Crystal morphology of biaryl YAP / TAZ-TEAD protein-protein interaction inhibitors

Abstract

The present invention relates generally to crystalline polymorphic forms of the biaryl YAP / TAZ-TEAD protein interaction inhibitors 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 and 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide and salts thereof and methods of using the forms in the treatment of cancer.

Description

[Technical field]

[0001] The present invention relates generally to crystalline polymorphic forms of the biaryl YAP / TAZ-TEAD protein interaction inhibitors 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 and 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide and salts thereof and methods of using the forms in the treatment of cancer. [Background technology]

[0002] Normal tissue growth and tissue repair and remodeling require a balance of specialized control and regulated transcriptional activity. Transcriptional output is coordinated through several key signaling modules, one of which is the Hippo pathway. Genetic studies in Drosophila and mammals have revealed a conserved core signaling cassette consisting of Mst1 / 2 and Lats1 / 2 kinases that inhibit the transcriptional coactivators YAP and TAZ (official gene name: WWTR1).

[0003] An activated Hippo pathway converts YAP and TAZ to phosphorylate and capture / degrade in the cytoplasm. Upon inactivation of the Hippo pathway, YAP and TAZ translocate to the nucleus and associate with transcription factors, namely members of the TEAD family (TEAD1-4). The YAP / TAZ-TEAD complex then promotes the transcription of downstream genes involved in cell proliferation, cell death and cell differentiation. Although YAP and TAZ can also interact with several other factors, it is generally accepted that TEADs are key mediators of the proliferation-promoting and tumorigenic potential of YAP and TAZ (pathways reviewed in Yu et al., 2015; Holden and Cunningham, 2018).

[0004] Thus, hyperactivation of YAP and / or TAZ (and subsequent hyperactivation of the YAP / TAZ-TEAD transcription complex) is commonly observed in several human cancers, as evidenced by elevated YAP / TAZ levels and nuclear localization in many tumors, including breast, lung (e.g., non-small cell; NSCLC), ovarian, colorectal, pancreatic, prostate, gastric, esophageal, liver, and bone (sarcoma) (extensively reviewed in Steinhardt et al., 2008; Harvey et al., 2013; Moroishi et al., 2015; Zanconato et al., 2016 and references therein).

[0005] Although genetic alterations of core Hippo pathway components have been detected with limited frequency in primary samples so far, the most prominent cancer malignancy associated with inactivating mutations in NF2 or Lats1 / 2 and associated with YAP / TEAD hyperactivation is malignant pleural mesothelioma (MPM) (reviewed in Sekido, 2018). Similarly, several human tumors are characterized by amplification of YAP at the 11p22.1 locus (e.g., hepatocellular carcinoma, medulloblastoma, esophageal squamous cell carcinoma), TAZ at the 3q25.1 locus (WWTR1) (e.g., rhabdomyosarcoma, triple-negative breast cancer), or gene fusions involving YAP or TAZ (epithelioid hemangioendothelioma, ependymal tumors) (reviewed in Yu et al., 2015 and references therein). As in the case of MPM, such tumors are also predicted to depend on their elevated YAP / TAZ-TEAD activity.

[0006] Interference with the YAP / TAZ-TEAD PPI, as the most distal effector node of the Hippo pathway, is predicted to abolish the oncogenic potential of this complex.

[0007] Notably, tumor cells with activated YAP / TAZ-TEAD show resistance to chemotherapeutic drugs, which is sometimes associated with YAP / TAZ, which confers cancer stem cell-like properties. Furthermore, activation of YAP / TAZ-TEAD also confers resistance to molecular targeted therapies such as BRAF, MEK or EGFR inhibitors, as reported from the results of various genetic and pharmacological screens (Kapoor et al., 2014; Shao et al., 2014; Lin et al., 2015). This suggests that inhibiting YAP / TAZ-TEAD activity (in parallel or sequentially with other cancer treatments) may similarly provide beneficial therapeutic impact by reducing the development of tumor resistance to other treatments.

[0008] Inhibition of YAP / TAZ-TEAD activity in disrupting PPIs by the above polymorphic forms may also blunt tumor evasion from immune surveillance. This is evidenced, for example, by data reported for YAP promoting the expression of the chemokine CXCL5 resulting in the recruitment of myeloid cells that suppress T cells (Wang et al., 2016). It has also been demonstrated that YAP in Tregs (regulatory T cells) supports FOXP3 expression via activin signaling and Treg function. Thus, loss of YAP leads to dysfunctional Tregs that are no longer able to suppress antitumor immunity. Thus, selective inhibition of YAP / TEAD activity may contribute to enhancing antitumor immunity by blocking Treg function (Ni et al., 2018). Recent literature also suggests that YAP upregulates PD-L1 expression and by this mechanism directly mediates the evasion of cytotoxic T cell immune responses, for example, in BRAF inhibitor-resistant melanoma cells (Kim et al., 2018).

[0009] For example, see below. Yu, FX., Zhao, B. and Guan, K.-L. (2015). Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell, 163, 811-828. Holden,JKand Cunningham,CN(2018).Targeting the Hippo pathway and cancer through the TEAD family of transcription factors.Cancers(Basel),10,E81. Steinhardt, AA, Gayyed, MF, Klein, AP, Dong, J., Maitra, A., Pan, D., Montgomery, EA, Anders, RA (2008). Expression of Yes-associated protein in common solid tumors. Hum. Pathol., 39, 1582-1589. Harvey,K.F.,Zhang,X.,and Thomas,D.M.(2013).The Hippo pathway and human cancer.Nat.Rev.Cancer,13,246-257. Moroishi,T.,Hansen,C.G.,and Guan,K.-L.(2015).Nat.Rev.Cancer,15,73-79. Zanconato,F.,Cordenonsi,M.,and Piccolo,S.(2016).YAP / TAZ at the roots of cancer.Cancer Cell,29,783-803. Sekido,Y.(2018).Cancers(Basel),10,E90. Kapoor,A.,Yao,W.,Ying,H.,Hua,S.,Liewen,A.,Wang,Q.,Zhong,Y.,Wu,C.J.,Sadanandam,A.,Hu,B.et al.(2014).Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.Cell,158,185-197. Shao,D.D.,Xue,W.,Krall,E.B.,Bhutkar,A.,Piccioni,F.,Wang,X.,Schinzel,A.C.,Sood,S.,Rosenbluh,J.,Kim,J.W.,et al.(2014).KRAS and YAP1 converge to regulate EMT and tumor survival.Cell,158,171-184. Lin,L.,Sabnis,A.J.,Chan,E.,Olivas,V.,Cade,L.,Pazarentzos,E.,Asthana,S.,Neel,D.,Yan,J.J.,Lu,X.et al.(2015).The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies.Nat.Genet.,47,250-256. Wang,G.,Lu,X.,Dey,P.,Deng,P.,Wu,C.C.,Jiang,S.,Fang,Z.,Zhao,K.,Konaprathi,R.,Hua,S.,et al.(2016).Cancer Discov.,6,80-95. Ni,X.,Tao,J.,Barbi,J.,Chen,Q.,Park B.V.,Li,Z.,Zhang,N.,Lebid,A.,Ramaswamy,A.,Wei,P.,et al.(2018).YAP is essential for Treg-mediated suppression of antitumor immunity.Cancer Discov.,8,1026-1043. Kim,M.H.,Kim,C.G.,Kim,S.K.,Shin,S.J.,Choe,E.A.,Park,S.H.,Shin,E.C.,and Kim,J.(2018).Cancer Immunol Res.,6,255-266.

[0010] The solid-state form of a particular drug's active pharmaceutical ingredient (API) is often an important determinant of the drug's ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and bioavailability in vivo. Crystal forms arise when substances of the same composition crystallize in different lattice arrangements, resulting in different thermodynamic properties and stability specific to a particular crystal form. Crystal forms may also include different hydrates or solvates of the same compound. To determine which form is preferred, multiple properties of the forms are compared and the preferred form is selected based on many physical property variables. It is quite possible that one form may be preferred in some situations where certain aspects such as ease of preparation, stability, etc. are important. In other situations, another form may be preferred due to a higher dissolution rate and / or better bioavailability.

[0011] Therefore, this ability of a chemical to crystallize in more than one crystalline form can have a large 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 a drug molecule.Different polymorphs can have different uptake rates in the body, resulting in lower or higher biological activity than desired.In extreme cases, undesired polymorphs can even be toxic.The occurrence of unknown crystalline forms during manufacturing can have a large effect.

[0012] It remains impossible 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 whether any polymorphs will exhibit such desirable properties. Summary of the Invention

[0013] The polymorphic forms of the present invention are designed and optimized to selectively bind TEAD and prevent them from interacting with YAP and TAZ, which is believed to result in drugs useful in the treatment of the above cancers. In particular, such cancers may be characterized by some of the abnormalities described (but are not limited to these). In certain embodiments, the advantages of the polymorphic forms of the present invention include improved stability, hygroscopicity and morphology (which can improve flow properties).

[0014] 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 and 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide. Such forms may have desirable physicochemical properties that are particularly advantageous in formulation development, for example exhibiting improved stability, hygroscopicity and / or morphology (such as improving flow properties).

[0015] According to a first aspect of the present invention, there is provided herein a crystalline form of 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Compound B) or a pharma- ceutically acceptable solvate and / or salt thereof.

[0016] According to a second aspect of the present invention, there is provided herein a crystalline form 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 (Compound A) or a pharma- ceutically acceptable solvate and / or salt thereof.

[0017] According to a third aspect of the invention, there is provided herein a pharmaceutical composition comprising the crystalline form of the first or second aspect of the invention and a pharma- ceutically acceptable carrier.

[0018] According to a fourth aspect of the invention, there is provided herein a crystalline form of the first or second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention, for use as a medicament.

[0019] According to a fifth aspect of the invention, there is provided herein a combination comprising a crystalline form of the first or second aspect of the invention and one or more therapeutically active agents.

[0020] According to a sixth aspect of the invention, there is provided herein a crystalline form of the first or second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention, 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 NF2 / LATS1 / LATS2 truncation mutations or deletions; or (iii) one or more functional YAP / TAZ fusions.

[0021] According to a seventh aspect of the present invention, there is provided herein a method of treating a disease or condition mediated by YAP overexpression, and / or YAP amplification, and / or YAP / TAZ-TEAD interaction, a method of treating a cancer or tumour 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, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form according to the present invention (e.g. the first or second aspect of the invention), a pharmaceutical composition of the third aspect of the invention or a combination of the fifth aspect of the invention. [Brief description of the drawings]

[0022] [Figure 1]This is the X-ray powder diffraction pattern of the succinate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) at room temperature. [Diagram 2] Differential scanning calorimetry (DSC) thermograms of the succinate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). 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 and closed with a pinhole lid. The heating rate was 10°C per minute in the temperature range of 0-300°C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peaks downwards. The endothermic melting peaks (melting points) were evaluated at the extrapolated onset temperatures. The accuracy of the measured sample temperature by 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 = 200.0°C (melting under decomposition) [Diagram 3] Figure 1 shows the thermogravimetric analysis (TGA) diagram of succinate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). The TGA 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 curves were measured at 30-300°C and a heating rate of 10°C / min. The LoD (loss on drying) was calculated from 30°C to 200°C. The weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss in %. Loss on drying: LoD = 0.45% [Figure 4]This is the X-ray powder diffraction pattern of the L-malate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) at room temperature. [Diagram 5] Differential scanning calorimetry (DSC) thermograms of the L-malate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) for each crystalline form. Differential scanning calorimetry was performed using a TA Discovery DSC instrument. For each analysis, 1-3 mg of sample was placed in an aluminum T-zero crucible and closed with a pinhole lid. The heating rate was 10 °C per minute in the temperature range of 0-300 °C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peaks downwards. The endothermic melting peaks (melting points) were evaluated at the extrapolated onset temperatures. The accuracy of the measured sample temperature by 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 = 195.4°C (melting under decomposition) [Figure 6] Figure 1 is a Thermogravimetric Analysis (TGA) diagram of the L-malate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). 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 at a heating rate of 10 °C / min from 30 to 300 °C. The LoD (loss on drying) was calculated from 30 °C to 200 °C. The weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss in %. Loss on drying: LoD = 0.81% [Figure 7]FIG. 1 is an X-ray powder diffraction pattern of the L-lactate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) at room temperature. [Figure 8] Differential scanning calorimetry (DSC) thermograms of the L-lactate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) for each crystalline form. Differential scanning calorimetry was performed using a TA Discovery DSC instrument. For each analysis, 1-3 mg of sample was placed in an aluminum T-zero crucible and closed with a pinhole lid. The heating rate was 10 °C per minute in the temperature range of 0-300 °C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peaks downwards. The endothermic melting peaks (melting points) were evaluated at the extrapolated onset temperatures. The accuracy of the measured sample temperature by 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 = 207.1°C (melting under decomposition) [Figure 9] Figure 1 is a thermogravimetric analysis (TGA) diagram of the L-lactate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). 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 at a heating rate of 10 °C / min from 30 to 300 °C. The LoD (loss on drying) was calculated from 30 °C to 200 °C. The weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss in %. Loss on drying: LoD = 0.91% [Figure 10]This is the X-ray powder diffraction pattern of the benzoate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) at room temperature. [Figure 11] Differential scanning calorimetry (DSC) thermograms of the benzoate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). 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 and closed with a pinhole lid. The heating rate was 10°C per minute in the temperature range of 0-300°C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peaks downwards. The endothermic melting peaks (melting points) were evaluated at the extrapolated onset temperatures. The accuracy of the measured sample temperature by 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 = 166.8°C (melting under decomposition) [Figure 12] Figure 1 is a Thermogravimetric Analysis (TGA) diagram of the benzoate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). 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 at a heating rate of 10 °C / min from 30 to 300 °C. The LoD (loss on drying) was calculated from 30 °C to 170 °C. The weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss in %. Loss on drying: LoD = 0.72% [Figure 13]FIG. 1 is an X-ray powder diffraction pattern of the glutamate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) at room temperature. [Figure 14] (Differential scanning calorimetry (DSC) thermogram of the glutamate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) from TA Discovery Differential scanning calorimetry was performed for each crystalline form using a DSC instrument. For each analysis, 1-3 mg of sample was placed in an aluminum T-zero crucible and closed with a pinhole lid. The heating rate was 10°C per minute in the temperature range of 0-300°C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peak downwards. The endothermic melting peak (melting point) was evaluated at the extrapolated onset temperature. The accuracy of the measured sample temperature by this method is within about ±1°C and the heat of fusion can be measured within a relative error of about ±5%. Melting endotherms: Tonset=26°C (dehydration) and Tonset=158.6°C (melting) [Figure 15] Figure 1 is a thermogravimetric analysis (TGA) diagram of the glutamate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). 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 at a heating rate of 10 °C / min from 30 to 300 °C. The LoD (loss on drying) was calculated from 30 °C to 135 °C. The weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss in %. Loss on drying: LoD = 1.45% [Figure 16]FIG. 1 is an X-ray powder diffraction pattern of the malate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) at room temperature. [Figure 17] Differential scanning calorimetry (DSC) thermograms of the malate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). 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 and closed with a pinhole lid. The heating rate was 10°C per minute in the temperature range of 0-300°C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peaks downwards. The endothermic melting peaks (melting points) were evaluated at the extrapolated onset temperatures. The accuracy of the measured sample temperature by 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 = 204.0°C (melting under decomposition) [Figure 18] Figure 1 is a Thermogravimetric Analysis (TGA) diagram of the malate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). 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 at a heating rate of 10°C / min from 30 to 300°C. The LoD (loss on drying) was calculated from 30°C to 200°C. The weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss in %. Loss on drying: LoD = 0.60% [Figure 19]This is an X-ray powder diffraction pattern of the malonate salt (Type I) of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) at room temperature. [Figure 20] Differential scanning calorimetry (DSC) thermogram of the malonate salt (Type I) of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). Differential scanning calorimetry was performed using a TA Discovery DSC instrument. 1-3 mg of sample was placed in an aluminum T-zero crucible and closed with a pinhole lid. The heating rate was 10 °C per minute in the temperature range of 0-300 °C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peak downwards. The endothermic melting peak (melting point) was evaluated at the extrapolated onset temperature. The accuracy of the measured sample temperature by 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 = 186.6°C (melting under decomposition) [Figure 21] Thermogravimetric analysis (TGA) diagram of the malonate salt (Type I) of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). TGA curves were obtained using a TA Discovery TGA instrument. 2-10 mg samples were placed in aluminum crucibles and closed with pinhole lids. TGA curves were measured at 30-300°C and a heating rate of 10°C / min. The LoD (loss on drying) was calculated from 30°C to 182°C. The weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss in %. Loss on drying: LoD=0.51% [Figure 22]This is an X-ray powder diffraction pattern of the malonate salt (type II) of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) at room temperature. [Diagram 23] Differential scanning calorimetry (DSC) thermogram of the malonate salt (type II) of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). Differential scanning calorimetry was performed using a TA Discovery DSC instrument. 1-3 mg of sample was placed in an aluminum T-zero crucible and closed with a pinhole lid. The heating rate was 10 °C per minute in the temperature range of 0-300 °C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peak downwards. The endothermic melting peak (melting point) was evaluated at the extrapolated onset temperature. The accuracy of the measured sample temperature by 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 = 122.2°C (melting and desolvation) [Figure 24] Thermogravimetric analysis (TGA) diagram of the malonate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) (Type II). The TGA curve was obtained using a TA Discovery TGA instrument. 2-10 mg samples were placed in aluminum crucibles and closed with pinhole lids. The TGA curves were measured at 30-300°C and at a heating rate of 10°C / min. The LoD (loss on drying) was calculated from 30°C to 200°C. The weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss in %. Type II: Loss on drying: LoD=26.7% [Diagram 25]FIG. 1 is an X-ray powder diffraction pattern of the mesylate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) at room temperature. [Figure 26] Differential scanning calorimetry (DSC) thermograms of the mesylate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). 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 and closed with a pinhole lid. The heating rate was 10°C per minute in the temperature range of 0-300°C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peaks downwards. The endothermic melting peaks (melting points) were evaluated at the extrapolated onset temperatures. The accuracy of the measured sample temperature by 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 = 22°C (dehydration) and Tonset = 267.9°C (melting) [Figure 27] Thermogravimetric analysis (TGA) diagram of the mesylate salt of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide). TGA curves were 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. TGA curves were measured at 30-300°C and a heating rate of 10°C / min. The LoD (loss on drying) was calculated from 30°C to 100°C. The weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss in %. Loss on drying: LoD=0.34% [Figure 28]FIG. 1 is an X-ray powder diffraction pattern of the free form (2-methyl-2-butanol solvate) of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) at room temperature. [Figure 29] Differential scanning calorimetry (DSC) thermograms of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) in free form (2-methyl-2-butanol solvate). 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 and closed with a pinhole lid. The heating rate was 10 °C per minute in the temperature range of 0-300 °C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peaks downwards. The endothermic melting peaks (melting points) were evaluated at the extrapolated onset temperatures. The accuracy of the measured sample temperature by 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 = 68°C (melting and desolvation) [Diagram 30] Thermogravimetric analysis (TGA) diagram of compound B (2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide) in free form (2-methyl-2-butanol solvate). TGA curves were 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. TGA curves were measured at 30-300°C and at a heating rate of 10°C / min. LoD (loss on drying) was calculated from 30°C to 100°C. Weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss in %. Loss on drying: LoD=5.91% [Diagram 31]FIG. 1 is an X-ray powder diffraction pattern of the free form of compound A (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), “Modification A” at room temperature. [Diagram 32] Figure 1 shows a differential scanning calorimetry (DSC) thermogram of "Modification Form A", the free form of Compound A (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). 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 and closed with a pinhole lid. The heating rate was 10 °C per minute in the temperature range of 0-300 °C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peaks downwards. The endothermic melting peaks (melting points) were evaluated at the extrapolated onset temperatures. The accuracy of the measured sample temperature by 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 (melting) [Diagram 33] Thermogravimetric analysis (TGA) diagram of "Variation A", the free form of compound A (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). TGA curves were 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. TGA curves were measured at 30-300°C and at a heating rate of 10°C / min. LoD (loss on drying) was calculated from 27°C to 110°C. Weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss is reported in %. Loss on drying: LoD = 0.38% [Diagram 34]FIG. 1 is an X-ray powder diffraction pattern of the 4-hydroxybenzoate salt of compound A (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) at room temperature. [Diagram 35] Differential scanning calorimetry (DSC) thermograms of the 4-hydroxybenzoate salt of compound A (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). 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 and closed with a pinhole lid. The heating rate was 10°C per minute in the temperature range of 0-300°C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peaks downwards. The endothermic melting peaks (melting points) were evaluated at the extrapolated onset temperatures. The accuracy of the measured sample temperature by 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 = 216.7°C (melting accompanied by decomposition) [Diagram 36] Thermogravimetric analysis (TGA) diagram of the 4-hydroxybenzoate salt of compound A (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). TGA curves were 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. TGA curves were measured at 30-300°C and a heating rate of 10°C / min. The LoD (loss on drying) was calculated from 27°C to 110°C. The weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss is reported in %. Loss on drying: LoD = 0.46% [Figure 37]FIG. 1 is an X-ray powder diffraction pattern of the 3,4-dihydroxybenzoate salt of compound A (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) at room temperature. [Figure 38] Differential scanning calorimetry (DSC) thermograms of the 3,4-dihydroxybenzoate salt of compound A (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). 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 and closed with a pinhole lid. The heating rate was 10°C per minute in the temperature range of 0-300°C. Temperatures are reported in degrees Celsius (°C) and enthalpies are reported in Joules per gram (J / g). The plot shows the endothermic peaks downwards. The endothermic melting peaks (melting points) were evaluated at the extrapolated onset temperatures. The accuracy of the measured sample temperature by 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 = 29°C (dehydration), Tonset = 216.5°C (melting with decomposition) [Figure 39] Thermogravimetric analysis (TGA) diagram of the 3,4-dihydroxybenzoate salt of compound A (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). TGA curves were 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. TGA curves were measured at 30-300°C and a heating rate of 10°C / min. The LoD (loss on drying) was calculated from 26°C to 80°C. The weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss is reported in %. Loss on drying: LoD = 1.63% DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] It is understood that in an X-ray powder diffraction spectrum or pattern, there is inherent variation in values ​​measured in degrees 2θ (°2θ), for example, as a result of instrumental variability (including instrument-to-instrument differences). As such, it is understood that there is variation in XRPD peak measurements of up to ±0.2°2θ, but such peak values ​​are still considered to be representative of the particular solid-state forms of the crystalline materials described herein. It is also understood that other measurements (e.g., relative intensities and water content) from XRPD and DSC / TGA experiments may vary, for example, as a result of sample preparation and / or storage and / or environmental conditions, but the measurements are still considered to be representative of the particular solid-state forms of the crystalline materials described herein.

[0024] There is a need in the art for novel 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 and 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide. Such forms may have desirable physicochemical properties that are particularly advantageous in formulation development, for example exhibiting improved stability, hygroscopicity and / or morphology (such as improving flow properties).

[0025] Accordingly, the present invention provides the following numbered embodiments:

[0026] Embodiment 1. A crystalline form of 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Compound B) or a pharma- ceutically acceptable solvate and / or salt thereof.

[0027] Embodiment 2. A crystalline form 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 (Compound A) or a pharma- ceutically acceptable solvate and / or salt thereof.

[0028] Embodiment 3. The crystalline form of embodiment 1, wherein compound B is in the form of a succinate salt.

[0029] Embodiment 4. The crystalline form according to embodiment 3, characterized by an X-ray powder diffraction pattern comprising peaks at 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, such as 10 or more, for example 11 or more, such as 12 or more, for example all 13 2θ values) selected from the group consisting of:

[0030] [Table 1]

[0031] Embodiment 5. The crystalline form of embodiment 3 or embodiment 4, having an X-ray powder diffraction pattern at about room temperature substantially the same as the X-ray powder diffraction spectrum as shown in FIG. 1, wherein the radiation used has a wavelength of 1.54060 Å.

[0032] Embodiment 6. The crystalline form of any one of embodiments 3-5, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG.

[0033] Embodiment 6a. A T of about 200.0° C. when heated from 0 to 300° C. at 10° C. per minute as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset The crystalline form of any one of embodiments 3 to 5, having a melting endotherm at

[0034] Embodiment 7. The crystalline form of any one of embodiments 3-6a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG.

[0035] Embodiment 7a. The crystalline form of any one of embodiments 3-6a, having a loss on drying of about 0.45% when heated from 30° C. to 200° C. at a heating rate of 10° C. / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0036] Embodiment 7b. The crystalline form of any one of embodiments 3-7a, wherein the crystalline form is substantially phase pure.

[0037] Embodiment 8. The crystalline form of embodiment 1, wherein compound B is in the form of a malate salt.

[0038] Embodiment 9. The crystalline form according to embodiment 8, characterized by an X-ray powder diffraction pattern comprising peaks at 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, such as 10 or more, for example 11 or more, such as 12 or more, for example 13 or more, such as all 14 2θ values) selected from the group consisting of:

[0039] [Table 2]

[0040] Embodiment 10. The crystalline form of embodiment 8 or embodiment 9, having an X-ray powder diffraction pattern at about room temperature substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 4, wherein the radiation used has a wavelength of 1.54060 Å.

[0041] Embodiment 11. The crystalline form of any one of embodiments 8-10, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG.

[0042] Embodiment 11a. A T of about 195.4° C. when heated from 0 to 300° C. at 10° C. per minute as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset The crystalline form of any one of embodiments 8 to 10, having a melting endotherm at

[0043] Embodiment 12. The crystalline form of any one of embodiments 8-11a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG.

[0044] Embodiment 12a. The crystalline form of any one of embodiments 8-11a, having a loss on drying of about 0.81% when heated from 30° C. to 200° C. at a heating rate of 10° C. / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0045] Embodiment 12b. The crystalline form of any one of embodiments 8-12a, wherein the crystalline form is substantially phase pure.

[0046] Embodiment 13. The crystalline form of embodiment 1, wherein Compound B is in the form of a lactate salt.

[0047] Embodiment 14. The crystalline form according to embodiment 13, characterized by an X-ray powder diffraction pattern comprising peaks at 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, such as 10 or more, for example 11 or more, such as 12 or more, for example all 13 2θ values) selected from the group consisting of:

[0048] [Table 3]

[0049] Embodiment 15. A crystalline form according to embodiment 13 or embodiment 14, having an X-ray powder diffraction pattern at about room temperature substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 7, wherein the radiation used has a wavelength of 1.54060 Å.

[0050] Embodiment 16. The crystalline form of any one of embodiments 13-15, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG.

[0051] Embodiment 16a. A T of about 207.1° C. when heated from 0 to 300° C. at 10° C. per minute as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset 16. The crystalline form of any one of embodiments 13-15, having a melting endotherm at

[0052] Embodiment 17. The crystalline form of any one of embodiments 13-16a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG.

[0053] Embodiment 17a. The crystalline form of any one of embodiments 13-16a, having a loss on drying of about 0.91% when heated from 30° C. to 200° C. at a heating rate of 10° C. / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0054] Embodiment 17b. The crystalline form of any one of embodiments 13-17a, wherein the crystalline form is substantially phase pure.

[0055] Embodiment 18. The crystalline form of embodiment 1, wherein compound B is in the form of a benzoate salt.

[0056] Embodiment 19. The crystalline form according to embodiment 18, characterized by an X-ray powder diffraction pattern comprising peaks at 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, such as 10 or more, for example 11 or more, such as 12 or more, for example all 13 2θ values) selected from the group consisting of:

[0057] [Table 4]

[0058] Embodiment 20. The crystalline form of embodiment 18 or embodiment 19, having an X-ray powder diffraction pattern at about room temperature substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 10, wherein the radiation used has a wavelength of 1.54060 Å.

[0059] Embodiment 21. The crystalline form of any one of embodiments 18-20, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG.

[0060] Embodiment 21a. A T of about 166.8° C. when heated from 0 to 300° C. at 10° C. per minute as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset The crystalline form of any one of embodiments 18 to 20, having a melting endotherm at

[0061] Embodiment 22. The crystalline form of any one of embodiments 18-21a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG.

[0062] Embodiment 22a. The crystalline form of any one of embodiments 18-21a, having a loss on drying of about 0.72% when heated from 30°C to 170°C at a heating rate of 10°C / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0063] Embodiment 22b. The crystalline form of any one of embodiments 18-22a, wherein the crystalline form is substantially phase pure.

[0064] Embodiment 23. The crystalline form of embodiment 1, wherein compound B is in the form of a glutamate salt.

[0065] Embodiment 24. The crystalline form according to embodiment 23, characterized by an X-ray powder diffraction pattern comprising peaks at 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, such as 10 or more, for example all 11 2θ values) selected from the group consisting of:

[0066] [Table 5]

[0067] Embodiment 25. A crystalline form according to embodiment 23 or embodiment 24, having at about room temperature an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 13, wherein the radiation used has a wavelength of 1.54060 Å.

[0068] Embodiment 26. The crystalline form of any one of embodiments 23-25, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 14.

[0069] Embodiment 26a. A TA Discovery DSC instrument has a T of about 26.0° C. and about 158.6° C. when heated from 0 to 300° C. at 10° C. per minute, as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset The crystalline form of any one of embodiments 23 to 25, having a melting endotherm at a value of

[0070] Embodiment 27. The crystalline form of any one of embodiments 23-26a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG.

[0071] Embodiment 27a. The crystalline form of any one of embodiments 23-26a, having a loss on drying of about 1.45% when heated from 30° C. to 135° C. at a heating rate of 10° C. / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0072] Embodiment 27b. The crystalline form of any one of embodiments 23-27a, wherein the crystalline form is substantially phase pure.

[0073] Embodiment 28. The crystalline form of embodiment 1, wherein compound B is in the form of a maleate salt.

[0074] Embodiment 29. The crystalline form according to embodiment 28, characterized by an X-ray powder diffraction pattern comprising peaks at 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, such as 10 or more, for example 11 or more, for example all 12 2θ values) selected from the group consisting of:

[0075] [Table 6]

[0076] Embodiment 30. A crystalline form according to embodiment 28 or embodiment 29, having at about room temperature an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 16, wherein the radiation used has a wavelength of 1.54060 Å.

[0077] Embodiment 31. The crystalline form of any one of embodiments 28-30, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 17.

[0078] Embodiment 31a. A T of about 204.0° C. when heated from 0 to 300° C. at 10° C. per minute as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset The crystalline form of any one of embodiments 28 to 30, having a melting endotherm at

[0079] Embodiment 32. The crystalline form of any one of embodiments 28-31a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG.

[0080] Embodiment 32a. The crystalline form of any one of embodiments 28-31a, having a loss on drying of about 0.60% when heated from 30° C. to 200° C. at a heating rate of 10° C. / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0081] Embodiment 32b. The crystalline form of any one of embodiments 28-32a, wherein the crystalline form is substantially phase pure.

[0082] Embodiment 33 The crystalline form of embodiment 1, wherein compound B is in the form of a malonate salt.

[0083] Embodiment 34. The crystalline form according to embodiment 33, characterized by an X-ray powder diffraction pattern comprising peaks at 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, such as 10 or more, for example 11 or more, such as 12 or more, for example all 13 2θ values) selected from the group consisting of:

[0084] [Table 7]

[0085] Embodiment 35. A crystalline form according to embodiment 33 or embodiment 34, having at about room temperature an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 19, wherein the radiation used has a wavelength of 1.54060 Å.

[0086] Embodiment 36. The crystalline form of any one of embodiments 33-35, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 20.

[0087] Embodiment 36a. A T of about 186.6° C. when heated from 0 to 300° C. at 10° C. per minute as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset The crystalline form of any one of embodiments 33-35, having a melting endotherm at

[0088] Embodiment 37. The crystalline form of any one of embodiments 33-36a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG. 21.

[0089] Embodiment 37a. The crystalline form of any one of embodiments 33-36a, having a loss on drying of about 0.51% when heated from 30° C. to 182° C. at a heating rate of 10° C. / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0090] Embodiment 37b. The crystalline form of any one of embodiments 34-37a, wherein the crystalline form is substantially phase pure.

[0091] Embodiment 38. The crystalline form according to embodiment 33, characterized by an X-ray powder diffraction pattern comprising peaks at 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, such as 10 or more, for example 11 or more, such as 12 or more, for example all 13 2θ values) selected from the group consisting of:

[0092] [Table 8]

[0093] Embodiment 39. A crystalline form according to embodiment 33 or embodiment 38, having at about room temperature an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 22, wherein the radiation used has a wavelength of 1.54060 Å.

[0094] Embodiment 40. The crystalline form of any one of embodiments 33, 38, and 39, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 23.

[0095] Embodiment 40a. A T of about 122.2° C. when heated from 0 to 300° C. at 10° C. per minute as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset The crystalline form of any one of embodiments 33, 38 and 39, having a melting endotherm at

[0096] Embodiment 41. The crystalline form of any one of embodiments 33 and 38-40a, having a thermogravimetric analysis (TGA) diagram substantially the same as that shown in FIG.

[0097] Embodiment 41a. The crystalline form of any one of embodiments 33 and 38-40a, having a loss on drying of about 26.7% when heated from 30°C to 200°C at a heating rate of 10°C / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0098] Embodiment 41b. The crystalline form of any one of embodiments 38-41a, wherein the crystalline form is substantially phase pure.

[0099] Embodiment 42. The crystalline form of embodiment 1, wherein compound B is in the form of a mesylate salt.

[0100] Embodiment 43. The crystalline form according to embodiment 42, characterized by an X-ray powder diffraction pattern comprising peaks at 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, such as 10 or more, for example 11 or more, such as 12 or more, for example all 13 2θ values) selected from the group consisting of:

[0101] [Table 9]

[0102] Embodiment 44. A crystalline form according to embodiment 42 or embodiment 43, having at about room temperature an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 25, wherein the radiation used has a wavelength of 1.54060 Å.

[0103] Embodiment 45. The crystalline form of any one of embodiments 42-44, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 26.

[0104] Embodiment 45a. A TA Discovery DSC instrument has a T of about 22° C. and about 267.9° C. when heated from 0 to 300° C. at 10° C. per minute. onset The crystalline form of any one of embodiments 42-44, having a melting endotherm at a value of

[0105] Embodiment 46. The crystalline form of any one of embodiments 42-45a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG. 27.

[0106] Embodiment 46a. The crystalline form of any one of embodiments 42-45a, having a loss on drying of about 0.34% when heated from 30° C. to 100° C. at a heating rate of 10° C. / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0107] Embodiment 46b. The crystalline form of any one of embodiments 42-46a, wherein the crystalline form is substantially phase pure.

[0108] Embodiment 47. The crystalline form of embodiment 1, wherein compound B is in free form.

[0109] Embodiment 48. The crystalline form of embodiment 47, wherein compound B is in the form of a 2-methyl-2-butanol solvate, which is the free form of compound B.

[0110] Embodiment 49. A crystalline form according to embodiment 47 or embodiment 48, characterized by an X-ray powder diffraction pattern comprising peaks at 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, such as 10 or more, for example 11 or more, such as 12 or more, for example all 13 2θ values) selected from the group consisting of:

[0111] [Table 10]

[0112] Embodiment 50. A crystalline form according to any one of embodiments 47 to 49, having at about room temperature an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 28, wherein the radiation used has a wavelength of 1.54060 Å.

[0113] Embodiment 51. The crystalline form of any one of embodiments 47-50, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 29.

[0114] Embodiment 51a. A T of about 68° C. when heated from 0 to 300° C. at 10° C. per minute as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset The crystalline form of any one of embodiments 47-50, having a melting endotherm at

[0115] Embodiment 52. The crystalline form of any one of embodiments 47-51a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG. 30.

[0116] Embodiment 52a. The crystalline form of any one of embodiments 47-51a, having a loss on drying of about 5.91% when heated from 30° C. to 100° C. at a heating rate of 10° C. / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0117] Embodiment 52b. The crystalline form of any one of embodiments 47-52a, wherein the crystalline form is substantially phase pure.

[0118] Embodiment 53. The crystalline form of embodiment 2, wherein compound A is compound A in free form or a solvate thereof.

[0119] Embodiment 54. The crystalline form of embodiment 53, characterized by an X-ray powder diffraction pattern comprising 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, for example all 10 2θ values) selected from the group consisting of:

[0120] [Table 11]

[0121] Embodiment 55. A crystalline form according to embodiment 53 or embodiment 54, having at about room temperature an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 31, wherein the radiation used has a wavelength of 1.54060 Å.

[0122] Embodiment 56. The crystalline form of any one of embodiments 53 to 55, wherein compound A is a solvate of compound A in free form.

[0123] Embodiment 57. The crystalline form of any one of embodiments 53-56, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 32.

[0124] Embodiment 57a. A T of about 117.5° C. when heated from 0 to 300° C. at 10° C. per minute as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset The crystalline form of any one of embodiments 53-56, having a melting endotherm at

[0125] Embodiment 58. The crystalline form of any one of embodiments 53-57a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG. 33.

[0126] Embodiment 58a. The crystalline form of any one of embodiments 53-57a, having a loss on drying of about 0.38% when heated from 27°C to 110°C at a heating rate of 10°C / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0127] Embodiment 58b. The crystalline form of any one of embodiments 53-58a, wherein the crystalline form is substantially phase pure.

[0128] Embodiment 59. The crystalline form of embodiment 2, wherein compound A is in the form of a 4-hydroxybenzoate salt.

[0129] Embodiment 60. The crystalline form of embodiment 59, characterized by an X-ray powder diffraction pattern comprising 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, such as 10 or more, for example all 11 2θ values) selected from the group consisting of:

[0130] [Table 12]

[0131] Embodiment 61. A crystalline form according to embodiment 59 or embodiment 60, having at about room temperature an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 34, wherein the radiation used has a wavelength of 1.54060 Å.

[0132] Embodiment 62. The crystalline form of any one of embodiments 59-61, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG.

[0133] Embodiment 62a. A T of about 216.7° C. when heated from 0 to 300° C. at 10° C. per minute as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset The crystalline form of any one of embodiments 59-61, having a melting endotherm at

[0134] Embodiment 63. The crystalline form of any one of embodiments 59-62a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG.

[0135] Embodiment 63a. The crystalline form of any one of embodiments 59-62a, having a loss on drying of about 0.46% when heated from 27°C to 110°C at a heating rate of 10°C / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0136] Embodiment 63b. The crystalline form of any one of embodiments 59-63a, wherein the crystalline form is substantially phase pure.

[0137] Embodiment 64. The crystalline form of embodiment 2, wherein compound A is in the form of a 3,4-dihydroxybenzoate salt.

[0138] Embodiment 65. The crystalline form according to embodiment 64, characterized by an X-ray powder diffraction pattern comprising 4 or more 2θ values ​​(e.g. 5 or more, such as 6 or more, for example 7 or more, such as 8 or more, for example 9 or more, for example all 10 2θ values) selected from the group consisting of:

[0139] [Table 13]

[0140] Embodiment 66. A crystalline form according to embodiment 64 or embodiment 65, having at about room temperature an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction spectrum as shown in FIG. 37, wherein the radiation used has a wavelength of 1.54060 Å.

[0141] Embodiment 67. The crystalline form of any one of embodiments 64-66, having a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 38.

[0142] Embodiment 67a. A TA Discovery DSC instrument having a T of about 29° C. and about 216.5° C. when heated from 0 to 300° C. at 10° C. per minute, as measured by differential scanning calorimetry using a TA Discovery DSC instrument. onset The crystalline form of any one of embodiments 64-66, having a melting endotherm at a value of

[0143] Embodiment 68. The crystalline form of any one of embodiments 64-67a, having a thermogravimetric analysis (TGA) diagram substantially similar to that shown in FIG.

[0144] Embodiment 68a. The crystalline form of any one of embodiments 64-67a, having a loss on drying of about 1.63% when heated from 26°C to 80°C at a heating rate of 10°C / min, as measured by thermogravimetric analysis using a TA Discovery TGA instrument.

[0145] Embodiment 68b. The crystalline form of any one of embodiments 64-68a, wherein the crystalline form is substantially phase pure.

[0146] Embodiment 69. A pharmaceutical composition comprising a crystalline form according to any one of the preceding embodiments and a pharma- ceutically acceptable carrier.

[0147] Embodiment 70. A crystalline form according to any one of embodiments 1 to 68a or a pharmaceutical composition according to embodiment 69 for use as a medicament.

[0148] Embodiment 71. A combination comprising the crystalline form of any one of embodiments 1 to 68a and one or more therapeutically active agents.

[0149] Embodiment 72. A crystalline form according to any one of embodiments 1 to 68a or a pharmaceutical composition according to embodiment 69 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 truncation mutations or deletions; or (iii) one or more functional YAP / TAZ fusions.

[0150] Embodiment 73. A method for treating a disease or condition mediated by YAP overexpression, and / or YAP amplification, and / or YAP / TAZ-TEAD interaction, or a method for treating a cancer or tumor having (i) one or more YAP / TAZ fusions; (ii) one or more NF2 / LATS1 / LATS2 truncation mutations or deletions; or (iii) one or more functional YAP / TAZ fusions, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form described in any one of embodiments 1 to 68a; or a pharmaceutical composition described in embodiment 69; or a combination described in embodiment 71.

[0151] Embodiment 74. For use in the treatment of cancer, preferably the cancer is mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the tunica vaginalis testis), 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), inflammatory induration (including benign inflammatory induration), pore carcinoma (including malignant pore carcinoma), supratentorial ependymoma (including pediatric supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumor, solid tumor, breast cancer (including triple negative breast cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer. 69. The crystalline form according to any one of embodiments 1-68a or the pharmaceutical composition according to embodiment 69, wherein the crystalline form according to any one of embodiments 1-68a or the pharmaceutical composition according to embodiment 69 is selected from a cancer or tumor selected from: colorectal carcinoma, 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's sarcoma, soft tissue sarcoma, and rare soft tissue sarcomas), bone cancer, brain tumor, medulloblastoma, glioma, meningioma, and head and neck cancer (including head and neck squamous cell carcinoma).

[0152] In embodiment 75, the cancer, tumor, disease or condition is mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the tunica vaginalis testis), carcinoma (including squamous cell carcinoma of the cervix, endometrial carcinoma, squamous cell carcinoma of the esophagus, adenocarcinoma of the esophagus, urothelial carcinoma of the bladder and squamous cell carcinoma of the skin), inflammatory induration (including benign inflammatory induration), pore carcinoma (including malignant pore carcinoma), supratentorial ependymoma (including pediatric supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumor, solid tumor, breast cancer (including triple negative breast cancer), lung cancer (including non-small cell lung cancer). 74. The method of embodiment 73, wherein the cancer is selected from cancers including 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, renal cancer, sarcoma (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcoma (UPS), Kaposi's sarcoma, soft tissue sarcoma, and rare soft tissue sarcomas), bone cancer, brain tumor, medulloblastoma, glioma, meningioma, and head and neck cancer (including head and neck squamous cell carcinoma).

[0153] Embodiment 76. The method of embodiment 73, wherein the disease or condition is selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the tunica vaginalis testis) and solid tumors with NF2 / LATS1 / LATS2 mutations.

[0154] Embodiment 77. Compound B in the form of a succinate salt.

[0155] Embodiment 78. Compound B in the form of a malate salt.

[0156] Embodiment 79. Compound B in the form of a lactate salt.

[0157] Embodiment 80. Compound B in the form of a benzoate salt.

[0158] Embodiment 81. Compound B in the form of a glutamate salt.

[0159] Embodiment 82. Compound B in the form of a maleate salt.

[0160] Embodiment 83. Compound B in the form of a malonate salt.

[0161] Embodiment 84. Compound B in the form of a mesylate salt.

[0162] Embodiment 85. Compound B in the free form, for example compound B in the form of a 2-methyl-2-butanol solvate, which is the free form of compound B.

[0163] Embodiment 86. Compound A in the form of the free form of compound A.

[0164] Embodiment 87. Compound A in the form of a 4-hydroxybenzoate salt.

[0165] Embodiment 88. Compound A in the form of a 3,4-dihydroxybenzoate salt.

[0166] definition As used herein, "polymorph" or "crystalline variation" or "crystalline form" refers to crystalline forms that have the same chemical composition but differ in the spatial arrangement of the molecules, atoms and / or ions that form the crystals.

[0167] As used herein, "solvate" refers to a crystalline form of a molecule, atom, and / or ion that further comprises one or more molecules of a solvent incorporated into the crystal lattice structure. The solvent molecules in a solvate may be in an ordered arrangement and / or a disordered arrangement. A solvate may comprise either stoichiometric or non-stoichiometric amounts of solvent molecules. For example, a solvate with a non-stoichiometric amount of solvent molecules may result from partial loss of solvent from a solvate. A solvate may occur within a crystal lattice structure as a dimer or an oligomer composed of two or more molecules, i.e., compound ABC. The solvent may be water, in which case the solvent may be referred to as a hydrate.

[0168] As used herein, the term "free form" of a given compound refers to the solid state form in which the only component present that is solid at ambient conditions (e.g., 20° C., 1 atm) is said compound. Thus, as used herein, the term "free form" encompasses both unsolvated / unhydrated and solvated / hydrated forms, but excludes salts and co-crystals in which the coformers are solid at ambient conditions.

[0169] As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acid and / or base salts due to 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 present invention can also form internal salts, e.g., zwitterionic molecules.

[0170] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0171] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0172] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0173] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0174] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I-XII of the periodic table, in certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0175] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0176] As used herein, "amorphous" refers to a solid form of molecules, atoms, and / or ions that is not crystalline. Amorphous solids do not exhibit distinct X-ray diffraction patterns.

[0177] As used herein, the term "substantially phase pure" in reference to a particular polymorphic form means a polymorphic form that contains less than 10% by weight, preferably less than 5% by weight, more preferably less than 3% by weight, and most preferably less than 1% by weight of any other phases (polymorphs) of the same compound.

[0178] The term "substantially the same" with respect to X-ray diffraction peak positions means that typical peak position and intensity variations are taken into account. For example, one skilled in the art will understand that peak positions (2θ) will show some inter-instrument variation (typically on the order of 0.2°). Furthermore, one skilled in the art will understand that relative peak intensities will show inter-instrument variation as well as variation due to crystallinity, preferred orientation, sample surface preparation, and other factors known to those skilled in the art, and should be interpreted only as a qualitative measure. One skilled in the art of X-ray powder diffraction can easily determine whether a given sample is derived from the same polymorph as a reference sample.

[0179] As used herein, the terms "about" and "substantially" indicate that these values ​​may vary with respect to features (e.g., endotherms, endothermic peaks, exotherms, baseline shifts, etc.). With respect to X-ray diffraction peak positions, "about" or "substantially" means that typical peak position and intensity variations are taken into account. For example, one of ordinary skill in the art will understand that peak positions (2θ) will exhibit some inter-instrument variation (typically on the order of 0.2°). In some cases, this variation may be higher than 0.2° depending on instrument calibration differences. Furthermore, one of ordinary skill in the art will understand that relative peak intensities exhibit inter-instrument variation as well as variation due to crystallinity, preferred orientation, sample surface prepared, and other factors known to those of ordinary skill in the art, and should be interpreted only as a qualitative measure. In the case of DSC, the observed temperature variation will depend on the rate of temperature change as well as the sample preparation technique and the particular instrument used. Thus, the endotherm / melting point values ​​reported herein for DSC / TGA thermograms may vary by ±5°C (and still be considered characteristic of the particular crystalline form described herein). When used in connection with other characteristics (eg, weight percent (wt %), reaction temperature), the term "about" indicates a variation of ±5%.

[0180] The term "therapeutically effective amount" of a crystalline form of the invention refers to an amount of a crystalline form of the invention that elicits a biological or medical response in a subject, such as reducing or inhibiting the activity of an enzyme or protein or ameliorating a symptom, alleviating a pathology, slowing or delaying the progression of a disease, or preventing a disease. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention 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 is (i) associated with overactivation of the YAP / TAZ-TEAD complex, (ii) mediated by overexpression of YAP and / or YAP amplification, or (iii) associated with YAP activity, or (iv) characterized by YAP activity (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 invention that, when administered to a cell, or tissue, or non-cellular biomaterial, or culture medium, is effective to at least partially reduce or inhibit the interaction of YAP and / or TAZ with TEAD.

[0181] As used herein, the terms "a," "an," "the," and similar terms used in connection with the present invention (particularly in connection with the claims) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0182] Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. The use of any examples or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the invention and does not limit the scope of the invention unless otherwise asserted.

[0183] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation 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.

[0184] As used herein, the terms "treat", "treating" or "treatment" of any disease or disorder, in one embodiment, refer to ameliorating the disease or disorder (i.e., slowing or preventing or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter, including one that 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 slowing the worsening of the disease or disorder.

[0185] As used herein, the terms "prevent", "preventing" or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder or delaying the onset of the disease or disorder.

[0186] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. Subjects include, 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.

[0187] As used herein, a subject is "in need of" or "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0188] The term "comprising" is intended to encompass "consisting of" as well as "including", e.g., a composition comprising X can be exclusive of X or can include in addition (e.g., X and Y).

[0189] The crystalline forms of the present invention may be administered either simultaneously with, before or after one or more other therapeutic agents. The crystalline forms of the present invention may be administered separately by the same or different administration route, or together with other agents in the same pharmaceutical composition. The therapeutic agent is, for example, a chemical compound, a peptide, an antibody, an antibody fragment, or a nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with the compound of the present invention.

[0190] In the combination therapy of the invention, the crystalline forms of the invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the crystalline forms of the invention and the other therapeutic agent may be combined into a combination therapy (i) prior to delivery of the combination product to the physician (e.g., in the case of a kit containing the crystalline forms of the invention and the other therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; or (iii) in the patient himself, e.g., during sequential administration of the crystalline forms of the invention and the other therapeutic agent.

[0191] The synthesis of the compounds of the present invention was originally described in PCT / IB2021 / 052136 (WO 2021 / 186324), the contents of which are incorporated by reference.

[0192] Solid-state chemical properties of compound B 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 Kα (λ=1.5418 Å). Patterns were measured from 2° to 40° 2-theta. Sample size: 5-10mg Sample holder: Zero background Si flat sample holder

[0193] [Table 14]

[0194] The most characteristic peaks in the XRPD of each form are highlighted in red and labeled A, B, C, and D.

[0195] 1. Fundamental characteristics of the crystalline form of compound B and preparation examples 1) Characterization of the succinate salt of compound B a. XRPD pattern of the succinate salt of compound B (See Figure 1 for XRPD pattern. Most intense peaks are shown below)

[0196] [Table 15]

[0197] b. Unit cell of the succinate salt of compound B A preliminary crystal structure of variant A of compound B (BDI35A) was determined at 100 K. The structure of BDI35A is in the space group P2 1 It contains one API cation and one hydrogen succinate anion in the asymmetric unit (Z'=1). The crystal structure information is listed in the table below.

[0198] [Table 16]

[0199] c. DSC thermogram of the succinate salt of compound B (See Figure 2)

[0200] d. TGA thermogram of the succinate salt of compound B (See Figure 3)

[0201] e. Method for preparing succinate salt of compound B Example 1: Approximately 70 mg of compound B and 19 mg of succinic acid were weighed into a vial, then 1 mL of ethyl acetate was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0202] Example 2: Approximately 70 mg of compound B and 19 mg of succinic acid were weighed into a vial, then 1 mL of THF was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0203] Example 3: Approximately 70 mg of compound B and 19 mg of succinic acid were weighed into a vial, then 1 mL of acetonitrile / water (95 / 5, v / v) was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0204] Example 4: Approximately 20 mg of compound B and 5.5 mg of succinic acid were weighed into a vial, and then 0.15 mL of methanol was added. Then, 1.35 mL of IPA was slowly added to the solution. The sample was shaken overnight at room temperature. The solid was collected by centrifugal filtration.

[0205] Example 5: Approximately 20 mg of compound B and 5.5 mg of succinic acid were weighed into a vial, and then 0.15 mL of methanol was added. Then, 1.35 mL of MIBK was slowly added to the solution. The sample was shaken overnight at room temperature. The solid was collected by centrifugal filtration.

[0206] Example 6: Approximately 20 mg of compound B and 5.5 mg of succinic acid were weighed into a vial, and then 0.15 mL of methanol was added. Then 1.35 mL of EA was slowly added to the solution. The sample was shaken overnight at room temperature. The solid was collected by centrifugal filtration.

[0207] Example 7: Approximately 20 mg of compound B and 5.5 mg of succinic acid were weighed into a vial, and then 0.15 mL of methanol was added. 1.35 mL of MTBE was then slowly added to the solution. The sample was shaken overnight at room temperature. The solid was collected by centrifugal filtration.

[0208] Example 8: 1.0g of free form (compound B) and 275mg of succinic acid are weighed into a reactor, 5.5ml of methanol is added to dissolve the solid at room temperature. 50ml of IPA is added as an anti-solvent while stirring at 300rpm for 1 hour at room temperature, then stirred at room temperature overnight. The solid is collected by vacuum filtration and dried at 50°C overnight. 0.95g of succinate salt is obtained with a yield of 75%.

[0209] Example 9: 8.0 g of free form (compound B) and 2.2 g of succinic acid are weighed into a reactor, then 62.7 mL of MeOH / IPA (9 / 2, vol / vol) is added, and stirring is performed with a paddle at 300 rpm at 55° C. to obtain a clear solution. 10.6 mL of IPA is added, followed by 50 mg of crystal seeds (0.5% w / w). Cool to 45° C. in 30 minutes. Then, 184 mL of IPA is added in about 5 hours. Cool to 5° C. at a rate of 0.2 K / min, and stir at 5° C. overnight. The solid is collected by filtration under vacuum and dried at 50° C. for 2 hours. 8.72 g of succinic acid salt is obtained in 86% yield.

[0210] 2) Characterization of the L-malate salt of compound B a. XRPD pattern of the L-malate salt of compound B (See Figure 4 for XRPD pattern. Most intense peaks are shown below)

[0211] [Table 17]

[0212] b. DSC thermogram of the L-malate salt of compound B (See Figure 5)

[0213] c. TGA thermogram of the L-malate salt of compound B (See Figure 6)

[0214] d. Method for preparing L-malate of compound B Example 1: Approximately 70 mg of compound B and 22 mg of L-malic acid were weighed into a vial, then 1 mL of ethyl acetate was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0215] Example 2: Approximately 20 mg of compound B and 6.2 mg of L-malic acid were weighed into a vial, and then 0.15 mL of methanol was added. Then, 1.35 mL of MIBK was slowly added to the solution. The sample was shaken at room temperature for 3 days. The solid was collected by centrifugal filtration.

[0216] Example 3: Approximately 20 mg of compound B and 6.2 mg of L-malic acid were weighed into a vial, and then 0.15 mL of methanol was added. Then 1.35 mL of EA was slowly added to the solution. The sample was shaken at room temperature for 3 days. The solid was collected by centrifugal filtration.

[0217] Example 4: Approximately 20 mg of compound B and 6.2 mg of L-malic acid were weighed into a vial, and then 0.15 mL of methanol was added. Then, 1.35 mL of MTBE was slowly added to the solution. The sample was shaken overnight at room temperature. The solid was collected by centrifugal filtration.

[0218] Example 5: 2.1 g of the free form (compound B) was weighed and dissolved in 21 mL of EA solvent at 60° C., resulting in the appearance of a cloudy solution. 663.6 mg of L-malic acid was weighed and dissolved in 21 mL of EA solvent at 60° C., resulting in the appearance of a clear solution. The dissolved L-malic acid solution was added dropwise to the solution of the free form at 60° C. at an addition rate of 0.2 mL / min by using a peristaltic pump. After the addition of the L-malic acid solution, a gel appeared in the system. Crystal seeds were added to the mixture and the following temperature profile was applied: cooling from 60° C. to 20° C. in 4 hours (i.e., cooling rate of 0.17° C. / min), heating from 20° C. to 50° C. in 3 hours, and cooling from 50° C. to 0° C. in 5 hours. This temperature profile was repeated and finally held at 0° C. overnight with a stirring speed of 300 rpm. The precipitated solid was filtered and dried at 40° C. for 3 hours to give 2.35 g of material (yield=87.2%).

[0219] Example 6: 1.0 g of free form (compound B) and 283 mg of L-malic acid are weighed into a vial, 3.5 mL of MEOH / EA (4 / 6, vol / vol) is added, and stirred at 25 under 300 rpm to obtain a clear solution. To this clear solution, 1.05 mL of EA is added. 5.1 mg (0.5%) of crystal seeds are added and stirred for another 10 minutes. Then, 9.45 mL of EA is added at a rate of 0.1 mL / min. Cool to 5° C. at a rate of 0.2 K / min and stir at 5° C. overnight. The solid is collected by vacuum filtration and dried at 40° C. under vacuum for 2 hours. 1.07 g of L-malate salt is obtained with a yield of 83.4%.

[0220] 3) Characterization of the L-lactate salt of compound B a. XRPD pattern of the L-lactate salt of compound B (See Figure 7 for XRPD pattern. Most intense peaks are shown below)

[0221] [Table 18]

[0222] b. DSC thermogram of the L-lactate salt of compound B (See Figure 8)

[0223] c. TGA thermogram of the L-lactate salt of compound B (See Figure 9)

[0224] d. Method for preparing the L-lactate salt of compound B Example 1: Approximately 70 mg of compound B and 15 mg of L-lactic acid were weighed into a vial, then 1 mL of ethyl acetate was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0225] Example 2: Approximately 70 mg of compound B and 15 mg of L-lactic acid were weighed into a vial, then 1 mL of THF was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0226] Example 3: Approximately 70 mg of compound B and 15 mg of L-lactic acid were weighed into a vial, then 1 mL of acetonitrile / water (95 / 5, vol / vol) was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. A clear solution was obtained and evaporated to dryness at room temperature. The solid was collected and dried at 40° C. for 2 hours.

[0227] Example 4: 2.1 g of the free form (compound B) was weighed and dissolved in 21 mL of EA solvent at 60° C., resulting in the appearance of a cloudy solution. 445.8 mg of L-lactic acid was weighed and dissolved in 21 mL of EA solvent at 60° C., resulting in the appearance of a clear solution. The solution of the free form was added dropwise to the dissolved L-lactic acid solution at 60° C. After the addition of the L-lactic acid solution, a suspension appeared. Crystal seeds were added to the mixture and the following temperature profile was applied: cooling from 60° C. to 20° C. in 4 hours (i.e., cooling rate of 0.17° C. / min), heating from 20° C. to 50° C. in 3 hours, and cooling from 50° C. to 0° C. in 5 hours. This temperature profile was repeated and finally held at 0° C. overnight with a stirring speed of 300 rpm. The precipitated solid was filtered and dried at 40° C. for 3 hours, resulting in 2.15 g of material (yield=86%).

[0228] 4) Characterization of the benzoate salt of compound B a. XRPD pattern of benzoate salt (See FIG. 10 for the XRPD pattern. The most intense peaks are shown below.)

[0229] [Table 19]

[0230] b. DSC thermogram of the benzoate salt of compound B (See Figure 11)

[0231] c. TGA thermogram of the benzoate salt of compound B (See Figure 12)

[0232] d. Method for preparing benzoate of compound B Example 1: Approximately 70 mg of compound B and 20 mg of benzoic acid were weighed into a vial, then 1 mL of ethyl acetate was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0233] Example 2: Approximately 70 mg of compound B and 20 mg of benzoic acid were weighed into a vial, then 1 mL of acetonitrile / water (95 / 5, vol / vol) was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0234] 5) Characterization of the glutamate salt of compound B a. XRPD pattern of the glutamate salt of compound B (See FIG. 13 for the XRPD pattern. The most intense peaks are shown below.)

[0235] [Table 20]

[0236] b. DSC thermogram of the glutamate salt of compound B (See Figure 14)

[0237] c. TGA thermogram of the glutamate salt of compound B (See Figure 15)

[0238] d. Preparation of the glutamate salt of compound B Example 1: Approximately 70 mg of compound B and 22 mg of glutamic acid were weighed into a vial, then 1 mL of ethyl acetate was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0239] Example 2: Approximately 70 mg of compound B and 22 mg of glutamic acid were weighed into a vial, then 1 mL of acetonitrile / water (95 / 5, vol / vol) was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. A clear solution was obtained and evaporated to dryness at room temperature. The solid was collected and dried at 40° C. for 2 hours.

[0240] 6) Characterization of the maleate salt of compound B a. XRPD pattern of the maleate salt of compound B (See FIG. 16 for the XRPD pattern. The most intense peaks are shown below.)

[0241] [Table 21]

[0242] b. DSC thermogram of the maleate salt of compound B (See Figure 17)

[0243] c. TGA thermogram of the maleate salt of compound B (See Figure 18)

[0244] d. Preparation of the maleate salt of compound B Example 1: Approximately 70 mg of compound B and 19 mg of maleic acid were weighed into a vial, then 1 mL of EA was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0245] Example 2: Approximately 70 mg of compound B and 19 mg of maleic acid were weighed into a vial, then 1 mL of THF was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0246] Example 3: Approximately 70 mg of compound B and 19 mg of maleic acid were weighed into a vial, then 1 mL of acetonitrile / water (95 / 5, vol / vol) was added. The sample was stirred at 50° C. for approximately 2-4 hours and then at room temperature overnight. A clear solution was obtained and evaporated to dryness at room temperature. The solid was collected and dried at 40° C. for 2 hours.

[0247] 7) Characterization of Compound B Malonate Type I a. XRPD pattern of malonate type I (See FIG. 19 for the XRPD pattern. The most intense peaks are shown below.)

[0248] [Table 22]

[0249] b. DSC thermogram of malonate type I of compound B (See Figure 20)

[0250] c. TGA thermogram of malonate type I of compound B (See Figure 21)

[0251] d. Preparation method of malonate type I of compound B Example 1: Approximately 70 mg of compound B and 17 mg of malonic acid were weighed into a vial, then 1 mL of EA was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0252] 8) Characterization of Compound B Malonate Type II a. XRPD pattern of malonate type II (See FIG. 22 for the XRPD pattern. The most intense peaks are shown below.)

[0253] [Table 23]

[0254] b. DSC thermogram of malonate type II of compound B (See Figure 23)

[0255] c. TGA thermogram of malonate type II of compound B (See Figure 24)

[0256] d. Method for preparing malonate type II of compound B Example 1: Approximately 70 mg of compound B and 17 mg of malonic acid were weighed into a vial, then 1 mL of THF was added. The sample was stirred at 50° C. for approximately 2-4 hours, then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0257] 9) Characterization of the mesylate salt of compound B a. XRPD pattern of the mesylate salt of compound B (See Figure 25 for XRPD pattern. Most intense peaks are shown below)

[0258] [Table 24]

[0259] b. DSC thermogram of the mesylate salt of compound B (See Figure 26)

[0260] c. TGA thermogram of the mesylate salt of compound B (See Figure 27)

[0261] d. Method for preparing mesylate salt of compound B Example 1: Approximately 70 mg of compound B was weighed into a vial and 1 mL of EA was added. Then, approximately 11 μL of methanesulfonic acid was added. The sample was stirred at 50° C. for approximately 2-4 hours and then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0262] Example 2: Approximately 70 mg of compound B was weighed into a vial and 1 mL of THF was added. Then, approximately 11 μL of methanesulfonic acid was added. The sample was stirred at 50° C. for approximately 2-4 hours and then at room temperature overnight. The solid was collected by centrifugal filtration and dried at 40° C. for 2 hours.

[0263] Example 3: Approximately 70 mg of compound B was weighed into a vial and 1 mL of acetonitrile / water (95 / 5, vol / vol) was added. Then, approximately 11 μL of methanesulfonic acid was added. The sample was stirred at 50° C. for approximately 2-4 hours and then at room temperature overnight. A clear solution was obtained and evaporated to dryness at room temperature. The solid was collected and dried at 40° C. for 2 hours.

[0264] 10) Characterization of the free form of compound B, the 2-methyl-2-butanol solvate a. XRPD pattern of the free form of compound B, 2-methyl-2-butanol solvate (See Figure 28 for XRPD pattern. Most intense peaks are shown below)

[0265] [Table 25]

[0266] b. DSC thermogram of the free form of compound B, 2-methyl-2-butanol solvate (See Figure 29)

[0267] c. TGA thermogram of the free form of compound B, 2-methyl-2-butanol solvate (See Figure 30)

[0268] d. Method for preparing 2-methyl-2-butanol solvate of compound B Example 1: 40 mg of the free form (Compound B) was weighed into a vial, 0.2 mL of 2-methyl-2-butanol was added, and stirred for 4 weeks at 25° C. The solid was collected by centrifugal filtration and dried at room temperature.

[0269] Example 2: 1 g of compound B was weighed into 5 mL of 2M2B, seeded and slurried at room temperature for 5 hours. The solid was filtered and washed with 5 mL of 2M2B, then dried at ambient conditions overnight, followed by drying at 40° C. for 0.5 hours.

[0270] [Table 26]

[0271] [Table 27]

[0272] [Table 28]

[0273] A brief explanation of succinate selection The succinate salt was chosen due to its advantages in counter ion, high crystallinity, bulk stability, hygroscopicity, morphology and process feasibility.

[0274] Solid-state chemical properties of compound A 1.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. Radiation was Cu Kα (λ=1.5418 Å). Patterns were measured from 2° to 40° 2-theta. Sample size: 5-10mg Sample holder: Zero background Si flat sample holder

[0275] [Table 29]

[0276] The most characteristic peaks in the XRPD of each form are highlighted in red and labeled A, B, C, and D.

[0277] 2. Fundamental characteristics of the crystalline form of compound A and preparation examples 1) Characterization of Modification Form A of Compound A a. XRPD pattern of modification A of compound A (See Figure 31 for XRPD pattern. Most intense peaks are shown below)

[0278] [Table 30]

[0279] b. DSC thermogram of modification A of compound A (See Figure 32)

[0280] c. TGA thermogram of Modification A of Compound A (See Figure 33)

[0281] d. Method for preparing variant A of compound A Example 1: Approximately 53 mg of Compound A (non-crystalline) was weighed into a vial, then 0.4 mL of acetone was added and mixed at 450 rpm at room temperature for 1 hour. The solid was then filtered and dried under vacuum at 40° C. for 2 hours.

[0282] Example 2: Approximately 53 mg of Compound A (non-crystalline) was weighed into a vial, then 0.4 mL of acetonitrile was added and mixed at 450 rpm at room temperature for 1 hour. The solid was then filtered and dried under vacuum at 40° C. for 2 hours.

[0283] Example 3: About 3 g of the amorphous free form of Compound A was added to 200 mL of 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 stirring was maintained overnight. The resulting solid was re-equilibrated in 20 mL of EtOH / water=1 / 9 at 50° C. for about 6 hours, then gradually cooled to 10° C. within 6 hours, and stirred overnight. The solid was isolated by suction filtration and dried under vacuum at 50° C. overnight.

[0284] Example 4: Approximately 18 g of the amorphous free form of Compound A was weighed into a crystallizer. 200 mL of ACN / water=1 / 9 (volume / volume) was added. The mixture was stirred at 150 rpm at 40° C. for approximately 6 hours, then gradually cooled to room temperature and stirred overnight. The solid was isolated by filtration, followed by drying overnight under vacuum at 50° C. Approximately 17.2 g of a white solid was obtained.

[0285] 2) Characterization of the 4-hydroxybenzoate salt of compound A a. XRPD pattern of 4-hydroxybenzoate of compound A (See Figure 34 for XRPD pattern. Most intense peaks are shown below)

[0286] [Table 31]

[0287] b. DSC thermogram of 4-hydroxybenzoate of compound A (See Figure 35)

[0288] c. TGA thermogram of 4-hydroxybenzoate of compound A (See Figure 36)

[0289] d. Method for preparing 4-hydroxybenzoate of compound A Example 1: Approximately 53 mg of compound A (non-crystalline) and 1 equivalent molar mass of 4-hydroxybenzoic acid were weighed into a vial, then 0.5 mL of ter-butyl methyl ether was added and mixed at 50° C. for approximately 2 hours. The sample was then cooled to 25° C. and the slurrying was continued overnight. The solid was collected and resuspended in 0.2 mL of tetrahydrofuran, then 0.2 mL of heptane was added and the mixture was slurried at 25° C. for 3 days. The solid was obtained by centrifugal filtration.

[0290] Example 2: Approximately 53 mg of compound A (non-crystalline) and 1 equivalent molar mass of 4-hydroxybenzoic acid were weighed into a vial, then 0.5 mL of ethyl acetate / heptane (volume / volume, 1 / 1) was added and mixed at 50° C. for approximately 2 hours. The sample was then cooled to 25° C. and the slurrying was continued overnight. The sample was evaporated to dryness, then 0.2 mL of acetone and 0.5 mL of heptane were added and the mixture was slurried at 25° C. for 3 days. The solid was obtained by centrifugal filtration.

[0291] Example 3: Approximately 212 mg of the free form of compound A and 1 equivalent molar mass of 4-hydroxybenzoic acid were weighed into a vial. 1 mL of THF was added to obtain a clear solution. 2 mL of heptane was then added slowly. A gel-like sample formed, and a small amount of seeding was added and slurried overnight. The resulting solid was filtered and dried under vacuum at 40° C. for 3 hours.

[0292] Example 4: Approximately 212 mg of the free form of compound A and 1 equivalent molar mass of 4-hydroxybenzoic acid were weighed into a vial. 1.2 mL of acetone was added. A clear solution was obtained initially, then after a few minutes some solid precipitated from the slurry. The resulting solid was filtered and dried under vacuum at 40° C. for 3 hours.

[0293] Example 5: Approximately 2.12 g of the free form of compound A and 1 equivalent molar mass of 4-hydroxybenzoic acid were weighed into a vial. 10 mL of acetone was added to obtain a clear solution at first, then after a few minutes some solid precipitated from the slurry. The obtained solid was filtered and dried overnight under vacuum at 50°C.

[0294] Example 6: Approximately 2.1 g of the amorphous free form of Compound A and 552 mg of 4-hydroxybenzoic acid were weighed and added to a crystallizer. Then, 15 mL of ethanol was added. A clear solution was obtained at 45° C. Then, the solution was gradually cooled to 40° C. and crystal seeds were added. The mixture was cooled to 40° C. within 6 hours and stirred overnight. The solid was isolated by filtration and then dried under vacuum at 50° C. for about 4 hours. Approximately 1.2 g of a white solid was obtained.

[0295] 3) Characterization of the 3,4-dihydroxybenzoate salt of compound A a. XRPD pattern of 3,4-dihydroxybenzoate of compound A (See Figure 37 for XRPD pattern. Most intense peaks are shown below)

[0296] [Table 32]

[0297] b. DSC thermogram of 3,4-dihydroxybenzoate of compound A (See Figure 38)

[0298] c. TGA thermogram of 3,4-dihydroxybenzoate of compound A (See Figure 39)

[0299] d. Method for preparing 3,4-dihydroxybenzoate of compound A Example 1: Approximately 53 mg of compound A (non-crystalline) and 1 equivalent molar mass of 3,4-dihydroxybenzoic acid were weighed into a vial, then 0.5 mL of acetone was added and mixed at 50° C. for approximately 2 hours. The sample was then cooled to 25° C. and the slurrying was continued overnight. The solid was obtained by centrifugal filtration.

[0300] Example 2: Approximately 53 mg of compound A (non-crystalline) and 1 equivalent molar mass of 3,4-dihydroxybenzoic acid were weighed into a vial, then 0.5 mL of acetonitrile was added and mixed at 50° C. for approximately 2 hours. The sample was then cooled to 25° C. and the slurrying was continued overnight. The solid was obtained by centrifugal filtration.

[0301] Example 3: Approximately 1 g of the free form of compound A and 1 equivalent molar mass of 3,4-hydroxybenzoic acid were weighed into a 20 ml vial. Then, 8 mL of acetone was added and mixed at 450 rpm at 50° C. for approximately 1 hour. A clear solution was initially obtained. After adding some crystal seeds to the solution and equilibrating for 1 hour, some solid precipitated. The sample was then cooled to 25° C. and the slurrying was continued overnight. Approximately 1 g of white solid was obtained.

[0302] [Table 33]

[0303] [Table 34]

[0304] [Table 35]

[0305] A brief explanation of free form selection The free form (also known as "Modification Form A") was selected for development because it exhibits superior properties in terms of crystallinity, solubility, stability and polymorphic behavior. In addition, due to the absence of a counter ion, there are no safety concerns regarding the choice of counter ion.

[0306] The 4-hydroxybenzoate salt also had superior properties in terms of crystallinity, solubility, stability and polymorphic behavior, however, it was not selected for development due to insufficient safety data on the counter ion.

Claims

1. 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Compound B) or a pharmaceutically acceptable solvate and / or salt thereof in crystalline form.

2. 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 (Compound A) or a pharmaceutically acceptable solvate and / or salt thereof in crystalline form.

3. The crystalline form according to claim 1, wherein the Compound B is in the form of i) succinate, ii) malate, iii) lactate, iv) benzoate, v) glutamate, vi) maleate, vii) malonate, viii) mesylate, or ix) free form.

4. The crystalline form according to claim 2, wherein the Compound A is the free form of Compound A or a solvate thereof.

5. Characterized by an X-ray powder diffraction pattern comprising four or more 2θ values selected from the group consisting of, the temperature being approximately room temperature, and the radiation used having a wavelength of 1.54060 Å, the crystalline form according to claim 4. 【Table 11】

6. The crystalline form according to claim 5, wherein the X-ray powder diffraction pattern comprises peaks at at least 7.00° ± 0.2°, 9.21° ± 0.2°, 10.98° ± 0.2° and 21.80° ± 0.2°.

7. The crystalline form according to claim 4, wherein the Compound A is a solvate of the free form of Compound A.

8. The crystalline form according to claim 2, wherein the Compound A is in the form of i) 4-hydroxybenzoate, or ii) 3,4-dihydroxybenzoate.

9. A pharmaceutical composition comprising the crystalline form according to claim 1 and a pharmaceutically acceptable carrier.

10. The crystalline form according to claim 1 for use as a medicament.

11. A combination comprising the crystalline form according to claim 1 and one or more therapeutic active agents.

12. For use in the treatment of cancer mediated by YAP overexpression, and / or YAP amplification, and / or YAP / TAZ-TEAD interaction; or for use in the treatment of cancer or tumor having (i) one or more YAP / TAZ fusions; (ii) one or more NF2 / LATS1 / LATS2 cleavage mutations or deletions; or (iii) one or more functional YAP / TAZ fusions, the crystalline form according to claim 1 or the pharmaceutical composition according to claim 9.

13. For use in the treatment of cancer, preferably, the cancer is selected from cancers or tumors selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the testicular 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), inflammatory induration (benign type inflammatory induration), porocarcinoma (including malignant porocarcinoma), epithelioma of the tentorium (including epithelioma of the tentorium in children), epitheloid hemangioendothelioma (EHE), epithelioma tumor, 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, 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 tumor, medulloblastoma, glioma, meningioma and head and neck cancer (including head and neck squamous cell carcinoma), the crystalline form according to claim 1.

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