New crystalline forms of MCL-1 inhibitors, processes for their preparation and pharmaceutical compositions containing them

Abstract

Powder X-ray diffraction diagram, solid 13 A crystalline form of Compound A:(I) characterized by C NMR spectrum, MIR spectrum and Raman spectrum, and a pharmaceutical composition containing the same.

Description

[Technical field]

[0001] The present invention relates to a new crystalline form of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid, herein referred to as Compound A. Crystalline forms of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid are described herein and are also referred to as Forms A and M. Additionally, two other crystalline forms of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid are also described herein, crystalline form M H and M HD It is called.

[0002] The present invention further discloses a process for preparing said crystalline form of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.

[0003] The present invention further discloses pharmaceutical compositions comprising said crystalline forms of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid and uses of said compositions for the treatment of cancer, immune system disorders and autoimmune disorders. [Background technology]

[0004] The formula:

[0005] [ka] 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid, represented by the formula (I), is an Mcl-1 inhibitor useful for the treatment of cancer, immune system diseases and autoimmune diseases, the preparation, use and pharmaceutical formulation of which have been previously reported in WO 2015 / 097123, the contents of which are incorporated by reference. Its preparation is specifically disclosed in Example 30 of WO 2015 / 097123.

[0006] In certain embodiments, compound A has the formula:

[0007] [ka] (2R)-2-{[(5S a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid. In a further embodiment, Compound A used in the compositions described herein is the free molecule (not a salt thereof).

[0008] Compound A is a very promising drug, but a difficult compound to formulate. It has a solubility in water below 0.001 mg / mL (at pH 7.5). This polymorphism of a drug molecule can affect shelf life, solubility, formulation properties, processing properties, and drug action, since a chemical may exhibit different physical properties in either crystalline form. Furthermore, different polymorphs may have different rates of uptake into the body, leading to lower or higher biological activity than desired. In extreme cases, undesired polymorphs may even be toxic. Understanding and controlling polymorphism therefore offers clear advantages in bringing to market new drugs that may be more active, more stable, or cheaper to produce. However, although polymorphism has been the subject of intensive research, understanding and controlling this phenomenon represents a considerable scientific challenge. It is difficult to predict whether a given molecule will crystallize in one or several crystalline forms, and to find the conditions that lead to such crystallization.

[0009] From an industrial point of view, it is essential to be able to synthesize, particularly in a completely reproducible manner, compounds of excellent purity that possess the beneficial properties of solubility, filtration, drying, ease of formulation and stability, and that can be stored for long periods without special requirements for temperature, light, humidity or oxygen levels.

[0010] The present invention relates to new crystalline forms of compound A having the above mentioned advantages and also describes a process for obtaining compound A in a well-defined and completely reproducible crystalline form (in particular either crystalline form A or crystalline form M) having very good stability that meets the industrial constraints of preparation, in particular filtration, and storage of pharmaceutical compositions. [Brief description of the drawings]

[0011] [Figure 1] 1 shows the powder X-ray diffraction pattern (XRPD) of compound A, crystalline form M. [Diagram 2] 1 shows a close-up of the XRPD of compound A, crystalline form M. [Diagram 3] 1 shows the moisture sorption profile (DVS) of Compound A, crystalline form M. [Figure 4] 1 shows the solid-state 13C NMR spectrum of compound A, crystalline form M. [Diagram 5] 1 shows the mid-infrared spectrum (MIR) of compound A, crystalline form M. [Figure 6] 1 shows an enlarged view of the MIR spectrum of compound A, crystalline form M. [Figure 7] 1 shows the Raman spectrum of compound A, crystalline form M. [Figure 8] 1 shows an enlarged view of the Raman spectrum of compound A, crystalline form M. [Figure 9] 1 shows an ORTEP diagram of compound A, crystal form M. [Figure 10] 1 shows the XRPD of compound A, crystalline form A. [Figure 11] 1 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of Compound A, crystalline form M. [Figure 12] 1 shows the XRPD of compound A, crystalline form MH. [Figure 13] 1 shows the XRPD of compound A, crystalline form MHD.

[0012] Detailed Description of the Invention "Compound A" refers to 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid, more specifically (2R)-2-{[(5S a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.

[0013] As used herein, the term "comprise" means "include" and does not exclude the presence of any additional components unless the context indicates otherwise, for example where the components total 100%.

[0014] "Cancer" refers to a category of diseases in which a group of cells grow uncontrollably. Types of cancer include blood cancers (lymphomas and leukemias) and solid tumors, including carcinomas, sarcomas, or blastomas. "Cancer" includes bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma (e.g., non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanoma, hematological malignancies (e.g., myelodysplastic syndrome), myeloma (e.g., multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell lung cancer.

[0015] "Free molecule" and "free base" are used interchangeably herein and refer to Compound A that is not in salt form.

[0016] "Substantially pure," when used in reference to a crystalline form of Compound A, means having a purity of greater than 90% by weight of Compound A, preferably greater than 95% by weight, more preferably greater than 97% by weight, and even more preferably greater than 99% by weight, based on the weight of the compound, and also encompasses the equivalent of about 100% by weight.

[0017] "ICH" means the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use.

[0018] EMBODIMENTS OF THE PRESENT DISCLOSURE Several embodiments of the present invention are described below. E1. Crystal form M of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid (Compound A). E2. Crystalline form M of compound A described in E1, in substantially pure form. E3. Crystalline form M of compound A according to E1 or E2, characterized in that it has an X-ray powder diffraction pattern exhibiting at least the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 8.94 and 18.24. E4. Crystalline form M of compound A according to E1 or E2, characterized in that it has an X-ray powder diffraction pattern exhibiting at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 6.27; 8.94; 9.09; 12.16; 13.67; 14.75; 15.06; 16.97; 17.22; 17.44; 18.24; 19.16; 19.93; 20.91; 25.88. E5. Crystalline form M of compound A according to E4, characterized in that it has an X-ray powder diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 8.94; 13.67; 14.75; 17.22; 18.24. E6. Crystalline form M of compound A according to E4, characterized in that it has an X-ray powder diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 6.27; 8.94; 9.09; 12.16; 13.67; 14.75; 15.06; 16.97; 17.22; 17.44; 18.24; 19.16; 19.93; 20.91; 25.88. E7. Crystalline form M of compound A according to E6, characterized in that it has the following powder X-ray diffraction pattern, expressed by line positions (expressed in degrees ±0.2°, Bragg angle 2θ) and interplanar spacings d (expressed in Å), measured in spinner transmission mode using a PANalytical Empyrean diffractometer equipped with a PIXCel 1D detector:

[0019] [Table 1] E8. A solid having the following peaks (expressed in ppm ± 0.2 ppm): 175.1, 153.7, 134.8, 108.9, 71.4, and 35.1. 13 A crystalline form M of compound A according to any one of E1 to E7, characterized by having a C CP / MAS NMR spectrum. E9. A solid having the following peaks (expressed in ppm ± 0.2 ppm): 175.1, 168.5, 167.4, 164.6, 162.6, 157.5, 156.3, 153.7, 135.5, 134.8, 130.4, 129.9, 128.4, 126.8, 120.9, 119.9, 118.5, 116.9, 112.5, 111.1, 108.9, 78.7, 71.4, 54.9, 42.1, 35.1, and 18.2. 13 A crystalline form M of compound A according to any one of E1 to E7, characterized by having a C CP / MAS NMR spectrum. E10. Peaks below (cm -1 The crystalline form M of compound A according to any one of E1 to E7, characterized by having a Raman spectrum with the following peaks: 1516.0, 1220.0, 770.0, 752.0, 380.0, represented by the formula: E11. The following peaks (cm-1 The crystalline form M of compound A according to any one of E1 to E7, characterized in that it has a Raman spectrum with the following peaks: 1602.0, 1544.0, 1518.0, 1478.0, 1376.0, 1286.0, 1220.0, 1164.0, 1130.0, 1048.0, 1034.0, 988.0, 812.0, 770.0, 752.0, 634.0, 566.0, 508.0, 414.0, 380.0, 254.0. E12. A pharmaceutical composition comprising as an active ingredient crystalline form M of compound A according to any one of E1-E11 together with one or more pharma- ceutically acceptable carriers, glidants, diluents, excipients or stabilizers. E13. The pharmaceutical composition of E12 for use in treating cancer, autoimmune diseases and immune system diseases. E14. The pharmaceutical composition for use according to E13, wherein the cancer is selected from bladder cancer, brain tumor, breast cancer, uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma (e.g., non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanoma, malignant hematological disease (e.g., myelodysplastic syndrome), myeloma (e.g., multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. E15. A crystalline form M of compound A according to any one of E1 to E11 for use as a medicament. E16. A crystalline form M of compound A according to any one of E1-E11 for use in the treatment of cancer, autoimmune diseases and immune system diseases. E17. The crystalline form M of compound A for use according to E16, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma (e.g., non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanoma, hematological malignancies (e.g., myelodysplastic syndrome), myeloma (e.g., multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. E18. The process for preparing crystalline form M of compound A according to any one of E1-E11, wherein compound A is crystallized in a solvent selected from toluene, 2-methyltetrahydrofuran (Me-THF) or a mixture of toluene and methyl tert-butyl ether (MTBE), more preferably toluene or a mixture of toluene and MTBE. E19. The process for preparing the crystalline form M of compound A according to E18, wherein the solvent is a mixture of toluene and MTBE, preferably a 75 / 25 m / m toluene / MTBE mixture. E20. The process for preparing crystalline form M of compound A according to E18, wherein the concentration of compound A in the solvent is 5-15% m / m, preferably 7-13% m / m, more preferably 10-12.5% ​​m / m. E21. The process for preparing crystalline form M of compound A according to any one of E18 to E20, wherein the suspension of compound A in the solvent obtained during the process is filtered and dried under vacuum at a temperature between 20°C and 80°C, preferably between 20°C and 75°C, more preferably between 35°C and 75°C. E22. A process for preparing crystalline form M of compound A according to E19, comprising: filtering a suspension of compound A in a solvent obtained during the process and subjecting the suspension to the following steps: A first step in which the filtered solid is dried under vacuum at 20° C. until the ICH residual solvent limit of MTBE is reached; and - A second step in which the solid obtained in the first step is vacuum dried at 70 °C until the ICH residual solvent limit of toluene is reached. The drying process involves two steps: E23. The process for preparing the crystalline form M of compound A according to any one of E18 to E22, wherein the crystallization is carried out by seeding with a very small amount of crystalline form M of compound A, in particular the crystallization is carried out by seeding with 0.5% to 5% m / m, preferably 0.5% to 3% of crystalline form M of compound A. E24. The process for preparing the crystalline form M of compound A according to E23, wherein the crystallization is carried out at a temperature between 20° C. and 60° C. with seeding. E25. The process for preparing crystalline form M of compound A according to E24, wherein the crystallization is carried out at a seeding temperature between 30° C. and 45° C. E26. Crystal form A of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid (Compound A). E27. Crystalline form A of compound A according to E26, in substantially pure form. E28. Crystalline form A of compound A according to E26 or E27, characterized in that it has an X-ray powder diffraction pattern exhibiting at least the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 7.52 and 16.61. E29. Crystalline form A of compound A according to E26 or E27, characterized in that it has an X-ray powder diffraction pattern exhibiting at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 7.52; 8.89; 9.58; 10.35; 11.25; 13.08; 14.44; 16.61; 17.07; 17.71; 19.10; 20.60; 20.80; 21.69; 22.14; 23.63; 27.36. E30. Crystalline form A of compound A according to E29, characterized in that it has an X-ray powder diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 7.52; 8.89; 10.35; 16.61; 19.10. E31. Crystalline form A of compound A according to E29, characterized in that it has a powder X-ray diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 7.52; 8.89; 9.58; 10.35; 11.25; 13.08; 14.44; 16.61; 17.07; 17.71; 19.10; 20.60; 20.80; 21.69; 22.14; 23.63; 27.36. E32. Crystalline form A of compound A according to E31, characterized in that it has the following powder X-ray diffraction pattern, expressed by line positions (expressed in degrees ±0.2°, Bragg angle 2θ) and interplanar spacings d (expressed in Å), measured in spinner transmission mode using a PANalytical Empyrean diffractometer equipped with a PIXCel 1D detector:

[0020] [Table 2] E33. A pharmaceutical composition comprising as an active ingredient crystalline form A of compound A according to any one of E26 to E32, together with one or more pharma- ceutically acceptable carriers, glidants, diluents, excipients or stabilizers. E34. The pharmaceutical composition of E33 for use in the treatment of cancer, autoimmune diseases and immune system diseases. E35. The pharmaceutical composition for use according to E34, wherein the cancer is selected from bladder cancer, brain tumor, breast cancer, uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma (e.g., non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanoma, malignant hematological disease (e.g., myelodysplastic syndrome), myeloma (e.g., multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. E36. The process for preparing crystalline form A of compound A according to any one of E26 to E32, wherein compound A is crystallized in a solvent selected from dimethoxy-1,2-ethane (DME) or a mixture of dimethoxy-1,2-ethane and diisopropyl ether (DIPE). E37. The process for preparing crystalline form M of compound A according to E18, wherein compound A is crystalline form A of compound A. E38. Crystal form M of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid (Compound A) H . E39. Crystalline form M of compound A according to E38, in substantially pure form. H . E40. Crystalline form M of compound A according to E38 or E39, characterized in that it has an X-ray powder diffraction pattern exhibiting at least the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 11.05 and 20.04. H . E41. Crystalline form M of compound A according to E38 or E39, characterized in that it has an X-ray powder diffraction pattern showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or all of the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 6.29, 7.26, 7.92, 8.35, 10.11, 11.05, 11.49, 12.74, 16.72, 17.36, 18.47, 20.04, 20.53, 21.07, 21.58, 22.22, 23.15, 24.41. H . E42. Crystalline form M of compound A according to E41, characterized in that it has an X-ray powder diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 7.26, 7.92, 11.05, 12.74, 20.04, 20.53, 24.41. H . E43. Crystalline form M of compound A according to E41, characterized in that it has an X-ray powder diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 6.29, 7.26, 7.92, 8.35, 10.11, 11.05, 11.49, 12.74, 16.72, 17.36, 18.47, 20.04, 20.53, 21.07, 21.58, 22.22, 23.15, 24.41. H . E44. Crystalline form M of compound A according to E43, characterized in that it has the following powder X-ray diffraction pattern, expressed by line positions (expressed in degrees ±0.2°, Bragg angle 2θ) and interplanar spacings d (expressed in Å), measured in spinner transmission mode using a PANalytical Empyrean diffractometer equipped with a PIXCel 1D detector: H :

[0021] [Table 3] E45. As an active ingredient, a crystalline form M of the compound A according to any one of E38 to E44. H together with one or more pharma- ceutically acceptable carriers, glidants, diluents, excipients or stabilizers. E46. The pharmaceutical composition according to E45 for use in the treatment of cancer, autoimmune diseases and immune system diseases. E47. The pharmaceutical composition for use according to E46, wherein the cancer is selected from bladder cancer, brain tumor, breast cancer, uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma (e.g., non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanoma, malignant hematological disease (e.g., myelodysplastic syndrome), myeloma (e.g., multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. E48. Crystal form M of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid (Compound A) HD . E49. Crystalline form M of compound A according to E48, in substantially pure form. HD . E50. Crystalline form M of compound A according to E48 or E49, characterized in that it has an X-ray powder diffraction pattern exhibiting at least the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 13.30 and 21.00. HD . E51. Crystalline form M of compound A according to E48 or E49, characterized in that it has an X-ray powder diffraction pattern showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or all of the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 6.03, 8.45, 10.14, 10.42, 11.29, 11.82, 13.30, 15.85, 17.07, 17.77, 18.05, 18.84, 19.14, 20.05, 21.00, 21.92, 22.99, 27.27. HD . E52. Crystalline form M of compound A according to E51, characterized in that it has an X-ray powder diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 10.14, 13.30, 15.85, 18.05, 18.84, 19.14, 21.00. HD . E53. Crystalline form M of compound A according to E51, characterized in that it has an X-ray powder diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 6.03, 8.45, 10.14, 10.42, 11.29, 11.82, 13.30, 15.85, 17.07, 17.77, 18.05, 18.84, 19.14, 20.05, 21.00, 21.92, 22.99, 27.27. HD . E54. Crystalline form M of compound A according to E53, characterized in that it has the following powder X-ray diffraction pattern, expressed by line positions (expressed in degrees ±0.2°, Bragg angle 2θ) and interplanar spacings d (expressed in Å), measured in spinner transmission mode using a PANalytical Empyrean diffractometer equipped with a PIXCel 1D detector: HD :

[0022] [Table 4] E55. As an active ingredient, a crystalline form M of the compound A according to any one of E48 to E54. HD together with one or more pharma- ceutically acceptable carriers, glidants, diluents, excipients or stabilizers. E56. The pharmaceutical composition according to E55 for use in the treatment of cancer, autoimmune diseases and immune system diseases. E57. The pharmaceutical composition for use according to E56, wherein the cancer is selected from bladder cancer, brain tumor, breast cancer, uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma (e.g., non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanoma, malignant hematological disease (e.g., myelodysplastic syndrome), myeloma (e.g., multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

[0023] Obtaining a crystalline form of compound A, specifically crystalline form M or crystalline form A of compound A, has the advantage that it is possible to prepare pharmaceutical formulations with consistent and reproducible composition and good stability characteristics. H or crystalline form M HD The advantage of obtaining such a compound is that it allows the preparation of pharmaceutical formulations with consistent and reproducible composition and good stability characteristics.

[0024] A further aspect of the invention is a pharmaceutical composition comprising the novel crystalline form of Compound A, particularly crystalline form M or crystalline form A of Compound A, which can be formulated according to standard pharmaceutical practice for use in the therapeutic treatment (including prophylactic treatment) of cancer, autoimmune diseases and immune system diseases in mammals, including humans. A further aspect of the invention is a pharmaceutical composition comprising the novel crystalline form of Compound A, particularly crystalline form M or crystalline form A of Compound A, which can be formulated according to standard pharmaceutical practice for use in the therapeutic treatment (including prophylactic treatment) of cancer, autoimmune diseases and immune system diseases in mammals, including humans. H or crystalline form M HD and which can be formulated in accordance with standard pharmaceutical practice for use in the therapeutic treatment (including prophylactic treatment) of cancer, autoimmune diseases and immune system diseases in mammals, including humans.

[0025] A further aspect of the invention is a pharmaceutical composition comprising the novel crystalline form of Compound A, particularly crystalline form M or crystalline form A of Compound A, which can be formulated according to standard pharmaceutical practice for use in combination therapy for the therapeutic treatment (including prophylactic treatment) of cancer, autoimmune diseases and immune system diseases in mammals, including humans. A further aspect of the invention is a pharmaceutical composition comprising the novel crystalline form of Compound A, particularly crystalline form M or crystalline form A of Compound A, which can be formulated according to standard pharmaceutical practice for use in combination therapy for the therapeutic treatment (including prophylactic treatment) of cancer, autoimmune diseases and immune system diseases in mammals, including humans. H or crystalline form M HD and which can be formulated according to standard pharmaceutical practice for use in combination therapy for the therapeutic treatment (including prophylactic treatment) of cancer, autoimmune diseases and immune system diseases in mammals, including humans.

[0026] A further aspect of the invention is a pharmaceutical composition comprising a crystalline form of Compound A, particularly crystalline form M or crystalline form A of Compound A, together with one or more pharma- ceutically acceptable carriers, glidants, diluents, excipients or stabilizers. Suitable carriers, diluents, glidants, excipients or stabilizers are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publ. Co., Easton, PA). A further aspect of the invention is a pharmaceutical composition comprising a crystalline form of Compound A, particularly crystalline form M of Compound A, together with one or more pharma- ceutically acceptable carriers, glidants, diluents, excipients or stabilizers. Suitable carriers, diluents, glidants, excipients or stabilizers are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publ. Co., Easton, PA). H or crystalline form M HD together with one or more pharma- ceutically acceptable carriers, glidants, diluents, excipients, or stabilizers. Suitable carriers, diluents, glidants, excipients, or stabilizers are well known to those skilled in the art and include such materials as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publ. Co., Easton, PA).

[0027] The pharmaceutical compositions of the present invention are dosed and administered in a manner consistent with good medical practice, i.e., amount, concentration, schedule, course, vehicle and route of administration. Factors to be considered in this regard include the particular disorder being treated, the clinical condition of the individual patient, etiology, site of delivery of the drug, method of administration, administration schedule, and other factors known to the physician.

[0028] Moreover, the crystalline form of compound A thus obtained, specifically crystalline form M or crystalline form A of compound A, is sufficiently stable to be stored for a long period of time without any specific conditions of temperature, light, humidity or oxygen level. In particular, crystalline form M of compound A was found to be highly stable to temperature and humidity after a storage period of 6 months under various conditions. More specifically, crystalline form M of compound A remains stable after a storage period of 12 months under 25°C / 60% RH or 30°C / 65% RH conditions.

[0029] The following examples are illustrative of the present invention, but do not limit the present invention.In the crystallization process of the present invention, compound A (free base) as starting material can be obtained by any process.For example, compound A can be synthesized according to WO 2015 / 097123. EXAMPLES

[0030] Example 1: Process for obtaining crystalline form M of compound A At ambient temperature, compound A was added to toluene to a concentration of 7% m / m (mass ratio). The mixture was stirred at ambient temperature for about 8 hours. The resulting suspension (slurry) was then filtered and dried under vacuum at 20°C to 70°C to obtain crystalline form M of compound A. The solid was characterized by powder X-ray diffraction pattern as described in Example 7. Melting point: 148.7°C (determined by DCS at 10°C / min under nitrogen using a TA Instruments Q1000 DSC) Alternatively, the resulting slurry before filtration can be directly used as seed for a crystallization process as shown in Examples 2-5 below.

[0031] Example 2: Process for obtaining crystalline form M of compound A (seeding) Compound A (9 g; free base) was added to toluene at a concentration of 6.5 mL / g or 15% m / m at ambient temperature. The mixture was then heated to 70° C. to solubilize compound A. The mixture was cooled and when the temperature reached about 30° C., the solution was seeded with a wet slurry of compound A obtained in Example 1 (4.4% by weight of starting material). The mixture was stirred at 5° C. for an additional 25 hours. The suspension was then filtered, washed with water and dried under vacuum at 70° C. After drying, crystalline form M of compound A was obtained in about 87% yield and 99.37% purity. The solid was characterized by powder X-ray diffraction pattern as described in Example 7.

[0032] Example 3: Alternative process for obtaining crystalline form M of compound A Compound A (10 g; free base) was placed in toluene at ambient temperature at a concentration of 10.4 mL / g or 10% m / m. The mixture was then heated at 70° C. and concentrated under vacuum at 60° C. to a concentration of 6.5 mL / g or 15% m / m. The mixture was cooled to 43° C. and seeded with a wet slurry of compound A obtained in Example 1 (4% by weight of starting material). MTBE was added to obtain a 75 / 25 m / m toluene / MTBE solution. The final concentration of compound A was 12% m / m. The mixture was cooled and stirred at 20° C. for 15 hours. The suspension was then filtered, washed with MTBE and dried under vacuum at 70° C. After drying, crystalline form M of compound A was obtained in about 89% yield and 99.6% purity. The solid was characterized by powder X-ray diffraction pattern as described in Example 7.

[0033] Example 4: Alternative process for obtaining crystalline form M of compound A Compound A (275 g; free base) was placed in a toluene / acetone binary system of 75 / 25 mass ratio toluene / acetone at a concentration of 16.5% m / m at ambient temperature. Acetone was removed from toluene by vacuum distillation at about 50° C. After addition of toluene to reach a concentration of 16.5% m / m, the mixture was heated to 40° C. and then seeded with a wet slurry of compound A obtained in Example 1 (1% to 2% by weight of starting material). After stirring at 40° C., MTBE was added slowly to obtain a 75 / 25 m / m toluene / MTBE solution. The final concentration of compound A was 12% m / m. The mixture was stirred at 40° C. for 30 minutes and cooled at 20° C. for 2 hours. The suspension was then filtered, washed with a 75 / 25 m / m toluene / MTBE solution, and vacuum dried first at 20° C. until the ICH residual solvent limit of MTBE was reached, and then at 70° C. until the ICH residual solvent limit of toluene was reached. After drying, crystalline form M of compound A was obtained in about 93% yield and greater than 99% purity. The solid was characterized by powder X-ray diffraction pattern as described in Example 7.

[0034] Example 5: Alternative process for obtaining crystalline form M of compound A Compound A (free base) was placed in a binary mixture of 2-methyltetrahydrofuran (Me-THF) / water with a water m / m ratio of about 10% at ambient temperature at a concentration of about 12% m / m. The mixture was heated at 40° C. under vacuum and water was replaced with Me-THF (by solvent switching). Me-THF was added until the water in the condensate reached less than 1% and the final volume of the mixture was reached with a 12% m / m ratio. At 40° C., the mixture was seeded (1% by weight of starting material) with a slurry of compound A (obtained in Example 1) in Me-THF with a concentration of about 7% m / m. After stirring for 1 hour, the suspension was cooled to 10° C. and stirred for another 2 hours. The suspension was then filtered, washed with Me-THF and dried under vacuum at 40° C. After drying, crystalline form M of compound A was obtained in a yield of about 62% and a purity of 99.6%. The solid was characterized by powder X-ray diffraction pattern as described in Example 7.

[0035] Example 6: Alternative process for obtaining crystalline form M of compound A Compound A (1 kg), toluene (4.2 kg) and acetone (1.4 kg) were introduced into the reactor at 20° C. for solubilization. Acetone was replaced with toluene by constant volume vacuum distillation (temperature about 50° C.) until toluene density was reached in the condensation trap. At this point, the volume was adjusted with toluene to reach a mass product rate of 16.5% and the temperature was held at 50° C. After cooling at 40° C., crystallization was induced by seeding with a suspension of compound A in toluene (7% mass product rate slurry prepared by the process of Example 1). After a 2-hour hold time at 40° C., MTBE (1.8 kg) was added at 40° C. for a minimum of 1 hour, and then the reaction was cooled to 20° C. Upon completion of the reaction, the suspension was filtered, washed with MTBE (3.8 kg), flushed with nitrogen until the residual solvent reached 10%, and dried under vacuum first at 20° C. until the ICH residual solvent limit of MTBE was reached, and then at 70° C. until the ICH residual solvent limit of toluene was reached. After drying, crystalline form M of compound A was obtained in about 93% yield and about 99.8% purity. The solid was characterized by powder X-ray diffraction pattern as described in Example 7.

[0036] Example 7: XRPD diagram of crystalline form M of compound A Recording of data in spinner transmission mode was performed using a PANalytical Empyrean diffractometer equipped with a PIXCel 1D detector under the following conditions: Voltage: 45kV Current: 40mA Mounting: θ / θ Anode: copper Kα1 wavelength: 1.54060Å Kα2 wavelength: 1.54443Å Kα2 / Kα1 ratio: 0.5 Measurement mode: 3.5°~55°(Bragg angle 2θ) continuous in 0.017° increments Measurement time per step: 34.9250s The powder X-ray diffraction diagram of the crystalline form M of compound A obtained by any one of the processes of Examples 1 to 6 is represented by line positions (expressed in degrees ±0.2°, Bragg angle 2θ) and interplanar spacings (expressed in Å) (Figures 1 and 2). The important lines are collated in the following table:

[0037] [Table 5]

[0038] Example 8: Hygroscopicity The hygroscopicity of crystalline form M of Compound A obtained by any one of the processes of Examples 1-6 was evaluated using the Dynamic Vapor Sorption (DVS) method. 5-10 mg of drug substance test sample was accurately weighed and placed in a DVS sample pan operated at 25° C. under humidity control. The mass of the sample was recorded at 50% RH (relative humidity) until a stable value was reached. The mass change was then recorded between 50% RH and 90% RH at a rate of 10% per hour. The mass change was also recorded between 90% RH and 0% RH and back to 50% RH. Once the relative humidity reached either 0 or 90% RH, the relative humidity was maintained constant until the mass change was less than 0.002% per minute within the time limit of 15 hours. An increase in sample mass of approximately 0.4% was recorded by DVS analysis when the samples were exposed to relative humidity ranging from 50% to 90% at 25 °C. A decrease of about 0.5% in sample mass was recorded between 90% and 0% RH, while an increase of about 0.1% in sample mass was recorded between 0% and 50% RH. The DVS profile (Figure 3) shows that moisture sorption and desorption are essentially reversible, with no change to crystalline form M observed in the powder X-ray diffraction pattern after moisture sorption / desorption / sorption cycles. Crystalline form M of compound A can be considered to be slightly hygroscopic according to the European Pharmacopoeia (Ph. Eur.).

[0039] Example 9: Coulometric titration The water content of crystalline form M of Compound A obtained by any one of the processes of Examples 1 to 6 was determined by coulometric titration using a Metrohm coulometer consisting of a 774 Oven Sample Processor, 774 SC Controller, 831 KF Coulometer and 846 Dosing Interface with Tiamo 1.2 Software. Approximately 10 mg of accurately weighed micronized drug substance was introduced into a vial and heated at 140° C. for 10 minutes. The moisture content in the test samples reached 0.1 wt%.

[0040] Example 10: Stability test of crystalline form M of compound A For all storage conditions and storage times, 20 mg of crystalline form M of compound A obtained by any one of the processes of Examples 1 to 6 was introduced into a 30 mL vial for HPLC analysis after storage (packaging: PVO = open glass container; VRAC PA = double polyethylene bag). The results are as follows:

[0041] [Table 6] The crystalline form M of Compound A remains stable to temperature and humidity even after a storage period of 6 months under various conditions. More specifically, the crystalline form M of Compound A remains stable after a storage period of 12 months under conditions of 25° C. / 60% RH or 30° C. / 65% RH.

[0042] Example 11: Solid Form M of Compound A 13 C NMR spectrum The crystalline form M of compound A obtained by any one of the processes of Examples 1 to 6 is a solid 13 The solid form of compound A crystalline form M was also characterized by C nuclear magnetic resonance spectroscopy (Figure 4). 13 C NMR spectra were recorded at ambient temperature using a Bruker SB Avance III 500 spectrometer equipped with a 4 mm CP / MAS SB VTN type probe under the following conditions: Frequency: 125.7MHz Spectral width: 37.5kHz Magic angle rotation speed: 13kHz Pulse program: SPINAL64 cross polarization with decoupling Recycle Delay: 10 seconds Acquisition time: 46 ms Contact time: 4 ms Number of scans: 2048 A line broadening of 5 Hz was applied prior to Fourier transformation. The spectra so obtained were referenced to a sample of adamantane (setting the high frequency peak of adamantane to 38.5 ppm). Compound A, crystalline form M, can be defined by the presence of the following peaks in the NMR spectrum (expressed in ppm ± 0.2 ppm):

[0043] [Table 7] More specifically, the characteristic peaks are at 175.1, 153.7, 134.8, 108.9, 71.4 and 35.1 (expressed in ppm±0.2 ppm).

[0044] Example 12: MIR spectrum of crystalline form M of compound A The crystalline form M of Compound A obtained by any one of the processes of Examples 1 to 6 was also characterized by mid-infrared spectroscopy, the data being recorded in ATR mode using a Bruker Vertex MIR spectrometer under the following conditions: Number of scans: 32 Resolution: 2cm -1 The MIR spectrum of crystalline form M of compound A is shown in FIGS. Characteristic peaks are 1603.7, 1569.0, 1556.5, 1544.9, 1517.9, 1498.6, 1475.5, 1457.1, 1434.0, 1401.2, 1374.2, 1364.6, 1278.7, 1239.2, 1226.7, 1187.1, 1163.0, 1118.7, 1072.4, 1031.9, 995.2, 884.3, 848.6, 811.0, 795.6, 770.5, 745.5, 690.5, and 670.2 (cm-1 (represented by More specifically, the characteristic peaks are 1475.5, 1457.1, 1434.0, 1278.7, 1226.7, 848.6, 770.5, 745.5 (cm -1 (represented by

[0045] Example 13: Raman spectrum of crystalline form M of compound A The crystalline form M of Compound A obtained by any one of the processes of Examples 1 to 6 was also characterized by Raman spectroscopy, the data being recorded using a Perkin-Elmer RS400 Raman spectrometer under the following conditions: Number of scans: 10 Exposure time: 0.5 seconds Laser power: 100% The Raman spectrum of crystalline form M of compound A is shown in Figures 7 and 8. Characteristic peaks are 1602.0, 1544.0, 1518.0, 1478.0, 1376.0, 1286.0, 1220.0, 1164.0, 1130.0, 1048.0, 1034.0, 988.0, 812.0, 770.0, 752.0, 634.0, 566.0, 508.0, 414.0, 380.0, and 254.0 (cm -1 (represented by More specifically, the characteristic peaks are 1516.0, 1220.0, 770.0, 752.0, 380.0 (cm -1 (represented by

[0046] Example 14: Purity of crystalline form M of compound A determined by synchrotron radiation (Soleil Synchrotron, Saclay, France) A suitable crystal of the crystalline form M of compound A was selected and mounted on the synchrotron beamline PROXIMA II diffractometer (SOLEIL, Saclay, France). The crystal was kept at 100 K during data collection. The structure was solved with the ShelXT structure solving program using Intrinsic Phasing (Sheldrick, Acta Cryst. 2015, A71, 3-8) and refined with the ShelXL refinement package using Least Squares Minimisation (Sheldrick, Acta Cryst. 2015, C71, 3-8) using Olex2 (Dolomanov et al., J. Appl. Cryst. 2009, 42, 339-3411). The positional and atomic displacement parameters were calculated using the F 2 The structure was refined by a full-matrix least-squares routine for . Hydrogen atoms were placed using a riding model. The absolute structure has been determined and is consistent with the enantiomerically pure phase of compound A. 1. Synchrotron data recorded at 100K and thermal ellipsoid diagram of the asymmetric unit (one molecule of compound A): Space group P212121(No.19) a=10.610Å b=17.400Å c=23.720Å V=4379.0Å 3 Z=4 T=100K FIG. 9 shows the thermal ellipsoid diagram of compound A, crystalline form M (obtained using the ORTEP program). 2. Crystal lattice constants obtained from the powder X-ray diffraction pattern of compound A (crystalline form M) at room temperature: space group P2 1 2 1 2 1 (No.19) a=10.6401Å b=17.3643Å c=24.0494Å V=4443.3Å 3 Z=4 T=293K 3. Peak positions and interplanar spacing (d hkl )(100K)

[0047] [Table 8] The set of peaks obtained from the single crystal data is in close agreement with those measured experimentally (see Example 7 for comparison). Thus, these results support the high purity of compound A, crystalline form M.

[0048] Example 15: Process for obtaining crystalline form A of compound A and its powder X-ray diffraction pattern Compound A was dissolved in 2-methyltetrahydrofuran at ambient temperature at a concentration of 8 mL / g, and dimethoxy-1,2-ethane (DME) was added to a concentration of 11 mL / g. The mixture was then stirred at 35° C. for 2 hours and at 20° C. for 3 hours. After crystallization, the solid was filtered, washed with acetone, and dried in vacuum at 50° C. and then at 70° C. After drying, crystalline form A of compound A was obtained in about 81% yield and 99.5% purity. The solid was characterized by powder X-ray diffraction pattern as described below. Melting point: 125.4°C (determined by DSC at 10°C / min under nitrogen using a TA Instruments Q1000 DSC) The process variant (seeding) for obtaining crystalline form A of compound A is as follows: Compound A was dissolved in 2-methyltetrahydrofuran at ambient temperature at a concentration of about 11 mL / g, and DME was added to a concentration of 11 mL / g. A quarter of the solvent was removed by distillation, and DME was added again to a concentration of 11 mL / g. The mixture was then heated at 35° C. and seeded with crystalline form A of compound A (2% by weight of starting material). The mixture was stirred at 35° C. for 2 hours and at 20° C. for 19 hours. After crystallization, the solid was filtered, washed with acetone, and dried under vacuum at 50° C. and then at 70° C. After drying, crystalline form A of compound A was obtained in a yield of about 93% and with a purity of more than 99.0%. The solid was characterized by powder X-ray diffraction pattern as described below. Recording of data in spinner transmission mode was performed using a PANalytical Empyrean diffractometer equipped with a PIXCel 1D detector under the following conditions: Voltage: 45kV Current: 40mA Mounting: θ / θ Anode: copper Kα1 wavelength: 1.54060Å Kα2 wavelength: 1.54443Å Kα2 / Kα1 ratio: 0.5 Measurement mode: 3.5°~55°(Bragg angle 2θ) continuous in 0.017° increments Measurement time per step: 34.9250s The powder X-ray diffraction diagram of crystalline form A of compound A is represented by line positions (expressed in degrees ±0.2°, Bragg angles 2θ) and interplanar spacings (expressed in Å) ( FIG. 10 ). Significant lines are collated in the following table:

[0049] [Table 9]

[0050] Example 16: Process for obtaining crystalline form M of compound A from crystalline form A of compound A At ambient temperature, crystalline form A of compound A obtained in Example 14 was added to toluene to a concentration of 7% m / m. The mixture was stirred at ambient temperature for 8 hours to complete the polymorphic transformation. The resulting suspension (slurry) was then filtered and dried in vacuum at 20°C to 70°C to obtain crystalline form M of compound A. The solid was characterized by powder X-ray diffraction diagram as described in Example 7.

[0051] Example 17: Stability test of crystalline form A of compound A For all storage conditions and storage times, 1.2 g of crystalline form A of compound A obtained by the process of Example 15 was introduced into a specific package for HPLC analysis after storage. The results are as follows:

[0052] [Table 10] Form A of Compound A remains stable after 24 months of storage at 25° C. / 60% RH conditions. Form A of Compound A remains stable to temperature and humidity after several months of storage under more extreme conditions.

[0053] Example 18: DSC and TGA profiles of compound A, crystalline form M The DSC profile of a sample of Compound A, crystalline form M (obtained by any one of the processes of Examples 1-6) weighing about 3 mg was recorded on a TA Instruments Q2000 Differential Scanning Calorimeter in a pinhole perforated aluminum pan under positive nitrogen flow at 10° C. / min from 25° C. to 220° C. The TGA profile of a sample of Compound A, crystalline form M (obtained by any one of the processes of Examples 1-6) weighing about 7.5 mg was recorded on a TA Instruments Q5000 Thermogravimetric Analyzer in an open aluminum pan under positive nitrogen flow at 10° C. / min from 25° C. to 220° C. The DSC and TGA profiles (Figure 11) show that crystalline form M of Compound A is anhydrous and melts at approximately 148°C.

[0054] Example 19: Crystalline form M of compound A H Process for obtaining the above-mentioned compound and its powder X-ray diffraction pattern The hydrated form of compound A (crystal form M H A hydrated form M (referred to as hydrated form A) was prepared by maturation of crystalline form M in water at 25°C. To 1 g of compound A in a 100 ml glass vessel, approximately 100 ml of purified water is added. The suspension is aged at 30°C for 4 days with stirring at a speed of 500 rpm. After 4 days, the suspension is filtered under slight vacuum and the filtrate is dried under vacuum for an additional 30 minutes. A white paste is recovered which slowly transforms into a white powder upon grinding. The recovered powder was analyzed by XRPD. Subsequent X-ray powder analysis combined with moisture content analysis revealed that the white powder is hydrated crystalline form M. H It was shown that. Data recording was performed in transmission mode using a PANalytical Empyrean diffractometer equipped with a PIXCel 1D detector under the following conditions: Voltage: 45kV Current: 40mA Mounting: θ / θ Anode: copper Kα1 wavelength: 1.54060Å Kα2 wavelength: 1.54443Å Kα2 / Kα1 ratio: 0.5 Measurement mode: 3°~55°(Bragg angle 2θ) continuous in 0.017° increments Measurement time per step: 35.5301s Crystal form M of compound A H The powder X-ray diffraction diagram of is represented by line positions (expressed in degrees ±0.2°, Bragg angle 2θ) and relative intensities (expressed as a percentage relative to the most intense line) (FIG. 12). The important lines are collated in the following table:

[0055] [Table 11] The moisture content of the powder was also determined by coulometry. The results showed that a new solid crystalline form, M H It was shown that it contained a significant amount of water (29.3%).

[0056] Example 20: Crystalline form M of compound A HD Process for obtaining the above-mentioned compound and its powder X-ray diffraction pattern Hydrated crystal form M H A new diffraction profile was recorded when crystalline form M was heated from 25 to 100 °C at 1 °C / min. The powder obtained after heat treatment was analyzed by XRPD. This new diffraction profile was consistent with that of crystalline form M HD (i.e., a dehydrated form of hydrated crystal form M). Data recording was performed in transmission mode using a PANalytical Empyrean diffractometer equipped with a PIXCel 1D detector under the following conditions: Voltage: 45kV Current: 40mA Mounting: θ / θ Anode: copper Kα1 wavelength: 1.54060Å Kα2 wavelength: 1.54443Å Kα2 / Kα1 ratio: 0.5 Measurement mode: 3°~55°(Bragg angle 2θ) continuous in 0.017° increments Measurement time per step: 35.5301s Crystal form M of compound A HD The powder X-ray diffraction diagram of is represented by line positions (expressed in degrees ±0.2°, Bragg angle 2θ) and relative intensities (expressed as a percentage relative to the most intense line) (FIG. 13). The important lines are collated in the following table:

[0057] [Table 12]

Claims

1. At least the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 8.94 and 18.24, as well as the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 6.27; 9.09; 12.16; 13.67; 14.75; 15.06; 16.97; 17.22; 17.44; 19.16; 19.93; 20.91; A crystalline form of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid (Compound A), characterized in that it has a powder X-ray diffraction pattern exhibiting at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all of 25.

88.

2. 2. The crystalline form M of compound A according to claim 1, in a form having a purity of greater than 90% by weight.

3. A crystalline M of compound A according to claim 1 or 2, characterized in that it has an X-ray powder diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 8.94; 13.67; 14.75; 17.22; 18.

24.

4. A crystalline M of compound A according to claim 1 or 2, characterized in that it has an X-ray powder diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 6.27; 8.94; 9.09; 12.16; 13.67; 14.75; 15.06; 16.97; 17.22; 17.44; 18.24; 19.16; 19.93; 20.91; 25.

88.

5. Crystalline M of compound A according to claim 4, characterized in that it has the following powder X-ray diffraction pattern, expressed in terms of line positions (expressed in degrees ±0.2°, Bragg angle 2θ) and interplanar spacings d (expressed in Å), measured in spinner transmission mode using a PANalytical Empyrean diffractometer equipped with a PIXCel 1D detector: 【Table 13】

6. A crystalline M of compound A according to any one of claims 1 to 5, characterized in that it has a solid-state 13C CP / MAS NMR spectrum with the following peaks (expressed in ppm ±0.2 ppm): 175.1, 153.7, 134.8, 108.9, 71.4 and 35.

1.

7. 6. A crystalline M of compound A according to any one of claims 1 to 5, characterized in that it has a solid-state 13C CP / MAS NMR spectrum with the following peaks (expressed in ppm ± 0.2 ppm): 175.1, 168.5, 167.4, 164.6, 162.6, 157.5, 156.3, 153.7, 135.5, 134.8, 130.4, 129.9, 128.4, 126.8, 120.9, 119.9, 118.5, 116.9, 112.5, 111.1, 108.9, 78.7, 71.4, 54.9, 42.1, 35.1 and 18.

2.

8. A pharmaceutical composition comprising as an active ingredient a crystalline form M of compound A according to any one of claims 1 to 7, together with one or more pharma- ceutically acceptable carriers, glidants, diluents, excipients or stabilizers.

9. 9. The pharmaceutical composition according to claim 8 for use in the treatment of cancer, autoimmune diseases and immune system diseases.

10. 10. The pharmaceutical composition for use according to claim 9, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma, melanoma, malignant blood disease, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

11. A crystalline form M of compound A according to any one of claims 1 to 7 for use as a medicament.

12. A crystalline form M of compound A according to any one of claims 1 to 7 for use in the treatment of cancer, autoimmune diseases and immune system diseases.

13. Crystal M of compound A for use according to claim 12, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma, melanoma, malignant blood disease, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

14. The process for preparing crystalline M of compound A according to any one of claims 1 to 7, wherein compound A is crystallized in a solvent selected from toluene, 2-methyltetrahydrofuran, or a mixture of toluene and methyl tert-butyl ether.

15. 15. The process for preparing a crystalline M of compound A according to claim 14, characterized in that compound A is a crystalline A of compound A, which has an X-ray powder diffraction pattern exhibiting at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 7.52 and 16.61, and the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 8.89; 9.58; 10.35; 11.25; 13.08; 14.44; 17.07; 17.71; 19.10; 20.60; 20.80; 21.69; 22.14; 23.63; 27.

36.

16. The process for preparing crystalline M of compound A according to claim 14 or claim 15, wherein the concentration of compound A in the solvent is 5-15% m / m.

17. The process for preparing crystalline M of compound A according to any one of claims 14 to 16, wherein the slurry obtained during the process is dried at between 20°C and 80°C.

18. 17. Process for the preparation of crystalline M of compound A according to any one of claims 14 to 16, wherein the crystallization is carried out by seeding with crystalline M of compound A at 0.5% to 5% m / m.

19. The process for preparing crystalline M of compound A according to claim 18, wherein the crystallization is carried out by seeding at a temperature between 20°C and 60°C.

20. At least the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 7.52 and 16.61, as well as the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 8.89; 9.58; 10.35; 11.25; 13.08; 14.44; 17.07; 17.71; 19.10; 20.60; 20.80; 21.69; 22.14; 23.63; A crystalline form of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid (Compound A), characterized in that it has a powder X-ray diffraction pattern showing at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of 27.

36.

21. 21. Crystal A of compound A according to claim 20, characterized in that it has an X-ray powder diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 7.52; 8.89; 10.35; 16.61; 19.

10.

22. Crystal A of compound A according to claim 20, characterized in that it has a powder X-ray diffraction pattern with the following diffraction lines (expressed in degrees ±0.2°, Bragg angle 2θ): 7.52; 8.89; 9.58; 10.35; 11.25; 13.08; 14.44; 16.61; 17.07; 17.71; 19.10; 20.60; 20.80; 21.69; 22.14; 23.63; 27.

36.

23. 23. A crystalline form of compound A according to claim 22, characterized in that it has the following powder X-ray diffraction pattern, measured in spinner transmission mode using a PANalytical Empyrean diffractometer equipped with a PIXCel 1D detector and expressed by line positions (expressed in degrees ±0.2°, Bragg angle 2θ) and interplanar spacings d (expressed in Å): 【Table 14】

24. A pharmaceutical composition comprising as an active ingredient a crystalline form of compound A according to any one of claims 20 to 23, together with one or more pharma- ceutically acceptable carriers, glidants, diluents, excipients or stabilizers.

25. 25. The pharmaceutical composition of claim 24 for use in the treatment of cancer, autoimmune diseases and immune system diseases.

26. 26. The pharmaceutical composition for use according to claim 25, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma, melanoma, malignant blood diseases, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

27. The process for preparing crystalline A of compound A according to any one of claims 20 to 23, wherein compound A is crystallized in a solvent selected from dimethoxy-1,2-ethane or a mixture of dimethoxy-1,2-ethane and diisopropyl ether.

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