Crystalline forms of biaryl YAP / TAZ-TEAD protein-protein interaction inhibitor

Abstract

The present invention relates to crystalline polymorphic forms of the biaryl YAP / TAZ-TEAD protein-protein interaction inhibitor 4-((2S, 4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2, 3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide (IAG933), and methods of using these forms in the treatment of cancer.

Description

TECHNICAL FIELD

[0001] The present invention relates generally to crystalline polymorphic forms of the bis-aryl YAP / TAZ-TEAD protein-protein interaction inhibitor 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methyl nicotinamide (IAG933), and methods of using these forms in the treatment of cancer. BACKGROUND

[0002] IAG933 is a YAP / TAZ-TEAD protein-protein interaction inhibitor useful for treating diseases or conditions mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction, such as cancer, particularly cancer having (i) one or more YAP / TAZ fusions; (ii) one or more NF2 / LATS1 / LATS2 truncating mutations or deletions; or (iii) one or more functional YAP / TAZ fusions. The synthesis of IAG933 is described in WO 2021 / 186324 (Example 155).

[0003] IAG933 has the following chemical structure:

[0004] Solid state forms of the active pharmaceutical ingredient (API) of a particular drug are often important determinants of the ease of manufacture, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids, and bioavailability in vivo of a drug. When the same composition of matter crystallizes in different lattice arrangements, crystalline forms arise, resulting in different thermodynamic properties and stabilities that are unique to a particular crystalline form. Crystalline forms can also include different hydrates or solvates of the same compound. In deciding which crystal form is preferred, many properties of the crystal forms are compared and the preferred crystal form is selected based on many physical property variables. In some cases where certain aspects, such as ease of manufacture, stability, etc., are considered key, it is entirely possible that one crystal form can be preferred. In other cases, a different form can be preferred for greater rate of dissolution and / or superior bioavailability.

[0005] Accordingly, this ability of a chemical substance to crystallize in more than one crystalline form can have profound effects on the shelf life, solubility, formulation characteristics, and processing characteristics of a drug. Furthermore, the effects of a drug can be influenced by the polymorphic form of the drug molecule. Different polymorphs can have different rates of uptake in the body, resulting in lower or higher bioactivity than desired. In extreme cases, an unwanted polymorph can even exhibit toxicity. The appearance of an unknown crystalline form during manufacturing can have significant impact.

[0006] It is not possible at this time to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in therapeutic compositions, or which polymorph will exhibit such desirable properties.

[0007] The free form of IAG933 (Variant A) is initially described in PCT / IB2022 / 058131, the contents of which are incorporated by reference. SUMMARY

[0008] The polymorphic forms of the present application are designed and optimized to bind to TEADs and selectively disrupt their interaction with YAP and TAZ, which is believed to result in a drug that can be used to treat the above-mentioned cancers. In particular, such cancers can be characterized by (but not limited to) some of the described aberrations. In certain aspects, advantages of the polymorphic forms of the present application include improved stability, hygroscopicity, and morphology, which can improve flow properties.

[0009] There is a need in the art for new polymorphic crystalline forms of 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methyl nicotinamide (IAG933) that are particularly advantageous in the development of a pharmaceutical product, for example, they exhibit improved properties, such as stability, hygroscopicity, and / or morphology (thereby improving flowability).

[0010] According to a first aspect of the present application, there is provided a succinate salt of 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methyl nicotinamide (IAG933).

[0011] According to a second aspect of the present application, there is provided a crystalline anhydrous 1 : 1 salt of 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methyl nicotinamide (IAG933) characterized by an X-ray powder diffraction pattern at room temperature (e.g. 20°C) comprising peaks at 12.34° ± 0.20°, 15.66° ± 0.20°, 21.98° ± 0.20° and 23.95° ± 0.20°, e.g. 12.34° ± 0.10°, 15.66° ± 0.10°, 21.98° ± 0.10° and 23.95° ± 0.10°, wherein the radiation used has a wavelength of .

[0012] According to a third aspect of the present application, there is provided a pharmaceutical composition comprising a succinate salt of the first or second aspect of the present application and a pharmaceutically acceptable carrier.

[0013] According to a fourth aspect of the application, there is provided a succinate salt according to the first or second aspect of the application or a pharmaceutical composition according to the third aspect of the application for use as a medicament.

[0014] According to a fifth aspect of the application, there is provided a combination comprising a succinate salt according to the first or second aspect of the application and one or more therapeutically active agents.

[0015] According to a sixth aspect of the application, there is provided a succinate salt according to the first or second aspect of the application or a pharmaceutical composition according to the third aspect of the application for use in the treatment of a disease or condition mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction; or for use in the treatment of a cancer or tumour having: (i) one or more YAP / TAZ fusions; (ii) one or more truncating mutations or deletions of NF2 / LATS1 / LATS2; or (iii) one or more functional YAP / TAZ fusions.

[0016] According to a seventh aspect of the application, there is provided a method of treating a disease or condition mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction; or a method of treating a cancer or tumour having: (i) one or more YAP / TAZ fusions; (ii) one or more truncating mutations or deletions of NF2 / LATS1 / LATS2; or (iii) one or more functional YAP / TAZ fusions; the method comprising administering to a subject in need thereof a therapeutically effective amount of a succinate salt according to the first or second aspect of the application; or a pharmaceutical composition according to the third aspect of the application; or a combination according to the fifth aspect of the application.

[0017] According to an eighth aspect of the application, there is provided a succinate salt according to the first or second aspect of the application or a pharmaceutical composition according to the third aspect of the application for use in the treatment of a cancer.

[0018] According to a ninth aspect of the application, there is provided a method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of a succinate salt according to the first or second aspect of the application; or a pharmaceutical composition according to the third aspect of the application; or a combination according to the fifth aspect of the application. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 X-ray powder diffraction pattern of the 1 :1 succinate salt (unsolvated) of IAG933 when using Cu Ka radiation at room temperature.

[0020] ​Figure 2 is a scanning electron microscope (SEM) image of 1 : 1 succinate crystals of IAG933.

[0021] Figure 3 is a differential scanning calorimetry (DSC) thermogram of 1 : 1 succinate of IAG933. Differential scanning calorimetry was performed for each crystalline form using a TA Discovery DSC instrument. 1-3 mg of sample was placed in an aluminum T-zero crucible closed with a pinhole lid. The heating rate was 10 °C / min over the temperature range between 0 °C and 300 °C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The endothermic peak is shown below. The extrapolated onset temperature of the endothermic melting peak (melting point) was evaluated. The accuracy of the sample temperature measured in this way is within about ±1 °C, and the heat of fusion can be measured within about ±5% relative error. Melting endotherm: T 起始 = 172 °C (melts upon decomposition)

[0022] Figure 4 is a thermogravimetric analysis (TGA) plot of 1 : 1 succinate of IAG933. TGA curves were obtained using a TA Discovery TGA instrument. 2-10 mg of sample was placed in an aluminum crucible and closed with a pinhole lid. TGA curves were measured at a heating rate of 10 °C / min between 30 °C-300 °C. LoD (loss on drying) was calculated between 30 °C and 200 °C. The weight loss was plotted against the measured sample temperature. Temperatures are reported in degrees Celsius (°C) and weight loss is reported in %. Loss on drying: LoD at 150 °C = 0.4%.

[0023] Figure 5 is an X-ray powder diffraction pattern of the free form “Variant A” of IAG933 using Cu K a radiation

[0024] Figure 6 is a differential scanning calorimetry (DSC) thermogram of the free form “Variant A” of IAG933. Differential scanning calorimetry was performed for each crystalline form using a TA Discovery DSC instrument. For each analysis, 1-3 mg of sample was placed in an aluminum T-zero crucible closed with a pinhole lid. The heating rate was 10 °C / min over the temperature range between 0 °C and 300 °C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The endothermic peak is shown below. The extrapolated onset temperature of the endothermic melting peak (melting point) was evaluated. The accuracy of the sample temperature measured in this way is within about ±1 °C, and the heat of fusion can be measured within about ±5% relative error. Melting endotherm: T 起始 = 117.5 °C (melts).

[0025] ​Figure 7 is a thermogravimetric analysis (TGA) plot of the free form "Variant A" of IAG933. The TGA curve was obtained using a TA Discovery TGA instrument. For each analysis, 2-10 mg of sample was placed in an aluminum crucible and closed with a pinhole lid. The TGA curve was measured between 30 °C - 300 °C at a heating rate of 10 °C / min. The LoD (loss on drying) was calculated between 27 °C and 110 °C. The weight loss was plotted against the sample temperature measured. The temperature is reported in degrees Celsius (°C) and the weight loss is reported in %. Loss on drying: LoD = 0.38%.

[0026] Figure 8 is an X-ray powder diffraction pattern of the 1 : 1 succinate salt (acetone solvate) of IAG933 at room temperature using Cu K a radiation DETAILED DESCRIPTION

[0027] There is a need in the art for new salt / crystalline forms of 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methyl nicotinamide. Such salt / crystalline forms can have desirable physicochemical properties that are particularly advantageous in the development of a pharmaceutical product, e.g., exhibit improved stability, hygroscopicity, and / or morphology (to improve flow properties).

[0028] According to a first aspect of the present application, there is provided a succinate salt of 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methyl nicotinamide (IAG933).

[0029] As shown in Example 3, the succinate salt of the present application has a number of positive features in terms of residual solvent content, melting point, hygroscopicity and stability compared to IAG933 free form Variant A. Furthermore, as shown in Example 3, the morphology of the IAG933 succinate salt is massive. This is generally advantageous as it typically leads to superior flow properties compared to needle or plate shaped crystals. Furthermore, as shown in Example 3, the succinate salt of the present application shows improved properties in terms of residual solvent content, melting point, hygroscopicity and stability compared to IAG933 free form Variant A. Figure 2

[0030] In one embodiment, the ratio of IAG933 to succinate salt is 1 : 1.

[0031] In one embodiment, the succinate salt has the following formula ​​

[0032] In one embodiment, the salt is crystalline.

[0033] In one embodiment, the salt is anhydrous.

[0034] In one embodiment, the salt is unsolvated.

[0035] In one embodiment, the salt is characterized by a room temperature (e.g., 20 °C) X-ray powder diffraction pattern comprising peaks at four or more 2-theta values selected from the group consisting of:

[0036] Angle (2 theta) 12.34°±0.20° 13.04°±0.20° 13.75°±0.20° 15.15°±0.20° 15.66°±0.20° 16.38°±0.20° 20.39°±0.20° 21.98°±0.20° 23.95°±0.20° 24.51°±0.20°

[0037] where the radiation used has a wavelength of

[0038] In one embodiment, the salt is characterized by a room temperature (e.g., 20 °C) X-ray powder diffraction pattern comprising peaks at five or more, e.g., six or more, e.g., seven or more, e.g., eight or more, e.g., nine or more, e.g., all 10 2-theta values selected from the group consisting of:

[0039] Angle (2 theta) 12.34°±0.20° 13.04°±0.20° 13.75°±0.20° 15.15°±0.20° 15.66°±0.20° 16.38°±0.20° 20.39°±0.20° 21.98°±0.20° 23.95°±0.20° 24.51°±0.20°

[0040] where the radiation used has a wavelength of

[0041] In one embodiment, the salt is characterized by an X-ray powder diffraction pattern at room temperature (e.g., 20 °C) comprising peaks at 12.34° ± 0.20°, 15.66° ± 0.20°, 21.98° ± 0.20°, and 23.95° ± 0.20°, e.g., 12.34° ± 0.10°, 15.66° ± 0.10°, 21.98° ± 0.10°, and 23.95° ± 0.10°, where the radiation used has a wavelength of

[0042] In one embodiment, at about room temperature, the salt has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction spectrum shown in Figure 1 where the radiation used has a wavelength of

[0043] According to a second aspect of the present application, there is provided herein an anhydrous (e.g., unsolvated) crystalline 1 : 1 ​​​​A salt characterized by an X-ray powder diffraction pattern at room temperature (e.g. 20°C) comprising peaks at 12.34° ± 0.20°, 15.66° ± 0.20°, 21.98° ± 0.20° and 23.95° ± 0.20°, e.g. peaks at 12.34° ± 0.10°, 15.66° ± 0.10°, 21.98° ± 0.10° and 23.95° ± 0.10°, wherein the radiation used has a wavelength of 0.15406 nm.

[0044] In embodiments of the first or second aspect of the application, at 100°K: a is 11.42 (± 0.2, e.g. ± 0.1) b is 14.59 (± 0.2, e.g. ± 0.1) c is 18.21 (± 0.2, e.g. ± 0.1) Z' is 1 ; and the space group is P2i2i2i.

[0045] In embodiments of the first or second aspect of the application, the X-ray powder diffraction pattern comprises one or more peaks selected from 9.09° ± 0.20°, 9.82° ± 0.20°, 10.93° ± 0.20°, 12.09° ± 0.20°, 13.04° ± 0.20°, 13.75° ± 0.20°, 14.36° ± 0.20°, 15.15° ± 0.20°, 16.19° ± 0.20°, 16.38° ± 0.20°, 17.29° ± 0.20°, 18.87° ± 0.20°, 19.21° ± 0.20°, 20.25° ± 0.20°, 20.39° ± 0.20°, 20.56° ± 0.20°, 22.80° ± 0.20°, 24.11° ± 0.20°, 24.51° ± 0.20° and 25.52° ± 0.20°, for example two or more, for example three or more, for example four or more, for example five or more, for example six or more, for example seven or more, for example eight or more, for example nine or more, for example 10 or more, for example 11 or more, for example 12 or more, for example 13 or more, for example 14 or more, for example 15 or more, for example 16 or more, for example 17 or more, for example 18 or more, for example 19 or more, for example all 20 peaks. In one embodiment, the X-ray powder diffraction pattern comprises one or more peaks selected from 9.09° ± 0.10°, 9.82° ± 0.10°, 10.93° ± 0.10°, 12.09° ± 0.10°, 13.04° ± 0.10°, 13.75° ± 0.10°, 14.36° ± 0.10°, 15.15° ± 0.10°, 16.19° ± 0.10°, 16.38° ± 0.10°, 17.29° ± 0.10°, 18.87° ± 0.10°, 19.21° ± 0.10°, 20.25° ± 0.10°, 20.39° ± 0.10°, 20.56° ± 0.10°, 22.80° ± 0.10°, 24.11° ± 0.10°, 24.51° ± 0.10° and 25.52° ± 0.10°, for example two or more, for example three or more, for example four or more, for example five or more, for example six or more, for example seven or more, for example eight or more, for example nine or more, for example 10 or more, for example 11 or more, for example 12 or more, for example 13 or more, for example 14 or more, for example 15 or more, for example 16 or more, for example 17 or more, for example 18 or more, for example all 19 or more, for example all 20 peaks.

[0046] According to a third aspect of the application, there is provided a pharmaceutical composition comprising a succinate salt according to the first or second aspect of the application and a pharmaceutically acceptable carrier.

[0047] According to a fourth aspect of the present application, there is provided a succinate salt according to the first or second aspect of the present application or a pharmaceutical composition according to the third aspect of the present application for use as a medicament.

[0048] According to a fifth aspect of the present application, there is provided a combination comprising a succinate salt according to the first or second aspect of the present application and one or more therapeutically active agents.

[0049] According to a sixth aspect of the present application, there is provided a succinate salt according to the first or second aspect of the present application or a pharmaceutical composition according to the third aspect of the present application for use in the treatment of a disease or disorder mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction; or for use in the treatment of a cancer or tumour having: (i) one or more YAP / TAZ fusions; (ii) one or more truncating mutations or deletions of NF2 / LATS1 / LATS2; or (iii) one or more functional YAP / TAZ fusions.

[0050] According to a seventh aspect of the present application, there is provided a method of treating a disease or disorder mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction, or a method of treating a cancer or tumour having: (i) one or more YAP / TAZ fusions; (ii) one or more truncating mutations or deletions of NF2 / LATS1 / LATS2; or (iii) one or more functional YAP / TAZ fusions; the method comprising administering to a subject in need thereof a therapeutically effective amount of a succinate salt according to the first or second aspect of the present application; or a pharmaceutical composition according to the third aspect of the present application; or a combination according to the fifth aspect of the present application.

[0051] According to an eighth aspect of the present application, there is provided a succinate salt according to the first or second aspect of the present application or a pharmaceutical composition according to the third aspect of the present application for use in the treatment of cancer.

[0052] According to a ninth aspect of the present application, there is provided a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a succinate salt according to the first or second aspect of the present application; or a pharmaceutical composition according to the third aspect of the present application; or a combination according to the fifth aspect of the present application.

[0053] In embodiments of the eighth or ninth aspect of the application, the cancer is selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and tunica vaginalis mesothelioma), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, oesophageal squamous cell carcinoma, oesophageal adenocarcinoma, urothelial carcinoma of the bladder and cutaneous squamous cell carcinoma), poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including childhood supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumour, solid tumour, breast cancer (including triple negative breast cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including large bowel cancer), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, oesophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma and hepatoblastoma), neuroblastoma, schwannoma, renal cancer, sarcoma (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcoma (UPS), Kaposi sarcoma, soft tissue sarcoma and rare soft tissue sarcoma), bone cancer, brain cancer, medulloblastoma, glioma, meningioma, and head and neck cancer (including head and neck squamous cell carcinoma).

[0054] Accordingly, the present application provides the following numbered embodiments:

[0055] Embodiment 1. A succinate salt of 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methyl nicotinamide (IAG933).

[0056] Embodiment 2. The succinate salt according to Embodiment 1, wherein the ratio of IAG933 to succinate salt is 1:1.

[0057] Embodiment 3. The succinate salt according to Embodiment 2, having the following formula

[0058] Embodiment 4. The succinate salt according to any one of the preceding embodiments, wherein the salt is crystalline.

[0059] Embodiment 5. The succinate salt according to any one of the preceding embodiments, wherein the salt is unsolvated.

[0060] Embodiment 6. The succinate salt according to any one of the preceding embodiments, characterised by a room temperature (e.g. 20°C) X-ray powder diffraction pattern comprising peaks at four or more 2 theta values selected from the group consisting of:

[0061] Angle (2 theta) 12.34°±0.20° 13.04°±0.20° 13.75°±0.20° 15.15°±0.20° 15.66°±0.20° 16.38°±0.20° 20.39°±0.20° 21.98°±0.20° 23.95°±0.20° 24.51°±0.20°

[0062] wherein the radiation used has a wavelength of

[0063] Example 7. The succinate salt according to any one of the preceding examples, characterized by a room temperature (e.g. 20°C) X-ray powder diffraction pattern comprising five or more, e.g. six or more, e.g. seven or more, e.g. eight or more, e.g. nine or more, e.g. all 10 peaks at 2-theta values selected from the group consisting of:

[0064]

[0065]

[0066] wherein the radiation used has a wavelength of

[0067] Example 8. The succinate salt according to any one of the preceding examples, characterized by a room temperature (e.g. 20°C) X-ray powder diffraction pattern comprising peaks at 12.34°±0.20°, 15.66°±0.20°, 21.98°±0.20° and 23.95°±0.20°, e.g. at 12.34°±0.10°, 15.66°±0.10°, 21.98°±0.10° and 23.95°±0.10°, wherein the radiation used has a wavelength of

[0068] Example 9. The succinate salt according to any one of the preceding examples, having at about room temperature, an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction spectrum shown in Figure 1 wherein the radiation used has a wavelength of

[0069] Example 10. An anhydrous crystalline 1 : 1 salt, characterized by a room temperature (e.g. 20°C) X-ray powder diffraction pattern comprising peaks at 12.34°±0.20°, 15.66°±0.20°, 21.98°±0.20° and 23.95°±0.20°, e.g. at 12.34°±0.10°, 15.66°±0.10°, 21.98°±0.10° and 23.95°±0.10°, wherein the radiation used has a wavelength of

[0070] Example 10a. The succinate salt according to any one of the preceding claims, wherein the succinate salt is unsolvated.

[0071] ​​​​​Example 11. The succinate salt according to any one of the preceding Examples, wherein at 100° K: a is 11.42 (± 0.2, e.g. ± 0.1) b is 14.59 (± 0.2, e.g. ± 0.1) c is 18.21 (± 0.2, e.g. ± 0.1) Z’ is 1 ; and the space group is P212121.

[0072] Example 12. A pharmaceutical composition comprising the succinate salt according to any one of the preceding Examples and a pharmaceutically acceptable carrier.

[0073] Example 13. The succinate salt according to any one of Examples 1 to 11 or the pharmaceutical composition according to Example 12 for use as a medicament.

[0074] Example 14. A combination comprising the succinate salt according to any one of Examples 1 to 11 and one or more therapeutically active agents.

[0075] Example 15. The succinate salt according to any one of Examples 1 to 11 or the pharmaceutical composition according to Example 12 for use in treating a disease or disorder mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction; or for use in treating a cancer or a tumor having: (i) one or more YAP / TAZ fusions; (ii) one or more NF2 / LATS1 / LATS2 truncating mutations or deletions; or (iii) one or more functional YAP / TAZ fusions.

[0076] Example 16. A method of treating a disease or disorder mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction; or a method of treating a cancer or a tumor having: (i) one or more YAP / TAZ fusions; (ii) one or more NF2 / LATS1 / LATS2 truncating mutations or deletions; or (iii) one or more functional YAP / TAZ fusions; the method comprising administering to a subject in need thereof a therapeutically effective amount of the succinate salt according to any one of Examples 1 to 11 ; or the pharmaceutical composition according to Example 12; or the combination according to Example 14.

[0077] Example 17. The succinate salt according to any one of Examples 1 to 11 or the pharmaceutical composition according to Example 12 for use in treating a cancer.

[0078] Example 18. The succinate salt for use according to Example 17, wherein the cancer is selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and tunica vaginalis mesothelioma), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, urothelial carcinoma of the bladder, and cutaneous squamous cell carcinoma), poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including childhood supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumors, solid tumors, breast cancer (including triple-negative breast cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including large bowel cancer), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma), neuroblastoma, schwannoma, renal cancer, sarcoma (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcoma (UPS), Kaposi sarcoma, soft tissue sarcoma, and rare soft tissue sarcoma), bone cancer, brain cancer, medulloblastoma, glioma, meningioma, and head and neck cancer (including head and neck squamous cell carcinoma).

[0079] Example 19. A method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of the succinate salt according to any one of Examples 1 to 11; or the pharmaceutical composition according to Example 12; or the combination according to Example 14.

[0080] Example 20. The method according to Example 19, wherein the cancer is selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and tunica vaginalis mesothelioma), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, urothelial carcinoma of the bladder, and cutaneous squamous cell carcinoma), poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including childhood supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumors, solid tumors, breast cancer (including triple-negative breast cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including large bowel cancer), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma), neuroblastoma, schwannoma, renal cancer, sarcoma (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcoma (UPS), Kaposi sarcoma, soft tissue sarcoma, and rare soft tissue sarcoma), bone cancer, brain cancer, medulloblastoma, glioma, meningioma, and head and neck cancer (including head and neck squamous cell carcinoma).

[0081] Example 21. A crystalline 1:1 A salt acetone solvate characterized by an X-ray powder diffraction pattern at room temperature (e.g., 20 °C) comprising peaks at 8.79° ± 0.20°, 10.38° ± 0.20°, 19.27° ± 0.20°, and 22.77° ± 0.20°, e.g., peaks at 8.79° ± 0.10°, 10.38° ± 0.10°, 19.27° ± 0.10°, and 22.77° ± 0.10°, wherein the radiation used has a wavelength of

[0082] Example 21a. A salt according to Example 21 characterized by one or more, e.g., two or more, e.g., three or more, e.g., four or more, e.g., five or more, e.g., six or more, e.g., seven or more, e.g., eight or more, e.g., nine or more, e.g., 10 or more, e.g., 11 or more, e.g., 12 or more, e.g., 13 or more, e.g., 14 or more, e.g., 15 or more, e.g., all 16 additional peaks selected from:

[0083] 10.04°±0.20° 10.62°±0.20° 12.23°±0.20° 14.33°±0.20° 14.99°±0.20° 16.28°±0.20° 16.69°±0.20° 16.98°±0.20° 18.06°±0.20° 20.07°±0.20° 21.95°±0.20° 22.95°±0.20° 24.59°±0.20° 25.45°±0.20° 25.82°±0.20° 26.01°±0.20°

[0084] Definitions

[0085] As used herein, "polymorph," "form," "crystal modification(s)" or "crystalline form" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions that form the crystal.

[0086] As used herein, the term "salt" or "salts" refers to either acid addition salts or base addition salts of the compounds of the application. "Salts" include, inter alia, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" means a salt that retains the biological effectiveness and properties of the compounds of the application and that is typically not biologically or otherwise undesirable. In many cases, the compounds of the application are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. When both basic and acidic groups are present in the same molecule, the compounds of the application can also form inner salts, e.g., zwitterionic molecules.

[0087] ​As used herein, the term "unsolvated" means that the ratio of IAG933 to solvent molecules (i.e., molecules that are liquid at ambient pressure and temperature) in the crystal structure is greater than 2: 1, e.g., greater than or equal to 3: 1, e.g., greater than or equal to 4: 1, e.g., greater than or equal to 5: 1, e.g., greater than or equal to 7.5: 1, e.g., greater than or equal to 10: 1, e.g., greater than or equal to 20: 1, e.g., greater than or equal to 50: 1, at ambient temperature (e.g., 20 °C) and 30% to 60% relative humidity (e.g., 40-50% relative humidity, e.g., about 45% relative humidity). In the case where water is the solvent, the "unsolvated" form is "anhydrous".

[0088] As used herein, the term "anhydrous" means that the ratio of IAG933 to water in the crystal structure is greater than 2: 1, e.g., greater than or equal to 3: 1, e.g., greater than or equal to 4: 1, e.g., greater than or equal to 5: 1, e.g., greater than or equal to 7.5: 1, e.g., greater than or equal to 10: 1, e.g., greater than or equal to 20: 1, e.g., greater than or equal to 50: 1, at ambient temperature (e.g., 20 °C) and 30% to 60% relative humidity (e.g., 40-50% relative humidity, e.g., about 45% relative humidity). In one particular embodiment, there is substantially no water (e.g., less than 1 mass%, e.g., less than 0.5 mass%) in the crystal structure at 20 °C at 45% relative humidity. It will be appreciated that even "anhydrous" forms (as defined herein) typically have slight hygroscopicity. For example, IAG933 1: 1 succinate of the application has a water uptake of 0.75% at 95% relative humidity after DVS (dynamic vapor sorption) testing.

[0089] As used herein, "amorphous" refers to a solid form that does not have molecules, atoms, and / or ions that are crystalline. Amorphous solids do not show a distinct X-ray diffraction pattern. Crystalline solids, on the other hand, show an X-ray diffraction pattern with distinct peaks resulting from Bragg diffraction.

[0090] The term "substantially the same" with respect to X-ray diffraction peak positions means that typical peak position and intensity variability is taken into account. For example, one skilled in the art will appreciate that peak positions (2 theta) will show some variability between instruments, typically up to 0.2°. Furthermore, one skilled in the art will appreciate that relative peak intensities will show variability between instruments as well as variability due to crystallinity, preferred orientation, sample surface prepared, and other factors known to one skilled in the art, and should be taken only as a qualitative measure. One skilled in the art of X-ray powder diffraction is able to readily determine whether a given sample is from the same polymorph as a reference sample.

[0091] As used herein, the terms“about” and“substantially” indicate that for features such as endotherms, endotherm peaks, exotherms, baseline shifts, etc., their values can vary. In reference to X-ray diffraction peak positions,“about” or“substantially” means to account for typical peak position and intensity variability. For example, it will be understood by those skilled in the art that peak positions (2 theta) will show some variability between instruments, typically up to 0.2°. Occasionally, the variability can be higher than 0.2° depending on differences in apparatus calibration. Furthermore, it will be understood by those skilled in the art that relative peak intensities will show variability between instruments as well as variability due to crystallinity, preferred orientation, sample surface prepared, and other factors known to those skilled in the art, and should be taken only as qualitative measurements. For DSC, the temperature changes observed will depend on the rate of temperature change as well as sample preparation techniques and the particular instrument used. Thus, the endothermic / melting point values reported herein in reference to DSC / TGA thermograms can vary by ± 5°C (and still be considered characteristic of the particular crystalline form described herein). When used in the context of other features such as, for example, weight percent (% by weight), reaction temperatures, the term“about” indicates a variation of ± 5%.

[0092] The term“therapeutically effective amount” of a crystalline form of the present application refers to an amount of a crystalline form of the present application that will elicit a biological or medical response of a subject, for example, a reduction or inhibition of enzyme or protein activity, or an improvement in symptoms, alleviation of a condition, slowing or delaying of disease progression, or prevention of a disease, etc. In one non-limiting embodiment, the term“therapeutically effective amount” refers to an amount of a compound of the present application that, when administered to a subject, is effective to: (1) at least partially alleviate, inhibit, prevent, and / or ameliorate a condition or disorder or disease that (i) is associated with over-activation of YAP / TAZ-TEAD complex, (ii) is mediated by YAP overexpression and / or YAP amplification, or (iii) is associated with YAP activity, or (iv) is characterized by activity of YAP (normal or abnormal); or (2) reduce or inhibit the interaction of YAP and / or TAZ with TEAD. In another non-limiting embodiment, the term“therapeutically effective amount” refers to an amount of a crystalline form of the present application that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit the interaction of YAP and / or TAZ with TEAD.

[0093] As used herein, the terms“a,”“an,”“the,” and similar pronouns used in the context of the present application, particularly in the context of the claims, should be interpreted to cover both the singular and plural unless otherwise indicated or clearly contradicted by the context.

[0094] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed.

[0095] As used herein, the terms "inhibit," "inhibition," or "inhibiting" means to reduce or suppress a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0096] As used herein, the terms "treat," "treating," or "treatment" with reference to any disease or disorder, in one embodiment, means to ameliorate the disease or disorder (i.e., to slow or arrest or reduce the development of the disease or at least one clinical symptom thereof). In another embodiment, "treatment" means to alleviate or ameliorate at least one physical parameter including those not endurable to the patient. In yet another embodiment, "treat," "treating," or "treatment" means to modulate, either physically or physiologically, the disease or disorder. In one embodiment, "treat" or "treating" means to delay the progression of the disease or disorder.

[0097] As used herein, the term "prevention" of any disease or disorder means prophylactic treatment of the disease or disorder; or delaying the onset of the disease or disorder.

[0098] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. The term "therapeutically effective amount" of a compound of the application refers to the amount of the compound of the application that will elicit the biological or medical response (e.g., reduction or inhibition of an enzyme or protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.) in a subject that is being sought. In one non-limiting embodiment, the term "therapeutically effective amount" refers to the amount of a compound of the application that, when administered to a subject, is effective to: (1) at least partially alleviate, inhibit, prevent and / or ameliorate a condition or disorder or disease that (i) is mediated by YAP / TAZ-TEAD protein-protein interaction (PPI), or (ii) is associated with YAP / TAZ TEAD PPI activity, or (iii) is characterized by activity of YAP / TAZ-TEAD PPI, or (2) reduce or inhibit the activity of YAP / TAZ-TEAD PPI; or (3) reduce or inhibit the expression of YAP / TAZ-TEAD. In another non-limiting embodiment, the term "therapeutically effective amount" refers to the amount of a compound of the application that, when administered to a cell, or tissue, or non-cellular biological material, or medium, is effective to at least partially reduce or inhibit the activity of YAP / TAZ-TEAD PPI.

[0099] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. A subject refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In preferred embodiments, the subject is a human.

[0100] As used herein, a subject is "in need of" or "in need thereof" if such subject would benefit biologically, medically or in quality of life from the treatment.

[0101] The term "comprising" encompasses "including" as well as "consisting"; e.g., a composition comprising X may consist exclusively of X, or may include something additional, e.g., X and Y.

[0102] The crystalline forms of the application can be administered simultaneously, or before or after, one or more other therapeutic agents. The crystalline forms of the application can be administered separately by the same or different routes of administration as the other agents, or together in the same pharmaceutical composition. A therapeutic agent is a chemical compound, peptide, antibody, antibody fragment, or nucleic acid that is, for example, therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the application.

[0103] In the combination therapy of the application, the crystalline forms of the application and other therapeutic agents can be manufactured and / or formulated by the same or different manufacturers. Also, the crystalline forms of the application and other therapeutic agents can be brought together into a combination therapy: (i) before release to the physician(s) for example in the case of a kit containing the crystalline forms of the application and other therapeutic agents; (ii) by the physician(s) shortly before administration, for example in the case of a kit containing the crystalline forms of the application and other therapeutic agents; (iii) in the patient themselves, for example in the case of a kit containing the crystalline forms of the application and other therapeutic agents which are to be taken separately according to some dosing regimen.

[0104] The synthesis of compound (IAG933) of the application and amorphous forms of IAG933 are initially described in WO 2021 / 186324, the contents of which are incorporated by reference. The free form of IAG933 (Variant A) is initially described in PCT / IB2022 / 058131, the contents of which are incorporated by reference. IAG933 has the following structure Another chemical name for IAG933 is (4P)-4-{(2S)-5-chloro-6-fluoro-2-phenyl-2-[(2S)-pyrrolidin-2-yl]-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2-hydroxyethoxy)-N-methylpyridine-3-carboxamide.

[0105] Examples

[0106] Example 1 - Preparation and characterisation of IAG933 1 :1 succinate (unsolvated)

[0107] a. Method of preparation of IAG933 1 :1 succinate (unsolvated)

[0108] In a 20 mL vial, 118 mg of succinic acid was added to 500 mg of IAG933 free form variant A (the formation of IAG933 free form variant A is described in Example 2 below). To the vial was added 10 mL of acetone which was then heated to 50 °C for four hours with stirring. The vial was then cooled to room temperature and held at that temperature with stirring overnight. The resulting mixture was filtered and dried under vacuum at 50 °C for 24 hours to form IAG933 1 :1 succinate (unsolvated).

[0109] b.XRPD pattern of IAG933 1 : 1 succinate (unsolvated)

[0110] XRPD method

[0111] X-ray powder diffraction (XRPD) patterns were obtained using a Bruker Advance D8 in reflection geometry. The powder was analysed using a zero background Si plate sample holder. The radiation used was Cu Ka The pattern was measured between 2° and 40° 2 theta.

[0112] Sample amount: 5-10 mg

[0113] Sample holder: Zero background Si plate sample holder

[0114] XRPD parameters

[0115]

[0116] (XRPD pattern see Figure 1 1) Figure 1 The most characteristic peaks in the XRPD are bolded and italicized and labelled A, B, C, D.

[0117]

[0118]

[0119] c.Unit cell of IAG933 1 : 1 succinate (unsolvated)

[0120] The crystal structure of IAG933 1 : 1 succinate (unsolvated) was determined at 100K. Its structure contains 1 IAG933 cation and 1 succinate anion (no solvent molecules) in the asymmetric unit (Z' = 1) in the space group P212121. The crystal structure information is listed in the table below.

[0121]

[0122] Example 2 - Preparation and characterisation of IAG933 free form (Variant A)

[0123] a.Method for preparation of IAG933 free form (Variant A)

[0124] al: About 53 mg of IAG933 (amorphous) was weighed into a vial, then 0.4 mL of acetone was added and mixed at 450 rpm for 1 hour at room temperature. The solid was then filtered and vacuum dried at 40 °C for 2 hours to form IAG933 free form (Variant A).

[0125] a2: About 53 mg of IAG933 (amorphous) was weighed into a vial, then 0.4 mL of acetonitrile was added and mixed at 450 rpm for 1 hour at room temperature. The solid was then filtered and dried under vacuum at 40 °C for 2 hours to form IAG933 free form (Variant A).

[0126] a3: About 3 g of IAG933 amorphous free form was added to 200 mL ACN / water = 1 / 1 at 40 °C, the mixture was stirred at 600 rpm for about 6 hours, then cooled to 10 °C over 6 hours and left stirring overnight. The obtained solid was re-equilibrated in 20 mL EtOH / water = 1 / 9 at 50 °C for about 6 hours, then gradually cooled to 10 °C over 6 hours and stirred overnight. The solid was isolated by suction filtration and dried under vacuum at 50 °C overnight to form IAG933 free form (Variant A).

[0127] a4: About 18 g of IAG933 amorphous free form was weighed into a crystallizer. 200 mL ACN / water = 1 / 9 (v / v) was added. The mixture was stirred at 40 °C at 150 rpm for about 6 hours, then gradually cooled to room temperature and stirred overnight. The solid was isolated by filtration and subsequently dried under vacuum at 50 °C overnight. About 17.2 g of white solid was obtained (IAG933 free form Variant A).

[0128] b. XRPD of IAG933 free form Variant A

[0129] XRPD method

[0130] X-ray powder diffraction (XRPD) patterns were obtained using a Bruker Advance D8 in reflection geometry. The powders were analysed using a zero background Si plate sample holder. The radiation used was Cu Ka The patterns were measured between 2° and 40° 2 theta.

[0131] Sample amount: 5-10 mg

[0132] Sample holder: Zero background Si plate sample holder

[0133] XRPD parameters

[0134]

[0135] (XRPD patterns see Figure Figure 5 , the strongest peaks are shown below and are bolded and italicized)

[0136]

[0137] Example 3 - Property comparison of IAG933 1 : 1 succinate (unsolvated) and IAG933 free form variant A

[0138] Stability studies

[0139]

[0140]

[0141]

[0142] ↓Suspension / Clear solution after pressure test / Not tested A: no color change / B: slight color change / C: moderate color change / D: strong color change

[0143]

[0144]

[0145] Solubility studies

[0146]

[0147]

[0148] Example 4 - Preparation and characterization of IAG933 1 : 1 succinate (acetone solvate)

[0149] a. Method of preparation of IAG933 1 : 1 succinate (acetone solvate)

[0150] An excess of IAG933 1 : 1 succinate (as prepared in Example 1) was added to acetone / water (94:6 v / v) to form a suspension. The suspension was then shaken at 25 °C for 34 days. A sample of the suspension was transferred to a filter centrifuge tube and the solid IAG933 1 : 1 succinate (acetone solvate) was isolated by centrifugation.

[0151] b. XRPD pattern of IAG933 1 : 1 succinate (acetone solvate)

[0152] XRPD method

[0153] X-ray powder diffraction (XRPD) patterns were obtained using a Bruker Advance D8 in reflection geometry. The powder was analysed using a zero background Si plate sample holder. The radiation used was Cu Ka The pattern was measured between 2° and 40° 2 theta.

[0154] Sample amount: 5-10 mg

[0155] Sample holder: Zero background Si plate sample holder

[0156] XRPD parameters

[0157]

[0158] (XRPD pattern see Figure 8 The most characteristic peaks in the XRPD are bolded and italicized and labeled A, B, C, D.

[0159]

Claims

1. A succinate salt of 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide (IAG933).

2. The succinate salt according to claim 1, wherein the ratio of IAG933 to succinate salt is 1:

1.

3. The succinate according to claim 2, having the formula 4. The succinate salt according to any one of the preceding claims, wherein the salt is crystalline.

5. The succinate salt according to any one of the preceding claims, wherein the salt is unsolvated.

6. The succinate according to any one of the preceding claims, characterized in that A room temperature X-ray powder diffraction pattern comprising peaks at four or more 2-theta values ​​selected from the group consisting of: The radiation used has wavelength.

7. The succinate according to any one of the preceding claims, characterized in that A room temperature X-ray powder diffraction pattern comprising peaks at five or more values ​​selected from the group consisting of: The radiation used has wavelength.

8. The succinate according to any one of the preceding claims, characterized in that An X-ray powder diffraction pattern at room temperature comprising peaks at 12.34°±0.20°, 15.66°±0.20°, 21.98°±0.20°, and 23.95°±0.20°, wherein the radiation used has wavelength.

9. The succinate salt according to any one of the preceding claims, which has an X-ray powder diffraction pattern substantially the same as that shown in Figure 1 at about room temperature, wherein the radiation used has wavelength.

10. Anhydrous crystal 1:1 Salt, characterized in that An X-ray powder diffraction pattern at room temperature comprising peaks at 12.34°±0.20°, 15.66°±0.20°, 21.98°±0.20°, and 23.95°±0.20°, wherein the radiation used has wavelength.

11. The succinate salt according to any one of the preceding claims, wherein at 100°K: a is b is c is Z' is 1; and The space group is P212121.

12. A pharmaceutical composition comprising the succinate salt according to any one of the preceding claims and a pharmaceutically acceptable carrier.

13. The succinate salt according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 for use as a medicament.

14. A combination comprising a succinate salt according to any one of claims 1 to 11 and one or more therapeutically active agents.

15. The succinate salt according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12, for use in the treatment of a disease or condition mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction; or for use in the treatment of a cancer or tumor having: (i) one or more YAP / TAZ fusions; (ii) one or more NF2 / LATS1 / LATS2 truncating mutations or deletions; or (iii) one or more functional YAP / TAZ fusions.

16. A method of treating a disease or condition mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction, or a method of treating a cancer or tumor having: (i) one or more YAP / TAZ fusions; (ii) one or more NF2 / LATS1 / LATS2 truncating mutations or deletions; or (iii) one or more functional YAP / TAZ fusions; the method comprising administering to a subject in need thereof a therapeutically effective amount of a succinate salt according to any one of claims 1 to 11; or a pharmaceutical composition according to claim 12; or a combination according to claim 14.

17. The succinate salt according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 for use in the treatment of cancer.

18. The succinate salt for use according to claim 17, wherein the cancer is selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the vagina), carcinoma (including cervical squamous cell carcinoma, endometrial cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, bladder urothelial carcinoma and skin squamous cell carcinoma), poromas (benign poromas), porocarcinomas (including malignant porocarcinomas), supratentorial ependymomas (including supratentorial ependymomas in children), epithelioid hemangioendothelioma (EHE), ependymal tumors, solid tumors, breast cancer (including triple negative breast cancer) ), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colorectal cancer), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma and hepatoblastoma), neuroblastoma, neurilemmoma, kidney cancer, sarcoma (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcoma (UPS), Kaposi sarcoma, soft tissue sarcoma and rare soft tissue sarcomas), bone cancer, brain cancer, medulloblastoma, glioma, meningioma, and head and neck cancer (including head and neck squamous cell carcinoma).

19. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a succinate salt according to any one of claims 1 to 11; or a pharmaceutical composition according to claim 12; or a combination according to claim 14.

20. The method of claim 19, wherein the cancer is selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the vagina), carcinoma (including cervical squamous cell carcinoma, endometrial cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, bladder urothelial carcinoma and skin squamous cell carcinoma), poromas (benign poromas), porocarcinomas (including malignant porocarcinomas), supratentorial ependymomas (including supratentorial ependymomas in children), epithelioid hemangioendothelioma (EHE), ependymal tumors, solid tumors, breast cancer (including triple-negative breast cancer), lung carcinoma (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colorectal cancer), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma and hepatoblastoma), neuroblastoma, schwannoma, kidney cancer, sarcoma (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcoma (UPS), Kaposi sarcoma, soft tissue sarcoma and rare soft tissue sarcomas), bone cancer, brain cancer, medulloblastoma, glioma, meningioma, and head and neck cancer (including head and neck squamous cell carcinoma).

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