension is stirred at room temperature for 1 hour, then cooled to 0-5°C and stirred for additional 30 minutes. The suspension is then filtered over a sintered glass Buchner funnel and the pad washed 2 times with 4 mL of 2-propanol/dichloromethane 1:1. The solid is collected and dried in oven at 45°C under vacuum (10-30 mmHg) until constant weight, affording 1.65 g of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrobromide form I as a white powder. ¹H NMR (401 MHz, DMSO-d6) δ ppm 2.87 (s, 3 H) 3.12 (br. s., 4 H) 3.52 (br. s., 2 H) 3.86 (dd, J=5.25, 3.66 Hz, 2 H) 4.05 (br. s., 2 H) 4.23 (dd, J=5.37, 3.54 Hz, 2 H) 4.70 (s, 2 H) 6.72 (dd, J=8.91, 2.07 Hz, 1 H) 6.87 (d, J=1.95 Hz, 1 H) 7.10 (d, J=9.03 Hz, 2 H) 7.59 (dd, J=8.48, 2.50 Hz, 3 H) 7.72 (d, J=8.06 Hz, 2 H) 8.01 (d, J=8.91 Hz, 2 H) 9.62 (br. s., 1 H) 10.47 (s, 1 H) 12.48 (s, 1 H). Example 3 gram-scale preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide besylate salt (form I) A mixture of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide (1.5 g, 2.71 mmol), dichloromethane (15 mL) and 2-propanol (15 mL) is treated with a suspension of benzenesulfonic acid (428 mg, 2.71 mmol) in 2 mL of absolute ethanol. The resulting suspension is stirred at room temperature for 4 hours, then cooled to 0-5°C and stirred for additional 30 minutes. The suspension is then filtered over a sintered glass Buchner funnel and the pad washed three times with 3 mL of 2-propanol/dichloromethane 1:1. The solid is collected and dried in oven at 45°C under vacuum (10-30 mmHg) until constant weight, affording 1.81 g of 4-(4-methyl-piperazin-1-yl)-N- {6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide besylate form I as a white powder. 1H NMR (401 MHz, DMSO-d6) δ ppm 2.87 (s, 3 H) 2.99 - 3.22 (m, 4 H) 3.52 (br. s., 2 H) 3.86 (dd, J=5.31, 3.72 Hz, 2 H) 4.05 (br. s., 2 H) 4.23 (dd, J=5.31, 3.60 Hz, 2 H) 4.70 (s, 2 H) 6.72 (dd, J=8.91, 2.20 Hz, 1 H) 6.87 (d, J=2.08 Hz, 1 H) 7.10 (d, J=9.03 Hz, 2 H) 7.23 - 7.37 (m, 3 H) 7.53 - 7.63 (m, 5 H) 7.72 (d, J=8.18 Hz, 2 H) 8.01 (d, J=8.91 Hz, 2 H) 9.58 (br. s., 1 H) 10.47 (s, 1 H) 12.48 (s, 1 H). Example 4 gram-scale preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide napsylate salt (form I) A mixture of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide (1.5 g, 2.71 mmol), dichloromethane (15 mL) and 2-propanol (15 mL) is treated with a solution of 2-naphthalenesulfonic acid monohydrate (613 mg, 2.71 mmol) in 1.5 mL of absolute ethanol. The resulting suspension is stirred at room temperature for 2 hours, then cooled to 0-5°C and stirred for additional 30 minutes. The suspension is then filtered over a sintered glass Buchner funnel and the pad washed 2 times with 4 mL of 2-propanol/dichloromethane 1:1. The solid is collected and dried in oven at 45°C under vacuum (10-30 mmHg) until constant weight, affording 1.91 g of 4- (4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide napsylate form I as a white powder. 1H NMR (401 MHz, DMSO-d₆) δ ppm 2.85 (s, 3 H) 3.86 (dd, J=5.31, 3.60 Hz, 2 H) 4.04 (br. s., 1 H) 4.23 (dd, J=5.31, 3.60 Hz, 2 H) 4.70 (s, 2 H) 6.72 (dd, J=8.91, 2.20 Hz, 1 H) 6.87 (d, J=2.08 Hz, 1 H) 7.10 (d, J=8.91 Hz, 2 H) 7.45 - 7.55 (m, 2 H) 7.59 (dd, J=8.42, 2.81 Hz, 3 H) 7.67 - 7.76 (m, 3 H) 7.85 (d, J=8.54 Hz, 1 H) 7.87 - 7.92 (m, 1 H) 7.92 - 7.99 (m, 1 H) 8.01 (d, J=9.03 Hz, 2 H) 8.14 (d, J=0.49 Hz, 1 H) 9.58 (br. s., 1 H) 10.46 (s, 1 H) 12.48 (s, 1 H). Example 5 gram-scale preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide tosylate salt (form I) [2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide (1.5

, 2-propanol (15 mL) is treated with a solution of p-toluenesulfonic acid monohydrate (515 mg, 2.71 mmol) in 1.5 mL of absolute ethanol. The resulting suspension is stirred at room temperature for 4 hours, then cooled to 0-5°C and stirred for additional 30 minutes. The suspension is then filtered over a sintered glass Buchner funnel and the pad washed three times with 3 mL of 2-propanol/dichloromethane 1:1. The solid is collected and dried in oven at 45°C under vacuum (10-30 mmHg) until constant weight, affording 1.83 g of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide tosylate form I as a white powder. ¹H NMR (401 MHz, DMSO-d6) δ ppm 2.29 (s, 3 H) 2.87 (s, 3 H) 2.93 - 3.24 (m, 4 H) 3.52 (br. s., 2 H) 3.74 - 3.90 (m, 2 H) 4.05 (br. s., 2 H) 4.23 (dd, J=5.31, 3.60 Hz, 2 H) 4.70 (s, 2 H) 6.72 (dd, J=8.91, 2.07 Hz, 1 H) 6.87 (d, J=2.08 Hz, 1 H) 7.04 - 7.18 (m, 4 H) 7.42 - 7.51 (m, 2 H) 7.59 (dd, J=8.48, 2.62 Hz, 3 H) 7.72 (d, J=8.06 Hz, 2 H) 8.01 (d, J=8.91 Hz, 2 H) 9.58 (br. s., 1 H) 10.47 (s, 1 H) 12.48 (s, 1 H). Example 6 gram-scale preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide L-malate salt (form I) A mixture of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide (1.5 g, 2.71 mmol), dichloromethane (15 mL) and 2-propanol (15 mL) is treated with a solution of L-malic acid (363 mg, 2.71 mmol) in 1.5 mL of absolute ethanol. The resulting suspension is stirred at room temperature for 3 hours, then is cooled to 0-5°C and stirred for additional 30 minutes. The suspension is then filtered over a sintered glass Buchner funnel and the pad washed with 2 mL of 2-propanol/dichloromethane 1:1. The solid is collected and dried in oven at 45°C under vacuum (10-30 mmHg) until constant weight, affording 1.52 g of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide L-malate form I as a white powder. ¹H NMR (401 MHz, DMSO-d₆) δ ppm 2.38 (s, 3 H) 2.39 - 2.45 (m, 1 H) 2.58 (dd, J=15.62, 6.35 Hz, 1 H) 2.62 - 2.71 (m, 4 H) 3.86 (dd, J=5.31, 3.72 Hz, 2 H) 4.15 (t, J=6.53 Hz, 1 H) 4.23 (dd, J=5.43, 3.60 Hz, 2 H) 4.70 (s, 2 H) 6.72 (dd, J=8.91, 2.20 Hz, 1 H) 6.87 (d, J=1.95 Hz, 1 H) 7.03 (d, J=9.03 Hz, 2 H) 7.59 (dd, J=8.48, 2.99 Hz, 3 H) 7.72 (d, J=8.06 Hz, 2 H) 7.97 (d, J=9.03 Hz, 2 H) 10.40 (s, 1 H) 12.46 (br. s., 1 H). Example 7 gram-scale preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrogensulfate salt (form I) A mixture of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide (1.5 g, 2.71 mmol), dichloromethane (15 mL) and 2-propanol (15 mL) is treated with a solution of 96% sulfuric acid (277 mg, 2.71 mmol) in 2 mL of absolute ethanol. The resulting suspension is stirred at room temperature for 2 hours, then cooled to 0-5°C and stirred for additional 30 minutes. The suspension is then filtered over a sintered glass Buchner funnel and the pad washed three times with 3 mL of 2-propanol/dichloromethane 1:1. The solid is collected and dried in oven at 45°C under vacuum (10-30 mmHg) until constant weight, affording 1.63 g of 4-(4-methyl-piperazin-1-yl)-N- {6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide sulfate form I as a white powder. ¹H NMR (401 MHz, DMSO-d₆) δ ppm 2.87 (s, 3 H) 3.81 - 3.91 (m, 2 H) 4.05 (br. s., 2 H) 4.23 (dd, J=5.37, 3.66 Hz, 2 H) 4.70 (s, 2 H) 6.72 (dd, J=8.91, 2.20 Hz, 1 H) 6.87 (d, J=2.08 Hz, 1 H) 7.10 (d, J=9.03 Hz, 2 H) 7.59 (dd, J=8.48, 2.62 Hz, 3 H) 7.72 (d, J=8.06 Hz, 2 H) 8.01 (d, J=9.03 Hz, 2 H) 9.59 (br. s., 1 H) 10.47 (s, 1 H) 12.48 (br. s., 1 H). Example 8 gram-scale preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hemioxalate salt (form I) To a stirred suspension of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide (1.5 g, 2.71 mmol) in 2-propanol (30 mL) at reflux, a solution of oxalic acid dihydrate (171 mg, 1.355 mmol) in 2 mL of absolute ethanol is added. The resulting suspension is stirred at reflux for 1 hour and then let to cool to room temperature over 2 hours. The suspension is further cooled to 0-5°C, stirred for 30 minutes and filtered over a sintered glass Buchner funnel. The pad is washed two times with 3 mL of 2-propanol, the solid collected and dried in oven at 45°C under vacuum (10-30 mmHg) until constant weight, affording 1.59 g of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate form I as a white powder. ¹H NMR (401 MHz, DMSO-d₆) δ ppm 2.83 (br. s., 6 H) 3.76 - 3.99 (m, 4 H) 4.23 (dd, J=5.49, 3.66 Hz, 4 H) 4.70 (s, 4 H) 6.72 (dd, J=8.91, 2.08 Hz, 2 H) 6.87 (d, J=1.95 Hz, 2 H) 7.04 (d, J=9.03 Hz, 4 H) 7.59 (dd, J=8.48, 2.99 Hz, 6 H) 7.72 (d, J=8.06 Hz, 4 H) 7.98 (d, J=8.91 Hz, 4 H) 10.42 (s, 2 H) 12.46 (br. s., 2 H). Example 9 scaled up preparation of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hemioxalate salt (form II) A solution of 0.22 Kg of oxalic acid dihydrate in 2 L of absolute ethanol is dropped into a stirred suspension of 1.98 Kg of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide in ethanol (12 L) at reflux. The mixture is stirred at reflux for 1 hour and then cooled to 20±5°C. The suspension is further cooled to 5±5°C, stirred for 1 hour and filtered washing with 2.5 L of ethanol. The wet product is dried under vacuum at 50°C, external temperature, for 20 hours. 2.045 Kg of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)- ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate form II have been obtained as a whitish powder. ¹H NMR (401 MHz, DMSO-d6) δ ppm 2.83 (br. s., 6 H) 3.76 - 3.99 (m, 4 H) 4.23 (dd, J=5.49, 3.66 Hz, 4 H) 4.70 (s, 4 H) 6.72 (dd, J=8.91, 2.08 Hz, 2 H) 6.87 (d, J=1.95 Hz, 2 H) 7.04 (d, J=9.03 Hz, 4 H) 7.59 (dd, J=8.48, 2.99 Hz, 6 H) 7.72 (d, J=8.06 Hz, 4 H) 7.98 (d, J=8.91 Hz, 4 H) 10.42 (s, 2 H) 12.46 (br. s., 2 H). Example 10 conversion of a mixture of crystalline form I and form II of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate salt to crystalline form II 1.0 g of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate salt (mixture of crystalline form I and crystalline form II) is mixed with 6mL (6V) of EtOH absolute grade and stirred. Mixture is heated at 78°C±2°C (reflux conditions) from 4 hrs to 10 hrs, until complete conversion to crystalline form II (complete conversion is monitored by DSC analysis). The reaction mixture is cooled to room temperature (20-25°C) and maintained overnight at room temperature (20±5°C) under stirring, if necessary. The mixture is cooled at 0-5°C and stirred for 1hr, filtered and washed with 1.25 mL (1.25V) of EtOH absolute grade. The solid thus obtained is dried in an oven under vacuum at 50°C for at least 12h. Yield:97.5% Example 11: Analytical results by means of Powder X-ray Diffraction (PXRD) The 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide salts were characterized by powder X-Ray Diffraction (PXRD) performed using a Thermo/ARL XTRA apparatus, irradiating powder samples with a Cu-Kα source (40 kV, 40 mA, 1.6 kW - Kα1 radiation, wavelength λ= 1.54060 Angstrom) between 2° and 40° 2-theta at room temperature. The scan rate was of 1.20°/min (0.020° step with count time of 1 seconds per step). In the X-Ray diffractograms, the angles of diffraction 2-theta are plotted on the horizontal axis (x-axis) and the line intensity on the vertical (y-axis). It is known in the art that an X-ray powder diffraction pattern may be obtained with one or more measurement errors depending on measurement conditions (such as, for example, equipment and/or sample preparation). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may vary depending on measurement conditions and sample preparation. For example, persons skilled in the art of X-ray powder diffraction will realise that the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and non-unitary aspect ratios, which may affect analysis of samples. The skilled person will also realise that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also affect the result. Hence a person skilled in the art will appreciate that the diffraction pattern data presented herein is not to be considered as absolute (for further information see “Fundamentals of Powder Diffraction and Structural Characterization, Pecharsky and Zavalij, Kluwer Academic Publishers, 2003). Therefore, it shall be understood that the crystalline form of the salts and free base of compound of formula (I) described in the present invention is not limited to the crystals that provide X-ray powder diffraction patterns identical to the X-ray powder diffraction patterns shown in the Figures below. Generally, a measurement error of a diffraction angle in an X-ray powder diffractogram is about 2-theta = 0.5 deg or less (or, more suitably, about 2-theta = 0.2 deg or less) and such degree of a measurement error should be taken into account when considering the X-ray powder diffraction pattern in figures 1-10, and when interpreting the peak positions referred to both in the text and in tables 3-12. Therefore, where it is stated, for example, that the salts and free base of a compound of formula (I) have an X-ray powder diffraction pattern with at least one specific peak at about 2-theta = 20.1 deg (or any one of the other mentioned angles) then this can be interpreted as being 2-theta = 20.1 deg plus or minus 0.5 deg, or 2-theta = 20.1 deg plus or minus 0.2 deg. Figure 1 and Table 3 report, respectively, the X-ray diffractogram and the diffraction peaks list of of 4-(4-methyl- piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide free base (form I). Figure 2 and Table 4 report, respectively, the X-ray diffractogram and the diffraction peaks list of 4-(4-methyl-piperazin- 1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hydrochloride salt (form I) as described in Example 1. Figure 3 and Table 5 report, respectively, the X-ray diffractogram and the diffraction peaks list of 4-(4-methyl-piperazin- 1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hydrobromide salt (form I) as described in Example 2. Figure 4 and Table 6 report, respectively, the X-ray diffractogram and the diffraction peaks list of 4-(4-methyl-piperazin- 1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide besylate salt (form I) as described in Example 3. Figure 5 and Table 7 report, respectively, the X-ray diffractogram and the diffraction peaks list of 4-(4-methyl-piperazin- 1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide napsylate salt (form I) as described in Example 4. Figure 6 and Table 8 report, respectively, the X-ray diffractogram and the diffraction peaks list of 4-(4-methyl-piperazin- 1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide tosylate salt (form I) as described in Example 5. Figure 7 and Table 9 report, respectively, the X-ray diffractogram and the diffraction peaks list of 4-(4-methyl-piperazin- 1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide L-malate salt (form I) as described in Example 6. Figure 8 and Table 10 report, respectively, the X-ray diffractogram and the diffraction peaks list of 4-(4-methyl- piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hydrogensulfate salt (form I) as described in Example 7. Figure 9 and Table 11 report, respectively, the X-ray diffractogram and the diffraction peaks list of 4-(4-methyl- piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate salt (form I) as described in Example 8. Figure 10 and Table 12 report, respectively, the X-ray diffractogram and the diffraction peaks list of 4-(4-methyl- piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate salt (form II) as described in Example 9.

Table 3 – 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide free base (form I) Position Intensity Relative Intensity (Deg) (CPS) (%)

Table 4 – 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide hydrochloride salt, form I Position Intensity Relative Intensity (Deg) (CPS) (%)

Table 5 – 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide hydrobromide salt, form I Position Intensity Relative Intensity (Deg) (CPS) (%)

Table 6 – 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide besylate salt, form I Position Intensity Relative Intensity (Deg) (CPS) (%)

Position Intensity Relative Intensity (Deg.) (CPS) (%)

Table 7 – 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide napsylate salt, form I Position Intensity Relative Intensity (Deg) (CPS) (%)

Table 8 – 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide tosylate salt, form I Position Intensity Relative Intensity (Deg) (CPS) (%)

Table 9 – 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide L-malate salt, form I Position Intensity Relative Intensity (Deg) (CPS) (%)

Table 10 – 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide hydrogensulfate salt, form I Position Intensity Relative Intensity (Deg) (CPS) (%)

Table 11 – 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide hemioxalate salt, form I Position Intensity Relative Intensity (Deg) (CPS) (%)

Table 12 – 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide hemioxalate salt, form II Position Intensity Relative Intensity (Deg) (CPS) (%)

Example 12: analytical results by means of Differential Scanning Calorimetry (DSC) DSC analyses were carried out with a Perkin-Elmer DSC-7 or a Perkin-Elmer Pyris 6 DSC, generally using 50 µL vented aluminum DSC pans loaded with about 2-4 mg of sample. An aluminum disc was placed over the powder obtaining a thin layer and improving thermal exchange. The reference was a void pan of the same kind. Indium, Tin and Lead (LGC certified reference materials) were used to assess the calibration of the apparatus with regard to the temperature scale and the enthalpy response. The samples were analyzed under nitrogen flow at a heating rate of 10°C/min. The explored thermal range was generally from 30°C to about 300°C. Both instruments were equipped with cooling unit allowing starting temperatures not higher than 30°C. Figure 11 reports the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]- 1H-indazol-3-yl}-benzamide free base (form I). Figure 12 reports the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrochloride salt (form I) as described in Example 1. Figure 13 reports the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrobromide salt (form I) as described in Example 2. Figure 14 reports the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide besylate salt (form I) as described in Example 3. Figure 15 reports the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide napsylate salt (form I) as described in Example 4. Figure 16 reports the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide tosylate salt (form I) as described in Example 5. Figure 17 reports the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide L-malate salt (form I) as described in Example 6. Figure 18 reports the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hydrogensulfate salt (form I) as described in Example 7. Figure 19 reports the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hemioxalate salt (form I) as described in Example 8. Figure 20 reports the DSC thermogram of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H- indazol-3-yl}-benzamide hemioxalate salt (form II) as described in Example 9. It will be understood that the onset and/or peak temperature values of the DSC may vary slightly from one machine to another, one method to another or from one sample to another, and so the values quoted are not to be considered as absolute. In fact, observed temperatures will depend on the rate of temperature change as well as sample preparation technique and the particular instrument employed. It will be estimated and taken into account that the temperature values obtained applying such different conditions may vary by plus or minus about 4°C. Example 13: Analytical results by means of Dynamic Vapour Sorption (DVS) The water uptake of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}- benzamide salts was investigated by submitting a sample of such substances to a hygroscopicity test by means of a DVS 1000 (SMS). The apparatus is a “controlled atmosphere microbalance” where the weighed sample is exposed to programmed variations of the relative humidity (RH) at a constant and controlled temperature. The measured parameters (weight, time and RH), reported in Excel worksheets, allow obtaining hygroscopicity curves over the tested RH range. Multiple sorption/desorption cycles between 0% and 90% RH are generally performed at controlled temperature of 25°C. Progressive variations of RH are of 10%; they are operated by the software at the equilibration of the sample weight. This condition can be defined at a constant rate of percent weight variation e.g.0.005%/min. The experimental results are reported both as in the DVS Isotherm Reports and Isotherm Plots. Examples of the DVS profiles of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol- 3-yl}-benzamide salts, prepared as described in examples 1-9 are reported in Fig.21A-H and in Fig.22. Example 14: percent compositions of a formulation for oral use Ingredient Range % 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- Example 15: P

p g y Male beagle dogs were administered with 10 mg/kg of the 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide free base or with its salt. The compounds were formulated as suspension in 0.5% Metylcellulose 400 cP solution and administered by oral gavage in 3 males per group. Food was withdrawn overnight prior to dose administration. Cynomolgus Monkeys were administered with 10 mg/kg of the 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl- benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide free base or with its salt. The compounds were formulated as suspension in 0.5% Metylcellulose 400 cP solution and administered by oral gavage in 3 males per group. Food was withdrawn overnight prior to dose administration. For each group, both dogs and monkeys, blood was collected at the following timepoints: predose, 15 and 30 minutes, 1, 3, 6, 24, 48, 72 and 168 hours after dosing. The compound was assayed in plasma by a LC-MS/MS method. The lower limit of quantification of the analytical method was 1 ng/mL, corresponding to 0.00181 µM.Plasma pharmacokinetic analyses were performed using Phoenix WinNonlin (v 6.3, Pharsight Inc, Certara Company, USA). For AUC calculations, BLQ pre-dose concentrations were set equal to zero. Maximal concentration, C_max, and related tmax, time at which the maximal concentration was achieved, were read from the raw data as the coordinates of the highest concentration. Tlast, time of the last detectable concentration, was also read from the raw data. Area under concentration vs. time curve up to the last detectable concentration, AUClast, was determined by the linear trapezoidal rule. The half-life of the apparent terminal phase, t_1/2,z, was determined by linear regression analysis of the natural-log concentration vs. time curve according to the formula: ln(2) t1/2, z ⁼ _λ slope of the regression line. AUC∞

was calculated by adding the portion of the area calculated as C^{last / λ z} _{assuming mono-exponential decay to AUClast.}

Claims

CLAIMS 1. A Salt of 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide of formula (I): N selected from the group

comprising solvates, hydrates and crystalline forms thereof. 2. The salt according to claim 1, which is hemioxalate. 3. Crystalline form of the salts according to claims 1 or 2, characterized by an X-ray powder diffraction pattern comprising peaks at reflection angle 2-theta, measured with Cu-Kα1 radiation of wavelength λ= 1.54060 Angstrom, of: hydrocloride Form I: 6.4, 12.8, 19.2 and 23.4°; besylate Form I: 4.2, 16.2, 17.9, 22.3 and 24.3°; hemioxalate Form I: 5.5, 18.5, 19.0 and 22.3°; hemioxalate Form II: 5.7, 11.5, 18.

2, 20.

3 and 23.0°. 4. The crystalline forms according to claim 3, wherein said X-ray powder diffraction pattern further comprises the significant peaks at a reflection angle 2-theta of: hydrocloride Form I: 19.7, 22.1, and 24.1°; besylate Form I: 8.

4, 10.8, 20.6, 21.8 and 22.7°; hemioxalate Form I: 11.1, 15.6, 16.6 and 20.0°; hemioxalate Form II: 9.6, 14.9, 15.6, 16.6, 17.3, 17.9, 18.6, 19.0, 19.5 and 21.7°.

5. The crystalline forms according to claims 3 or 4 wherein the salt is hemioxalate Form I or hemioxalate Form II.

6. A pharmaceutical composition comprising a salt according to claims 1 or 2 or a crystalline form of the salt according to any one of claims 3 to 5 as active ingredient and at least a pharmaceutically acceptable excipient and/or carrier.

7. A salt according to claims 1 or 2 or a crystalline form of the salt according to any one of claims 3 to 5 for use as a medicament.

8. A salt according to claims 1 or 2 or a crystalline form of the salt according to any one of claims 3 to 5, for use in a method of treating a disease state treatable by c-KIT, FLT3 or CSF-1R inhibition, characterized in that the disease state is selected from cancer, cellular proliferative disorder, and immune cell-associated disease.

9. The salt or the crystalline form of the salt for use according to claim 8, characterized in that the cancer is selected from carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage; tumors of mesenchymal origin, tumors of the central and peripheral nervous systems and other tumors, including mast cell disease, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer, Kaposi's sarcoma and mesothelioma.

10. The salt or the crystalline form of the salt for use according to claim 8 or 9, wherein the cancer is selected from the group consisting of acute myelogenous leukemias (AML) and chronic myelomonocytic leukemia (CMML).

11. A method for treating disease state in a mammal, including a human being, in need of c-KIT, FLT3 or CSF-1R inhibition, comprising administering to said mammal a therapeutically effective amount of a salt according to claims 1 or 2 or a crystalline form of the salt according to any one of claims 3 to 5.

12. The method according to claim 11, characterized in that the disease state is selected from cancer, cellular proliferative disorder, and immune cell-associated disease.

13. The method according to claim 12 wherein the cancer is selected from the group consisting of acute myelogenous leukemias (AML) and chronic myelomonocytic leukemia (CMML).

14. Use of a salt according to claims 1 or 2 or a crystalline form of the salt according to any one of claims 3 to 5 for the manufacture of a medicament for the treatment of a disease state treatable by KIT, FLT3 or CSF-1R inhibition, characterized in that the disease is selected from cancer, cellular proliferative disorder, and immune cell-associated disease.

15. The use according to claim 14 wherein the cancer is selected from the group consisting of acute myelogenous leukemias (AML) and chronic myelomonocytic leukemia (CMML).

16. A pharmaceutical composition comprising a salt according to claims 1 or 2 or a crystalline form of the salt according to any one of claims 3 to 5 for treating a mammal, comprising a human being, suffering from a disease state treatable by FLT3 or c-KIT inhibition, characterized in that the disease is is selected from cancer, cellular proliferative disorder, and immune cell-associated disease.

17. The pharmaceutical composition according to claim 16 wherein the cancer is selected from the group consisting of acute myelogenous leukemias (AML) and chronic myelomonocytic leukemia (CMML).

18. A combination comprising a salt according to claims 1 or 2 or a crystalline form the salt according to any one of claims 3 to 5 and one or more chemotherapeutic agents.

19. A kit comprising a salt according to claims 1 or 2 or a crystalline form of the salt according to any one of claims 3 to 5, and one or more antineoplastic agents as a combined preparation for simultaneous, separate or sequential use in the treatment of cancer.

20. A process for obtaining the salts according to claims 1 or 2 or the crystalline forms of the salts according to any one of claims 3 to 5, which process comprises reacting the starting material 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4- trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide, with from 0.5 to 2 equivalents of hydrochloric acid, benzenesulfonic acid or oxalic acid, respectively, in an organic solvent.

21. The process according to claim 20 for obtaining 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)- ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate salt (half mole of counterion) as crystalline Form I, wherein the organic solvent is 2-propanol and ethanol mixture.

22. The process according to claim 20 for obtaining 4-(4-methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)- ethoxy]-1H-indazol-3-yl}-benzamide hemioxalate salt (half mole of counterion) as crystalline Form II, wherein the organic solvent is absolute ethanol.