HK1259405B - New crystalline form of benzamide compound - Google Patents

Description

New crystal form of benzamide compounds

Technical Field

The present application relates to a new crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, a method for its preparation, its use in treating diseases caused by disordered protein kinase activity and a pharmaceutical composition containing it.

Background Art

Malfunction of protein kinases (PKs) is a hallmark of many diseases. A significant proportion of oncogenes and proto-oncogenes have been implicated in encoding PKs in human cancers. Enhanced PK activity has also been implicated in numerous non-malignant diseases, such as benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and postoperative stenosis and restenosis.

PK is also implicated in inflammatory conditions and the proliferation of viruses and parasites. PK may also play a major role in the pathogenesis and development of neurodegenerative disorders.

For general references to PK dysfunction or disorder, see, for example, Current Opinion in Chemical Biology, 1999, 3, 459-465; Nature Rev. Drug Discov. 2002; and Carcinogenesis, 2008, 29, 1087-1091.

A subgroup of PKs is a group of membrane receptors that have endogenous protein-tyrosine kinase activity (RPTKs). Upon binding to growth factors, RPTKs are activated and phosphorylate themselves and a series of substrates in the cytoplasm. Through this mechanism, they can transduce intracellular signals for proliferation, differentiation or other biological changes. Structural abnormalities, overexpression and activation of RTPKs are frequently observed in human tumors, suggesting that constitutive stimulation of signal transduction leading to cell proliferation can lead to malignant transformation. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that belongs to the insulin receptor subfamily of RPTKs: the ALK gene is located on chromosome 2 and is mainly expressed in neuronal cells, particularly during development. The ALK gene is involved in a chromosomal translocation with the nucleophosmin (NPM) gene on chromosome 5 in a large subgroup of anaplastic large cell lymphoma (ALCL). In ALK+ ALCL, as a result of translocation, the ubiquitous promoter of NPM drives the ectopic expression of a fusion protein in which the NPM moieties dimerize and the ALK kinase domain undergoes autophosphorylation and becomes constitutively active.

Numerous data from the literature have demonstrated that the NPM-ALK fusion protein has potent oncogenic potential and that its ectopic expression is responsible for cellular transformation. Furthermore, constitutive expression of human NPM-ALK in mouse T-cell lymphocytes is sufficient to induce the development of lymphoid tumors in transgenic animals with a short latency period.

ALCL is a well-defined disease characterized by surface expression of the CD30 antigen (Ki-1) and accounts for 2% of adult and 13% of pediatric non-Hodgkin's lymphomas, primarily affecting young male patients. ALK+ ALCL accounts for 70% of all ALCLs and is an aggressive disease with systemic manifestations and frequent extranodal involvement (bone marrow, skin, bone, soft tissue).

Approximately 15-20% of ALCLs expressing ALK were found to carry different chromosomal translocations involving the cytoplasmic portion of ALK with different N-terminal moieties, all leading to constitutive activation of the ALK kinase domain.

Furthermore, cell lines established from solid tumors of ectodermal origin such as melanoma, breast cancer, as well as neuroblastoma, glioblastoma, Ewing sarcoma, and retinoblastoma were found to express the ALK receptor.

ROS1 belongs to the insulin receptor superfamily. Like other tyrosine kinase receptor molecules, it plays a role in transmitting growth signals from the extracellular environment to the cell nucleus. It is one of two members of the orphan receptor tyrosine kinase family that do not have a known binding ligand. Genetic alterations in ROS1, such as gene rearrangements, mutations, or copy number gains, generate oncogenes that can cause cancer (Stumpfova and Janne, 2012). ROS1 is found in NSCLC patients as a fusion protein (with six different partners of ROS1) and is present in approximately 2% of patients with NSCLC (Bergethon et al., 2012; Davies et al., 2012). Two other ROS1 gene rearrangements have been detected in many other cancers, including glioblastoma, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, and epithelioid hemangioendothelioma (Lee et al., 2013; Davies and Doebele, 2013; Davies et al., 2012; Shaw et al., 2013).

Rearrangements in the ROS1 gene generate fusion proteins with constitutively active kinase domains that activate downstream signaling pathways that lead to oncogenic properties in cells, including uncontrolled proliferation, resistance to cell death, and prolonged tumor cell survival. These pathways include the Ras-ERK pathway for cell proliferation, as well as the JAK-STAT and PI3K/AKT pathways, which regulate cell survival (anti-apoptosis) and proliferation. ROS1 fusion proteins can also activate the mTOR pathway, which is important for regulating protein translation. Cancers with activated these pathways are more aggressive, with increased invasion and metastasis, leading to poor patient survival (Davies and Doebele, 2013).

Trk is a high-affinity receptor tyrosine kinase activated by a group of soluble growth factors called neurotrophins (NTs). The Trk receptor family has three members: TrkA, TrkB, and TrkC. Among the neurotrophins, (i) nerve growth factor (NGF) activates TrkA; (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 activate TrkB; and (iii) NT3 activates TrkC. Trk is widely expressed in neural tissue and is involved in the maintenance, signaling, and survival of neuronal cells (Patapoutian, A. et al., Current Opinion in Neurobiology, 2001, 11, 272-280). NTRK1 encodes the TrkA receptor tyrosine kinase. TrkA activates the PI3K/AKT, PKC, and ERK1/2 pathways, which promote cell growth and survival.

Current literature has also shown that overexpression, activation, amplification and/or mutation of Trks are associated with many cancers, including neuroblastoma (Brodeur, G.M., Nat. Rev. Cancer 2003, 3, 203-216), ovarian cancer (Davidson.B. et al., Clin. Cancer Res. 2003, 9, 2248-2259), breast cancer (Kruettgen et al., Brain Pathology 2006, 16:304-310), prostate cancer (Dionne et al., Clin. Cancer Res. 1998, 4(8):1887-1898), pancreatic cancer (Dang et al., Journal of Gastroenterology and Hepatology 2006, 21(5):850-858), multiple myeloma (Hu et al., Cancer Genetics and Cytogenetics 2007, 178:1-10), astrocytomas and medulloblastomas (Kruettgen et al., Brain Pathology 2006, 16:304-310), gliomas (Hansen et al., Journal of Neurochemistry 2007, 103:259-275), melanomas (Truzzi et al., Journal of Investigative Dermatology 2008, 128(8):2031-2040), thyroid cancer (Brzezianska et al., Neuroendocrinology Letters 2007, 28(3), 221-229.), lung adenocarcinoma (Perez-Pinera et al., Molecular and Cellular Biochemistry 2007, 295(1&2), 19-26), large cell neuroendocrine tumors (Marchetti et al., Human Mutation 2008, 29(5), In preclinical models of cancer, Trk inhibitors are effective in inhibiting tumor growth and preventing tumor metastasis. In particular, non-selective small molecule inhibitors of Trk A, B, and C, as well as Trk/Fc chimeras, are effective in inhibiting tumor growth and preventing tumor metastasis. (Nakagawara, A. (2001) Cancer Letters 169: 107-114; Meyer, J. et al., (2007), Leukemia, 1-10; Pierotti, M.A. and Greco A., (2006) Cancer Letters 232: 90-98; Eric Adriaenssens, E. et al., Cancer Res (2008) 68: (2) 346-351; Truzzi et al., Journal of Investigative Dermatology 2008, 128 (8): 2031-2040). Therefore, inhibitors of the Trk kinase family are expected to be useful in the treatment of cancer.

In summary, interfering with ALK or ROS1 signaling may represent a specific and effective way to block tumor cell proliferation in ALCL and possibly other indications. The insulin-like growth factor 1 receptor (IGF-1R, IGF1R) is also a member of the insulin receptor subfamily of RTKs. In addition, interfering with TrkA, TrkB, and/or TrkC signaling, or a combination thereof, represents a specific and effective way to block tumor cell proliferation in various cancers, including, but not limited to, non-small cell lung cancer, papillary thyroid cancer, neuroblastoma, pancreatic cancer, and colorectal cancer.

Summary of the Invention

International patent application WO 2009/013126 (in the name of Nerviano Medical Sciences Srl) describes and claims the free base form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, which has the following formula (I)

It has been assigned Chemical Abstracts Registry Number 1108743-60-7 and has been assigned the International Nonproprietary Name (INN) entrectinib.

Compounds of formula (I) are active as kinase inhibitors, more particularly inhibitors of ALK, ROS1, TrkA, TrkB, and TrkC kinases, and are therefore useful in treating a variety of cancers and cell proliferative disorders, as disclosed in International Patent Application WO 2015/124697 (in the names of Ignyta Inc. and Nerviano Medical Sciences Srl) and as demonstrated in clinical trials in human patients with cancer. Entrectinib has been clinically tested in cancer patients with various types of solid tumors, whose cells contain one or more genetic alterations in at least one target gene identified in the cancer patient, wherein the at least one target gene is selected from ALK, ROS1, SORT1, NTRK1, NTRK2, and NTRK3. As of August 15, 2015, findings from these clinical trials revealed that a total of 92 patients with various solid tumors had been dosed in two clinical trials, of which nine patients had been treated at or above the recommended Phase II dose for more than six months and one patient for more than one year. In the Phase I study, the most common (>10% incidence) treatment-related adverse events were fatigue, dysgeusia, paresthesia, nausea, and myalgia. Seven of these were grade 3 in severity, including fatigue (4 patients), cognitive impairment (2 patients), and diarrhea (1 patient). No grade 4 or 5 treatment-related adverse events were observed. In the Phase I study, there were three treatment-related serious adverse events: grade 3 cognitive impairment and grade 3 myocarditis (both occurring at doses higher than the recommended Phase II dose) and grade 2 fatigue. All events were reversible and resolved upon dose change. Pharmacokinetic measurements showed a dose-proportional increase in the daily dosing regimen evaluated, with a half-life compatible with once-daily dosing. The recommended Phase II dose was determined to be 600 mg, taken orally once daily. A total of 18 patients in the Phase I study met our anticipated Phase 2 eligibility criteria, which included the presence of NTRK1, NTRK2, NTRK3, ROS1, or ALK genetic alterations that were fusions but not other types of molecular alterations; patients not previously treated with an ALK inhibitor or ROS1 inhibitor; and treatment at or above the recommended Phase II dose. In the Phase I clinical trial, the response rate, defined as complete and partial responses by Response Evaluation Criteria in Solid Tumors, or RECIST, among the 18 patients who met the anticipated Phase 2 eligibility criteria was 72% across both studies, based on 13 responders among the 18 treated patients, as assessed by the clinical center. Nine of these responders remain on study treatment, with ongoing responses for up to 21 treatment cycles. An additional three patients remain on study with stable disease. Responses included (a) 3 of 4 patients with NTRK1, NTRK2, or NTRK3 gene rearrangements, including patients with non-small cell lung cancer, or NSCLC, colorectal cancer, and salivary gland cancer, with one of the responding patients remaining on treatment for 6 months; a fourth patient with an astrocytoma remains on study after two months with stable disease; (b) 6 of 8 patients with ROS1 gene rearrangements (all in NSCLC) responded (including one complete response). All responding patients remain on treatment for up to 21 months; and (c) 4 of 6 patients with ALK gene rearrangements, including two patients with NSCLC and two patients with other solid tumors; two of the 4 responders subsequently progressed.

Two preparations of this compound are described in Example 2 (step i') and Example 7, respectively, of the above-cited application WO2009/013126. The process described in Example 2 essentially involves the addition of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine to 4-(4-methyl-piperazin-1-yl)-2-[(tetrahydropyran-4-yl)-(2,2,2-trifluoroacetyl)-amino]-benzoyl chloride, followed by deprotection with an organic base at high temperature to give the desired amide of formula (I) after purification by column chromatography and crystallization.

Another method described in Example 7 of the above-cited patent application is a transformation which essentially consists of reacting 2-amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide with tetrahydropyran-4-one in the presence of trifluoroacetic acid and tetramethylammonium triacetoxyborohydride to give the desired amide of formula (I) after purification by column chromatography.

However, these prepared solid forms are not disclosed in WO 2009/013126. The products obtained by following the experimental procedures described in Example 2 (Step i') and Example 7 of WO 2009/013126 are disclosed in WO 2013/174876 (in the name of Nerviano Medical Sciences Srl). In particular, the procedure disclosed in Example 2 (Step i') was found to produce a crystalline solvate of the compound of formula (I) containing ethyl acetate and n-hexane (hereinafter referred to as "Form 3"). Following the experimental procedure described in Example 7 of WO 2009/013126, an amorphous form of the compound of formula (I) was found to be produced.

Two new solid forms of the compound of formula (I) have been disclosed in application WO2013/174876, along with their preparation methods, which provide products with high purity and properties suitable for administration to humans in an industrially advantageous and highly reproducible manner and at a reduced cost. The new method is characterized by the reaction of an acyl chloride with an indazole-3-ylamine, followed by deprotection under mild alkaline conditions and treatment of the final amorphous compound with a mixture of ethanol and water in the presence of seed crystals to produce the desired compound of formula (I) in a crystalline form designated as "Form 1," or with a mixture of ethanol and water to produce the desired compound of formula (I) in a crystalline form designated as "Form 2." A crystalline solvate form of the compound of formula (I) as a solvate of ethyl acetate and hexane, produced according to the experimental procedures in application WO2009/013126, has been found to be also disclosed in application WO2013/174876 and designated therein as "Form 3."

However, there is still a need to understand the polymorphic behavior of the potential pharmaceutical compounds defined above and to standardize the methods for obtaining their different solid forms in therapy. Indeed, the identification and characterization of polymorphs, together with the definition of the experimental conditions for obtaining them, are very important for pharmacologically active compounds such as the compounds of formula (I) defined above, since polymorphism of compounds that can be used as active ingredients in pharmaceutical compositions can affect many aspects of the final drug, such as pharmacokinetics and bioavailability, its toxicological profile, solubility and other physicochemical properties of the bulk powder.

In this regard, it has now been unexpectedly and surprisingly discovered that the compound of formula (I) described above may also exist in a previously undisclosed crystalline unsolvated form. Unless otherwise indicated, this new crystalline form of compound (I) may be referred to herein as "Form 4" or "Form 4" of the compound of formula (I).

It has been unexpectedly discovered that Form 4 of the compound of Formula (I) exhibits greater thermodynamic stability at temperatures above about 40°C relative to the three known crystalline forms disclosed in WO2013/174876, one of which is a solvate with ethyl acetate and hexane. Form 4 of the compound of Formula (I) may also provide advantages in preparing dosage forms or medicaments useful for treating cancer patients suffering from various types of cancerous solid tumors, the cells of which contain one or more genetic alterations in at least one target gene, wherein the at least one target gene is selected from ALK, ROS1, SORT1, NTRK1, NTRK2, and NTRK3. Form 4 of the compound of Formula (I) may also provide advantages in methods of treating patients suffering from cancer, the methods comprising administering to the patient a therapeutically effective amount of Form 4 of the compound of Formula (I). Preparation of dosage forms or medicaments useful for treating cancer patients having various types of cancerous solid tumors, wherein cells of the solid tumor contain one or more genetic alterations in at least one target gene, wherein the at least one target gene is selected from the group consisting of ALK, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

The novel form 4 has been characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) techniques.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is further illustrated by reference to the accompanying drawings described hereinafter.

Figure 1 shows the X-ray powder diffraction pattern (XRPD) of Form 4; 2Θ angles (degrees) are reported on the x-axis, while intensity (CPS) is reported on the y-axis.

Figure 2 shows a differential scanning calorimetry (DSC) thermogram of Form 4. The thermogram reports temperature (°C) and time (min) on the x-axis, while heat flow (mW) is reported on the y-axis.

DETAILED DESCRIPTION

As used herein, the term "N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide" refers to a compound having the following chemical structure:

It has been assigned the Chemical Abstracts Registry Number 1108743-60-7 and has been assigned the International Nonproprietary Name (INN) entrectinib.

The term "about" is used to include and describe the value or parameter itself. For example, "about x" includes and describes "x" itself. In some embodiments, unless otherwise indicated, the term "about" when used in conjunction with a measurement or to define a value, unit, constant, or range of values, refers to a deviation of ±10%. For example, "about 40°C" in some embodiments includes 36°C to 44°C.

As used herein, the term "addition" does not limit the order, method, or combination of the substances added. For example, "adding A to B" can also describe "adding B to A."

As used herein, the terms "administering" and "administering" refer to delivering a biologically active composition or formulation to a subject via a route of administration, including, but not limited to, oral, intravenous, intraarterial, intramuscular, intraperitoneal, subcutaneous, intramuscular, topical, or a combination thereof. In some embodiments, administration to a subject is oral.

As used herein, the term "ALK" means anaplastic lymphoma kinase receptor or CD246 (cluster of differentiation 246), an enzyme that in humans is encoded by the ALK gene and also has the UniProt designation ALK_HUMAN.

As used herein, the terms "cancer" and "tumor" are used interchangeably. These terms refer to the presence of cells that possess typical characteristics of oncogenic cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rates, and certain characteristic morphological features. Cancer cells typically take the form of tumors, but such cells may exist alone within an animal or may be non-tumorigenic cancer cells, such as leukemic cells. These terms encompass solid tumors, soft tissue tumors, or metastatic lesions. As used herein, the term "cancer" encompasses precancerous and cancerous cancers. In certain embodiments, a cancer is a solid tumor, soft tissue tumor, or metastatic lesion. The term also refers to solid tumors, named after the cell type that forms them, and cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. Examples of blood cancers include, but are not limited to, leukemias, lymphomas, and myelomas. The term includes, but is not limited to, primary cancers that originate in a specific site in the body, metastatic cancers that have spread from the site where they began to other parts of the body, recurrences after relapses from the original primary cancer, and second primary cancers that are new primary cancers of a different type in a person with a history of previous cancers. As used herein, "cancer" refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth.

As used herein, the term "crystalline" means a solid phase in which the substance has a regularly arranged internal structure at the molecular level and produces a specific X-ray diffraction pattern with defined peaks.

As used herein, the term "other therapeutic agent" means, but is not limited to, antihormonal agents such as antiestrogens, antiandrogens and aromatase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-targeting agents, platinum-based agents, alkylating agents, DNA-damaging or intercalating agents, anti-neoplastic agents, antimetabolites, other kinase inhibitors, other antiangiogenic agents, inhibitors of kinesins, therapeutic monoclonal antibodies, inhibitors of mTOR, histone deacetylase inhibitors, farnesyl transferase inhibitors, and inhibitors of the hypoxic response.

As used herein, the terms "patient" and/or "subject" refer to an animal, such as a mammal (including a human), that has been or is to be the subject of treatment, observation, or experiment. In some embodiments, the subject or patient is a human.

The term "pharmaceutically acceptable excipient" means a diluent, disintegrant, precipitation inhibitor, surfactant, glidant, lubricant or other excipients and carriers with which the compound is administered to a subject or patient.

As used herein, "ROS1" means the ROS1 receptor tyrosine-protein kinase, which has the UniProt designation ROS1_HUMAN and is encoded by the ROS1 gene.

As used herein, the term "therapeutically effective amount" means an amount of a compound or pharmaceutical composition that, when administered to a subject, is sufficient to affect therapy to provide a therapeutic benefit, such as improving symptoms or slowing disease progression. For example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease or condition that responds to inhibition of ALK, TrkA, TrkB, TrkC, and ROS1 activity, or a combination thereof.

As used herein, the term "tropomyosin receptor kinase" refers to the tropomyosin receptor kinase (Trk) family of proteins activated by peptide hormones of the neurotrophin family, including, but not limited to, TrkA, TrkB, and TrkC. As used herein, the term "TrkA" refers to wild-type tropomyosin receptor kinase A, which has the UniProt identifier NTRK1_HUMAN and is encoded by the NTRK1 gene. As used herein, the term "TrkB" refers to wild-type tropomyosin receptor kinase B, which has the UniProt identifier NTRK2_HUMAN and is encoded by the NTRK2 gene. As used herein, the term "TrkC" refers to wild-type tropomyosin receptor kinase C, which has the UniProt identifier NTRK3_HUMAN and is encoded by the NTRK3 gene. TrkA, TrkB, and TrkC are also referred to by those of ordinary skill in the art as Trk1, Trk2, and Trk3, respectively. References to TrkA are references to Trk1. References to TrkB are references to Trk2. References to TrkC are references to Trk3.

In one embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 8.6 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 8.6±0.5 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 8.6±0.2 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In one embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6 ± 0.5 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6 ± 0.2 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In one embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 17.9 degrees. In another embodiment, the crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 17.9 ± 0.5 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 17.9 ± 0.2 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 ± 0.5 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 ± 0.2 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6, 17.9, and 39.0 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6, 17.9, and 39.0 ± 0.5 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6, 17.9, and 39.0 ± 0.2 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a range of about 8.6, 10.3, 11.0, 11.9, 14.3, 14.6, 15.1, 15.3, 15.6, 16.1, 17.1, 17.9, 19.0, 19.2, 19.6, 19.7, 20.1, 20.7, 21.3, 22.1, 22.7, 24.3, 24.6, 25.3, 25.5, 25.9, 26.7, 26.9, In another embodiment, the crystalline form is provided wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a range of about 8.6, 10.3, 11.0, 11.9, 14.3, 14.6, 15.1, 15.3, 15.6, 16.1, 17.1, 17.9, 19.0, 19.2, 19.6, 19.7, 20.1, 20.7, 21.3, 22.1, 22.7, 24.3, 24.6, 25.3, 25.5, 25.9, 26.7, 26.9, Peaks at 2θ values of 27.3, 27.7, 28.1, 28.6, 29.0, 29.5, 29.9, 30.5, 31.0, 31.6, 32.2, 33.3, 34.0, 35.4, 36.4, 36.8, and 39.0 ± 0.5 degrees. In another embodiment, a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a range of about 8.6, 10.3, 11.0, 11.9, 14.3, 14.6, 15.1, 15.3, 15.6, 16.1, 17.1, 17.9, 19.0, 19.2, 19.6, 19.7, 20.1, 20.7, 21.3, 22.1, 22.7, 24.3, 24.6, 25.3, 25.5, 25.9, 26.7, 26.9, Peaks at 2θ values of 27.3, 27.7, 28.1, 28.6, 29.0, 29.5, 29.9, 30.5, 31.0, 31.6, 32.2, 33.3, 34.0, 35.4, 36.4, 36.8, and 39.0 degrees ± 0.2 degrees. In another embodiment, a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C and an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C and an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6±0.5 degrees. In another embodiment, a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C and an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6±0.2 degrees. In another embodiment, a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C and an X-ray powder diffraction pattern comprising peaks at 2θ values of about 15.6 and 17.9 degrees. In another embodiment, the crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C and an X-ray powder diffraction pattern comprising peaks at 2θ values of about 15.6 and 17.9 ± 0.5 degrees. In another embodiment, the crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide is provided, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C and an X-ray powder diffraction pattern comprising peaks at 2θ values of about 15.6 and 17.9 ± 0.2 degrees. In another embodiment, the crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6 degrees, and one or more pharmaceutically acceptable excipients.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6±0.5 degrees, and one or more pharmaceutically acceptable excipients.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6±0.2 degrees, and one or more pharmaceutically acceptable excipients.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 degrees.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 ± 0.5 degrees.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 ± 0.2 degrees.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C and an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6 degrees.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C and an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6±0.5 degrees.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C and an X-ray powder diffraction pattern comprising a peak at a 2θ value of about 15.6±0.2 degrees.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200° C. and about 205° C. and an X-ray powder diffraction pattern comprising peaks at 2θ values of about 15.6 and 17.9 degrees. In another embodiment, such a crystalline form is provided, wherein the crystalline form is unsolvated.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C and an X-ray powder diffraction pattern comprising peaks at 2θ values of about 15.6 and 17.9 ± 0.5 degrees.

In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by exhibiting a peak in a differential scanning calorimetry scan between about 200°C and about 205°C and an X-ray powder diffraction pattern comprising peaks at 2θ values of about 15.6 and 17.9 ± 0.2 degrees.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of approximately 15.6 degrees.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of approximately 15.6±0.5 degrees.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of approximately 15.6±0.2 degrees.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 degrees.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 ± 0.5 degrees.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 ± 0.2 degrees.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of approximately 15.6 degrees, and one or more pharmaceutically acceptable excipients.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of approximately 15.6±0.5 degrees, and one or more pharmaceutically acceptable excipients.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2θ value of approximately 15.6±0.2 degrees, and one or more pharmaceutically acceptable excipients.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 degrees.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 ± 0.5 degrees.

In another embodiment, a method of treating a patient suffering from cancer is provided, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2θ values of approximately 15.6 and 17.9 ± 0.2 degrees.

In other embodiments, any of the methods described herein for treating a patient having cancer is provided, wherein the cancer is selected from breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, renal clear cell carcinoma, infiltrating ductal carcinoma (breast cancer), uveal melanoma, multiple myeloma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, pancreatic cancer, medulloblastoma, anaplastic large cell lymphoma (ALCL), neuroblastoma, rhabdomyosarcoma, glioblastoma, inflammatory myofibroblastic tumor, melanoma, retinoblastoma, non-small cell lung cancer (NSCLC), salivary gland cancer, and mammary analog secretory carcinoma (MASC).

In other embodiments, any of the methods described herein for treating a patient having cancer is provided, wherein the cancer is selected from breast cancer, lung cancer, colorectal cancer, prostate cancer, gastric cancer, medulloblastoma, neuroblastoma, glioblastoma, melanoma, non-small cell lung cancer (NSCLC), salivary gland cancer, and mammary-like secretory carcinoma (MASC).

In other embodiments, any of the methods described herein for treating a patient having cancer is provided, wherein the cancer is selected from breast cancer, lung cancer, colorectal cancer, medulloblastoma, neuroblastoma, glioblastoma, melanoma, non-small cell lung cancer (NSCLC), salivary gland cancer, and mammary-like secretory carcinoma (MASC).

In other embodiments, any of the methods described herein for treating a patient having cancer is provided, wherein the cancer is selected from colorectal cancer, neuroblastoma, glioblastoma, melanoma, non-small cell lung cancer (NSCLC), salivary gland cancer, and mammary-like secretory carcinoma (MASC).

In other embodiments, any of the methods described herein for treating a patient having cancer is provided, wherein the cancer is colorectal cancer.

In other embodiments, provided are any of the methods described herein for treating a patient having cancer, wherein the cancer is neuroblastoma.

In other embodiments, any of the methods described herein for treating a patient having cancer is provided, wherein the cancer is glioblastoma.

In other embodiments, any of the methods described herein for treating a patient having cancer is provided, wherein the cancer is melanoma.

In other embodiments, any of the methods described herein for treating a patient having cancer is provided, wherein the cancer is non-small cell lung cancer (NSCLC).

In other embodiments, any of the methods described herein for treating a patient having cancer is provided, wherein the cancer is salivary gland cancer.

In other embodiments, any of the methods described herein for treating a patient having cancer is provided, wherein the cancer is mammary-like secretory carcinoma (MASC).

In other embodiments, any of the methods described herein for treating a patient having cancer, wherein the cancer is locally advanced or metastatic, is provided.

The present invention also discloses a method for preparing the above-defined crystalline form 4, comprising the following steps:

a) an acyl chloride of formula (II):

Addition to the indazol-3-ylamine of formula (III):

The addition is stopped when the indazol-3-ylamine of formula (III) is completely reacted;

b) deprotecting the obtained compound of formula (IV) under mild alkaline conditions:

to obtain a compound of formula (I) as defined above;

c) suspending the obtained compound of formula (I) in ethanol;

d) heating the suspension of step c) to a temperature of about 50°C to about 70°C and cooling to room temperature; and

e) adding water, filtering and drying to produce Form 4 of the compound of formula (I) as defined above;

Preferably, the suspension obtained in step c) is heated to a temperature of about 60°C.

The present invention also discloses a process for preparing Form 4 as defined above by converting Form 2 into Form 4, which is facilitated by adding an amount of Form 4 seeds to Form 2.

Thus, provided herein is a method for preparing Form 4 of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, comprising:

f) heating a slurry of Form 2 of the compound of formula (I) as defined above in ethanol at reflux temperature (about 78°C) and cooling the mixture to a temperature of about 50°C to about 65°C;

g) adding an amount of the crystalline form 4 obtained as defined in steps a) to e) to the mixture of step f), followed by addition of water;

h) heating the mixture of step g) at reflux temperature for a period of time ranging from 30 to 90 minutes, then cooling the mixture to room temperature and stirring for about 12 hours; and

i) The mixture of step h) is filtered and dried at about 40°C to obtain Form 4 of the compound of formula (I) as defined above.

Preferably, there is provided a process as defined above, wherein the solution of step f) is cooled to a temperature of 55°C to 60°C.

In another aspect, there is provided a process as defined above, wherein the mixture of step g) is heated at reflux temperature for about 60 minutes.

Preferably, the amount of Form 4 seeds added to Form 2 is 0.05 to 0.5 weight percent of Form 2. More preferably, the amount of Form 4 seeds added to Form 2 is about 0.2 weight percent of Form 2.

In another aspect, there is provided Form 4 as defined above, prepared by any of the aforementioned methods.

The preparation of the compound of formula (I) in the form of Form 2 is described in the patent application WO 2013/174876 cited above.

The crystalline form 4 as defined above may then be formulated with a pharmaceutically acceptable carrier or diluent to provide a pharmaceutical composition.

According to steps a) and b), the reaction conditions are the same as described in WO 2013/174876, page 4, lines 15-28.

According to step c), the compound of amorphous form (I) obtained in step b) is suspended in ethanol.

According to step d), the suspension thus obtained is heated to a temperature of about 50° C. to about 70° C., preferably to about 60° C., until a solution is obtained, and then cooled to room temperature.

According to step e), water is added to the suspension obtained from step d), and the resulting precipitate is then filtered and dried under vacuum to obtain Form 4 of the compound of formula (I).

According to step f), a slurry of form 2 of the compound of formula (I) obtained as described in the previously cited patent application WO 2013/174876 (page 4, step c2) in ethanol is heated at reflux temperature until a solution is obtained and then cooled to a temperature of about 50°C to about 65°C, preferably from 55°C to 60°C.

According to step g), the suspension from step f) is seeded with Form 4 and then water is added (dropwise over at least 15 minutes) to obtain complete precipitation.

According to step h), the mixture of step g) is heated at reflux temperature for a period of time ranging from 30 to 90 minutes, preferably about 60 minutes, and slowly cooled to room temperature. The mixture is then stirred for at least 12 hours.

According to step i), the product obtained in step h) is filtered and dried under vacuum at about 40°C to produce the compound of formula (I) in the form of crystalline form 4.

It is to be understood that the methods detailed herein can be performed on a production scale or on a non-production scale.

The new procedure allows obtaining Form 4 of the compound of formula (I) in high purity and in a controlled solid form. This form is suitable for developing oral formulations.

The crystalline form 4 as defined above can be administered by any route of administration, for example by oral, parenteral, topical, rectal and nasal routes.

The compositions of the present invention may be in a form suitable for oral administration. Examples of such forms include tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders, or granules. The compositions of the present invention may also be in a form suitable for topical administration. Examples of such forms include creams, ointments, gels, or aqueous or oily solutions or suspensions. The compositions of the present invention may also be in a form suitable for administration by inhalation, such as a finely divided powder or liquid aerosol. The compositions of the present invention may also be in a form suitable for administration by insufflation, such as a finely divided powder. The compositions of the present invention may also be in a form suitable for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, or intramuscular administration) or as suppositories for rectal administration.

The compositions of the present invention can 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 coloring, sweetening, flavoring and preservatives.

For example, solid oral forms may contain, along with the active compound, an acidifier, a diluent such as lactose, dextrose, sucrose, sucrose, mannitol, cellulose, corn starch, or potato starch; a lubricant such as silicon dioxide, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycol; a glidant such as colloidal silicon dioxide; a binder such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; a disintegrant such as starch, alginic acid, alginates, or sodium carboxymethyl starch; an effervescent mixture; a dye; a sweetener; a wetting agent such as phospholipids, polysorbates, or lauryl sulfate; and nontoxic and pharmaceutically inactive substances commonly used in pharmaceutical formulations. These pharmaceutical formulations can be manufactured in a known manner, for example, by mixing, granulating, tableting, sugar coating, or film coating.

Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions. As an example, syrups can contain sucrose or sucrose with glycerol and/or mannitol and sorbitol as a carrier.

Suspensions and emulsions may contain, as examples of carriers, natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

Suspensions or solutions for intramuscular injection may contain the active compound together with a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.

Solutions for intravenous injection or infusion may contain sterile water as a vehicle, or preferably they may be sterile, aqueous, isotonic, saline solutions or they may contain propylene glycol as a vehicle.

Suppositories may contain the active compound together with a pharmaceutically acceptable carrier such as cocoa butter, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

In another embodiment there is provided crystalline Form 4 as defined above for use as a medicament.

In another embodiment there is provided Form 4 as defined above, alone or in combination with other therapeutic agents or radiotherapy, for use in treating a disease state treatable by inhibition of ALK, ROS1, TrkA, TrkB, TrkC or a combination thereof.

In another embodiment, any method of treating a patient having cancer is provided, wherein the cancer contains at least one genetic alteration in at least one target gene selected from ALK, ROS1, NTRK1, NTRK2, and NTRK3.

Another object of the present invention is to provide a method for treating cancer in a mammal, including a human, in need of ALK inhibition and/or in a patient having at least one genetic alteration in at least one target gene selected from ALK, ROS1, NTRK1, NTRK2 and NTRK3, such a method comprising administering to the mammal a therapeutically effective amount of form 4 as defined above.

Another object of the present invention is to provide the use of form 4 as defined above, alone or in combination with other therapeutic agents or radiotherapy, for the manufacture of a medicament for the treatment of a disease state treatable by ALK inhibition or for use in a patient having at least one genetic alteration in at least one target gene selected from ROS1, NTRK1, NTRK2 and NTRK3, selected from cancer and cell proliferative disorders.

As used in this specification, the following words and phrases are generally intended to have the meanings set out below, unless the context dictates otherwise.

In the sections defining the X-ray powder diffraction peaks of Form 4 of the compound of Formula (I), the term "about" as used, for example, in the expressions "at 2θ values of about ..." and "at 2θ values of about ..." indicates that the precise position of the peak (i.e., the recited 2θ angle value) should not be taken as an absolute value because, as will be appreciated by those skilled in the art, the precise position of the peak may vary slightly from one machine to another, from one sample to another, or because the measurement conditions used are slightly changed. Typically, the measurement error of the diffraction angle in an X-ray powder diffraction pattern is about 2θ = 0.5 degrees or less (or more suitably about 2θ = 0.2 degrees or less) and this degree of measurement error should be taken into account when considering the X-ray powder diffraction pattern. Thus, for example, when an X-ray powder diffraction pattern of Form 4 of a compound of Formula (I) is described as having at least one specific peak at about 2θ = 17.9 degrees (or any of the angles otherwise mentioned), this can be interpreted as 2θ = 17.9 ± 0.5 degrees or 2θ = 17.9 ± 0.2 degrees. It will be appreciated that ± 0.5 degrees can also be expressed as "plus or minus 0.5 degrees 2θ".

When the term "substantially the same as shown in..." is used in reference to an X-ray powder diffraction pattern, it is intended that the 2θ values of the pattern may vary slightly from one machine to another, from one sample to another, or due to slight changes in measurement conditions, and therefore, the peak positions shown in the figures or quoted in the tables are again not absolute values. In this regard, it is known in the art that X-ray powder diffraction patterns can be obtained with one or more measurement errors that depend on the measurement conditions (e.g., the equipment and/or sample preparation). In particular, it is generally known that the intensities in an X-ray powder diffraction pattern can vary depending on the measurement conditions and sample preparation. For example, those skilled in the art of X-ray powder derivatization will recognize that the relative intensities of peaks can be affected by, for example, particles with a size greater than 30 microns and non-uniform aspect ratios, which can affect the analysis of the sample. Such persons will also recognize that the position of reflections can be affected by the precise height at which the sample is positioned in the diffractometer and the zero point calibration of the diffractometer. The surface flatness of the sample can also affect the results.

Those skilled in the art will therefore appreciate that the diffraction pattern data presented herein should not be considered as absolute values (for further information see "Fundamentals of Powder Diffraction and Structural Characterization", Pecharsky and Zavalij, Kluwer Academic Publishers, 2003).

The term "treatable disease state" means that treatment according to the present invention provides relief from the disease state or at least an improvement in the quality of life and condition of the treated mammal.

Examples of such disease states include, among others, various cancers that may include specific types of cancer, including carcinoma, squamous cell carcinoma, hematopoietic tumors of the myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous systems, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthomas, follicular thyroid carcinoma, and Kaposi's sarcoma.

Examples of such disease states are specific types of cancer, such as, but not limited to, breast cancer, lung cancer such as non-small cell lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, pancreatic cancer, papillary thyroid cancer, clear cell renal carcinoma, uveal melanoma, multiple myeloma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, and medulloblastoma.

Other examples of such disease states are ALK+ anaplastic large cell lymphoma (ALCL) and possible other indications in which ALK activity may play a role, such as neuroblastoma, rhabdomyosarcoma, glioblastoma, inflammatory myofibroblastic tumor, as well as some types of melanoma, breast cancer, Ewing's sarcoma, retinoblastoma, and non-small cell lung cancer (NSCLC).

Still other examples of such disease states are cell proliferative disorders such as, but not limited to, benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and post-operative stenosis and restenosis.

In some embodiments, the crystalline forms disclosed herein are formulated for oral administration using pharmaceutically acceptable carriers well known in the art.

In some embodiments, the therapeutically effective dose of Form 4 or a pharmaceutically acceptable salt of a compound of Formula (I) as defined above can vary depending on the severity of the disease, disorder, and condition of the patient to be treated. Therefore, the physician, as always, must determine the optimal dose for each patient. Regardless, an effective dose range can be from about 10 mg to about 1 g per dose (calculated as the free base), 1 to 3 times daily.

In some embodiments, the therapeutically effective dose of Form 4 of the compound of Formula (I) is from about 100 mg to about 2000 mg, or from about 100 mg to about 1750 mg, or from about 100 mg to about 1500 mg, or from about 100 mg to about 1250 mg, or from about 150 mg to 1250 mg, or from about 175 mg to about 1250 mg, or from about 200 mg to about 1250 mg, or from 250 mg to about 1250 mg, or from about 300 mg to about 1250 mg, or from about 350 mg to about 1250 mg, or from about 400 mg to about 1250 mg, or from about 400 mg to about 1000 mg, or from about 450 mg to about 950 mg, or from about 450 mg to about 900 mg, or from about 450 mg to about 850 mg, or from about 500 mg to about 850 mg, or from about or about 500 mg to about 800 mg, or about 525 mg to about 800 mg, or about 525 mg to about 775 mg, or about 550 mg to about 800 mg, or about 575 mg to about 800 mg, or about 575 mg to about 775 mg, or about 600 mg to 800 mg, or about 600 mg to 775 mg, or about 600 mg to 750 mg, or about 600 mg to about 725 mg, or about 500 mg to about 725 mg or about about 500 mg to about 700 mg.

In some embodiments, the therapeutically effective dose of Form 4 of the compound of Formula (I) is about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg. In some embodiments, the therapeutically effective dose of Form 4 of the compound of Formula (I) is about 600 mg, taken orally once daily.

Experimental part

The following examples are included to illustrate embodiments of the present disclosure and are not intended to limit the scope of the disclosure.

The crystalline forms described herein can be characterized by various methods known in the art, such as X-ray powder diffraction patterns (XRPD) and differential scanning calorimetry (DSC), including, for example, the methods described in Examples 3 and 4.

In one embodiment of the present invention, Form 4 is characterized by an X-ray diffraction pattern substantially the same as that shown in Figure 1, wherein the significant peak intensities are at approximately the 2θ values (degrees) described in Table 1. In a sample that does not contain any additional substances (other crystalline forms, excipients), the diffraction peaks at approximately the 2θ values (degrees) described in Table 2 should be observed.

Table 1 - Figure/table references and description of solid state properties of Form 4 of the compound of formula (I).

In the following examples, temperatures are measured in degrees Celsius (°C) and unless otherwise indicated, reactions or experiments were carried out at room temperature (RT).

Example 1: Preparation of Form 4 of the compound of formula (I).

Steps a) and b) are described in application WO 2013/174876, page 4, lines 15-28.

Step c)

2.88 kg of dried amorphous N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide (compound of formula (I)) obtained by the procedure described in WO2013/174876 (steps a and b on pages 3-4) were suspended in approximately 10 volumes of ethanol (suspension A).

Step d)

20 mL of the suspension A obtained in step c) was heated to about 60° C. to obtain a solution, which was then cooled to room temperature.

Step e)

20 mL of water was added to the suspension obtained from step d) and the precipitate was filtered. The product was dried under vacuum to obtain N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide in the form of Form 4 (DSC analysis is reported in Figure 2).

Example 2: Preparation of Form 4 by seeding.

Step f)

110 mL of ethanol was added to 11.3 g of Form 2 of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, obtained as described in WO2013/174876 (step c2, pages 4 and 11-12), and the mixture was heated under reflux until a solution was obtained. The mixture was then cooled to about 58°C.

Step g)

20 mg of seeds of Form 4 prepared as described in Example 1 were added to the mixture of step f); 220 mL of water were then added dropwise to the mixture within about 15 min, obtaining a complete precipitation.

Step h)

The mixture thus obtained was heated to reflux again for about 60 min and slowly cooled to room temperature; it was then stirred at room temperature for 12 hours.

Step i)

The precipitate was filtered and dried under vacuum at about 40°C to yield 9.5 g of Form 4 of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide.

Example 3: Analytical results by X-ray powder diffraction (XRPD)

Form 4 of Compound (I) was characterized by X-ray powder diffraction (XRPD) using a Thermo/ARL XTRA instrument, irradiating the powder sample at room temperature with a CuKα source (45 kV, 40 mA, 1.8 kW-Kα1 radiation, wavelength λ = 1.54060 angstroms) from 2° to 40° 2θ.

The scanning rate was 1.20°/min (0.020° step, 1 second counting time per step).

In an X-ray diffraction pattern, the angle 2θ of diffraction is plotted on the horizontal axis (x-axis) and the line intensity on the vertical axis (y-axis).

As reported in the preceding paragraphs, Form 4 of the compound of Formula (I) provides an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 1 , and having substantially the most prominent peaks at the 2θ angle values set forth in Tables 1 and 2.

It should be understood that the crystalline Form 4 of the compound of Formula (I) described herein is not limited to crystals that provide an X-ray powder diffraction pattern identical to the X-ray powder diffraction pattern shown in FIG1 , and that any sample or batch of crystalline Form 4 of the compound of Formula (I) that provides an X-ray powder diffraction pattern substantially identical to that shown in FIG1 below falls within the scope of the present invention. Those skilled in the art of X-ray powder diffraction will be able to assess that the X-ray powder diffraction patterns are substantially identical.

The X-ray diffraction peak positions of Form 4 are reported in Table 2 below.

Table 2 - Crystalline Form 4 of the Compound of Formula (I)

Example 4: Analysis results by means of differential scanning calorimetry (DSC)

DSC analysis was performed using a Mettler Toledo Star system. An aluminum DSC pan was loaded with 2-4 mg of sample. The analysis temperature range was 25°C to a maximum of 300°C. Samples were analyzed under a nitrogen atmosphere at a heating rate of 10°C/min.

FIG2 reports the DSC thermogram of Form 4.

The observed melting endotherm of Form 4 lies in the range of approximately 200°C-205°C (peak temperature), with a ΔH in the range of 70–82 J/g. It will be appreciated that DSC onset and/or peak temperature values can vary slightly from one instrument to another, one method to another, or one sample to another, and therefore the quoted values should not be considered absolute. In fact, the observed temperature will depend on the rate of temperature change, as well as the sample preparation technique and the specific instrument used. It is estimated and taken into account that the temperature values obtained using such different conditions may vary by plus or minus approximately 4°C.

Claims (15)

1. The crystal form of the compound of formula (I) 4, The crystal form is characterized in that its X-ray powder diffraction pattern contains peaks with the following reflection angles 2θ: 8.6±0.2°, 15.6±0.2°, 17.9±0.2°, 19.0±0.2°, 19.2±0.2°, 19.6±0.2°, 19.7±0.2°, 20.7±0.2°, 21.3±0.2°, 22.1±0.2°, 22.7±0.2°, 24.3±0.2°, and 24.6±0.2°. 2. The crystal form 4 according to claim 1, wherein the crystal form is characterized in that its X-ray powder diffraction pattern comprises peaks with the following reflection angles 2θ: 8.6±0.2°, 10.3±0.2°, 11.0±0.2°, 11.9±0.2°, 14.3±0.2°, 14.6±0.2°, 15.1±0.2°, 15.3±0.2°, 15.6±0.2°, 16.1±0.2°, 17.1±0.2°, 17.9±0.2°, 19.0±0.2°, 19.2±0.2°, 19.6±0.2°, 19.7±0.2°, 20.1±0.2°, 20.7±0.2°, 21.3±0.2°, 22.1±0.2°, 22.7±0.2°, 24.3±0.2°, 24.6±0.2°, 25.3±0.2°, 25.5±0.2°, 25.9±0.2°, 26.7±0.2°, 26.9±0.2°, 27.3±0.2°, 27.7±0.2°, 28.1±0.2°, 28.6±0.2°, 29.0± 0.2°, 29.5±0.2°, 29.9±0.2°, 30.5±0.2°, 31.0±0.2°, 31.6±0.2°, 32.2±0.2°, 33.3±0.2°, 34.0±0.2°, 35.4±0.2°, 36.4±0.2°, 36.8±0.2° and 39.0±0.2°. 3. The crystal form 4 according to claim 1, wherein the crystal form is characterized by the X-ray powder diffraction pattern shown in Figure 1. 4. The crystal form 4 according to any one of claims 1-3, wherein the crystal form is further characterized by exhibiting a peak at about 200°C to about 205°C in differential scanning calorimetry. 5. A pharmaceutical composition comprising crystal form 4 of a compound of formula (I) as defined in any one of claims 1-4 as an active ingredient and a pharmaceutically acceptable excipient. 6. The pharmaceutical composition according to claim 5, wherein the composition is in the form of tablets, capsules, suspensions, emulsions, dispersible powders, or granules. 7. The pharmaceutical composition according to claim 5 or 6, wherein the composition comprises, per dose, 10 mg to 1 g of the crystal form 4 of the compound as defined in claim 1. 8. The pharmaceutical composition according to claim 5 or 6, wherein the pharmaceutically acceptable excipient comprises a pharmaceutically acceptable carrier or diluent. 9. Crystal form 4 as defined in any one of claims 1-4, used as a pharmaceutical. 10. Use of crystal form 4 as defined in any one of claims 1-4 in the manufacture of a medicament for treating a treatable disease state by inhibiting ALK, alone or in combination with other therapeutic agents or radiotherapy, wherein the disease is selected from cancer and proliferative disorders. 11. Use of crystal form 4 as defined in any one of claims 1-4 in the manufacture of a medicament for treating cancer in a patient, alone or in combination with other therapeutic agents or radiotherapy, said patient having at least one genetic alteration in at least one target gene selected from ROS1, NTRK1, NTRK2 and NTRK3. 12. The use according to claim 10 or 11, wherein the cancer is selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer. 13. A method for preparing crystal form 4 of the compound of formula (I) according to any one of claims 1-4, The method includes the following steps: a) The acyl chloride of formula (II): Addition of indazole-3-ylamine to formula (III): The addition was stopped when the indazole-3-ylamine of formula (III) had completely reacted; b) Deprotecting the compound of formula (IV) under mild alkaline conditions: To obtain the compound of formula (I); c) The obtained compound of formula (I) is suspended in ethanol; d) Heat the suspension from step c) to a temperature of approximately 50°C to approximately 70°C and then cool it to room temperature; and e) Add water, filter and dry to produce crystal form 4 of the compound of formula (I) as defined in claim 1; Or alternatively: f) The slurry of crystal form 2 of the compound of formula (I) in ethanol is heated at reflux temperature to obtain a solution and the solution is cooled to a temperature of about 50°C to about 65°C. g) Add a certain amount of seed crystals obtained as defined in steps a) to e) to the solution in step f), and then add water; h) Heat the mixture from step g) at reflux temperature for a period of 30 to 90 minutes, then cool the mixture to room temperature and stir for about 12 hours; i) Filter the mixture from step h) and dry it at about 40°C to obtain the crystal form of the compound of formula (I) as defined in claim 1. 14. The method of claim 13, wherein the solution of step f) is cooled at a temperature of 55°C to 60°C. 15. The method according to claim 13 or 14, wherein the mixture of step g) is heated at reflux temperature for 60 minutes.