EP4669643A1

EP4669643A1 - CRYSTALLINE FORMS OF A BIARYL-YAP/TAZ-TEAD PROTEIN INTERACTION INTAKER

Info

Publication number: EP4669643A1
Application number: EP24707928.8A
Authority: EP
Inventors: Yu GAI; Anett Perlberg; Haihao Tang; Zhixiang Shen
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2023-02-23
Filing date: 2024-02-21
Publication date: 2025-12-31
Also published as: CN120769852A; WO2024176128A1; JP2026506785A; TW202434575A

Abstract

The 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), as well as methods of using the forms in the treatment of cancer.

Description

CRYSTALLINE FORMS OF A BIARYL YAP/TAZ-TEAD PROTEIN-PROTEIN INTERACTION INHIBITOR

FIELD OF THE DISCLOSURE

The present invention generally 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), as well as methods of using the forms in the treatment of cancer.

BACKGROUND

IAG933 is a YAP/TAZ-TEAD protein-protein interaction inhibitor useful in the treatment of diseases or conditions mediated by YAP overexpression and/or YAP amplification and/or YAP/TAZ-TEAD interaction, such as cancers, particularly cancers harboring (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 WO2021/186324 (Example 155).

IAG933 has the following chemical structure:

Solid state form of the active pharmaceutical ingredient (API) of a particular drug is often an important determinant of the drug's ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids and in vivo bioavailability. Crystalline forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and stabilities specific to the particular crystalline form. Crystalline forms may also include different hydrates or solvates of the same compound. In deciding which form is preferable, the numerous properties of the forms are compared and the preferred form chosen based on the many physical property variables. It is entirely possible that one form can be preferable in some circumstances where certain aspects such as ease of preparation, stability, etc. are deemed to be critical. In other situations, a different form may be preferred for greater dissolution rate and/or superior bioavailability. Therefore, this ability of a chemical substance to crystallize in more than one crystalline form can have a profound effect on the shelf life, solubility, formulation properties, and processing properties of a drug. In addition, the action of a drug can be affected by the polymorphism of the drug molecule. Different polymorphs can have different rates of uptake in the body, leading to lower or higher biological activity than desired. In extreme cases, an undesired polymorph can even show toxicity. The occurrence of an unknown crystalline form during manufacture can have a significant impact.

It is not yet possible 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 a therapeutic composition, or which polymorphs will display such desirable properties.

The free form of IAG933 (Modification A) was originally described in PCT/IB2022/058131 , the contents of which are incorporated by reference.

SUMMARY

The polymorphic forms of this invention are designed and optimized to bind to TEADs and selectively disrupt their interaction with YAP and TAZ, which is believed to result in drugs useful in the treatment of above-mentioned cancers. In particular, such cancers may be characterized by (but not restricted to) some of the described aberrations. In certain aspects, advantages of the polymorphic forms of the invention include improved stability, hygroscopicity and morphology (which can improves flow properties).

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- methylnicotinamide (IAG933) which are particularly advantageous in drug product development, e.g. which exhibit improved properties such as stability, hygroscopicity and/or morphology (so as to improve flow properties).

According to a first aspect of the invention, there is hereby 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-methylnicotinamide (IAG933). According to a second aspect of the invention, there is hereby provided an anhydrous crystalline salt, characterized by an 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. 12.34° ± 0.10°, 15.66° ± 0.10°, 21.98° ± 0.10° and 23.95° ± 0.10° at room temperature (e.g. 20 °C), wherein the radiation used has a wavelength of 1.54060 A.

According to a third aspect of the invention, there is hereby provided a pharmaceutical composition comprising the succinate salt of the first or second aspect of the invention and a pharmaceutically acceptable carrier.

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

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

According to a sixth aspect of the invention, there is hereby provided the succinate salt according to the first or the second aspect of the invention, or the pharmaceutical composition according to the third aspect of the invention, for use in treating a disease or condition mediated by YAP overexpression and/or YAP amplification and/or YAP/TAZ-TEAD interaction; or for use in treating a cancer or tumor harboring (i) one or more YAP/T AZ fusions; (ii) one or more NF2/LATS1/LATS2 truncating mutations or deletions; or (iii) one or more functional YAP/T AZ fusions.

According to a seventh aspect of the invention, there is hereby 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 tumor harboring (i) one or more YAP/T AZ fusions; (ii) one or more NF2/LATS1/LATS2 truncating mutations or deletions; or (iii) one or more functional YAP/TAZ fusions; said method comprising administering to a subject in need thereof, a therapeutically effective amount of the succinate salt according to the first or the second aspect of the invention; or a pharmaceutical composition according to the third aspect of the invention; or a combination according to the fifth aspect of the invention.

According to a eighth aspect of the invention, there is hereby provided the succinate salt according to the first or the second aspect of the invention, or the pharmaceutical composition according to the third aspect of the invention for use in the treatment of cancer.

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

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an X-ray powder diffraction pattern of the 1 :1 succinate salt (unsolvated) of IAG933 at room temperature using Cu Ka radiation (A = 1.5418 A).

Figure 2 is a scanning electron microscope (SEM) image of crystals of the 1 :1 succinate salt of IAG933.

Figure 3 is a differential scanning calorimetry (DSC) thermogram of the 1 :1 succinate salt of IAG933. Differential scanning calorimetry was conducted for each crystalline form using a TA Discovery DSC instrument. 1-3 mg of sample was placed in an aluminium T-zero crucible that closed with a pin-hole lid. The heating rate was 10°C per minute in the temperature range between 0 and 300°C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J/g). Plots are showing endothermic peaks as down. The endothermic melt peak (melting point) was evaluated for extrapolated onset temperature. The accuracy of the measured sample temperature with this method is within about ±1 °C, and the heat of fusion can be measured within a relative error of about ±5%. Melting endotherm: T_onSet = 172° C (melting under decomposition)

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

Figure 5 is an X-ray powder diffraction pattern of the “Modification A” free form of IAG933 using Cu Ka radiation (A = 1.5418 A).

Figure 6 is a differential scanning calorimetry (DSC) thermogram of the “Modification A” free form of IAG933. Differential scanning calorimetry was conducted for each crystalline form using a TA Discovery DSC instrument. For each analysis, 1-3 mg of sample was placed in an aluminium T- zero crucible that closed with a pin-hole lid. The heating rate was 10°C per minute in the temperature range between 0 and 300°C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J/g). Plots are showing endothermic peaks as down. The endothermic melt peak (melting point) was evaluated for extrapolated onset temperature. The accuracy of the measured sample temperature with this method is within about ±1 °C, and the heat of fusion can be measured within a relative error of about ±5%. Melting endotherm: Tonset = 117.5° C (melt).

Figure 7 is a thermogravimetric analysis (TGA) diagram of the “Modification A” free form of IAG933. TGA curves were obtained using a TA Discovery TGA instrument. For each analysis, 2- 10mg of sample was placed into an aluminum crucible and closed with a pin-hole lid. The TGA curve was measured at a heating rate of 10°C/min between 30-300°C. The LoD (Loss of drying) was calculated between 27°C and 110°C. The weight loss is plotted against the measured sample temperature. Temperatures are reported in degrees Celsius (°C) and weight loss in %. Loss of drying: LoD = 0.38%.

Figure 8 is an X-ray powder diffraction pattern of the 1 :1 succinate salt (acetone solvate) of IAG933 at room temperature using Cu Ka radiation (A = 1.5418 A).

DETAILED DESCRIPTION OF THE INVENTION

There is a need in the art for new salts I 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- methylnicotinamide. Such salts I crystalline forms may possess desirable physicochemical properties which are particularly advantageous in drug product development, e.g. which exhibit improved stability, hygroscopicity and/or morphology (so as to improve flow properties). According to a first aspect of the invention, there is hereby 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-methylnicotinamide (IAG933).

The succinate salt of the invention is associated with a number of positive characteristics with respect to residual solvent content, melting point, hygroscopicity and stability when compared to IAG933 free form modification A, as shown in Example 3. Further, as shown in Figure 2, the morphology of the IAG933 succinate salt is blocky. This is generally advantageous, as it typically results in superior flow properties compared to needle like or plate like crystals. Further, as demonstrated in the Examples, the succinate salt of the invention shows improved properties with respect to residual solvent content, melting point, hygroscopicity and stability when compared to IAG933 free form modification A.

In an embodiment, the ratio of IAG933 to succinate is 1 :1.

In an embodiment, the succinate salt is of the formula

In an embodiment, the salt is crystalline.

In an embodiment, the salt is anhydrous.

In an embodiment, the salt is unsolvated.

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

, wherein the radiation used has a wavelength of 1 .54060 A.

In an 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 20 values selected from the group consisting of:

, wherein the radiation used has a wavelength of 1 .54060 A.

In an embodiment, the salt is characterized by an 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. 12.34° ± 0.10°, 15.66° ± 0.10°, 21 .98° ± 0.10° and 23.95° ± 0.10° at room temperature (e.g. 20 °C), wherein the radiation used has a wavelength of 1 .54060 A.

In an embodiment, the salt has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction spectrum as shown in FIG. 1 , at about room temperature wherein the radiation used has a wavelength of 1 .54060 A. According to a second aspect of the invention, there is hereby provided an anhydrous (e.g. unsolvated) crystalline salt, characterized by an 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. 12.34° ± 0.10°, 15.66° ± 0.10°, 21.98° ± 0.10° and 23.95° ±

0.10° at room temperature (e.g. 20 °C), wherein the radiation used has a wavelength of 1.54060 A.

In an embodiment of the first or the second aspect of the invention, at 100 °K: a is 11 .42 (± 0.2, e.g. ± 0.1) A; b is 14.59 (± 0.2, e.g. ± 0.1) A; c is 18.21 (± 0.2, e.g. ± 0.1) A; Z’ is 1 ; and the space group is P2i2i2i .

In an embodiment of the first or the second aspect of the invention, the X-ray powder diffraction pattern comprises one or more peaks, 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. 16 or more, e.g. 17 or more, e.g. 18 or more, e.g. 19 or more, e.g. all 20 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°. In an embodiment, the X-ray powder diffraction pattern comprises one or more peaks, 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. 16 or more, e.g. 17 or more, e.g. 18 or more, e.g. all 19 or more, e.g. all 20 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°. According to a third aspect of the invention, there is hereby provided a pharmaceutical composition comprising the succinate salt according to the first or the second aspect of the invention and a pharmaceutically acceptable carrier.

According to a seventh aspect of the invention, there is hereby 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 tumor harboring (i) one or more YAP/T AZ fusions; (ii) one or more NF2/LATS1/LATS2 truncating mutations or deletions; or (iii) one or more functional YAP/T AZ fusions; said method comprising administering to a subject in need thereof, a therapeutically effective amount of the succinate salt according to the first or the second aspect of the invention; or a pharmaceutical composition according to the third aspect of the invention; or a combination according to the fifth aspect of the invention.

According to an eighth aspect of the invention, there is hereby provided the succinate salt according to the first or the second aspect of the invention, or the pharmaceutical composition according to the third aspect of the invention for use in the treatment of cancer.

According to a ninth aspect of the invention, there is hereby provided a method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the succinate salt according to the first or the second aspect of the invention; or a pharmaceutical composition according to the third aspect of the invention; or a combination according to the fifth aspect of the invention. In an embodiment of the eighth or the ninth aspect of the invention, the cancer is selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the tunica vaginalis), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, urothelial carcinoma of the bladder and squamous cell carcinoma of the skin), poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including childhood supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumor, a solid tumor, breast cancer (including triple negative breast cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colorectal carcinoma), 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, embryonic rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcomas (UPS), Kaposi’s sarcoma, soft-tissue sarcoma and rare soft-tissue sarcoma), bone cancer, brain cancer, medulloblastoma, glioma, meningioma, and head and neck cancer (including head and 1 neck squamous cell carcinoma).

The invention therefore provides the following numbered embodiments:

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-methylnicotinamide (IAG933). Embodiment 2. The succinate salt according to Embodiment 1 , wherein the ratio of IAG933 to succinate is 1 :1.

Embodiment s. The succinate salt according to Embodiment 2, having the formula

Embodiment 4. The succinate salt according to any one of the preceding Embodiments, wherein the salt is crystalline. Embodiment 5. The succinate salt according to any one of the preceding Embodiments, wherein the salt is unsolvated.

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

, wherein the radiation used has a wavelength of 1 .54060 A.

Embodiment 7. The succinate salt according to any one of the preceding Embodiments, 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 20 values selected from the group consisting of:

, wherein the radiation used has a wavelength of 1 .54060 A.

Embodiment 8. The succinate salt according to any one of the preceding Embodiments, characterized by an 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. 12.34° ± 0.10°, 15.66° ± 0.10°, 21.98° ± 0.10° and 23.95° ± 0.10° at room temperature (e.g. 20 °C), wherein the radiation used has a wavelength of 1.54060 A.

Embodiment 9. The succinate salt according to any one of the preceding Embodiments, having an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction spectrum as shown in FIG. 1 , at about room temperature wherein the radiation used has a wavelength of 1 .54060 A.

Embodiment 10. An anhydrous crystalline 1 :1 salt, characterized by an 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. 12.34° ± 0.10°, 15.66° ± 0.10°, 21.98° ± 0.10° and 23.95° ± 0.10° at room temperature (e.g. 20 °C), wherein the radiation used has a wavelength of 1.54060 A.

Embodiment 10a. The succinate salt of any one of the preceding claims, wherein the succinate salt is unsolvated. Embodiment 11. The succinate salt according to any one of the preceding Embodiments, wherein at 100 °K: a is 11.42 (± 0.2, e.g. ± 0.1) A; b is 14.59 (± 0.2, e.g. ± 0.1) A; c is 18.21 (± 0.2, e.g. ± 0.1) A; Z’ is 1 ; and the space group is P2 i2i2i .

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

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

Embodiment 14. A combination comprising the succinate salt according to any one of Embodiments 1 to 11 , and one or more therapeutically active agents.

Embodiment 15. The succinate salt according to any one of Embodiments 1 to 11 , or the pharmaceutical composition according to Embodiment 12, for use in treating a disease or condition mediated by YAP overexpression and/or YAP amplification and/or YAP/TAZ-TEAD interaction; or for use in treating a cancer or tumor harboring (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.

Embodiment 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 harboring (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; said method comprising administering to a subject in need thereof, a therapeutically effective amount of the succinate salt according to any one of Embodiments 1 to 11 ; or a pharmaceutical composition according to Embodiment 12; or a combination according to Embodiment 14.

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

Embodiment 18. The succinate salt for use according to Embodiment 17, wherein the cancer is selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the tunica vaginalis), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, urothelial carcinoma of the bladder and squamous cell carcinoma of the skin), poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including childhood supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumor, a solid tumor, breast cancer (including triple negative breast cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colorectal carcinoma), 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, embryonic rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcomas (UPS), Kaposi’s 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).

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

Embodiment 20. The method according to Embodiment 19, wherein the cancer is selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the tunica vaginalis), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, urothelial carcinoma of the bladder and squamous cell carcinoma of the skin), poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including childhood supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumor, a solid tumor, breast cancer (including triple negative breast cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colorectal carcinoma), 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, embryonic rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcomas (UPS), Kaposi’s 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).

Embodiment 21. acetone solvate, characterized by an X-ray powder diffraction pattern comprising peaks at 8.79° ± 0.20°, 10.38° ± 0.20°, 19.27° ± 0.20° and 22.77° ± 0.20°, e.g. 8.79° ± 0.10°, 10.38° ± 0.10°, 19.27° ± 0.10° and 22.77° ± 0.10° at room temperature (e.g. 20 °C), wherein the radiation used has a wavelength of 1 .54060 A.

Embodiment 21 a. The salt according to Embodiment 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: 5

Definitions

As used herein “polymorph”, “form”, “crystalline 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 forming the crystal.

As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the present invention. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention 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 a basic group and an acid group are present in the same molecule, the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.

As used herein, the term “unsolvated” means that the ratio of IAG933 to solvent molecule (i.e. a molecule which is liquid under ambient pressure and temperature) in the crystal structure is greater than 2:1 , for example greater than or equal to 3:1 , for example greater than or equal to 4:1 , for example greater than or equal to 5:1 , for example greater than or equal to 7.5:1 , for example greater than or equal to 10:1 , for example greater than or equal to 20:1 , for example greater than or equal to 50:1 at ambient temperature (e.g. 20 °C) and at 30 to 60% relative humidity, e.g. 40-50% relative humidity, e.g. about 45% relative humidity. The “unsolvated” form is ’’anhydrous”, given that water is a solvent.

As used herein, the term “anhydrous” means that the ratio of IAG933 to water in the crystal structure is greater than 2:1 , for example greater than or equal to 3:1 , for example greater than or equal to 4:1 , for example greater than or equal to 5:1 , for example greater than or equal to 7.5:1 , for example greater than or equal to 10:1 , for example greater than or equal to 20:1 , for example greater than or equal to 50:1 at ambient temperature (e.g. 20 °C) and at 30 to 60% relative humidity, e.g. 40-50% relative humidity, e.g. about 45% relative humidity. In a particular embodiment, there is substantially no water (e.g. less than 1 % by mass, e.g. less than 0.5% by mass) in the crystal structure at 45% relative humidity at 20 °C. It should be understood that even “anhydrous” forms (as defined herein) are typically slightly hygroscopic. For instance, the IAG933 1 : 1 succinate salt of the invention has water uptake of 0.75% at 95% relative humidity following a DVS (dynamic vapor sorption) test.

As used herein “amorphous” refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern. A crystalline solid on the other hand displays an X-ray diffraction pattern with distinct peaks resulting from Bragg diffraction.

The term “substantially the same” with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (20) will show some inter-apparatus variability, typically as much as 0.2°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only. The person skilled in the art of X-ray powder diffraction is readily able to determine whether a given sample comes from the same polymorph as a reference sample.

As used herein, the terms “about” and “substantially” indicate with respect to features such as endotherms, endothermic peak, exotherms, baseline shifts, etc., that their values can vary. With reference to X-ray diffraction peak positions, “about” or “substantially” means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (20) will show some inter-apparatus variability, typically as much as 0.2°. Occasionally, the variability could be higher than 0.2° depending on apparatus calibration differences. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only. For DSC, variation in the temperatures observed will depend upon the rate of temperature change as well as sample preparation technique and the particular instrument employed. Thus, the endotherm/melting point values reported herein relating to DSC/TGA thermograms can vary ± 5°C (and still be considered to be characteristic of the particular crystalline form described herein). When used in the context of other features, such as, for example, percent by weight (% by weight), reaction temperatures, the term “about” indicates a variance of ± 5%.

The term "a therapeutically effective amount" of a crystalline form of the present invention refers to an amount of the crystalline form of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease associated with (i) hyperactivation of the YAP/TAZ-TEAD complex (ii) mediated by YAP overexpression and/or YAP amplification, or (iii) associated with YAP activity, or (iv) characterized by activity (normal or abnormal) of YAP; or (2) reducing or inhibiting the interaction of YAP and/or TAZ with TEAD. In another non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the crystalline form of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the interaction of YAP and/or TAZ with TEAD.

As used herein, the term "a,” "an,” "the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

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 invention and does not pose a limitation on the scope of the invention otherwise claimed.

As used herein, the term “inhibit”, "inhibition" or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

As used herein, the terms “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (/.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In one embodiment, “treat” or “treating” refers to delaying the progression of the disease or disorder.

As used herein, the term “prevent”, “preventing" or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset of the disease or disorder.

As used herein, the term "pharmaceutically acceptable carrier" includes any one or more selected from 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 "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by YAP/TAZ-TEAD protein-protein interaction (PPI), or (ii) associated with YAP/T AZ TEAD PPI activity, or (iii) 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 "a therapeutically effective amount" refers to the amount of the compound of the present invention 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 activity of YAP/TAZ-TEAD PPI. 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 a preferred embodiment, the subject is a human.

As used herein, a subject is “in need of’ or “in need thereof” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

The term “comprising” encompasses “including” as well as “consisting”; e.g., a composition comprising X may consist exclusively of X or may include additional, e.g. X and Y.

The crystalline form of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent. The crystalline form of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the present invention.

In the combination therapies of the invention, the crystalline form of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the crystalline form of the present invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the crystalline form of the present invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the crystalline form of the present invention and the other therapeutic agent.

Synthesis of the compound of the invention (IAG933) and the amorphous form of IAG933 were originally described in WO2021/186324, the contents of which are incorporated by reference. The free form of IAG933 (Modification A) was originally described in PCT/IB2022/058131 , the contents of which are incorporated by reference. IAG933 has the following structure . An alternative 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.

EXAMPLES

Example 1 - IAG933 1 :1 succinate salt (unsolvated) preparation and characterization a. Preparation method for IAG933 1 :1 succinate salt (unsolvated)

118 mg succinic acid was added to 500 mg IAG933 free form modification A (Example 2 below describes the formation of IAG933 free form modification A) in a 20 mL vial. 10 mL acetone was added to the vial, which was then heated to 50°C for four hours and stirred. The vial was then cooled to room temperature, and kept at that temperature and stirred overnight. The resultant mixture was filtered and vacuumed dried at 50°C for 24 hours to form IAG933 1 :1 succinate salt (unsolvated). b. XRPD pattern of IAG933 1 :1 succinate salt (unsolvated)

XRPD method

X-ray powder diffraction (XRPD) patterns were obtained using a Bruker Advance D8 in reflection geometry. Powders were analyzed using a zero background Si flat sample holder. The radiation used was Cu Ka (A = 1 .5418 A). Patterns were measured between 2° and 40° 2theta.

Sample amount: 5-10 mg

Sample holder: zero background Si flat sample holder

(See Figure 1 for the XRPD pattern. The most characteristic peaks in the XRPD are emboldened and italicised and marked as A, B, C, D). c. Unit cell of IAG933 1 :1 succinate salt (unsolvated)

A crystal structure of IAG933 1 :1 succinate salt (unsolvated) was determined at 100 K. The structure of contains 1 IAG933 cation and 1 succinate anion (and no solvent molecules) in the asymmetric unit (Z’=1) with a space group of P2i2i2i. The crystal structure information is listed in the Table below.

Parameter Value

Crystal system Orthorhombic

Space group P2i2i2i

Cell lengths (A) a 11.4233, b 14.5915, c 18.2097

Cell angles (°) a 90.0 , p 90 , y 90.0

Cell volume (A³) 3035.25

Example 2 - IAG933 free form (Modification A) preparation and characterization a. Preparation method for IAG933 free form (Modification A) a1 : About 53 mg of IAG933 (amorphous) was weighed into a vial, then 0.4 mL of acetone was added and mixed with 450 rpm at room temperature for 1 h. Then the solid was filtrated and dried at 40 degree C for 2 hours under vacuum to form IAG933 free form (Modification A). a2: About 53 mg of IAG933 (amorphous) was weighed into a vial, then 0.4 mL of acetonitrile was added and mixed with 450 rpm at room temperature for 1 h. Then the solid was filtrated and dried at 40 degree C for 2 hours under vacuum to form IAG933 free form (Modification A). a3: About 3 g of IAG933 amorphous free form was added into 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 within 6 hours and kept 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 in 6 hours and stirred overnight. The solid was separated by suction filtration and dried at 50 °C under vacuum overnight to form IAG933 free form (Modification A). a4: About 18 g IAG933 amorphous free form was weighed into crystallizer. 200 mL of ACN/water=1/9 (v/v) was added. The mixture was stirred at 150 rpm at 40 °C for about 6 hours, then gradually cooled to room temperature and stirred overnight. The solid was isolated by filtration and subsequently dried at 50 °C under vacuum overnight. About 17.2 g of white solid (IAG933 free form Modification A) was obtained. b. XRPD of IAG933 free form Modification A

XRPD method X-ray powder diffraction (XRPD) patterns were obtained using a Bruker Advance D8 in reflection geometry. Powders were analyzed using a zero background Si flat sample holder. The radiation used was Cu Ka (A = 1 .5418 A). Patterns were measured between 2° and 40° 2theta.

Sample amount: 5-10 mg

Sample holder: zero background Si flat sample holder XRPD parameter

(See Figure 5. for XRPD pattern, strongest peaks are shown below, and are emboldened and italicized)

Example 3 - Comparison of the properties of IAG933 1 :1 succinate salt (unsolvated) and

IAG933 free form Modification A

Stability Study i i i i i i j Suspension / * Clear solution after stress test / - Test not performed

A: No change of color / B: Slight discoloration / C: Medium discoloration / D: Strong discoloration

Morphic Property Study i i Solubility Study

Example 4 - IAG933 1 :1 succinate salt (acetone solvate) preparation and characterization a. Preparation method for IAG933 1 :1 succinate salt (acetone solvate)

An excess of IAG933 1 : 1 succinate salt (as prepared in Example 1 ) was added into acetone/water (94:6 v/v) to form a suspension. The suspension was then shaken at 25 °C for 34 days. The suspension sample was transferred into an filter centrifugal tube and solid IAG933 1 :1 succinate salt (acetone solvate) isolated by centrifuging. b. XRPD pattern of IAG933 1 :1 succinate salt (acetone solvate) XRPD method X-ray powder diffraction (XRPD) patterns were obtained using a Bruker Advance D8 in reflection geometry. Powders were analyzed using a zero background Si flat sample holder. The radiation used was Cu Ka (A = 1 .5418 A). Patterns were measured between 2° and 40° 2theta.

Sample amount: 5-10 mg

Sample holder: zero background Si flat sample holder XRPD parameter Primary: fixed illuminated sample size 10 mm; secondary: open

Slits angle 2.2°, axial soller: 2.5°

(See Figure 8 for the XRPD pattern. The most characteristic peaks in the XRPD are emboldened and italicised and marked as A, B, C, D).

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 of claim 1 , wherein the ratio of IAG933 to succinate is 1 :1. 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 salt according to any one of the preceding claims, characterized by a room temperature X-ray powder diffraction pattern comprising peaks at four or more 20 values selected from the group consisting of: , wherein the radiation used has a wavelength of 1 .54060 A.

7. The succinate salt according to any one of the preceding claims, characterized by a room temperature X-ray powder diffraction pattern comprising peaks at five or more values selected from the group consisting of:

, wherein the radiation used has a wavelength of 1 .54060 A.

8. The succinate salt according to any one of the preceding claims, characterized by an 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° at room temperature, wherein the radiation used has a wavelength of 1 .54060 A.

9. The succinate salt according to any one of the preceding claims, having an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction spectrum as shown in FIG. 1 , at about room temperature wherein the radiation used has a wavelength of 1.54060 A.

An anhydrous crystalline salt, characterized by an 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° at room temperature, wherein the radiation used has a wavelength of 1 .54060 A.

11 . The succinate salt according to any one of the preceding claims, wherein at 100 °K: a is 11.42 (± 0.2) A; b is 14.59 (± 0.2) A; c is 18.21 (± 0.2) A;

Z’ is 1 ; and the space group is P2i2i2i.

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 the 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 treating a disease or condition mediated by YAP overexpression and/or YAP amplification and/or YAP/TAZ-TEAD interaction; or for use in treating a cancer or tumor harboring (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 harboring (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; said method comprising administering to a subject in need thereof, a therapeutically effective amount of the 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 tunica vaginalis), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, urothelial carcinoma of the bladder and squamous cell carcinoma of the skin), poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including childhood supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumor, a solid tumor, breast cancer (including triple negative breast cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colorectal carcinoma), 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, embryonic rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcomas (UPS), Kaposi’s 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).

19. A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the 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 according to claim 19, wherein the cancer is selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the tunica vaginalis), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, urothelial carcinoma of the bladder and squamous cell carcinoma of the skin), poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including childhood supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumor, a solid tumor, breast cancer (including triple negative breast cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colorectal carcinoma), 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, embryonic rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcomas (UPS), Kaposi’s 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).