Solid forms of condensed pyridines for the treatment of cancer

Abstract

The present invention relates to a solid form of Compound A, and a pharmaceutical composition comprising said solid form. The solid form of Compound A of the present invention or the pharmaceutical composition of the present invention can be used as a medicament. [Formula 1] TIFF2025538506000012.tif38170

Description

[Technical Field]

[0001] The present invention relates to a solid form of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide, hereinafter referred to as "Compound A." Compound A is an inhibitor of Werner syndrome RecQ DNA helicase (WRN), and therefore can be used, inter alia, as a pharmaceutical agent for the treatment of diseases such as cancer, particularly cancers treated by inhibition of WRN. The compound is particularly intended for use in the treatment of cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). [Background technology]

[0002] Loss of DNA mismatch repair (MMR) is a common initiating event in cancer development, occurring in 10–30% of colorectal, endometrial, ovarian, and gastric cancers (Aaltonen, LA et al., Clues to the pathogenesis of familial colorectal cancer, Science 260, 812–816 (1993); Bonneville R et al., Landscape of Microsatellite Instability Across 39 Cancer Types. JCO Precis Oncol. 1:PO.17.00073 (2017)). Cancers with MMR loss have high mutational burden and frequent deletion and insertion events in repetitive DNA tracts, a phenotype known as microsatellite instability (MSI). While progress has been made in the treatment of microsatellite instability-high (MSI-H) cancers, with pembrolizumab (anti-PD1) recently approved for the first-line treatment of MSI-H-dMMR metastatic colorectal cancer after it was demonstrated to result in significantly longer progression-free survival compared with chemotherapy, significant unmet medical needs remain in CRC and other MSI-H indications (Andre T., et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med 383(23):2207-2218(2020)).Multiple large-scale functional genomic screens of large panels of cell lines, including Novartis, using 398 cell lines from the Cancer Cell Line Encyclopedia (CCLE) (McDonald ER et al., Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. Cell 170(3):577-592 (2017)) have identified the selective requirement of the Werner syndrome RecQ helicase (WRN) for survival in mismatch repair-deficient cell lines that have become MSI-H (Behan, FM et al., Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 568, 511-516 (2019); Chan, EM et al., WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 568, 551-556 (2019). Kategaya, L., Perumal, SK, Hager, JH & Belmont, LD. Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability. iScience 13, 488-497 (2019). Lieb, S. et al. Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. eLife 8, e43333 (2019). WRN is synthetically lethal in MSI cancers.Depletion of WRN leads to antiproliferative effects, activating multiple DNA damage signaling markers, inducing cell cycle arrest, and apoptosis in MMR cancer models, but not in cancer cells with an intact MMR pathway. These findings indicate that WRN provides DNA repair and maintenance functions essential for cell survival in MSI cancers. Recently, the mechanism of WRN dependence has been elucidated. Dinucleotide TA repeats have been shown to be selectively unstable and undergo large expansions in MSI cells. These expanded TA repeats form secondary DNA structures that require WRN helicase for unwinding (van Wietmarschen, N. et al. Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature 586, 292-298, 2020). In the absence of WRN (or when WRN helicase is inhibited), expanded TA repeats in MSI cells undergo nuclease cleavage and chromosome breakage. Therefore, inhibiting WRN helicase is an attractive strategy for treating mismatch repair-deficient cancers.

[0003] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide, designated herein as "Compound A," is an inhibitor of Werner syndrome RecQ DNA helicase (WRN) and is disclosed in patent application PCT / IB2022 / 054850, published as WO 2022 / 249060. The contents of patent application PCT / IB2022 / 054850 are incorporated herein by reference.

[0004] Compound A, or N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide, has the structure: [ka] It has.

[0005] The preparation method of Compound A is disclosed in the synthetic procedure of patent application PCT / IB2022 / 054850. Compound A is specifically disclosed in Examples 42 and 123 of said patent application, and these Examples are incorporated herein by reference. A crystalline form of Compound A, "Modification A," also referred to as "Form A," is disclosed in patent application PCT / IB2022 / 054850. Additional novel crystalline forms are disclosed herein. All forms herein are the free form (not salt) of Compound A.

[0006] Different solid-state forms of an active pharmaceutical ingredient often have different properties. Differences in the physicochemical properties of the solid forms can play an important role in improving pharmaceutical compositions; for example, pharmaceutical formulations with improved dissolution profiles or improved stability or shelf life may become available through improvements in the solid-state forms of the active pharmaceutical ingredient. The processing or handling of the active pharmaceutical ingredient during the formulation process may also be improved. Thus, novel solid-state forms of the active pharmaceutical ingredient may have desirable processing properties. They may be easier to handle, more suitable for storage, and / or allow for better purification compared to previously known solid forms. Thus, the present invention provides alternative solid-state forms of compound A having different physicochemical properties. Summary of the Invention

[0007] In a first aspect of the present invention, there is provided a crystalline form of Compound A (Modification B), characterized by an X-ray powder diffraction pattern comprising four or more reflections at 2-theta angles selected from the group consisting of 5.6±0.2°, 11.2±0.2°, 12.6±0.2°, 14.8±0.2°, 17.4±0.2°, 18.1±0.2°, 19.2±0.2°, 22.0±0.2°, 22.4±0.2°, 25.1±0.2°, 25.3±0.2°, 26.2±0.2°, 27.3±0.2°, 29.7±0.2° and 34.5±0.2° when measured at a temperature in the range of 20-30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0008] In a second aspect of the present invention, there is provided a crystalline form of Compound A (Modification C), which has the following molecular weights when measured at a temperature in the range of 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm: 4.0±0.2°, 8.0±0.2°, 8.7±0.2°, 12.1±0.2°, 14.5±0.2°, 15.1±0.2°, 15.5±0.2°, 16. The compound is characterized by an X-ray powder diffraction pattern containing four or more reflections at 2-theta angles selected from the group consisting of 2±0.2°, 16.7±0.2°, 17.9±0.2°, 19.8±0.2°, 20.2±0.2°, 20.6±0.2°, 23.4±0.2°, 24.2±0.2°, 25.4±0.2°, 26.5±0.2°, 28.5±0.2°, and 32.1±0.2°.

[0009] In a third aspect of the present invention, there is provided a crystalline form of Compound A (Modification D), which has a viscosity index of 8.5±0.2°, 9.1±0.2°, 11.6±0.2°, 13.7±0.2°, 14.3±0.2°, 15.0±0.2°, 15.4±0.2°, 16.9±0.2°, when measured at a temperature in the range of 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm. The compound is characterized by an X-ray powder diffraction pattern comprising four or more reflections at 2-theta angles selected from the group consisting of 17.5±0.2°, 19.1±0.2°, 19.9±0.2°, 20.2±0.2°, 21.5±0.2°, 22.6±0.2°, 23.5±0.2°, 25.6±0.2°, 26.4±0.2°, 26.8±0.2°, 28.8±0.2°, and 30.3±0.2°.

[0010] In a fourth aspect of the present invention, a crystalline form of Compound A (hydrate H A ), wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising four or more reflections at 2-theta angles selected from the group consisting of: 7.8±0.2°, 8.4±0.2°, 11.8±0.2°, 15.7±0.2°, 16.4±0.2°, 16.8±0.2°, 17.4±0.2°, 17.7±0.2°, 19.7±0.2°, 20.2±0.2°, 24.3±0.2°, 24.7±0.2°, 25.1±0.2°, 26.6±0.2°, and 29.0±0.2° when measured at a temperature in the range of 20-30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0011] In a fifth aspect of the present invention, a crystalline form of Compound A (hydrate H B), wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising four or more reflections at 2-theta angles selected from the group consisting of 9.0±0.2°, 13.6±0.2°, 14.7±0.2°, 15.8±0.2°, 16.1±0.2°, 16.4±0.2°, 17.4±0.2°, 18.4±0.2°, 19.3±0.2°, 20.3±0.2°, 22.1±0.2°, 22.7±0.2°, 23.1±0.2°, 24.8±0.2°, 25.4±0.2°, 29.6±0.2°, and 30.1±0.2° when measured at a temperature in the range of 20-30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0012] In a sixth aspect of the present invention, a crystalline form of Compound A (hydrate H C ) is provided, and this crystalline form has an optical transparency of 8.0±0.2°, 8.7±0.2°, 11.8±0.2°, 12.2±0.2°, 14.9±0.2°, 15.2±0.2°, 15.6±0.2°, 16.4±0.2°, and 16.8±0.2° when measured at temperatures ranging from 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm. The compound is characterized by an X-ray powder diffraction pattern containing four or more reflections at 2-theta angles selected from the group consisting of: 2°, 19.7±0.2°, 20.1±0.2°, 20.5±0.2°, 21.1±0.2°, 24.3±0.2°, 24.5±0.2°, 25.1±0.2°, 25.6±0.2°, 26.6±0.2°, and 33.9±0.2°.

[0013] In a seventh aspect of the present invention, a crystalline form of Compound A (solvate S A ), wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising four or more reflections at 2-theta angles selected from the group consisting of 7.8±0.2°, 11.8±0.2°, 15.3±0.2°, 15.7±0.2°, 16.8±0.2°, 19.6±0.2°, 20.8±0.2°, 21.9±0.2°, 23.6±0.2°, 24.3±0.2°, and 27.6±0.2° when measured at a temperature in the range of 20-30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0014] In an eighth aspect of the present invention, a crystalline form of Compound A (solvate S B ) is provided, and the crystalline form exhibits 9.5±0.2°, 11.3±0.2°, 14.4±0.2°, 14.8±0.2°, 15.2±0.2°, 16.9±0.2°, 17.1±0.2°, 17.7±0.2°, 18.0±0.2°, 19.0±0.2°, 20.0±0.2°, 21.0±0.2°, 22.0±0.2°, 23.0±0.2°, 24.0±0.2°, 25.0±0.2°, 26.0±0.2°, 27.0±0.2°, 28.0±0.2°, 29.0±0.2°, 30.0±0.2°, 31.0±0.2°, 32.0±0.2°, 33.0±0.2°, 34.0±0.2°, 35.0±0.2°, 36.0±0.2°, 37.0±0.2°, 38.0±0.2°, 39.0±0.2°, 40.0±0.2°, 41.0±0.2°, 42.0±0.2°, 43.0±0.2°, 44.0±0.2°, 45.0±0.2°, 46.0±0.2°, 47.0±0.2°, 48.0±0.2°, 49.0±0.2°, 50.0±0.2°, 51.0±0.2°, 52.0±0.2°, 53.0±0.2°, 54.0±0.2°, 55.0 It is characterized by an X-ray powder diffraction pattern containing four or more reflections at 2-theta angles selected from the group consisting of 8.5±0.2°, 18.7±0.2°, 19.1±0.2°, 19.6±0.2°, 20.3±0.2°, 20.9±0.2°, 22.1±0.2°, 23.4±0.2°, 27.1±0.2°, 28.4±0.2°, and 28.8±0.2°.

[0015] In a ninth aspect of the present invention there is provided a method of treating and / or preventing cancer, in particular cancer characterized as microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), said method comprising the step of administering an effective amount of a solid form according to any of the first to eighth aspects.

[0016] In a tenth aspect of the present invention, there is provided a pharmaceutical composition comprising a crystalline form according to any of the first to eighth aspects and at least one pharmaceutically acceptable excipient. [Brief explanation of the drawings]

[0017] [Figure 1] 1 shows the XRPD pattern of Compound A Variant A. [Figure 2] 1 shows the XRPD pattern of Compound A Modification B. [Figure 3] 1 shows the XRPD pattern of Compound A Variant C. [Figure 4] 1 shows the XRPD pattern of Compound A Variant D. [Figure 5] 1 shows the XRPD pattern of Compound A hydrate HA. [Figure 6] 1 shows the XRPD pattern of Compound A hydrate HB. [Figure 7] 1 shows the XRPD pattern of Compound A hydrate HC. [Figure 8] 1 shows the XRPD pattern of Compound A solvate SA. [Figure 9] 1 shows the XRPD pattern of Compound A solvate SB. [Figure 10] 1 shows the XRPD pattern of Compound A hydrate HA. [Figure 11] 1 shows the XRPD pattern of Compound A amorphous form. [Figure 12] 1 shows the XRPD pattern of Compound A Variant A using a different instrumental method compared to FIG. DETAILED DESCRIPTION OF THE INVENTION

[0018] In one embodiment, there is provided a crystalline form of Compound A (Modification B), characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of 5.6±0.2°, 11.2±0.2°, 12.6±0.2°, 14.8±0.2°, 17.4±0.2°, 18.1±0.2°, 19.2±0.2°, 22.0±0.2°, 22.4±0.2°, 25.1±0.2°, 25.3±0.2°, 26.2±0.2°, 27.3±0.2°, 29.7±0.2°, and 34.5±0.2°, when measured at a temperature in the range of 20 to 30°C using Cu—K alpha radiation having a wavelength of 0.15418 nm.

[0019] In another embodiment, there is provided a crystalline form of Compound A (Variant B), said crystalline form being characterized by an X-ray powder diffraction pattern substantially the same as the X-ray diffraction pattern displayed in FIG. 2 when measured at a temperature ranging from 20 to 30° C. using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0020] In another embodiment, there is provided a crystalline form of Compound A (Modification C), which has the following molecular weights when measured using Cu-K alpha radiation having a wavelength of 0.15418 nm at a temperature ranging from 20 to 30° C.: 4.0±0.2°, 8.0±0.2°, 8.7±0.2°, 12.1±0.2°, 14.5±0.2°, 15.1±0.2°, 15.5±0.2°, 16.2±0.2°, 16.7±0.2°, 17.9±0.2°, 18.7±0.2°, 19.7±0.2°, 20.7±0.2°, 21.7±0.2°, 22.7±0.2°, 23.7±0.2°, 24.7±0.2°, 25.7±0.2°, 26.7±0.2°, 27.7±0.2°, 28.7±0.2°, 29.7±0.2°, 30.7±0.2°, 31.7±0.2°, 32.7±0.2°, 33.7±0.2°, 34.7±0.2°, 35.7±0.2°, 36.7±0.2°, 37.7±0.2°, 38.7±0.2°, 39.7±0.2°, 40.7±0.2°, 41.7±0.2°, 42.7±0.2°, 43.7±0.2°, 44.7±0.2°, 45.7±0.2°, 46.7±0.2°, 47.7±0.2°, 48.7±0.2 and an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of 19.8±0.2°, 20.2±0.2°, 20.6±0.2°, 23.4±0.2°, 24.2±0.2°, 25.4±0.2°, 26.5±0.2°, 28.5±0.2°, and 32.1±0.2°.

[0021] In another embodiment, there is provided a crystalline form of Compound A (Modification C), said crystalline form being characterized by an X-ray powder diffraction pattern substantially the same as the X-ray diffraction pattern displayed in FIG. 3 when measured at a temperature ranging from 20 to 30° C. using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0022] In another embodiment, there is provided a crystalline form of Compound A (Modification D), which has the following peaks when measured using Cu-K alpha radiation having a wavelength of 0.15418 nm at a temperature ranging from 20 to 30°C: 8.5±0.2°, 9.1±0.2°, 11.6±0.2°, 13.7±0.2°, 14.3±0.2°, 15.0±0.2°, 15.4±0.2°, 16.9±0.2°, 17.5±0.2°, 19.1±0.2°, 19. The compound is characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of 9±0.2°, 20.2±0.2°, 21.5±0.2°, 22.6±0.2°, 23.5±0.2°, 25.6±0.2°, 26.4±0.2°, 26.8±0.2°, 28.8±0.2°, and 30.3±0.2°.

[0023] In another embodiment, there is provided a crystalline form of Compound A (Variant D), said crystalline form being characterized by an X-ray powder diffraction pattern substantially the same as the X-ray diffraction pattern displayed in FIG. 4 when measured at a temperature ranging from 20 to 30° C. using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0024] In another embodiment, the crystalline form of Compound A (hydrate H A ), wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of: 7.8±0.2°, 8.4±0.2°, 11.8±0.2°, 15.7±0.2°, 16.4±0.2°, 16.8±0.2°, 17.4±0.2°, 17.7±0.2°, 19.7±0.2°, 20.2±0.2°, 24.3±0.2°, 24.7±0.2°, 25.1±0.2°, 26.6±0.2°, and 29.0±0.2°, when measured at a temperature in the range of 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0025] In another embodiment, the crystalline form of Compound A (hydrate H A ), wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 5 or FIG. 10 when measured at a temperature in the range of 20-30° C. using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0026] In another embodiment, the crystalline form of Compound A (hydrate H B), which has a crystal form with a refractive index of 9.0±0.2°, 13.6±0.2°, 14.7±0.2°, 15.8±0.2°, 16.1±0.2°, 16.4±0.2°, 17.4±0.2°, 18.4±0.2°, 19.3±0.2°, 20.3±0.2° when measured at a temperature ranging from 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm. , 22.1±0.2°, 22.7±0.2°, 23.1±0.2°, 24.8±0.2°, 25.4±0.2°, 29.6±0.2°, 30.1±0.2°, 31.1±0.2°, 32.1±0.2°, 32.7±0.2°, 33.1±0.2°, 34.8±0.2°, 35.4±0.2°, 36.1±0.2°, 37.1±0.2°, 38.1±0.2°, 39.1±0.2°, 40.1±0.2°, 41.1±0.2°, 42.1±0.2°, 42.7±0.2°, 43.1±0.2°, 44.8±0.2°, 45.4±0.2°, 46.1±0.2°, 47.1±0.2°, 48.1±0.2°, 49.1±0.2°, 50.1±0.2°, 51.1±0.2°, 52.1±0.2°, 53.1±0.2°, 54.1±0.2°, 55.1±0.2°, 56.1±0.2°, 57.1±0.2°, 58.1±0.2°, 59.1±0.2°, 60.1±0.2°, 61.1±0.2°, 62.1±0.2°, 63.1±0.2°, 64.1±0.2°, 65.1±0.2°, 66.1±0.2°, 67.1±0.2°, 68

[0027] In another embodiment, the crystalline form of Compound A (hydrate H B ) is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 6 when measured at a temperature in the range of 20-30° C. using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0028] In another embodiment, the crystalline form of Compound A (hydrate H C ), which has a crystal form with a refractive index of 8.0±0.2°, 8.7±0.2°, 11.8±0.2°, 12.2±0.2°, 14.9±0.2°, 15.2±0.2°, 15.6±0.2°, 16.4±0.2°, 16.8±0.2°, 19.7±0.2°, 20.1±0.2° when measured at a temperature ranging from 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm. , 20.5±0.2°, 21.1±0.2°, 24.3±0.2°, 24.5±0.2°, 25.1±0.2°, 25.6±0.2°, 26.6±0.2°, 33.9±0.2°, 40.5±0.2°, 41.5±0.2°, 42.5±0.2°, 43.5±0.2°, 44.5±0.2°, 45.1±0.2°, 45.6±0.2°, 46.6±0.2°, 47.5±0.2°, 48.5±0.2°, 49.5±0.2°, 50.5±0.2°, 51.5±0.2°, 52.5±0.2°, 53.5±0.2°, 54.5±0.2°, 55.5±0.2°, 56.5±0.2°, 57.5±0.2°, 58.5±0.2°, 59.5±0.2°, 60.5±0.2°, 61.5±0.2°, 62.5±0.2°, 63.5±0.2°, 64.5±0.2°, 65.5±0.2°, 66.5±0.2°, 67.5±0.2°, 68.5±0.2°, 69.5±0.2°, 70.5±0.2°, 71.5±0.2°, 72.5±0.2°, 73.5±0.2°, 74.5±0.2°, 75.5±0.2°, 76.5±0.2°, 77

[0029] In another embodiment, the crystalline form of Compound A (hydrate H C) is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 7 when measured at a temperature in the range of 20-30° C. using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0030] In another embodiment, the crystalline form of Compound A (solvate S A ), wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of: 7.8±0.2°, 11.8±0.2°, 15.3±0.2°, 15.7±0.2°, 16.8±0.2°, 19.6±0.2°, 20.8±0.2°, 21.9±0.2°, 23.6±0.2°, 24.3±0.2°, and 27.6±0.2°, when measured at a temperature in the range of 20-30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0031] In another embodiment, the crystalline form of Compound A (solvate S A ) is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 8 when measured at a temperature in the range of 20-30° C. using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0032] In another embodiment, the crystalline form of Compound A (solvate S B), which has a crystal form having a refractive index of 9.5±0.2°, 11.3±0.2°, 14.4±0.2°, 14.8±0.2°, 15.2±0.2°, 16.9±0.2°, 17.1±0.2°, 17.7±0.2°, 18.0±0.2°, 18.5±0.2°, 18.7±0.2°, 19.1±0.2°, 20.0±0.2°, 21.0±0.2°, 22.0±0.2°, 23.0±0.2°, 24.0±0.2°, 25.0±0.2°, 26.0±0.2°, 27.0±0.2°, 28.0±0.2°, 29.0±0.2°, 30.0±0.2°, 31.0±0.2°, 32.0±0.2°, 33.0±0.2°, 34.0±0.2°, 35.0±0.2°, 36.0±0.2°, 37.0±0.2°, 38.0±0.2°, 39.0±0.2°, 40.0±0.2°, 41.0±0.2°, 42.0±0.2°, 43.0±0.2°, 44.0±0.2°, 45.0±0.2°, 46.0±0.2°, 47.0±0.2°, 48.0±0.2°, 49.0±0.2°, 50.0±0.2°, 51.0±0.2°, 52.0±0.2°, 53.0 and an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of 19.6±0.2°, 20.3±0.2°, 20.9±0.2°, 22.1±0.2°, 23.4±0.2°, 27.1±0.2°, 28.4±0.2°, and 28.8±0.2°.

[0033] In another embodiment, the crystalline form of Compound A (solvate S B ) is provided, wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 9 when measured at a temperature in the range of 20-30° C. using Cu-K alpha radiation having a wavelength of 0.15418 nm.

[0034] composition In another embodiment, the invention relates to a composition comprising at least 90 wt. % of the crystalline form of Compound A as defined in any one of the embodiments herein, for example at least 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 wt. %, and even equal to about 100 wt. %, based on the total weight of the composition. The remaining material may include other solid forms of Compound A and / or reaction and / or process impurities resulting from the preparation of the composition.

[0035] Pharmaceutical Compositions and Uses In a further aspect, the present invention provides a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis or a pulmonary edema ... a method for treating a pulmonary arthritis or a pulmonary edema, a method for treating a pulmonary arthritis or a solid form, such as a crystalline or amorphous form, of compound A of the invention, or A composition containing an amorphous or crystalline form of Compound A of the present invention The present invention relates to the use of the compound of the present invention for the preparation of a pharmaceutical composition.

[0036] In another aspect, the present invention relates to a pharmaceutical composition comprising a solid form of Compound A as defined in any of the embodiments herein and at least one pharmaceutically acceptable excipient.

[0037] The at least one pharmaceutically acceptable excipient included in the pharmaceutical composition of the present invention is preferably selected from the group consisting of fillers, diluents, binders, disintegrants, lubricants, glidants, and combinations thereof.

[0038] In a preferred embodiment, the pharmaceutical composition is an oral solid dosage form. Preferably, the oral solid dosage form is selected from the group consisting of tablets, capsules, etc. In a particularly preferred embodiment, the oral dosage form is a tablet or a capsule, most preferably a tablet.

[0039] In a further aspect, the present invention relates to a solid form of Compound A, or a composition comprising a solid form of Compound A, as defined in any one of the embodiments herein, for use as a medicament.

[0040] In yet another aspect, the invention relates to a solid form of Compound A, or a composition comprising a solid form of Compound A, as defined in any of the embodiments herein, for use in the treatment of cancer, particularly cancers characterized as microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR).

[0041] In another preferred embodiment, the present invention relates to a method for treating and / or preventing cancer, in particular cancers characterized as microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), said method comprising the step of administering to a patient in need of such treatment an effective amount of a solid form as defined in any of the embodiments herein.

[0042] Crystalline forms disclosed herein

[0043] [Table 1]

[0044] Nine crystalline forms of Compound A are disclosed herein: four anhydrous forms (Variant A, Variant B, Variant C, and Variant D), three hydrates (Variant H), and three hydrates (Variant H). A , hydrate H B and hydrate H C ) and two solvates (solvate S A and solvate S B Included herein are figures illustrating the XRPD characterization data for all crystalline forms.

[0045] Modification B was converted to Modification A by suspension equilibration in most solvents at 25°C and 50°C, and in competitive suspension equilibration experiments with Modification A at 4°C. In methanol, dioxane, and methanol / water mixtures, hydrate H A A (partial) conversion to was observed. The formation of a hydrate from the anhydrous form requires the presence of water. Therefore, it is likely that the methanol and dioxane used in each experiment still contained traces of water.

[0046] Hydrate H B was obtained by anti-solvent precipitation from THF / water into water.

[0047] Transformation C only formed hydrate H when the relative humidity was less than 10%RH. A and absorbs moisture to form hydrate H C was converted to.

[0048] Variant D was found to be a hydrate H during DSC analysis. B was only obtained by heating above about 84°C.

[0049] Solvate S A was crystallized by evaporating a saturated solution of the drug substance in dichloromethane.

[0050] Solvate S B was found during crystallization process development after cooling crystallization from THF / IPAc. [Example]

[0051] Specific Examples and XRPD Data

[0052] [Table 2]

[0053] Preparation of morphogen B: 3.85 g of compound A was dissolved in 300 mL of EtOH and 250 mL of DCM at 40° C., and the solution was concentrated to 150 mL under reduced pressure. After standing at room temperature for 2 days, the resulting suspension was sonicated in an ultrasonic bath for 1.5 hours and then stirred at 0° C. for 2 hours. The crystalline material was filtered and washed with cold EtOH.

[0054] Modification B of Compound A (free form, not a salt) is a crystalline powder consisting of plate-like particles. This material is highly pure and exhibits a melting point of approximately 239°C with simultaneous recrystallization, followed by a second melt at approximately 274°C.

[0055] [Table 3]

[0056] Preparation of Plasmodiolus C: Compound A (crystal form: hydrate H A Approximately 50 mg of morph C was exposed to dry nitrogen (0% relative humidity) at room temperature for approximately 3 hours. Full conversion to morph C is observed.

[0057] [Table 4]

[0058] Preparation of morphogen D: Compound A (crystal form: hydrate H B) about 50 mg was heated to 100° C. using a heating rate of 20 K / min or less. Full conversion to variant D is observed.

[0059] [Table 5]

[0060] Hydrate H A Preparation of: Example 1 H A Approximately 50 mg of Compound A (Variant B) was mixed with 1 mL of the solvent mixture methanol / water 97:3 v / v. The mixture was stirred at 800 rpm at 25°C for 4 weeks. Additional solid drug substance may need to be added after a few days to ensure suspension. After 4 weeks, the resulting suspension was centrifuged at 13000 rpm for 3 minutes. The solid residue was analyzed by XRPD and the hydrate H A Conversion to was observed.

[0061] Example 2. H A A similar experiment was carried out using the solvent mixture methanol / water 90:10 v / v. In this experiment, the hydrate H A was formed.

[0062] Example 3 H A Approximately 200 mg of morph B was slurried in 4 mL of methanol overnight. The solid was separated by centrifugation and dried in air. Hydrate H A A satisfactory conversion to was observed.

[0063] [Table 6]

[0064] Hydrate H B Preparation of: Approximately 100 g of Compound A variant B was completely dissolved in 1 mL of THF / water (90 / 10) by sonication. Approximately 1 mL of water was added dropwise as an antisolvent until precipitation occurred. The suspension was stirred overnight, and the solid was separated by centrifugation and dried in air. Hydrate H B A satisfactory conversion to was observed.

[0065] [Table 7]

[0066] Hydrate H C Preparation of: Compound A (hydrate H A Approximately 50 mg of hydrate H was exposed to dry nitrogen for 3 hours, followed by an additional 72 hours at 40% relative humidity (all at room temperature). C A satisfactory conversion to was observed.

[0067] [Table 8]

[0068] Solvate S A Preparation of A saturated solution of Compound A Modification B in dichloromethane was prepared at room temperature. The solution was filtered to obtain a clear solution, which was allowed to evaporate slowly at room temperature. Solvate S A Crystallization of was observed.

[0069] [Table 9]

[0070] Solvate S B Preparation of 2 g of Compound A Modification B was added to 40 mL of tetrahydrofuran at 50° C., and the mixture was stirred for 30 minutes. The resulting solution was cooled to 35° C. in 10 minutes and kept at this temperature for 30 minutes. 10 mg of Modification B was added, followed by the slow addition of 40 mL of isopropyl acetate within 8 hours. The resulting mixture was cooled to 0° C. and stirred overnight. A suspension was obtained, which was filtered, and the filter cake was dried for 2 days. The resulting solid was found to be a new crystalline form, solvate S B The yield was 84%.

[0071] Amorphous form of Compound A An amorphous form of Compound A is also disclosed herein. The amorphous form was prepared as follows: Approximately 2 g of Compound A Variant B was completely dissolved in 40 mL of THF by sonication. This clear solution was added directly to excess heptane (1:10 v / v). The solid formed was immediately separated by centrifugation and dried under vacuum at 80° C. to remove residual solvent. Crystallinity was determined by XRPD, residual solvent by NMR, and T g was checked by mDSC.

[0072] XRPD (Variant B, C, D and all hydrates, solvates and non-crystalline forms) Equipment Bruker D8 Advance Detector: LynxEye (1D mode), aperture angle: 2.948° Radiation CuKα(0.15418nm) Monochromator Ni-filter X-ray generator power: 40kV, 40mA Step size 0.0164° or 0.0410° (2-theta) Time per step: 0.3 seconds Scanning range: 2°~40° 2-theta Scan time: 768 seconds or 279 seconds Slit Primary fixed irradiation sample size: 10 mm, Secondary: Opening angle: 2.2°, Axial solar: 2.5°

[0073] XRPD method (transformed body A) The instrumentation and synthesis methods for Variant A are described in WO 2022 / 249060.

[0074] definition In the context of the present invention, the following definitions have the indicated meanings unless expressly stated otherwise.

[0075] As used herein, the term "room temperature" refers to a temperature in the range of 20-30°C.

[0076] As used herein, with respect to X-ray powder diffraction, the term "reflection" refers to a peak in an X-ray diffractogram at a specific diffraction angle (Bragg angle) caused by constructive interference from X-rays scattered by parallel planes of atoms in a solid material that are distributed in a regularly repeating pattern with long-range positional order. Such solid materials are classified as crystalline, while amorphous materials are defined as solid materials that lack long-range order and exhibit only short-range order, resulting in widespread scattering. According to the literature, long-range order spans, for example, approximately 100-1000 atoms, while short-range order spans only a few atoms (see "Fundamentals of Powder Diffraction and Structural Characterization of Materials," by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, p. 3).

[0077] With respect to X-ray powder diffraction, the terms "essentially the same" or "substantially the same" mean that variations in the positions of reflections and the relative intensities of reflections should be taken into account. For example, typical 2-theta values ​​have an accuracy within ±0.2° 2-theta, preferably within ±0.1° 2-theta. Furthermore, one skilled in the art will understand that relative reflection intensities represent variations due to instrument-to-instrument variations, as well as crystallinity, preferred orientation, particle size, sample preparation, and other factors known to those skilled in the art, and should be viewed only as a qualitative measure.

[0078] The crystalline forms of Compound A of the present invention may be referred to herein as being characterized by graphical data "shown in" the drawings. Such data may include, for example, X-ray powder diffraction. Those skilled in the art will appreciate that factors such as variations in instrument type, sample orientation, sample concentration, and sample purity may lead to minor variations in such data when presented in graphical form, such as variations in the exact peak positions and peak intensities. However, comparison of the graphical data of the drawings herein with graphical data generated for another or unknown solid form, and confirmation that the two sets of graphical data relate to the same crystalline form, is well within the knowledge of those skilled in the art.

[0079] The terms "solid form" or "solid state form," as used herein, refer to any crystalline and / or amorphous phase of a compound.

[0080] As used herein, the term "amorphous" refers to a non-crystalline solid form of a compound. Amorphous compounds do not possess long-range order and do not exhibit X-ray powder diffraction patterns with distinct reflections.

[0081] "X-ray powder diffraction pattern" means an X-ray powder diffractogram.

[0082] As used herein, the term "variant" is used to refer to different crystalline forms that have the same chemical composition but differ in the spatial arrangement of the molecules, atoms, and / or ions that form the crystal.

[0083] The term "hydrate," as used herein, refers to a crystalline solid in which water is associated with or accommodated by the crystal structure, e.g., a crystalline solid in which water is part of the crystal structure or is enclosed within the crystal (water inclusions). Therefore, water can be present in stoichiometric or non-stoichiometric amounts. When water is present in stoichiometric amounts, the hydrate can be designated by adding a Greek multiple prefix. For example, a hydrate can be referred to as a hemihydrate or monohydrate, depending on the water / compound stoichiometry. Water content can be measured, for example, by Karl Fischer coulometry.

[0084] As used herein, "solvate" refers to a crystalline form of a molecule, atom, and / or ion that further comprises one or more solvent molecules incorporated into the crystal lattice structure. The solvent molecules in a solvate may be in an ordered and / or disordered arrangement. A solvate may comprise either a stoichiometric or non-stoichiometric amount of solvent molecules. For example, a solvate with a non-stoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate. A solvate may occur as a dimer or oligomer containing more than one molecule or compound A within the crystal lattice structure.

[0085] The term "anhydrous form" or "anhydrous" as used herein refers to a crystalline solid in which water is not associated with or accommodated by the crystal structure. The anhydrous form may still contain residual water that is not part of the crystal structure but may be adsorbed onto the surface of the crystal or absorbed into disordered regions of the crystal. Typically, the anhydrous form does not contain more than 2.0 wt. % water, preferably 1.0 wt. % or less water, based on the weight of the crystalline form.

[0086] The term "effective amount," as used herein with respect to Compound A, encompasses an amount of Compound A that produces the desired therapeutic and / or prophylactic effect.

[0087] As used herein, the term "about" means within a statistically significant range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1% of a given value or range. Such a range may also be within experimental error typical of the standard method used to measure and / or determine a given value or range.

[0088] As used herein, "substantially pure" when used with respect to a form means a compound having a purity of greater than 90 wt.%, e.g., greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 wt.%, and even equal to about 100 wt.%, based on the weight of the compound. The remaining material includes other forms of the compound and / or reaction and / or process impurities resulting from its preparation. For example, a crystalline form of Compound A can be considered substantially pure in that it has a purity of greater than 90 wt.%, as measured by means currently known and generally accepted in the art, with the remaining less than 10 wt.% material including other forms of Compound A and / or reaction and / or process impurities.

[0089] The term "pharmaceutically acceptable excipient," as used herein, refers to a substance that does not exhibit significant pharmacological activity at a given dose and that is added to a pharmaceutical composition in addition to an active pharmaceutical ingredient. Excipients can function as vehicles, diluents, release agents, disintegrants, dissolution modifiers, absorption enhancers, stabilizers, or manufacturing aids, among others. Excipients can include fillers (diluents), binders, disintegrants, lubricants, and glidants.

[0090] Biological Assays, Data and Synthesis The activity of Compound A according to the present invention was evaluated using in vitro and in vivo methods described in published patent application WO 2022 / 249060, in which activity data and synthetic routes for the compounds of Examples 42 and 123 (Compound A) are described.

Claims

1. 1. A crystalline form of Compound A (Modification B), characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of 5.6±0.2°, 11.2±0.2°, 12.6±0.2°, 14.8±0.2°, 17.4±0.2°, 18.1±0.2°, 19.2±0.2°, 22.0±0.2°, 22.4±0.2°, 25.1±0.2°, 25.3±0.2°, 26.2±0.2°, 27.3±0.2°, 29.7±0.2°, and 34.5±0.2°, when measured at a temperature in the range of 20-30°C using Cu—K alpha radiation having a wavelength of 0.15418 nm.

2. A crystalline form of Compound A (Modification B), characterized by an X-ray powder diffraction pattern substantially the same as the X-ray diffraction pattern shown in Figure 2, when measured at a temperature in the range of 20-30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm.

3. When measured at temperatures ranging from 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm, the values ​​were: 4.0±0.2°, 8.0±0.2°, 8.7±0.2°, 12.1±0.2°, 14.5±0.2°, 15.1±0.2°, 15.5±0.2°, 16.2±0.2°, 16.7±0.2°, 17.9±0.2°, 19.8±0.2°, 20.2±0.2°, 20.6±0.2° 1. A crystalline form of Compound A (Variant C) characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of 0.2°, 23.4±0.2°, 24.2±0.2°, 25.4±0.2°, 26.5±0.2°, 28.5±0.2°, and 32.1±0.2°.

4. A crystalline form of Compound A (Modification C), characterized by an X-ray powder diffraction pattern substantially the same as the X-ray diffraction pattern shown in Figure 3, when measured at a temperature ranging from 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm.

5. When measured at temperatures ranging from 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm, the values ​​were: 8.5±0.2°, 9.1±0.2°, 11.6±0.2°, 13.7±0.2°, 14.3±0.2°, 15.0±0.2°, 15.4±0.2°, 16.9±0.2°, 17.5±0.2°, 19.1±0.2°, 19.9±0.2°, 20.2±0.2°, 21.5±0.2°, 1. A crystalline form of Compound A (Variant D), characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of 22.6±0.2°, 23.5±0.2°, 25.6±0.2°, 26.4±0.2°, 26.8±0.2°, 28.8±0.2°, and 30.3±0.2°.

6. A crystalline form of Compound A (Variant D), characterized by an X-ray powder diffraction pattern substantially the same as the X-ray diffraction pattern shown in Figure 4, when measured at a temperature ranging from 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm.

7. 1. A crystalline form of Compound A (hydrate H), characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of: 7.8±0.2°, 8.4±0.2°, 11.8±0.2°, 15.7±0.2°, 16.4±0.2°, 16.8±0.2°, 17.4±0.2°, 17.7±0.2°, 19.7±0.2°, 20.2±0.2°, 24.3±0.2°, 24.7±0.2°, 25.1±0.2°, 26.6±0.2°, and 29.0±0.2°, when measured at a temperature in the range of 20 to 30°C using Cu—K alpha radiation having a wavelength of 0.15418 nm. Ａ ).

8. A crystalline form of Compound A (hydrate H) characterized by an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 5 or FIG. 10 when measured at a temperature in the range of 20 to 30° C. using Cu—K alpha radiation having a wavelength of 0.15418 nm. Ａ ).

9. When measured at temperatures ranging from 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm, the values ​​were 9.0±0.2°, 13.6±0.2°, 14.7±0.2°, 15.8±0.2°, 16.1±0.2°, 16.4±0.2°, 17.4±0.2°, 18.4±0.2°, 19.3±0.2°, 20.3±0.2°, 22.1±0.2°, and 23.

2. A crystalline form of Compound A (hydrate H) characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of: 7.7±0.2°, 23.1±0.2°, 24.8±0.2°, 25.4±0.2°, 29.6±0.2°, and 30.1±0.2°. Ｂ ).

10. A crystalline form of Compound A (hydrate H), characterized by an X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern shown in FIG. 6, when measured at a temperature ranging from 20 to 30° C. using Cu—K alpha radiation having a wavelength of 0.15418 nm. Ｂ ).

11. When measured at temperatures ranging from 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm, the values ​​were 8.0±0.2°, 8.7±0.2°, 11.8±0.2°, 12.2±0.2°, 14.9±0.2°, 15.2±0.2°, 15.6±0.2°, 16.4±0.2°, 16.8±0.2°, 19.7±0.2°, 20.1±0.2°, 20.5±0.2°, 21.1±0.2°, and 22.1±0.2°.

2. A crystalline form of Compound A (hydrate H) characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of 24.3±0.2°, 24.3±0.2°, 24.5±0.2°, 25.1±0.2°, 25.6±0.2°, 26.6±0.2°, and 33.9±0.2°. Ｃ ).

12. A crystalline form of Compound A (hydrate H), characterized by an X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern shown in FIG. 7, when measured at a temperature ranging from 20 to 30° C. using Cu—K alpha radiation having a wavelength of 0.15418 nm. Ｃ ).

13. 2. A crystalline form of Compound A (solvate S), characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of: 7.8±0.2°, 11.8±0.2°, 15.3±0.2°, 15.7±0.2°, 16.8±0.2°, 19.6±0.2°, 20.8±0.2°, 21.9±0.2°, 23.6±0.2°, 24.3±0.2°, and 27.6±0.2°, when measured at a temperature in the range of 20 to 30°C using Cu—K alpha radiation having a wavelength of 0.15418 nm. Ａ ).

14. A crystalline form of Compound A (solvate S) characterized by an X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern shown in FIG. 8 when measured at a temperature ranging from 20 to 30° C. using Cu—K alpha radiation having a wavelength of 0.15418 nm. Ａ ).

15. When measured at temperatures ranging from 20 to 30°C using Cu-K alpha radiation having a wavelength of 0.15418 nm, the values ​​were: 9.5±0.2°, 11.3±0.2°, 14.4±0.2°, 14.8±0.2°, 15.2±0.2°, 16.9±0.2°, 17.1±0.2°, 17.7±0.2°, 18.0±0.2°, 18.5±0.2°, 18.7±0.2°, 19.1±0.2°, 19.6±0.2° 20.3±0.2°, 20.9±0.2°, 22.1±0.2°, 23.4±0.2°, 27.1±0.2°, 28.4±0.2°, and 28.8±0.2°, characterized by an X-ray powder diffraction pattern comprising four or more reflections, preferably five or more reflections, more preferably six or more reflections, and even more preferably seven or more reflections at 2-theta angles selected from the group consisting of 20.3±0.2°, 20.9±0.2°, 22.1±0.2°, 23.4±0.2°, 27.1±0.2°, 28.4±0.2°, and 28.8±0.2°. Ｂ ).

16. A crystalline form of Compound A (solvate S) characterized by an X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern spectrum shown in FIG. 9 when measured at a temperature ranging from 20 to 30° C. using Cu—K alpha radiation having a wavelength of 0.15418 nm. Ｂ ).

17. A crystalline form according to any one of claims 1 to 16 for the preparation of a pharmaceutical composition.

18. A crystalline form according to any one of claims 1 to 16 for use as a pharmaceutical.

19. 19. The crystalline form of any one of claims 1 to 16, for use according to claim 18, wherein the medicament is for the treatment of cancer, in particular a cancer characterized as microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR).

20. a solid form of compound A according to any one of claims 1 to 16, or a composition comprising a solid form of compound A according to any one of claims 1 to 16, at least one pharmaceutically acceptable excipient; A pharmaceutical composition comprising:

21. 17. A method for treating and / or preventing cancer, in particular cancer characterized as microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), said method comprising the step of administering to a patient in need of such treatment an effective amount of a solid form according to any one of claims 1 to 16.

22. A process for the preparation of the crystalline form of any one of claims 1 to 16.

Images