Ras inhibitors

Abstract

The disclosure provides crystalline and amorphous forms of Ras inhibitors, salts of Ras inhibitors, pharmaceutical compositions thereof, and their uses in the treatment of cancers.

Description

[0001] PATENT

[0002] ATTORNEY DOCKET NO. 51432-053WO2

[0003] RAS INHIBITORS

[0004] Background

[0005] The vast majority of small molecule drugs act by binding a functionally important pocket on a target protein, thereby modulating the activity of that protein. For example, cholesterol-lowering drugs known as statins bind the enzyme active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrates. The fact that many such drug / target interacting pairs are known may have misled some into believing that a small molecule modulator could be discovered for most, if not all, proteins provided a reasonable amount of time, effort, and resources. This is far from the case. Current estimates are that only about 10% of all human proteins are targetable by small molecules. Bojadzic and Buchwald, CurrTop Med Chem 18: 674-699 (2019). The other 90% are currently considered refractory or intractable toward above-mentioned small molecule drug discovery. Such targets are commonly referred to as “undruggable.” These undruggable targets include a vast and largely untapped reservoir of medically important human proteins. Thus, there exists a great deal of interest in discovering new molecular modalities capable of modulating the function of such undruggable targets.

[0006] It has been well established in literature that Ras proteins (K-Ras, H-Ras, and N-Ras) play an essential role in various human cancers and are therefore appropriate targets for anticancer therapy. Indeed, mutations in Ras proteins account for approximately 30% of all human cancers in the United States, many of which are fatal. Dysregulation of Ras proteins by activating mutations, overexpression or upstream activation is common in human tumors, and activating mutations in Ras are frequently found in human cancer. For example, activating mutations at codon 12 in Ras proteins function by inhibiting both GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of Ras mutant proteins to the “on” (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, enabling Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13C) and 61 (e.g., Q61 K) of Ras are also responsible for oncogenic activity in some cancers.

[0007] Despite extensive drug discovery efforts against Ras during the last several decades, only two agents targeting the K-Ras G12C mutant have been approved in the U. S. (sotorasib and adagrasib). Additional efforts are needed to uncover additional medicines for cancers driven by the various Ras mutations.

[0008] Summary

[0009] The invention features crystalline and amorphous forms of compound, and compound salts, useful for the treatment of a disease or condition (e.g., cancer, Ras protein-related disorder). PATENT

[0010] ATTORNEY DOCKET NO. 51432-053WO2

[0011] In an aspect, this disclosure describes a crystalline form of Compound A:

[0012]

[0013] Compound A.

[0014] In some embodiments, the crystalline form of Compound A is selected from Form 1, Form 2, Form 3, Form 4, and Form 5. In some embodiments, the crystalline form of Compound A is a solvate. In some embodiments, the crystalline form of Compound A or the solvate thereof is selected from Form 1, Form 2, Form 3, Form 4, and Form 5. In some embodiments, the crystalline solid form of Compound A is a Compound A solvate. In some embodiments, the crystalline form of Compound A or the solvate thereof is Form 1. In some embodiments, the crystalline form of Compound A or the solvate thereof is Form 2. In some embodiments, the crystalline form of Compound A or the solvate thereof is Form 3. In some embodiments, the crystalline form of Compound A or the solvate thereof is Form 4. In some embodiments, the crystalline form of Compound A or the solvate thereof is Form 5. In some embodiments, the Compound A solvates are substantially crystalline. In some embodiments, the Compound A solvates have a crystallinity greater than about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75 %, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%,

[0015] In some embodiments, provided herein is a crystalline form of Compound A, wherein the crystalline form is Form 1. In some embodiments, Form 1 is a solvate. In some embodiments, Form 1 is not a solvate. In some embodiments, the crystalline Form 1 of Compound A has at least one peak at diffraction angle 20 (°) of 8.2 ± 0.5, 23.9 ± 0.5, or 24.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has peaks at diffraction angles 20 (°) of 8.2 ± 0.5, 23.9 ± 0.5, and 24.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has at least one peak at diffraction angle 20 (°) of 8.2 ± 0.5, 25.2 ± 0.5, or 26.1 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has peaks at diffraction angles 20 (°) of 8.2 ± 0.5, 25.2 ± 0.5, and 26.1 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has at least one peak at diffraction angle 20 (°) of 8.2 ± 0.5, 28.3 ± 0.5, or 30.8 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has peaks at diffraction angles 20 (°) of 8.2 ± 0.5, 32.9 ± 0.5, and 35.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray PATENT

[0016] ATTORNEY DOCKET NO. 51432-053WO2

[0017] diffractometry. In some embodiments, the crystalline Form 1 of Compound A has the X-ray powder diffractogram as shown in FIG. 1. In some embodiments, the crystalline Form 1 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0018] In some embodiments, the crystalline Form 1 of Compound A is a mixed methanol and water solvate. In some embodiments, the crystalline Form 1 of Compound A is a mixed ethanol and water solvate. In some embodiments, the crystalline Form 1 of Compound A is a mixed acetone and water solvate. In some embodiments, the crystalline Form 1 is a Compound A isopropyl acetate / heptane solvate.

[0019] In some embodiments, the crystalline Form 1 of Compound A has an endothermic onset at about 163.2°C in a differential scanning calorimetry (DSC) profile. In some embodiments, the crystalline Form 1 of Compound A has an endothermic onset at 163.2°C ± 0.5 in a differential scanning calorimetry (DSC) profile. In some embodiments, the crystalline Form 1 of Compound A has a DSC thermogram shown in FIG. 3. In some embodiments, the crystalline Form 1 of Compound A exhibits a weight loss of 7.1% ± 0.5 (w / w) between ambient and 190.0°C ± 0.5 in a thermogravimetric analysis (TGA) profile. In some embodiments, the crystalline Form 1 of Compound A has a TGA graph shown in FIG. 4. In some embodiments, the crystalline Form 1 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0020] In some embodiments, the crystalline Form 1 of Compound A has at least one peak at diffraction angle 20 (°) of 8.2 ± 0.5, 14.3 ± 0.5, or 14.4 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has peaks at diffraction angles 20 (°) of 8.2 ± 0.5, 14.3 ± 0.5, and 14.4 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has at least one peak at diffraction angle 20 (°) of 8.2 ± 0.5, 18.0 ± 0.5, or 18.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has peaks at diffraction angles 20 (°) of 8.2 ± 0.5, 18.0 ± 0.5, and 18.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has at least one peak at diffraction angle 20 (°) of 8.2 ± 0.5, 21.6 ± 0.5, or 22.2 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has peaks at diffraction angles 20 (°) of 8.2 ± 0.5, 21.6 ± 0.5, and 22.2 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has at least one peak at diffraction angle 20 (°) of 8.2 ± 0.5, 24.6 ± 0.5, or 28.6 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has peaks at diffraction angles 20 (°) of 8.2 ± 0.5, 24.6 ± 0.5, and 28.6 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 1 of Compound A has the X-ray powder diffractogram as shown in FIG. 5. In some embodiments, the crystalline Form 1 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0021] In some embodiments, crystalline Form 1 of Compound A is characterized by having a peak at diffraction angle 20 (°) of 8.2 ± 0.5; and one or more peaks selected from the group consisting of 9.5 ± PATENT

[0022] ATTORNEY DOCKET NO. 51432-053WO2

[0023] 0.5, 10.6 ± 0.5, 10.7 ± 0.5, 10.8 ± 0.5, 13.2 ± 0.5, 13.4 ± 0.5, 14.1 ± 0.5, 15.5 ± 0.5, 16.7 ± 0.5, 16.9 ± 0.5, 18.6 ± 0.5, and 19.5 ± 0.5, as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some such embodiments, crystalline Form 1 is characterized by having two, three, four, five, six, seven, eight, or more peaks at diffraction angle 20 (°) selected from the group consisting of 9.5 ± 0.5, 10.6 ± 0.5, 10.7 ± 0.5, 10.8 ± 0.5, 13.2 ± 0.5, 13.4 ± 0.5, 14.1 ± 0.5, 15.5 ± 0.5, 16.7 ± 0.5, 16.9 ± 0.5, 18.6 ± 0.5, and 19.5 ± 0.5. In some embodiments, crystalline Form 1 of Compound A is characterized by having peaks at diffraction angles 20 (°) of 8.2 ± 0.5 and 10.7 ± 0.5; and one or more peaks selected from the group consisting of 9.5 ± 0.5, 10.6 ± 0.5, 10.8 ± 0.5, 13.2 ± 0.5, 13.4 ± 0.5, 14.1 ± 0.5, 15.5 ± 0.5, 16.7 ± 0.5, 16.9 ± 0.5, 18.6 ± 0.5, and 19.5 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some such embodiments, crystalline Form 1 is characterized by having two, three, four, five, six, seven, eight, or more peaks at diffraction angle 20 (°) selected from the group consisting of 9.5 ± 0.5, 10.6 ± 0.5, 10.8 ± 0.5, 13.2 ± 0.5, 13.4 ± 0.5, 14.1 ± 0.5, 15.5 ± 0.5, 16.7 ± 0.5, 16.9 ± 0.5, 18.6 ± 0.5, and 19.5 ± 0.5. In some embodiments, crystalline Form 1 is a solvate.

[0024] In some embodiments, the crystalline Form 1 of Compound A is a mixed methanol and water solvate. In some embodiments, the crystalline Form 1 of Compound A is a mixed ethanol and water solvate. In some embodiments, the crystalline Form 1 of Compound A is a mixed acetone and water solvate.

[0025] In some embodiments, the crystalline Form 1 of Compound A has an endothermic onset at 162.6°C ± 0.5 in differential scanning calorimetry (DSC) profile. In some embodiments, the crystalline Form 1 of Compound A has an endothermic onset at about 162.6°C in differential scanning calorimetry (DSC) profile. In some embodiments, the crystalline Form 1 of Compound A has a DSC thermogram shown in FIG. 6. In some embodiments, the crystalline Form 1 of Compound A exhibits a weight loss of 6.4% ± 0.5 (w / w) between ambient and 185.0°C ± 0.5 in a thermogravimetric analysis (TGA) profile. In some embodiments, the crystalline Form 1 of Compound A has a TGA graph shown in FIG. 7. In some embodiments, the crystalline Form 1 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0026] In some embodiments, provided herein is a crystalline form of Compound A, wherein the crystalline form is Form 2. In some embodiments, Form 2 is a solvate. In some embodiments, Form 2 is not a solvate. In an aspect, the invention features a crystalline Form 2 of Compound A having at least one peak at diffraction angle 20 (°) of 3.3 ± 0.5, 4.3 ± 0.5, or 16.6 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 2 of Compound A has at least one peak at diffraction angle 20 (°) of 10.1 ± 0.5, 13.1 ± 0.5, or 16.6 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 2 of Compound A has peaks at diffraction angles 20 (°) of 10.1 ± 0.5, 13.1 ± 0.5, and 16.6 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 2 of Compound A has at least one peak at diffraction angle 20 (°) of 13.8 ± 0.5, 16.6 ± 0.5, or 17.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 2 of Compound A has peaks at diffraction angles 20 (°) of 13.8 ± 0.5, 16.6 ± 0.5, and 17.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the PATENT

[0027] ATTORNEY DOCKET NO. 51432-053WO2

[0028] crystalline Form 2 of Compound A has at least one peak at diffraction angle 20 (°) of 16.6 ± 0.5, 19.2 ± 0.5, 19.9 ± 0.5, 20.1 ± 0.5, 20.2 ± 0.5, or 20.3 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 2 of Compound A has peaks at diffraction angles 20 (°) of 16.6 ± 0.5, 19.2 ± 0.5, 19.9 ± 0.5, 20.1 ± 0.5, 20.2 ± 0.5, and 20.3 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 2 of Compound A has at least one peak at diffraction angle 20 (°) of 16.6 ± 0.5, 22.3 ± 0.5, or 23.5 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 2 of Compound A has peaks at diffraction angles 20 (°) of 16.6 ± 0.5, 22.3 ± 0.5, and 23.5 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has at least one peak at diffraction angle 20 (°) of 16.6 ± 0.5, 24.2 ± 0.5, 24.9 ± 0.5, 25.5 ± 0.5, 27.0 ± 0.5, 27.7 ± 0.5, 28.2 ± 0.5, 31.0 ± 0.5, or 36.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 2 of Compound A has peaks at diffraction angles 20 (°) of 16.6 ± 0.5, 24.2 ± 0.5, 24.9 ± 0.5, 25.5 ± 0.5, 27.0 ± 0.5, 27.7 ± 0.5, 28.2 ± 0.5, 31.0 ± 0.5, and 36.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 2 of Compound A has the X-ray powder diffractogram as shown in FIG. 9. In some embodiments, the crystalline Form 2 of Compound A is a hydrate. In some embodiments, the crystalline Form 2 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0029] In some embodiments, crystalline Form 2 of Compound A is characterized by having a peak at diffraction angle 20 (°) of 15.3 ± 0.5; and one or more peaks selected from the group consisting of 8.1 ± 0.5, 9.3 ± 0.5, 10.1 ± 0.5, 10.2 ± 0.5, 14.1 ± 0.5, 15.2 ± 0.5, 15.3 ± 0.5, 16.6 ± 0.5, 18.3 ± 0.5, 18.5 ± 0.5, 19.4 ± 0.5, 20.4 ± 0.5, 20.5 ± 0.5, 22.1 ± 0.5, 22.3 ± 0.5, and 22.4 ± 0.5, as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some such embodiments, crystalline Form 2 is characterized by having two, three, four, five, six, seven, eight, or more peaks at diffraction angle 20 (°) selected from the group consisting of 8.1 ± 0.5, 9.3 ± 0.5, 10.1 ± 0.5, 10.2 ± 0.5, 14.1 ± 0.5, 15.2 ± 0.5, 15.3 ± 0.5, 16.6 ± 0.5, 18.3 ± 0.5, 18.5 ± 0.5, 19.4 ± 0.5, 20.4 ± 0.5, 20.5 ± 0.5, 22.1 ± 0.5, 22.3 ± 0.5, and 22.4 ± 0.5. In some embodiments, crystalline Form 2 of Compound A is characterized by having peaks at diffraction angles 20 (°) of 15.3 ± 0.5 and 18.3 ± 0.5; and one or more peaks selected from the group consisting of 8.1 ± 0.5, 9.3 ± 0.5, 10.1 ± 0.5, 10.2 ± 0.5, 14.1 ± 0.5, 15.2 ± 0.5, 15.3 ± 0.5, 16.6 ± 0.5, 18.5 ± 0.5, 19.4 ± 0.5, 20.4 ± 0.5, 20.5 ± 0.5, 22.1 ± 0.5, 22.3 ± 0.5, and 22.4 ± 0.5, as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some such embodiments, crystalline Form 2 is characterized by having two, three, four, five, six, seven, eight, or more peaks at diffraction angles 20 (°) selected from the group consisting of 8.1 ± 0.5, 9.3 ± 0.5, 10.1 ± 0.5, 10.2 ± 0.5, 14.1 ± 0.5, 15.2 ± 0.5, 15.3 ± 0.5, 16.6 ± 0.5, 18.5 ± 0.5, 19.4 ± 0.5, 20.4 ± 0.5, 20.5 ± 0.5, 22.1 ± 0.5, 22.3 ± 0.5, and 22.4 ± 0.5. In some embodiments, crystalline Form 2 is a solvate.

[0030] In some embodiments, the crystalline Form 2 of Compound A has an endothermic onset at 56.7 ± 0.5 in differential scanning calorimetry (DSC) profile. In some embodiments, the crystalline Form 2 of Compound A has an endothermic onset at about 56.7 in differential scanning calorimetry (DSC) profile. In PATENT

[0031] ATTORNEY DOCKET NO. 51432-053WO2

[0032] some embodiments, the crystalline Form 2 of Compound A has a DSC thermogram shown in FIG. 10. In some embodiments, the crystalline Form 2 of Compound A exhibits a weight loss of 12.8 % ± 0.5 (w / w) between ambient and 180.0°C ± 0.5 in a thermogravimetric analysis (TGA) profile. In some embodiments, the crystalline Form 2 of Compound A has a TGA graph shown in FIG. 11. In some embodiments, the crystalline Form 2 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0033] In some embodiments, provided herein is a crystalline form of Compound A, wherein the crystalline form is Form 3. In some embodiments, Form 3 is a solvate. In some embodiments, Form 3 is not a solvate. In an aspect, the invention features a crystalline Form 3 of Compound A having at least one peak at diffraction angle 20 (°) of 7.0 ± 0.5, 7.8 ± 0.5, or 7.9 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has peaks at diffraction angles 20 (°) of 7.0 ± 0.5, 7.8 ± 0.5, and 7.9 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has at least one peak at diffraction angle 20 (°) of 7.8 ± 0.5, 10.0 ± 0.5, or 12.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has peaks at diffraction angles 20 (°) of 7.8 ± 0.5, 10.0 ± 0.5, and 12.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has at least one peak at diffraction angle 20 (°) of 7.8 ± 0.5, 14.6 ± 0.5, or 17.6 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has peaks at diffraction angles 20 (°) of 7.8 ± 0.5, 14.6 ± 0.5, and 17.6 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has at least one peak at diffraction angle 20 (°) of 7.8 ± 0.5, 17.6 ± 0.5, 19.1 ± 0.5, 25.3 ± 0.5, or 28.5 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has peaks at diffraction angles 20 (°) of 7.8 ± 0.5, 17.6 ± 0.5, 19.1 ± 0.5, 25.3 ± 0.5, and 28.5 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has the X-ray powder diffractogram as shown in FIG. 13. In some embodiments, crystalline Form 3 of Compound A is a hydrate. In some embodiments, the crystalline Form 3 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0034] In some embodiments, crystalline Form 3 of Compound A is characterized by having a peak at diffraction angle 20 (°) of 7.8 ± 0.5; and one or more peaks selected from the group consisting of 5.2 ± 0.5, 7.6 ± 0.5, 8.3 ± 0.5, 10.4 ± 0.5, 10.6 ± 0.5, 16.7 ± 0.5, 16.8 ± 0.5, 17.1 ± 0.5, and 19.1 ± 0.5, as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some such embodiments, crystalline Form 3 is characterized by having two, three, four, five, six, seven, eight, or more peaks at diffraction angle 20 (°) selected from the group consisting of 5.2 ± 0.5, 7.6 ± 0.5, 8.3 ± 0.5, 10.4 ± 0.5, 10.6 ± 0.5, 16.7 ± 0.5, 16.8 ± 0.5, 17.1 ± 0.5, and 19.1 ± 0.5. In some embodiments, crystalline Form 3 of Compound A is characterized by having peaks at diffraction angles 20 (°) of 7.8 ± 0.5 and 16.7 ± 0.5; and one or more peaks selected from the group consisting of 5.2 ± 0.5, 7.6 ± 0.5, 8.3 ± 0.5, 10.4 ± 0.5, 10.6 ± 0.5, 16.8 ± 0.5, 17.1 ± 0.5, and 19.1 ± 0.5, as measured by X-ray PATENT

[0035] ATTORNEY DOCKET NO. 51432-053WO2

[0036] diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some such embodiments, crystalline Form 3 is characterized by having two, three, four, five, six, seven, eight, or more peaks at diffraction angle 20 (°) selected from the group consisting of 5.2 ± 0.5, 7.6 ± 0.5, 8.3 ± 0.5, 10.4 ± 0.5, 10.6 ± 0.5, 16.8 ± 0.5, 17.1 ± 0.5, and 19.1 ± 0.5. In some embodiments, crystalline Form 3 is a solvate.

[0037] In some embodiments, the crystalline Form 3 of Compound A has an endothermic onset at 155.6°C ± 0.5 in differential scanning calorimetry (DSC) profile. In some embodiments, the crystalline Form 3 of Compound A has an endothermic onset at about 155.6°C in differential scanning calorimetry (DSC) profile. In some embodiments, the crystalline Form 3 of Compound A has a DSC thermogram shown in FIG. 14. In some embodiments, the crystalline Form 3 of Compound A exhibits a weight loss of 8.1% ± 0.5 (w / w) between ambient and 170.0°C ± 0.5 in a thermogravimetric analysis (TGA) profile. In some embodiments, the crystalline Form 3 of Compound A has a TGA graph shown in FIG. 15. In some embodiments, the crystalline Form 3 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0038] In an aspect, the invention features a crystalline Form 3 of Compound A having at least one peak at diffraction angle 20 (°) of 7.8 ± 0.5, 8.5 ± 0.5, or 11.3 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has peaks at diffraction angles 20 (°) of 7.8 ± 0.5, 8.5 ± 0.5, and 11.3 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has at least one peak at diffraction angle 20 (°) of 7.8 ± 0.5, 12.4 ± 0.5, or 15.0 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has peaks at diffraction angles 20 (°) of 7.8 ± 0.5, 12.4 ± 0.5, and 15.0 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has at least one peak at diffraction angle 20 (°) of 7.8 ± 0.5, 15.9 ± 0.5, or 17.2 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has peaks at diffraction angles 20 (°) of 7.8 ± 0.5, 15.9 ± 0.5, and 17.2 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has at least one peak at diffraction angle 20 (°) of 7.8 ± 0.5, 18.9 ± 0.5, 19.3 ± 0.5, 19.6 ± 0.5, 19.7 ± 0.5, or 21.4 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has peaks at diffraction angles 20 (°) of 7.8 ± 0.5, 18.9 ± 0.5, 19.3 ± 0.5, 19.6 ± 0.5, 19.7 ± 0.5, and 21.4 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has at least one peak at diffraction angle 20 (°) of 7.8 ± 0.5, 22.9 ± 0.5, or 23.0 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has peaks at diffraction angles 20 (°) of 7.8 ± 0.5, 22.9 ± 0.5, and 23.0 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has at least one peak at diffraction angle 20 (°) of 7.8 ± 0.5, 25.7 ± 0.5, or 28.0 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. PATENT

[0039] ATTORNEY DOCKET NO. 51432-053WO2

[0040] In some embodiments, the crystalline Form 3 of Compound A has peaks at diffraction angles 20 (°) of 7.8 ± 0.5, 25.7 ± 0.5, and 28.0 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 3 of Compound A has the X-ray powder diffractogram as shown in FIG. 17. In some embodiments, the solvate is a hydrate. In some embodiments, the crystalline Form 3 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0041] In some embodiments, provided herein is a crystalline form of Compound A, wherein the crystalline form is Form 4. In some embodiments, Form 4 is a solvate. In some embodiments, Form 4 is not a solvate. In an aspect, the invention features a crystalline Form 4 of Compound A having at least one peak at diffraction angle 20 (°) of 3.8 ± 0.5, 4.9 ± 0.5, or 5.3 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 4 of Compound A has peaks at diffraction angles 20 (°) of 3.8 ± 0.5, 4.9 ± 0.5, and 5.3 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 4 of Compound A has at least one peak at diffraction angle 20 (°) of 5.3 ± 0.5, 6.2 ± 0.5, or 12.1 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 4 of Compound A has peaks at diffraction angles 20 (°) of 5.3 ± 0.5, 6.2 ± 0.5, and 12.1 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 4 of Compound A has the X-ray powder diffractogram as shown in FIG. 19. In some embodiments, the solvate is a hydrate. In some embodiments, the crystalline Form 4 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0042] In an aspect, the invention features a crystalline Form 4 of Compound A having at least one peak at diffraction angle 20 (°) of 5.7 ± 0.5, 8.2 ± 0.5, or 11.1 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 4 of Compound A has peaks at diffraction angles 20 (°) of 5.7 ± 0.5, 8.2 ± 0.5, and 11.1 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 4 of Compound A has at least one peak at diffraction angle 20 (°) of 8.2 ± 0.5, 12.2 ± 0.5, or 28.8 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 4 of Compound A has peaks at diffraction angles 20 (°) of 8.2 ± 0.5, 12.2 ± 0.5, and 28.8 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 4 of Compound A has the X-ray powder diffractogram as shown in FIG. 21. In some embodiments, crystalline Form 4 is a hydrate. In some embodiments, the crystalline Form 4 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0043] In some embodiments, crystalline Form 4 of Compound A is characterized by having a peak at diffraction angle 20 (°) of 5.3 ± 0.5; and one or more peaks selected from the group consisting of 5.1 ± 0.5, 5.4 ± 0.5, 7.5 ± 0.5, 7.6 ± 0.5, 7.8 ± 0.5, 8.1 ± 0.5, 8.2 ± 0.5, 9.5 ± 0.5, 10.5 ± 0.5, 10.7 ± 0.5, 13.3 ± 0.5, 14.1 ± 0.5, 15.3 ± 0.5, 15.7 ± 0.5, 16.6 ± 0.5, and 17.0 ± 0.5, as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some such embodiments, crystalline Form 4 is characterized by having two, three, four, five, six, seven, eight, or more peaks at PATENT

[0044] ATTORNEY DOCKET NO. 51432-053WO2

[0045] diffraction angle 20 (°) selected from the group consisting of 5.1 ± 0.5, 5.4 ± 0.5, 7.5 ± 0.5, 7.6 ± 0.5, 7.8 ± 0.5, 8.1 ± 0.5, 8.2 ± 0.5, 9.5 ± 0.5, 10.5 ± 0.5, 10.7 ± 0.5, 13.3 ± 0.5, 14.1 ± 0.5, 15.3 ± 0.5, 15.7 ± 0.5, 16.6 ± 0.5, and 17.0 ± 0.5. In some embodiments, crystalline Form 4 of Compound A is characterized by having peaks at diffraction angles 20 (°) of 5.3 ± 0.5 and 9.5 ± 0.5; and one or more peaks at diffraction angles 20 (°) selected from the group consisting of 5.1 ± 0.5, 5.4 ± 0.5, 7.5 ± 0.5, 7.6 ± 0.5, 7.8 ± 0.5, 8.1 ± 0.5, 8.2 ± 0.5, 10.5 ± 0.5, 10.7 ± 0.5, 13.3 ± 0.5, 14.1 ± 0.5, 15.3 ± 0.5, 15.7 ± 0.5, 16.6 ± 0.5, and 17.0 ± 0.5. In some such embodiments, crystalline Form 4 is characterized by having two, three, four, five, six, seven, eight, or more peaks at diffraction angles 20 (°) selected from the group consisting of 5.1 ± 0.5, 5.4 ± 0.5, 7.5 ± 0.5, 7.6 ± 0.5, 7.8 ± 0.5, 8.1 ± 0.5, 8.2 ± 0.5, 10.5 ± 0.5, 10.7 ± 0.5, 13.3 ± 0.5, 14.1 ± 0.5, 15.3 ± 0.5, 15.7 ± 0.5, 16.6 ± 0.5, and 17.0 ± 0.5. In some embodiments, crystalline Form 4 is a solvate.

[0046] In some embodiments, the crystalline Form 4 of Compound A has an endothermic onset at 124.1°C ± 0.5 and 157.0°C ± 0.5 in differential scanning calorimetry (DSC) profile. In some embodiments, the crystalline Form 4 of Compound A has an endothermic onset at about 124.1 °C and about 157.0°C in differential scanning calorimetry (DSC) profile. In some embodiments, the crystalline Form 4 of Compound A has a DSC thermogram shown in FIG. 22. In some embodiments, the crystalline Form 4 of Compound A exhibits a weight loss of 7.6% ± 0.5 (w / w) between ambient and 180.0°C ± 0.5 in a thermogravimetric analysis (TGA) profile. In some embodiments, the crystalline Form 4 of Compound A has a TGA graph shown in FIG. 23. In some embodiments, the crystalline Form 4 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0047] In some embodiments, provided herein is a crystalline form of Compound A, wherein the crystalline form is Form 5. In some embodiments, Form 5 is a solvate. In some embodiments, Form 4 is not a solvate. In an aspect, the invention features a crystalline Form 5 of Compound A having at least one peak at diffraction angle 20 (°) of 7.3 ± 0.5, 8.2 ± 0.5, or 8.6 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 5 of Compound A has peaks at diffraction angles 20 (°) of 7.3 ± 0.5, 8.2 ± 0.5, and 8.6 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 5 of Compound A has at least one peak at diffraction angle 20 (°) of 8.2 ± 0.5, 13.0 ± 0.5, or 23.3 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 5 of Compound A has peaks at diffraction angles 20 (°) of 8.2 ± 0.5, 13.0 ± 0.5, and 23.3 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 5 of Compound A has at least one peak at diffraction angle 20 (°) of 8.2 ± 0.5, 23.3 ± 0.5, or 24.8 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 5 of Compound A has peaks at diffraction angles 20 (°) of 8.2 ± 0.5, 23.3 ± 0.5, and 24.8 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X-rays or calculated from X-ray diffractometry. In some embodiments, the crystalline Form 5 of Compound A has the X-ray powder diffractogram as shown in FIG. 25. In some embodiments, crystalline Form 5 is a hydrate. In some embodiments, the crystalline Form 5 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0048] In some embodiments, crystalline Form 5 of Compound A is characterized by having a peak at diffraction angle 20 (°) of 17.3 ± 0.5; and one or more peaks at diffraction angle 20 (°) selected from the PATENT

[0049] ATTORNEY DOCKET NO. 51432-053WO2

[0050] group consisting of 5.4 ± 0.5, 7.6 ± 0.5, 7.7 ± 0.5, 7.8 ± 0.5, 8.2 ± 0.5, 8.3 ± 0.5, 9.7 ± 0.5, 10.8 ± 0.5, 14.1 ± 0.5, 15.4 ± 0.5, 17.1 ± 0.5, 17.3 ± 0.5, 18.4 ± 0.5, and 20.7 ± 0.5, as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some such embodiments, crystalline Form 5 is characterized by having two, three, four, five, six, seven, eight, or more peaks at diffraction angle 20 (°) selected from the group consisting of 5.4 ± 0.5, 7.6 ± 0.5, 7.7 ± 0.5, 7.8 ± 0.5, 8.2 ± 0.5, 8.3 ± 0.5, 9.7 ± 0.5, 10.8 ± 0.5, 14.1 ± 0.5, 15.4 ± 0.5, 17.1 ± 0.5, 17.3 ± 0.5, 18.4 ± 0.5, and 20.7 ± 0.5. In some embodiments, crystalline Form 5 of Compound A is characterized by having peaks at diffraction angles 20 (°) of 17.3 ± 0.5 and 7.6 ± 0.5; and one or more peaks at diffraction angle 20 (°) selected from the group consisting of 5.4 ± 0.5, 7.7 ± 0.5, 7.8 ± 0.5, 8.2 ± 0.5, 8.3 ± 0.5, 9.7 ± 0.5, 10.8 ± 0.5, 14.1 ± 0.5, 15.4 ± 0.5, 17.1 ± 0.5, 17.3 ± 0.5, 18.4 ± 0.5, and 20.7 ± 0.5, as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some such embodiments, crystalline Form 5 is characterized by having two, three, four, five, six, seven, eight, or more peaks at diffraction angle 20 (°) selected from the group consisting of 5.4 ± 0.5, 7.7 ± 0.5, 7.8 ± 0.5, 8.2 ± 0.5, 8.3 ± 0.5, 9.7 ± 0.5, 10.8 ± 0.5, 14.1 ± 0.5, 15.4 ± 0.5, 17.1 ± 0.5, 17.3 ± 0.5, 18.4 ± 0.5, and 20.7 ± 0.5. In some embodiments, crystalline Form 5 is a solvate.

[0051] In some embodiments, the crystalline Form 5 of Compound A has an endothermic onset at 158.6 ± 0.5 in differential scanning calorimetry (DSC) profile. In some embodiments, the crystalline Form 5 of Compound A has an endothermic onset at about 158.6 in differential scanning calorimetry (DSC) profile. In some embodiments, the crystalline Form 5 of Compound A has a DSC thermogram shown in FIG. 26. In some embodiments, the crystalline Form 5 of Compound A exhibits a weight loss of 7.6% ± 0.5 (w / w) between ambient and 180.0°C ± 0.5 in a thermogravimetric analysis (TGA) profile. In some embodiments, the crystalline Form 5 of Compound A has a TGA graph shown in FIG. 27. In some embodiments, the crystalline Form 5 of Compound A has any one of these listed characteristics, and is optionally a solvate, such as is not a solvate.

[0052] In another aspect, the invention provides a citrate salt of Compound A. In some embodiments, the citrate salt is a 1:1 citrate salt. In some embodiments, the citrate salt is a 2:1 citrate salt. In some embodiments, the citrate salt is a 3:1 citrate salt. In some embodiments, the Compound A citrate salt is amorphous.

[0053] In another aspect, the invention provides a fumarate salt of Compound A. In some embodiments, the fumarate salt is a 1:1 fumarate salt. In some embodiments, the fumarate salt is a 2:1 fumarate salt. In some embodiments, the Compound A fumarate salt is amorphous. In another aspect, the invention provides a maleate salt of Compound A. In some embodiments, the maleate salt is a 1:1 maleate salt. In some embodiments, the maleate salt is a 2:1 maleate salt. In some embodiments, the Compound A maleate salt is amorphous.

[0054] In another aspect, the invention provides a malate salt of Compound A. In some embodiments, the malate salt is a 1:1 malate salt of Compound A. In some embodiments, the L-malate salt is a 2:2 malate salt of Compound A. In another aspect, the invention provides an L-malate salt of Compound A. In some embodiments, the L-malate salt is an L-malate salt of Compound A. In some embodiments, the L-malate salt is a 1:1 L-malate salt of Compound A. In some embodiments, the L-malate salt is a 2:2 L-malate salt of Compound A. In some embodiments, the Compound A L-malate salt is amorphous. PATENT

[0055] ATTORNEY DOCKET NO. 51432-053WO2

[0056] In another aspect, the invention provides a nicotinate salt of Compound A. In some embodiments, the nicotinate salt is a 1:1 nicotinate salt. In some embodiments, the Compound A nicotinate salt is amorphous.

[0057] In another aspect, the invention provides a phosphate salt of Compound A. In some embodiments, the phosphate salt is a 1:1 phosphate salt. In some embodiments, the phosphate salt is a 2:1 phosphate salt. In some embodiments, the phosphate salt is a 3:1 phosphate salt. In some embodiments, the Compound A phosphate salt is amorphous.

[0058] In another aspect, the invention provides a tartrate salt of Compound A. In some embodiments, the tartrate salt is a 1:1 tartrate salt of Compound A. In some embodiments, the tartrate salt is a 2:1 tartrate salt of Compound A. In another aspect, the invention provides an L-tartrate salt of Compound A. In some embodiments, the tartrate salt is a 1:1 L-tartrate salt of Compound A. In some embodiments, the tartrate salt is a 2:1 L-tartrate salt of Compound A. In some embodiments, the Compound A tartrate salt is amorphous.

[0059] In another aspect, the invention provides a benzoate salt of Compound A. In some embodiments, the benzoate salt of Compound A is a 1:1 benzoate salt of Compound A. In some embodiments, the Compound A benzoate salt is amorphous.

[0060] In another aspect, the invention provides an amorphous solid form of Compound A.

[0061] In some embodiments, the invention features a method of treating cancer in a subject in need thereof, and the method including administering to the subject a therapeutically effective amount of a crystalline form of Compound A or a pharmaceutical composition comprising the crystalline Compound A solvate.

[0062] In some embodiments, the invention features a method of treating a Ras protein-related disorder in a subject in need thereof, and the method including administering to the subject a therapeutically effective amount of a crystalline form of Compound A ora pharmaceutical composition comprising the crystalline Compound A solvate.

[0063] Further provided is a method of inhibiting a Ras protein in a cell, the method including administering to the subject a therapeutically effective amount of a crystalline form of Compound A or a pharmaceutical composition comprising the crystalline Compound A solvate.

[0064] In some embodiments, the invention features a method of treating cancer in a subject in need thereof, and the method including administering to the subject a therapeutically effective amount of a citrate salt, fumarate salt, maleate salt, L-malate salt, nicotinate salt, phosphate salt, L-tartrate salt, or benzoate salt described herein, the amorphous salt form described herein, or the pharmaceutical composition the amorphous salt form.

[0065] In some embodiments, the invention features a method of treating a Ras protein-related disorder in a subject in need thereof, and the method including administering to the subject a therapeutically effective amount of a citrate salt, fumarate salt, maleate salt, L-malate salt, nicotinate salt, phosphate salt, L-tartrate salt, or benzoate salt described herein, the amorphous salt form described herein, or the pharmaceutical composition the amorphous salt form.

[0066] Further provided is a method of inhibiting a Ras protein in a cell, the method including administering to the subject a therapeutically effective amount of citrate salt, fumarate salt, maleate salt, L-malate salt, nicotinate salt, phosphate salt, L-tartrate salt, or benzoate salt described herein, the amorphous salt form described herein, or the pharmaceutical composition the amorphous salt form. PATENT

[0067] ATTORNEY DOCKET NO. 51432-053WO2

[0068] In some embodiments, the invention provides a method of treating cancer in a subject in need thereof, and the method including administering to the subject a therapeutically effective amount of an amorphous form of Compound A, or a pharmaceutical composition comprising the amorphous form of Compound A.

[0069] In some embodiments, the invention provides a method of treating a Ras protein-related disorder in a subject in need thereof, and the method including administering to the subject a therapeutically effective amount of an amorphous form of Compound A, or a pharmaceutical composition.

[0070] Further provided is a method of inhibiting a Ras protein in a cell, the method including administering to the subject a therapeutically effective amount of an amorphous form of Compound A, or a pharmaceutical composition comprising the amorphous form of Compound A.

[0071] It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any compound or composition of the invention.

[0072] Definitions and Chemical Terms

[0073] In this application, unless otherwise clear from context, (i) the term “a” means “one or more”; (ii) the term "or" is used to mean "and / or" unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or”; (iii) the terms “comprising” and “including” are understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and (iv) where ranges are provided, endpoints are included.

[0074] As used herein, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. In certain embodiments, the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of a stated value, unless otherwise stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value).

[0075] As used herein, the term “adjacent” in the context of describing adjacent atoms refers to bivalent atoms that are directly connected by a covalent bond.

[0076] A “crystalline form of the compound” and similar terms as used herein, whether explicitly noted or not, refers to Ras inhibitors described herein, including crystalline forms of Compound A, solvates, hydrates, and tautomers thereof. In some embodiments, the solvate is a channel solvate. In some embodiments, the solvate is a hydrate. For clarity, a crystalline form of the compound may be both a tautomer and a solvate, that is, a crystalline form of a tautomer of Compound A, which is also a solvate.

[0077] The term “wild-type” refers to an entity having a structure or activity as found in nature in a “normal” (as contrasted with mutant, diseased, altered, etc.) state or context. Those of ordinary skill in the art will appreciate that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).

[0078] “XRPD” refers the analytical method of X-Ray Powder Diffraction. The repeatability of the angular values is in the range of 20 ±0.5°. The terms “approximately” and “about” given in combination with an angular value denote the repeatability which is in the range of degrees (°) 20 ± 0.5. The relative XRPD PATENT

[0079] ATTORNEY DOCKET NO. 51432-053WO2

[0080] peak intensity is dependent upon many factors such as structure factor, temperature factor, crystallinity, polarization factor, multiplicity, and Lorentz factor. Relative intensities may vary considerably from one measurement to another due to preferred orientation effects. Anisotropic materials adopting preferred orientation may lead to anisotropic distribution of properties such as modulus, strength, ductility, toughness, electrical conductivity, thermal expansion, etc. In both XRPD and Raman spectroscopy, preferred orientations cause a change in the intensity distribution. In some embodiments, unless otherwise described, X-ray spectra provided herein are obtained with diffractometry by irradiation with Cu Ka X rays.

[0081] Those skilled in the art will appreciate that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., in which one or more atoms has been substituted with a different isotope of the atom, such as hydrogen substituted for deuterium) forms. Unless otherwise indicated or clear from context, a depicted structure can be understood to represent any such isomeric or isotopic form, individually or in combination.

[0082] Compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.

[0083] Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0084] In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms. As will be clear from context, unless explicitly excluded, references to such compounds encompass all such tautomeric forms. In some embodiments, tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form. Examples of moieties with prototropic tautomeric forms are ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. In some embodiments, tautomeric forms can be in equilibrium orsterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion.

[0085] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

[0086] Brief Description of the Drawings

[0087] FIG. 1 is an X-ray powder diffractogram of crystalline Form 1 of Compound A. PATENT

[0088] ATTORNEY DOCKET NO. 51432-053WO2

[0089] FIG. 2 is a differential scanning calorimetry (DSC) thermogram of crystalline Form 1 of Compound A.

[0090] FIG. 3 is a thermogravimetric analysis (TGA) of crystalline Form 1 of Compound A. FIG. 4 is an1H NMR spectrum of crystalline Form 1 of Compound A.

[0091] FIG. 5 is a set of X-ray powder diffractograms of crystalline Form 1 of Compound A. FIG. 6 is a DSC thermogram of crystalline Form 1 of Compound A.

[0092] FIG. 7 is a TGA of crystalline Form 1 of Compound A.

[0093] FIG. 8 is a1H NMR spectrum of crystalline Form 1 of Compound A.

[0094] FIG. 9 is a set of X-ray powder diffractogram of crystalline Form 2 of Compound A. FIG. 10 is a DSC thermogram of crystalline Form 2 of Compound A.

[0095] FIG. 11 is a TGA of crystalline Form 2 of Compound A.

[0096] FIG. 12 is an1H NMR spectrum of crystalline Form 2 of Compound A.

[0097] FIG. 13 is a set of X-ray powder diffractogram of crystalline Form 3 of Compound A. FIG. 14 is a differential DSC thermogram of crystalline Form 3 of Compound A. FIG. 15 is a TGA of crystalline Form 3 of Compound A.

[0098] FIG. 16 is an1H NMR spectrum of crystalline Form 3 of Compound A.

[0099] FIG. 17 is a set of X-ray powder diffractogram of crystalline Form 3 of Compound A. FIG. 18 is an1H NMR spectrum of crystalline Form 3 of Compound A.

[0100] FIG. 19 is a set of X-ray powder diffractogram of crystalline Form 4 of Compound A. FIG. 20 is an1H NMR spectrum of crystalline Form 4 of Compound A.

[0101] FIG. 21 is a set of X-ray powder diffractogram of crystalline Form 4 of Compound A. FIG. 22 is a DSC thermogram of crystalline Form 4 of Compound A.

[0102] FIG. 23 is a TGA of crystalline Form 4 of Compound A.

[0103] FIG. 24 is an1H NMR spectrum of crystalline Form 4 of Compound A.

[0104] FIG. 25 is a set of X-ray powder diffractogram of crystalline Form 5 of Compound A. FIG. 26 is a DSC thermogram of crystalline Form 5 of Compound A.

[0105] FIG. 27 is a TGA of crystalline Form 5 of Compound A.

[0106] FIG. 28 is an1H NMR spectrum of crystalline Form 5 of Compound A.

[0107] FIG 29 is an X-ray powder diffraction pattern of amorphous form of Compound A. FIG. 30 is a DSC thermogram of amorphous form of Compound A.

[0108] FIG. 31 is a TGA of amorphous form of Compound A.

[0109] FIG. 32 is an1H NMR spectrum of amorphous form of Compound A.

[0110] FIG. 33 is an X-ray powder diffraction pattern of citrate salt of Compound A.

[0111] FIG. 34 is an1H NMR spectrum of citrate salt of Compound A.

[0112] FIG. 35 is an X-ray powder diffraction pattern of fumarate salt of Compound A. FIG. 36 is an1H NMR spectrum of fumarate salt of Compound A.

[0113] FIG. 37 is an X-ray powder diffraction pattern of maleate salt of Compound A.

[0114] FIG. 38 is an1H NMR spectrum of maleate salt of Compound A.

[0115] FIG. 39 is an X-ray powder diffraction pattern of L-malate salt of Compound A. FIG. 40 is an1H NMR spectrum of L-malate salt of Compound A.

[0116] FIG. 41 is an X-ray powder diffraction pattern of nicotinate salt of Compound A. FIG. 42 is an1H NMR spectrum of nicotinate salt of Compound A. PATENT

[0117] ATTORNEY DOCKET NO. 51432-053WO2

[0118] FIG. 43 is an X-ray powder diffraction pattern of phosphate salt of Compound A.

[0119] FIG. 44 is an1H NMR spectrum of phosphate salt of Compound A.

[0120] FIG. 45 is an X-ray powder diffraction pattern of L-tartrate salt of Compound A.

[0121] FIG. 46 is an1H NMR spectrum of L-tartrate salt of Compound A.

[0122] FIG. 47 is an X-ray powder diffraction pattern of benzoate salt of Compound A.

[0123] FIG. 48 is an1H NMR spectrum of benzoate salt of Compound A.

[0124] Detailed Description

[0125] Compounds

[0126] In general, the invention provides crystalline and amorphous forms of Compound A and salts of Compound A. Compound A has the following structure:

[0127]

[0128] Compound A

[0129] In some embodiments, the crystalline form of Compound A is Form 1, Form 2, Form 3, Form 4, or Form 5. In some embodiments, the crystalline form is a solvate.

[0130] In some embodiments, provided herein is a crystalline Form 1 of Compound A. In some embodiments, the crystalline Form 1 is a solvate. The crystalline Form 1 of Compound Amay have one or more peaks at diffraction angle 20 (°) of 8.2 ± 0.5, 23.9 ± 0.5, 24.7 ± 0.5, 25.2 ± 0.5, 26.1 ± 0.5, 28.3 ± 0.5, 30.8 ± 0.5, 32.9 ± 0.5, or 35.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, Form 1 of Compound A has the X-ray powder diffractogram as shown in FIG. 1. In some embodiments, Form 1 has an endothermic onset at about 163.2°C in differential scanning calorimetry (DSC) (see FIG. 3). In some embodiments, Form 1 has an endothermic onset at 163.2°C ± 0.5 in differential scanning calorimetry (DSC) (see FIG. 3). In some embodiments, Form 1 has a weight loss of 7.1% ± 0.5 (w / w) between ambient and 190.0°C ± 0.5 in a thermogravimetric analysis profile (see FIG. 4). In some embodiments, the crystalline Form 1 of Compound A has one or more of these described characteristics, and is optionally a solvate, for example is not a solvate.

[0131] In some embodiments, the crystalline Form 1 of Compound A solvate has one or more peaks at diffraction angle 20 (°) of 8.2 ± 0.5, 14.3 ± 0.5, 14.4 ± 0.5, 18.0 ± 0.5, 18.7 ± 0.5, 21.6 ± 0.5, 22.2 ± 0.5, 24.6 ± 0.5, or 28.6 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, Form 1 of Compound A has the X-ray powder diffractogram as shown in FIG. 5. In some embodiments, Form 1 has an endothermic onset at PATENT

[0132] ATTORNEY DOCKET NO. 51432-053WO2

[0133] about 162.6°C in differential scanning calorimetry (DSC) (see FIG. 6). In some embodiments, Form 1 has an endothermic onset at 162.6°C ± 0.5 in differential scanning calorimetry (DSC) (see FIG. 6). In some embodiments, Form 1 solvate has a weight loss of 6.4% ± 0.5 (w / w) between ambient and 185.0°C ± 0.5 in a thermogravimetric analysis profile (see FIG. 7). In some embodiments, the crystalline Form 1 of Compound A has one or more of these described characteristics, and is optionally a solvate, for example is not a solvate.

[0134] In some embodiments, provided herein is a crystalline Form 2 of Compound A. In some embodiments, the crystalline Form 2 is a solvate. The crystalline Form 2 of Compound A may have one or more peaks at diffraction angle 20 (°) of 3.3 ± 0.5, 4.3 ± 0.5, 10.1 ± 0.5, 13.1 ± 0.5, 13.8 ± 0.5, 16.6 ± 0.5, 17.7 ± 0.5, 19.2 ± 0.5, 19.9 ± 0.5, 20.1 ± 0.5, 20.2 ± 0.5, 20.3 ± 0.5, 22.3 ± 0.5, and 23.5 ± 0.5, 24.2 ± 0.5, 24.9 ± 0.5, 25.5 ± 0.5, 27.0 ± 0.5, 27.7 ± 0.5, 28.2 ± 0.5, 31.0 ± 0.5, or 36.7 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, Form 2 has the X-ray powder diffractogram as shown in FIG. 9. In some embodiments, Form 2 has an endothermic onset at about 56.7°C in differential scanning calorimetry (DSC) (see FIG. 10). In some embodiments, Form 2 has an endothermic onset at 56.7°C ± 0.5 in differential scanning calorimetry (DSC) (see FIG. 10). In some embodiments, Form 2 has a weight loss of 12.8% ± 0.5 (w / w) between ambient and 180.0°C in a thermogravimetric analysis profile (see FIG. 11). In some embodiments, the crystalline Form 3 of Compound A has one or more of these described characteristics, and is optionally a solvate, for example is not a solvate.

[0135] In some embodiments, provided herein is a crystalline Form 3 of Compound A. In some embodiments, the crystalline Form 3 is a solvate. The crystalline Form 3 of Compound A may have one or more peaks at diffraction angle 20 (°) of 7.0 ± 0.5, 7.8 ± 0.5, 7.9 ± 0.5, 10.0 ± 0.5, 12.7 ± 0.5, 14.6 ± 0.5, 17.6 ± 0.5, 19.1 ± 0.5, 25.3 ± 0.5, or 28.5 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, Form 3 has the X-ray powder diffractogram as shown in FIG. 13. In some embodiments, Form 3 has an endothermic onset at about 155.6°C in differential scanning calorimetry (DSC) (see FIG. 14). In some embodiments, Form 3 has an endothermic onset at 155.6°C ± 0.5 in differential scanning calorimetry (DSC) (see FIG. 14). In some embodiments, Form 3 has a weight loss of 8.1% ± 0.5 (w / w) between ambient and 170.0°C in a thermogravimetric analysis profile (see FIG. 15). In some embodiments, the crystalline Form 3 of Compound A has one or more of these described characteristics, and is optionally a solvate, for example is not a solvate.

[0136] In some embodiments, the crystalline Form 3 of Compound A has one or more peaks at diffraction angle 20 (°) of 7.8 ± 0.5, 8.5 ± 0.5, 11.3 ± 0.5, 12.4 ± 0.5, 15.0 ± 0.5, 15.9 ± 0.5, 17.2 ± 0.5, 18.9 ± 0.5, 19.3 ± 0.5, 19.6 ± 0.5, 19.7 ± 0.5, 21.4 ± 0.5, 22.9 ± 0.5, 23.0 ± 0.5, 25.7 ± 0.5, or 28.0 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, Form 3 has the X-ray powder diffractogram as shown in FIG. 17. In some embodiments, the crystalline Form 3 of Compound A has one or more of these described characteristics, and is optionally a solvate, for example is not a solvate.

[0137] In some embodiments, provided herein is a crystalline Form 4 of Compound A. In some embodiments, the crystalline Form 4 is a solvate. The crystalline Form 4 of Compound A may have one or more peaks at diffraction angle 20 (°) of 3.8 ± 0.5, 4.9 ± 0.5, 5.3 ± 0.5, 6.2 ± 0.5, or 12.1 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. PATENT

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[0139] In some embodiments, Form 4 of Compound A has the X-ray powder diffractogram as shown in FIG. 19. In some embodiments, the crystalline Form 4 of Compound A has one or more of these described characteristics, and is optionally a solvate, for example is not a solvate.

[0140] In some embodiments, the crystalline Form 4 of Compound A has one or more peaks at diffraction angle 20 (°) of 5.7 ± 0.5, 8.2 ± 0.5, 11.1 ± 0.5, 12.2 ± 0.5, or 28.8 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, Form 4 has the X-ray powder diffractogram as shown in FIG. 21. In some embodiments, Form 4 has an endothermic onset at about 124.1°C and about 157.0°C in differential scanning calorimetry (DSC) (see FIG. 22). In some embodiments, Form 4 has an endothermic onset at 124.1 °C ± 0.5 and 157.0°C ± 0.5 in differential scanning calorimetry (DSC) (see FIG. 22). In some embodiments, Form 4 has a weight loss of 7.6% ± 0.5 (w / w) between ambient and 180.0°C ± 0.5 in a thermogravimetric analysis profile (see FIG. 23). In some embodiments, the crystalline Form 4 of Compound A has one or more of these described characteristics, and is optionally a solvate, for example is not a solvate.

[0141] In some embodiments, provided herein is a crystalline Form 5 of Compound A. In some embodiments, the crystalline Form 5 is a solvate. In some embodiments, crystalline Form 5 of Compound A has one or more peaks at diffraction angle 20 (°) of 7.3 ± 0.5, 8.2 ± 0.5, 8.6 ± 0.5, 13.0 ± 0.5, 23.3 ± 0.5, or 24.8 ± 0.5 as measured by X-ray diffractometry by irradiation with Cu Ka X rays or calculated from X-ray diffractometry. In some embodiments, Form 5 has the X-ray powder diffractogram as shown in FIG.

[0142] 25. In some embodiments, Form 5 has the X-ray powder diffractogram as shown in FIG. 25. In some embodiments, Form 5 has an endothermic onset at 158.6°C ± 0.5 in differential scanning calorimetry (DSC) (see FIG. 26). In some embodiments, Form 5 has a weight loss of 8.7% ± 0.5 (w / w) between ambient and 175.0°C ± 0.5 in a thermogravimetric analysis profile (see FIG. 27). In some embodiments, the crystalline Form 5 of Compound A has one or more of these described characteristics, and is optionally a solvate, for example is not a solvate.

[0143] In some embodiments, an amorphous form of Compound A has the X-ray powder diffractogram as shown in FIG. 29. The amorphous form of Compound A may have an endothermic onset at about 152.7°C in differential scanning calorimetry (DSC) (see FIG. 30). The amorphous form of Compound A may have an endothermic onset at 152.7°C ± 0.5 in differential scanning calorimetry (DSC) (see FIG. 30). The amorphous form of Compound A may have a weight loss of 4.2% ± 0.5 (w / w) between ambient and 180.0°C ± 0.5 in a thermogravimetric analysis profile (see FIG. 31).

[0144] In some embodiments, crystalline Form 1 is a Compound A isopropyl acetate / heptane solvate. In certain instances, the molar ratio of isopropyl acetate and heptane is from about 0.9: 1.6 to about 0.4:0.3 with respect to one equivalent of Compound A.

[0145] In some embodiments, crystalline Form 2 is a Compound A anisole / methyl t-butyl ether solvate. In certain instances, the molar ratio of anisole and methyl t-butyl ether is about 2.3 to about 0.1 with respect to one equivalent of Compound A.

[0146] In some embodiments, crystalline Form 3 is a Compound A ethyl acetate solvate. In certain instances, the molar ratio of Compound A and ethyl acetate is about 1 to about 1.7.

[0147] In some embodiments, the crystalline Form 4 is a Compound A anisole / methyl t-butyl ether solvate. In certain instances, the molar ratio of anisole and methyl t-butyl ether is about 1.5:0.1 to about 0.9:0.1 with respect to one equivalent of Compound A. In some embodiments, Form 4 contains about 0.05 equivalent of acetone. PATENT

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[0149] In some embodiments, the crystalline Form 4 is a Compound A anisole / methyl t-butyl ether solvate, wherein the molar ratio of anisole and methyl t-butyl ether is about 0.6 to about 0.8 with respect to one equivalent of Compound A.

[0150] The invention also provides a citrate salt of Compound A. The invention also provides a fumarate salt of Compound A. The invention also provides a maleate salt of Compound A. The invention also provides a malate salt of Compound A. The invention also provides an L-malate salt of Compound A. The invention also provides a nicotinate salt of Compound A. The invention also provides a phosphate salt of Compound A. The invention also provides a tartrate salt of Compound A. The invention also provides an L-tartrate salt of Compound A. The invention also provides a benzoate salt of Compound A.

[0151] Further provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline or an amorphous compound of the present invention, ora salt of a compound of the present invention. The cancer may, for example, be pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, or squamous cell lung carcinoma. In some embodiments, the cancer comprises a Ras mutation, such as K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras mutations are described herein.

[0152] Further provided is a method of treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline or amorphous compound of the present invention, or a salt of a compound of the present invention.

[0153] Further provided is a method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a crystalline compound of the present invention. In some embodiments, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras proteins are described herein. The cell may be a cancer cell, such as a pancreatic cancer cell, a colorectal cancer cell, a non-small cell lung cancer cell, an acute myeloid leukemia cell, a multiple myeloma cell, a thyroid gland adenocarcinoma cell, a myelodysplastic syndrome cell, ora squamous cell lung carcinoma cell. Other cancer types are described herein. The cell may be in vivo or in vitro.

[0154] In some embodiments, a method or use described herein further comprises administering an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy is a HER2 inhibitor, an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORCI inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, or a combination thereof. In some embodiments, the additional anticancer therapy is a SHP2 inhibitor. Other additional anti-cancer therapies are described herein.

[0155] Further provided is a method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a crystalline compound of the present invention, or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras proteins are described herein. The cell may be a cancer cell, such as a pancreatic cancer cell, a colorectal cancer cell, a non-small cell lung cancer cell, an acute myeloid leukemia cell, a multiple myeloma cell, a thyroid gland adenocarcinoma cell, PATENT

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[0157] a myelodysplastic syndrome cell, or a squamous cell lung carcinoma cell. Other cancer types are described herein. The cell may be in vivo or in vitro.

[0158] Further provided is a method of treating a K-Ras G13C mutant cancer with a crystalline form of Compound A. Further provided is a method of treating a K-Ras G13C mutant cancer with Form 1 of crystalline form of Compound A. Further provided is a method of treating a K-Ras G13C mutant cancer with Form 2 of crystalline form of Compound A. Further provided is a method of treating a K-Ras G13C mutant cancer with Form 3 of crystalline form of Compound A. Further provided is a method of treating a K-Ras G13C mutant cancer with Form 4 of crystalline form of Compound A. Further provided is a method of treating a K-Ras G13C mutant cancer with Form 5 of crystalline form of Compound A.

[0159] Pharmaceutical Compositions and Methods of Use

[0160] The crystalline, amorphous and salt forms of compounds with which the invention is concerned are Ras inhibitors and are useful in the treatment of cancer. Accordingly, one embodiment of the present invention provides pharmaceutical compositions containing a crystalline form of a compound disclosed herein, an amorphous form of a compound disclosed herein, or a salt form of a compound disclosed herein, and a pharmaceutically acceptable excipient, as well as methods of using the compounds of the invention to prepare such compositions.

[0161] As used herein, the term “pharmaceutical composition” refers to a compound or crystalline form, such as a crystalline compound of the present invention, formulated together with a pharmaceutically acceptable excipient.

[0162] In some embodiments, the crystalline form(s) of the compound is present in a pharmaceutical composition in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0163] A “pharmaceutically acceptable excipient,” as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and non-inflammatory in a subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, dis integrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Excipients include, but are not limited to: butylated optionally substituted hydroxyltoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxylpropyl cellulose, optionally substituted hydroxylpropyl methylcellulose, lactose, magnesium PATENT

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[0165] stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients. See, e.g., Ansel, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, a composition includes at least two different pharmaceutically acceptable excipients.

[0166] As used herein, the term “subject” refers to any member of the animal kingdom. In some embodiments, “subject” refers to humans, at any stage of development. In some embodiments, “subject” refers to a human patient. In some embodiments, “subject” refers to non-human animals. In some embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In some embodiments, subjects include, but are not limited to, mammals, birds, reptiles, amphibians, fish, or worms. In some embodiments, a subject may be a transgenic animal, genetically-engineered animal, or a clone.

[0167] As used herein, the term “dosage form” refers to a physically discrete unit of a compound (e.g., a crystalline compound of the present invention) for administration to a subject. Each unit contains a predetermined quantity of compound. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0168] As used herein, the term “dosing regimen” refers to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic compound (e.g., a crystalline compound of the present invention) has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0169] A “therapeutic regimen” refers to a dosing regimen whose administration across a relevant population is correlated with a desired or beneficial therapeutic outcome. PATENT

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[0171] The term “treatment” (also “treat” or “treating”), in its broadest sense, refers to any administration of a substance (e.g., a crystalline compound of the present invention) that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, or reduces incidence of one or more symptoms, features, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment may be administered to a subject who does not exhibit signs of the relevant disease, disorder, or condition or of a subject who exhibits only early signs of the disease, disorder, or condition. Alternatively, or additionally, in some embodiments, treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder, or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, or condition.

[0172] The term “therapeutically effective amount” means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence or severity of, or delays onset of, one or more symptoms of the disease, disorder, or condition. Those of ordinary skill in the art will appreciate that the term “therapeutically effective amount” does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. It is specifically understood that particular subjects may, in fact, be “refractory” to a “therapeutically effective amount.” In some embodiments, reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those of ordinary skill in the art will appreciate that, in some embodiments, a therapeutically effective amount may be formulated or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated or administered in a plurality of doses, for example, as part of a dosing regimen.

[0173] For use as treatment of subjects, the crystalline forms of the compounds of the invention can be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or therapy, the compounds, are formulated in ways consonant with these parameters. A summary of such techniques may be found in Remington: The Science and Practice of Pharmacy, 21stEdition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0174] Compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the present pharmaceutical compositions can contain from 0.1% to 99%, from 5% to 90%, or from 1% to 20% of a crystalline compound of the present invention, by weight or volume. In some embodiments, crystalline forms of the compounds, described herein may be present in amounts totaling 1-95% by weight of the total weight of a composition, such as a pharmaceutical composition.

[0175] The composition may be provided in a dosage form that is suitable for intraarticular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, PATENT

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[0177] sublingual, nasal, vaginal, intravesicular, intraurethral, intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with the nasal, genitourinary, reproductive, or oral mucosa. Thus, the pharmaceutical composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice.

[0178] As used herein, the term “administration” refers to the administration of a composition (e.g., a crystalline form of Compound A, or a preparation that includes a crystalline form of Compound A described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreal.

[0179] Formulations may be prepared in a manner suitable for systemic administration or topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration. A formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, preservatives and the like. Crystalline forms of compounds can be administered also in liposomal compositions or as microemulsions.

[0180] For injection, formulations can be prepared in conventional forms as liquid solutions or suspensions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol and the like. Such compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, and so forth.

[0181] Various sustained release systems for drugs have also been devised. See, for example, U. S. Patent No. 5,624,677.

[0182] Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration. Oral administration is also suitable for compounds of the invention. Suitable forms include syrups, capsules, and tablets, as is understood in the art.

[0183] Each crystalline form of a compound as described herein, may be formulated in a variety of ways that are known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Other modalities of combination therapy are described herein.

[0184] The individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include optional components that aid in the administration of the unit dose to subjects, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, the unit dose kit can contain instructions for preparation and administration of the compositions. The kit may be manufactured as a PATENT

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[0186] single use unit dose for one subject, multiple uses for a particular subject (at a constant dose or in which the individual compounds, may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple subjects (“bulk packaging”). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.

[0187] Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, oralginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, optionally substituted hydroxylpropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0188] Two or more compounds may be mixed together in a tablet, capsule, or other vehicle, or may be partitioned. In one example, the first compound is contained on the inside of the tablet, and the second compound is on the outside, such that a substantial portion of the second compound is released prior to the release of the first crystalline compound.

[0189] Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus ora spray drying equipment.

[0190] Dissolution or diffusion-controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of crystalline compounds, or by incorporating the crystalline compound, into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-optionally substituted hydroxylmethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbon.

[0191] The liquid forms in which the crystalline forms of compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. PATENT

[0192] ATTORNEY DOCKET NO. 51432-053WO2

[0193] Generally, when administered to a human, the oral dosage of any of the crystalline compounds of the invention will depend on the nature of the crystalline compound, and can readily be determined by one skilled in the art. A dosage may be, for example, 0.001 mg to 2000 mg per day, 1 mg to 1000 mg per day, 5 mg to 500 mg per day, 100 mg to 1500 mg per day, 500 mg to 1500 mg per day, 500 mg to 2000 mg per day, or any range derivable therein. In some embodiments, a dosage may be 10 mg per day. In some embodiments, the dosage may be 20 mg per day. In some embodiments, the dosage may be 40 mg per day. In some embodiments, the dosage may be 80 mg per day. In some embodiments, the dosage may be 120 mg per day.

[0194] In some embodiments, the pharmaceutical composition may further comprise an additional compound having antiproliferative activity. Depending on the mode of administration, compounds, or a pharmaceutically acceptable salt thereof, will be formulated into suitable compositions to permit facile delivery. Each compound, or a pharmaceutically acceptable salt thereof, of a combination therapy may be formulated in a variety of ways that are known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Desirably, the first and second agents are formulated together for the simultaneous or near simultaneous administration of the agents.

[0195] It will be appreciated that the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects).

[0196] Administration of each drug in a combination therapy, as described herein, can, independently, be one to four times daily for one day to one year, and may even be for the life of the subject. Chronic, long-term administration may be indicated.

[0197] Methods of Use

[0198] In some embodiments, the invention discloses a method of treating a disease or disorder that is characterized by aberrant Ras activity due to a Ras mutant. In some embodiments, the disease or disorder is a cancer.

[0199] Accordingly, also provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt. Also provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a salt form of the compound of the present invention. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small-cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, Gl neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal, endometrial or melanoma. Also provided is a method of treating PATENT

[0200] ATTORNEY DOCKET NO. 51432-053WO2

[0201] a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0202] In some embodiments, the invention discloses crystalline forms of the compound of the present invention or pharmaceutical compositions comprising such crystalline forms, and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. In some embodiments, the invention discloses salt forms of the compound of the present invention or pharmaceutical compositions comprising such salt forms, and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds or salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. Other cancers include, for example:

[0203] Cardiac, for example: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

[0204] Lung, for example: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

[0205] Gastrointestinal, for example: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract, for example: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);

[0206] Liver, for example: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0207] Biliary tract, for example: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma;

[0208] Bone, for example: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors;

[0209] Nervous system, for example: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, PATENT

[0210] ATTORNEY DOCKET NO. 51432-053WO2

[0211] retinoblastoma, congenital tumors), spinal cord neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma);

[0212] Gynecological, for example: uterus (endometrial carcinoma, uterine carcinoma, uterine corpus endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma);

[0213] Hematologic, for example: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases (e.g., myelofibrosis and myeloproliferative neoplasms), multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0214] Skin, for example: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and

[0215] Adrenal glands, for example: neuroblastoma.

[0216] In some embodiments, the cancer comprises a Ras mutation, such as a Ras mutation described herein. In some embodiments, a mutation is selected from:

[0217] (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof;

[0218] (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof; and

[0219] (c) the following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof;

[0220] or a combination of any of the foregoing. In some embodiments, a crystalline solid form of Compound A inhibits RasWTin addition to one or more additional Ras mutations (e.g., K-, H- or N-RasWTand K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, orG13V; K, H or N-Raswrand H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, orG12R; or K, H orN-RasWTand N- Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T). In some embodiments, a crystalline solid form of Compound A inhibits Rasampin addition to one or more additional Ras mutations (e.g., K-, H- or N-Rasampand K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K, H or N-Rasampand H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H orN-Rasampand N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or PATENT

[0221] ATTORNEY DOCKET NO. 51432-053WO2

[0222] A59T). In some embodiments, a cancer comprises a K-Ras G12V Ras mutation. In some embodiments, a cancer comprises a K-Ras G13C Ras mutation. In some embodiments, a cancer comprises a K-Ras G13C Ras mutation and an STK11LOF, a KEAP1, an EPHA5 or an NF1 mutation.

[0223] Methods of detecting Ras mutations are known in the art. Such means include, but are not limited to direct sequencing, and utilization of a high-sensitivity diagnostic assay (with CE-IVD mark), e.g., as described in Domagala, et al., Pol J Pathol 3: 145-164 (2012), incorporated herein by reference in its entirety, including TheraScreen PCR; AmoyDx; PNACIamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro. See, also, e.g., WO 2020 / 106640. Also provided is a method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a crystalline solid form of Compound A. A method of inhibiting RAF-Ras binding, the method comprising contacting the cell with an effective amount of a crystalline solid form of Compound A is also provided. The cell may be a cancer cell. The cancer cell may be of any type of cancer described herein. The cell may be in vivo or in vitro.

[0224] Combination Therapy

[0225] The methods of the invention may include a crystalline form, crystalline solvate form, or salt form of the compound of the invention used alone or in combination with one or more additional therapies (e.g., non-drug treatments or therapeutic agents). The dosages of one or more of the additional therapies (e.g., non-drug treatments or therapeutic agents) may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65: S3-S6 (2005)).

[0226] A crystalline compound as described herein or a salt form of the compound of the present invention may be administered before, after, or concurrently with one or more of such additional therapies. When combined, dosages of a compound of the invention and dosages of the one or more additional therapies (e.g., non-drug treatment or therapeutic agent) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). A crystalline compound of the present invention and an additional therapy, such as an anti-cancer agent, may be administered together, such as in a unitary pharmaceutical composition, or separately and, when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be close or remote in time.

[0227] In certain embodiments, compositions of the disclosure comprise a crystalline solid form of Compound A and one additional therapeutic agent. In certain embodiments, compositions of the disclosure comprise a crystalline solid form of Compound A and two additional therapeutic agents. In certain embodiments, compositions of the disclosure comprise a crystalline solid form of Compound A and three additional therapeutic agents. In certain embodiments, compositions of the disclosure comprise a crystalline solid form of Compound A and four or more additional therapeutic agents.

[0228] Also provided are pharmaceutical compositions including the combinations, ora pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Compositions comprising a combination of therapeutic agents may be used in methods of modulating RAS (e.g., in a subject or in a cell) and in methods of treating RAS related diseases and disorders (e.g., cancer), as described herein. The present disclosure provides, inter alia, compositions, methods, and kits for treating or preventing a RAS related disease or disorder. PATENT

[0229] ATTORNEY DOCKET NO. 51432-053WO2

[0230] Exemplary agents that may be used in combination with a crystalline solid form of Compound A are described below. All references herein are incorporated by reference for the agents described, including compound or molecular structures disclosed therein, whether explicitly stated as such or not. a) RAS(ON) Inhibitors

[0231] Compositions and methods of the present disclosure may include a crystalline solid form of Compound A plus a RAS(ON) inhibitor. A crystalline solid form of Compound A may be administered or formulated in combination with an additional therapeutic agent described herein.

[0232] One or more RAS(ON) multi-selective inhibitors useful according to the present disclosure can be found in any of the following patent applications: WO 2025228373, WO 2025215536, WO 2025214350, WO 2025209533, WO 2025201453, WO 2025162395, WO 2025119392, WO2025087431, WO 2025051241, WO 2025045233, WO 2024249299, WO 2024222864, WO 2024206858, WO 2024169914, WO 2024153208, WO 2024149214, WO 2024104364, WO 2024067857, WO 2024060966, WO 2024017859, WO 2024008834, WO 2023240263, WO 2023025832, WO 2022060836, WO 2021091956, CN119350371, CN 117903169, CN 117720556, CN 117720555, CN 117720554, CN 117534687, CN 117534685, or CN 117534684, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein.

[0233] In some embodiments, the RAS(ON) inhibitor is a RAS(ON) multi-selective inhibitor (e.g., daraxonrasib (RMC-6236), AN9025, BPI-572270, compound 6A of WO 2024 / 067857, ERAS-0015, GFH276, GFH547, HJ-099, RMC-7977, RCZY-680, RCZY-690, RG6505, or AUBE00).

[0234] In some embodiments, the RAS(ON) multi-selective inhibitor is daraxonrasib (RMC-6236):

[0235]

[0236] In some embodiments, the RAS(ON) multi-selective inhibitor is compound 6A of WO 2024 / 067857:

[0237]

[0238] Some embodiments of combinations comprising a crystalline solid form of Compound A include a composition comprising a RAS(ON) multi-selective inhibitor. The RAS(ON) multi-selective compounds useful according to the present disclosure exhibit inhibitory activities across a variety of RAS mutants. In some embodiments, a RAS(ON) multi-selective compound inhibits wild type RAS. In some embodiments, a RAS(ON) multi-selective compound inhibits wild type KRAS. In some embodiments, a RAS(ON) multi- PATENT

[0239] ATTORNEY DOCKET NO. 51432-053WO2

[0240] selective compound inhibits a RAS mutant with one or more mutations at G12X, G13X, and / or Q61X, wherein X represents any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S, R, H, K, or L amino acid residue.

[0241] In certain embodiments, a RAS(ON) multi-selective compound inhibits a RAS mutant with one or more mutations at G12X, wherein X represents any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S or R amino acid residue.

[0242] In other embodiments, a RAS(ON) multi-selective compound inhibits a RAS mutant with one or more mutations at G13X, wherein X is any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S or R amino acid residue.

[0243] In other embodiments, a RAS(ON) multi-selective compound inhibits a RAS mutant with one or more mutations at Q61X, wherein X is any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S, R, H, K, or L amino acid residue. In other instances, X is H, K, R, or L amino acid residue.

[0244] A variety of RAS proteins may be inhibited by a RAS(ON) multi-selective compound (e.g., KRAS, NRAS, HRAS, and mutants thereof at positions 12, 13 and 61, such as G12A, G12C, G12D, G12V, G12S, G12R, G13C, G13D, Q61H, Q61K, Q61R and Q61L, and others described herein, ora combination thereof). In some embodiments, a RAS(ON) multi-selective compound inhibits a G12A, G12C, G12D, G12R, G12S, G12V, orQ61H mutant of RAS, ora combination thereof.

[0245] Compositions and methods described herein may include one or more RAS(ON) mutant-selective inhibitors. Numerous RAS(ON) mutant-selective inhibitors have been disclosed.

[0246] Some embodiments of combinations comprising a crystalline solid form of Compound A include a composition comprising a RAS(ON) mutant-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12C-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12D-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G13C-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) Q61H-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12V-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G13D-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12R-selective inhibitor.

[0247] RAS(ON) mutant-selective inhibitors useful according to the methods of the present disclosure can be found in any one of the following patent applications: WO 2025214350, WO 2025104149, WO 2025093625, WO 2025080946, WO 2024249299, WO 2024211663, WO 2024211712, WO 2024208934, WO 2024149819, WO 2024008610, WO 2024102421, WO 2023240263, WO 2023133543, WO 2023015559, WO 2023086341, WO 2023208005, WO 2023232776, WO 2023086341, WO 2023060253, WO 2023015559, WO 2022235870, WO 2022235864, WO 2021091967, WO 2021091982, WO 2021108683, WO 2020132597, or International Patent Application No. PCTUS2025015061, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein.

[0248] In some embodiments, the RAS(ON) mutant-selective inhibitor useful according to the present disclosure is a G12D-selective inhibitor, such as zoldonrasib (RMC-9805) or RMC-9945.

[0249] In some embodiments, the RAS(ON) mutant-selective inhibitor is a G12C-selective inhibitor, such as elironrasib (RMC-6291) or RMC-4998. PATENT

[0250] ATTORNEY DOCKET NO. 51432-053WO2

[0251] In some embodiments, the RAS(ON) mutant-selective inhibitor is a G12V-selective inhibitor, such as RMC-5127.

[0252] In some embodiments, the RAS(ON) mutant-selective inhibitor is a G13C-selective inhibitor, such as RMC-8839. In some embodiments, the RAS(ON) mutant-selective inhibitor is a Q61H-selective inhibitor, such as RMC-0708. In some embodiments, the RAS(ON) mutant-selective inhibitor is a G12R-selective inhibitor, such as RMC-8264.

[0253] The crystalline solid form of Compound A may be made from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes. Byway of example, the RAS(ON) compounds can be synthesized using the methods described in WO 2022060836, WO 2021091956, or WO 2021091982, or any of the other RAS(ON) references cited herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.

[0254] A RAS(ON) inhibitor may be an antibody-drug conjugate, such as WO 2025051241 and WO 2024189481. See also Parry, C. W. et al., Reversible Small Molecule Multivariant Ras Inhibitors Display Tunable Affinity for the Active and Inactive Forms of Ras. J. Med. Chem. 2025, 68, 9, 9129-9161.

[0255] RAS(OFF) inhibitors are also known, such as WO 2025171055.

[0256] In some embodiments, the combination therapy comprising a crystalline solid form of Compound A may include one or more RAS(ON) inhibitors, for example, a crystalline solid form of Compound A plus one or more RAS(ON) multi-selective inhibitors and / or one or more RAS(ON) mutant-selective inhibitors. b) RAS / MAPK Inhibitors

[0257] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more RAS / MAPK pathway inhibitors. The RAS / MAPK pathway is a signal transduction cascade downstream of various cell surface growth factor receptors in which activation of RAS (and its various isoforms and allotypes) is a central event that drives a variety of cellular effector events that determine the proliferation, activation, differentiation, mobilization, and other functional properties of the cell. SHP2 conveys positive signals from growth factor receptors to the RAS activation / deactivation cycle, which is modulated by guanine nucleotide exchange factors (GEFs, such as SOS1) that load GTP onto RAS to produce functionally active GTP-bound RAS as well as GTP-accelerating proteins (GAPs, such as NF1) that facilitate termination of the signals by conversion of GTP to GDP. GTP-bound RAS produced by this cycle conveys essential positive signals to a series of serine / threonine kinases including RAF and MAP kinases, from which emanate additional signals to various cellular effector functions. In some embodiments, a therapeutic agent that may be combined with a RAS(ON) inhibitor is an inhibitor of the MAP kinase (MAPK) pathway (or “MAPK pathway inhibitor”). MAPK pathway inhibitors include, but are not limited to, one or more MAPK pathway inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758-1784. For example, the MAPK inhibitor may be selected from one or more of trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA 119 / BAY 86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche, described in PLoS One. 2014 Nov 25;9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res. 2011 Mar 1;17(5):989-1000). The MAPK pathway inhibitor may be PLX8394, LXH254, GDC-5573, or LY3009120. A MAPK pathway inhibitor may be a PI3Ka: RAS breaker, such as BBO-10203. PATENT

[0258] ATTORNEY DOCKET NO. 51432-053WO2

[0259] i) RAS(OFF) inhibitors, RAS(OFF) degraders and other RAS inhibitor types

[0260] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more RAS(OFF) inhibitors. Numerous mutant-selective and pan-KRAS inhibitors have been disclosed and are known in the art. A RAS(OFF) inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor described herein. RAS(OFF) inhibitors are designed to inhibit RAS activity by targeting different regions of the RAS protein in its inactive state (GDP bound state), preventing its activation and downstream signaling.

[0261] In some embodiments, a RAS(OFF) inhibitor is a KRAS(OFF) inhibitor that has a molecular weight of under 700 Da. In some embodiments, the KRAS(OFF) inhibitor is specific for a KRASG12Cmutation. KRASG12C(OFF) inhibitors use a covalent binding group that allows them to selectively target the KRASG12Cmutant protein, and many such inhibitors comprise a pyrimidine core. KRASG12C(OFF) inhibitors all target the same cysteine residue in the KRASG12Cmutant protein, leading to a conformational change that locks the protein in an inactive state. KRASG12C(OFF) inhibitors include, but are not limited to, adagrasib (MRTX849), divarasib (RG6330 / GDC-6036), fulzerasib (IBI351 / GFH925), garsorasib (D-1553), glecirasib (JAB-21822), olomorasib (LY3537982), opnurasib (JDQ443), sotorasib (AMG 510), ARS-853, ARS-1620, BI-0474, Bl 1823911, BPI-421286, D3S-001, ERAS-3490, GEC255, GH35, HBI-2438, HS-10370, JAB-21000, JAB-21822, JMKX001899, JNJ-74699157 (ARS-3248), MK-1084, SK-17, YL-15293, and HRS-7058. In some embodiments, the KRAS(OFF) inhibitor is selected from AMG510 and MRTX849. In some embodiments, the KRAS(OFF) inhibitor is AMG510. In some embodiments, the KRAS(OFF) inhibitor is MRTX849. In some embodiments, the KRAS(OFF) inhibitor is GDC-6036. A RAS(OFF) inhibitor may be an antibody-drug conjugate. See also doi.org / 10.1021 / acs.jmedchem.4c02929.

[0262] In some embodiments, a KRAS(OFF) inhibitor is specific for a KRASG12Dmutation. Non-limiting examples of KRASG12D(OFF) inhibitors include ASP3082, AST2169, BPI-501836, DN022150, ERAS-4693, ERAS-5024, GDC-7035 (RG6620), HBW-012-D, HBW-012-E, HBW-012336, HRS-4642, HS-10529, INCB186748, JAB-22000, KD-8, KRB-456, LY3962673, MRTX282, MRTX1133, Q2a, QLC1101, RNK08954, SHR1127, TH-Z827, TH-Z835, TSN1611, VRTX153, HJ-119, JR-6000, NKT-G12D, FWD-K02, JAB-BX600, EB-TM1, ABSK141, BPI-2491, HRS-6093, and HRS-7172.

[0263] In some embodiments, the small molecule RAS(OFF) inhibitor is specific for a KRASG12Vmutation (e.g., JAB-23000, QTX3544). In some embodiments, the small molecule RAS(OFF) inhibitor is specific for a KRASG13Dmutation.

[0264] In some embodiments, reference to the term RAS(OFF) inhibitor includes any such RAS(OFF) inhibitor disclosed in any one of the following patent applications: WO 2025240706, WO 2025240582, WO 2025236100, WO 2025235740, WO 2025232765, WO 2025231410, WO 2025231310, WO 2025230961, WO 2025230878, WO 2025230862, WO 2025230860, WO 2025218730, WO 2025217430, WO 2025217319, WO 2025217247, WO 2025214344, WO 2025194134, WO 2025194057, WO 2025194054, WO 2025190342, WO 2025188668, WO 2025179058, WO 2025170938, WO 2025168072, WO 2025167948, WO 2025165972, WO 2025162091, WO 2025157289, WO 2025157260, WO 2025157246, WO 2025157162, WO 2025153038, WO 2025151738, WO 2025151594, WO 2025148979, WO 2025146194, WO 2025136346, WO 2025132549, WO 2025130912, WO 2025129002, WO 2025124415, WO 2025123318, WO 2025123007, WO 2025122619, WO 2025117828, WO 2025111586, WO 2025111582, WO 2025108443, WO 2025106905, WO 2025106901, WO 2025101776, WO PATENT

[0265] ATTORNEY DOCKET NO. 51432-053WO2

[0266] 2025096984, WO 2025096957, WO 2025096738, WO 2025092986, WO 2025092798, WO 2025085748, WO 2025085580, WO 2025080653, WO 2025077770, WO 2025077663, WO 2025076523, WO 2025072649, WO 2025072457, WO 2025072451, WO 2025067459, WO 2025067453, WO 2025064848, WO 2025064542, WO 2025061125, WO 2025059366, WO 2025059040, WO 2025054530, WO 2025054347, WO 2025054270, WO 2025053850, WO 2025051242, WO 2025045141, WO 2025049641, WO 2025049619, WO 2025049402, WO 2025049274, WO 2025040767, WO 2025038936, WO 2025036475, WO 2025036470, WO 2025034883, WO 2025034849, WO 2025026903, WO 2025019688, WO 2025018418, WO 2025016899, WO 2025016432, WO 2025011443, WO 2025010415, WO 2025007000, WO 2025006967, WO 2025006962, WO 2025006720, WO 2025006704, WO 2025002430, WO 2025002302, WO 2024259169, WO 2024254404, WO 2024254334, WO 2024255795, WO 2024246099, WO 2024243025, WO 2024238633, WO 2024238343, WO 2024236452, WO 2024235286, WO 2024235225, WO 2024233776, WO 2024230734, WO 2024230707, WO 2024229447, WO 2024229444, WO 2024229442, WO 2024229317, WO 2024227091, WO 2024220645, WO 2024220532, WO 2024218686, WO 2024215862, WO 2024215754, WO 2024213979, WO 2024213122, WO 2024208305, WO 2024209339, WO 2024206766, WO 2024206747, WO 2024197503, WO 2024193698, WO 2024192424, WO 2024179546, WO 2024178313, WO 2024178304, WO 2024173842, WO 2024167922, WO 2024160225, WO 2024159471, WO 2024159470, WO 2024158778, WO 2024158242, WO 2024153119, WO 2024153116, WO 2024138486, WO 2024138206, WO 2024138052, WO 2024131829, WO 2024125642, WO 2024125600, WO 2024123913, WO 2024123102, WO 2024120433, WO 2024120419, WO 2024119277, WO 2024118926, WO 2024109233, WO 2024112654, WO 2024104453, WO 2024104425, WO 2024107686, WO 2024104453, WO 2024103010, WO 2024097559, WO 2024091409, WO 2024088273, WO 2024085661, WO 2024083258, WO 2024083256, WO 2024083246, WO 2024083168, WO 2024078555, WO 2024076674, WO 2024076672, WO 2024076670, WO 2024067714, WO 2024067575, WO 2024064335, WO 2024063578, WO 2024063576, WO 2024061370, WO 2024061333, WO 2024061267, WO 2024056063, WO 2024055112, WO 2024054926, WO 2024054647, WO 2024054625, WO 2024051763, WO 2024051721, WO 2024050742, WO 2024050640, WO 2024046406, WO 2024046370, WO 2024045066, WO 2024044667, WO 2024044649, WO 2024044334, WO 2024041621, WO 2024041606, WO 2024041589, WO 2024041573, WO 2024040131, WO 2024040109, WO 2024040080, WO 2024036270, WO 2024034657, WO 2024034593, WO 2024034591, WO 2024034123, WO 2024032747, WO 2024032704, WO 2024032703, WO 2024032702, WO 2024031088, WO 2024030647, WO 2024030633, WO 2024029613, WO 2024022507, WO 2024022444, WO 2024020159, WO 2024019103, WO 2024017859, WO 2024017392, WO 2024015731, WO 2024015262, WO 2024012456, WO 2024009191, WO 2024008179, WO 2024008178, WO 2024008068, WO 2024006445, WO 2024006424, WO 2024002373, WO 2023287896, WO 2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO 2023283933, WO 2023283213, WO 2023280280, WO 2023280136, WO 2023280026, WO 2023278600, WO 2023274383, WO 2023327324, WO 2023246914, WO 2023246903, WO 2023246777, WO 2023244713, WO 2023244615, WO 2023244604, WO 2023244600, WO 2023244599, WO 2023230190, WO 2023226630, WO 2023225302, WO 2023225252, WO 2023220421, WO 2023219941, WO 2023217148, WO 2023215802, WO 2023215801, WO 2023213269, WO 2023212548, WO 2023208005, WO 2023205719, WO 2023199180, WO 2023198191, WO 2023197984, WO 2023190748, WO 2023185864, WO 2023183755, WO 2023183585, WO 2023179703, WO 2023179629, WO 2023173017, WO 2023173016, WO PATENT

[0267] ATTORNEY DOCKET NO. 51432-053WO2

[0268] 2023173014, WO 2023172737, WO 2023171781, WO 2023159087, WO 2023159086, WO 2023154766, WO 2023152255, WO 2023151674, WO 2023151621, WO 2023150394, WO 2023150284, WO 2023143623, WO 2023143605, WO 2023143352, WO 2023143352, WO 2023143312, WO 2023141570, WO 2023141300, WO 2023138662, WO 2023138601, WO 2023138589, WO 2023138524, WO 2023133183, WO 2023133181, WO 2023130012, WO 2023125989, WO 2023125627, WO 2023122662, WO 2023122154, WO 2023120742, WO 2023119677, WO 2023117681, WO 2023116934, WO 2023116895, WO 2023114733, WO 2023105491, WO 2023104018, WO 2023103906, WO 2023103523, WO 2023101928, WO 2023099624, WO 2023099624, WO 2023099620, WO 2023099612, WO 2023099608, WO 2023099592, WO 2023098832, WO 2023098425, WO 2023097227, WO 2023081840, WO 2023081476, WO 2023078424, WO 2023077441, WO 2023072297, WO 2023072188, WO 2023066371, WO 2023064857, WO 2023061463, WO 2023061294, WO 2023057985, WO 2023056951, WO 2023056421, WO 2023051586, WO 2023049697, WO 2023046135, WO 2023045960, WO 2023041059, WO 2023041059, WO 2023040989, WO 2023040513, WO 2023039240, WO 2023039020, WO 2023036282, WO 2023034290, WO 2023030517, WO 2023030495, WO 2023030385, WO 2023030495, WO 2023030517, WO 2023030685, WO 2023030687, WO 2023034290, WO 2023036282, WO 2023039240, WO 203020347, WO 2023025116, WO 2023287896, WO 2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO 2023283933, WO 2023283213, WO 2023280280, WO 2023280136, WO 2023280026, WO 2023278600, WO 2023274383, WO 2023327324, WO 2023040989, WO 2023039240, WO 2023039020, WO 2023036282, WO 2023034290, WO 2023030517, WO 2023030495, WO 2023030385, WO 2023025116, WO 2023020523, WO 2023020521, WO 2023020519, WO 2023020518, WO 2023020347, WO 2023018812, WO 2023018810, WO 2023018809, WO 2023018699, WO 2023014979, WO 2023014006, WO 2023004102, WO 2023003417, WO 2023001141, WO 2023001123, WO 2022271658, WO 2022269508, WO 2022266167, WO 2022266069, WO 2022266015, WO 2022265974, WO 2022261154, WO 2022261154, WO 2022251576, WO 2022251296, WO 2022237815, WO 2022232332, WO 2022232331, WO 2022232320, WO 2022232318, WO 2022223037, WO 2022221739, WO 2022221528, WO 2022221386, WO 2022216762 (e.g., Compound 44 or Compound 66a), WO 2022212894, WO 2022192794, WO 2022192790, WO 2022188729, WO 2022187411, WO 2022184178, WO 2022173870, WO 2022173678, WO 2022135346, WO 2022133731, WO 2022133038, WO 2022133345, WO 2022132200, WO 2022119748, WO 2022109485, WO 2022109487, WO 2022066805, WO 2022002102, WO 2022002018, WO 2021259331, WO 2021257828, WO 2021252339, WO 2021248095, WO 2021248090, WO 2021248083, WO 2021248082, WO 2021248079, WO 2021248055, WO 2021245051, WO 2021244603, WO 2021239058, WO 2021231526, WO 2021228161, WO 2021219090, WO 2021219090, WO 2021219072, WO 2021218939, WO 2021217019, WO 2021216770, WO 2021215545, WO 2021215544, WO 2021211864, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199, 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO 2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO 2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO 2021139678, WO 2021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO 2021126799, WO 2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO 2021113595, WO 2021107160, WO 2021106231, WO 2021088458, WO 2021086833, WO 2021085653, WO 2021081212, WO 2021058018, WO 2021057832, WO 2021055728, WO 2021031952, WO 2021027911, WO 2021023247, WO 2020259513, WO 2020259432, WO 2020234103, WO PATENT

[0269] ATTORNEY DOCKET NO. 51432-053WO2

[0270] 2020233592, WO 2020216190, WO 2020178282, WO 2020146613, WO 2020118066, WO 2020113071, WO 2020106647, WO 2020102730, WO 2020101736, WO 2020097537, WO 2020086739, WO 2020081282, WO 2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO

[0271] 2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO 2018218071, WO 2018218069, WO 2018217651, WO 2018206539, WO 2018143315, WO 2018140600, WO 2018140599, WO 2018140598, WO 2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO 2018068017, WO 2018064510, WO

[0272] 2017201161, WO 2017172979, WO 2017100546, WO 2017087528, WO 2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659, WO 2013155223, KR 20250100539, KR102819454, KR 20240159370, KR 20240101190, KR 20240101189, KR 20240041720, KR 20240041719, JP 2025100453, CN 120230123, CN 119607214, CN 119930639, CN 119909188, CN 119751476, CN 119733053, CN 119684316, CN 119684315, CN 119684314, CN 119661556, CN 119661555, CN 119661539, CN 119606974, CN 119528902, CN 119528810, CN 119504612, CN 119490514, CN 119490512, CN 119462648, CN 119371353, CN 119350242, CN 119264124, CN 119241566, CN 119060049, CN 119060066, CN 119019382, CN 118994158, CN 118994031, CN 118806919, CN 118791505, CN 118772176, CN 118754899, CN 118745175, CN 118666870, CN118666869, CN 118580238, CN 118307563, CN 118221700, CN 118221699, CN 118221698, CN 118221685, CN 118126064, CN 118078802, CN 118078801, CN 118005656, CN 117986263, CN 117986263, CN 117946135, CN 117924327, CN 117903117, CN 117800990, CN 117800989, CN 117800976, CN 117736226, CN 117683051, CN 117645627, CN 117624194, CN 117624190, CN 117586280, CN 117486901, CN 117466917, CN 117462688, CN 117362315, CN 117327102, CN 117327094, CN 117327074, CN 117285590, CN 117263959, CN 117247382, CN 117186095, CN 117164605, CN 116969977, CN 116925075, CN 116891489, CN 116731045, CN 116731044, CN 116554208, CN 116514846, CN 116478184, CN 116478141, CN 116410145, CN 116375742, CN 116354988, CN 116332948, CN 116332938, CN 116327956, CN 116262759, CN 116217592, CN 116199703, CN 116162099, CN 116143806, CN 116143805, CN 116120315, CN 116102559, CN 115960105, CN 115894520, CN 115872979, CN 115850267, CN 115785199, CN 115785124, CN 115724842, CN 115724842, CN 115721720, CN 115716840, CN 115703775, CN 115611923, CN 115611898, CN 115583937, CN 115572278, CN 115557949, CN 115521312, CN 115504976, CN 115490709, CN 115466272, CN 115433183, CN 115433179, CN 115403575, CN 115385938, CN 115385937, CN 115385912, CN 115381786, CN 115368383, CN 115368382, CN 115368381, CN 115353506, CN 115322158, CN 115304623, CN 115304602, CN 115197245, CN 115181106, CN 114989195, CN 114989166, CN 114989147, CN 114920741, CN 114920739, CN 114907387, CN 114874234, CN 114874201, CN 114716436, CN 114716435, CN 114685532, CN 114685460, CN 114591319, CN 114539293, CN 114539286, CN 114539246, CN 114437107, CN 114437084, CN 114409653, CN 114380827, CN 114195804, CN 114195788, CN 114437107, CN 114409653, CN 114380827, CN 114195804, CN 114057776, CN 114057744, CN 114057743, CN 113999226, CN 113980032, CN 113980014, CN 113960193, CN 113929676, CN 113754653, CN 113683616, CN 113563323, CN 113527299, CN 113527294, CN 113527293, CN 113493440, CN 113429405, CN 113321654, CN PATENT

[0273] ATTORNEY DOCKET NO. 51432-053WO2

[0274] 113248521, CN 113087700, CN 113024544, CN 113004269, CN 112920183, CN 112778284, CN 112390818, CN 112390788, CN 112300196, CN 112300194, CN 112300173, CN 112225734, CN 112142735, CN 112110918, CN 112094269, CN 112047937, CN 109574871, US 12331063, US 2025115603, US 2025114346, US 2025114339, US 20240358702, US 2024270736, EP 4574151, or EP 4389751, each of which is incorporated herein by reference in its entirety, including the RAS compound structures disclosed therein which are specifically incorporated herein by reference.

[0275] In some embodiments, reference to the term RAS(OFF) inhibitor refers to a pan-KRAS inhibitor, such as selected from one disclosed in any of the following: WO 2025217319, WO 2025214344, WO 2025194057, WO 2025194054, WO 2025165972, WO 2025153038, WO 2025151594, WO 2025136346, WO 2025130912, WO 2025129002, WO 2025123007, WO 2025117828, WO 2025106905, WO 2025106901, WO 2025101776, WO 2025096738, WO 2025092798, WO 2025085748, WO 2025077770, WO 2025077663, WO 2025076523, WO 2025064848, WO 2025059366, WO 2025059040, WO 2025049641, WO 2025049619, WO 2025049402, WO 2025045141, WO 2025038936, WO 2025026903, WO 2025016899, WO 2025007000, WO 2025006967, WO 2025006962, WO 2025006720, WO 2025006704, WO 2024255795, WO 2024254404, WO 2024246099, WO 2024238633, WO 2024238343, WO 2024236452, WO 2024235286, WO 2024235225, WO 2024230734, WO 2024220645, WO 2024220532, WO 2024218686, WO 2024215754, WO 2024213979, WO 2024213122, WO 2024209339, WO 2024206766, WO 2024206747, WO 2024192424, WO 2024178313, WO 2024178304, WO 2024173842, WO2024153180, WO 2024119277, WO 2024120433, WO 2024115890, WO 2024112654, WO 2024104453, WO 2024104425, WO 2024107686, WO 2024104453, WO 2024103010, WO 2024085661, WO 2024083246, WO 2024083168, WO 2024067575, WO 2024064335, WO 2024063578, WO 2024063576, WO 2024051852, WO 2024051763, WO 2024046370, WO 2024044667, WO 2024041621, WO 2024041606, WO 2024041589, WO 2024040131, WO 2024040109, WO 2024032747, WO 2024032704, WO 2024032703, WO 2024032702, WO 2024031088, WO 2024030647, WO 2024030633, WO 2024015262, WO 2024009191, WO 2024008068, WO 2024002373, WO 2023287896, WO 2023274324, WO 2023246914 (e.g., compound 14), WO 2023246777, WO 2023230190, WO 2023215802, WO 2023215801, WO 2023197984, WO 2023190748, WO 2023183585, WO 2023179703, WO 2023173017, WO 2023173016, WO 2023173014, WO 2023172737, WO 2023154766, WO 2023143352, WO 2023143312, WO 2023138589, WO 2023133183, WO 2023122662, WO 2023114733, WO 2023099624, WO 2023099623, WO 2023099612, WO 2023099608, WO 2023099592, WO 2023097227, WO 2023064857, WO 2023056421, WO 2023049697, WO 2023046135, WO 2023039240, WO 2023034290, WO 2023020523, WO 2023020521, WO 2023020519, WO 2023020518, WO 2023001123, WO 2022271823, WO 2022261210, WO 2022258974, WO 2022256459, WO 2022250170, WO 2022248885, WO 2022228543, WO 2022216762, WO 2022072783, WO 2016161361, KR 20250100539, KR 20240101190, KR 20240101189, KR 20240041720, KR 20240041719, JP 2025100453, CN 119751476, CN 119661539, CN 119371353, CN 119019382, CN 118791505, CN 118221700, CN 118126064, CN 117924327, CN 117946135, CN 117800990, CN 117800989, CN 117683051, CN 117486901, CN 117263959, CN 116969977, CN 116332948, or US 12331063, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein. In some embodiments, combination comprising a pan-KRAS inhibitor therapy comprises ERAS-4001. In some embodiments, the pan-KRAS inhibitor is a pan-KRAS inhibitor in a patent application filed in the name of Medshine Discovery, Inc. In some embodiments, a combination comprising a pan-KRAS PATENT

[0276] ATTORNEY DOCKET NO. 51432-053WO2

[0277] inhibitor therapy includes A2A-03, ABREV01, ADT-007, ABT-200, ADT-030, ADT-1004, BBP-454, BGB-53038, BI-2865, BI-2493, Bl 3706674, BRSD-143, ERAS-4, ERAS-254, ERAS-4001, HB-700 (G12X+G13D), HZ-V068, ID12241161, JAB-23400, LY4066434, OC211, PF-07985045, PF-07934040, PF-4040, QTX2024, QTX3034, RSC-1255, SIL204, SYNB021225, YL-17231, ZG2001, WEF-001.

[0278] In some embodiments, a RAS inhibitor binds to the OFF form as well as the ON form. Nonlimiting examples of such inhibitors include, e.g., pan-KRAS: ALTA3263, AMG 410, BBO-11818, HBW-016-K, HEC211909, JAB-23E73, JAB-23425, JAB-23E73; G12C: BBO-8520, FMC-376; G12D: AZD0022, GFH375 (VS-7375), INCB161734, QTX3046, TSN1611 TH-Z835, TLN-372, CGT1263.

[0279] In some embodiments, a RAS inhibitor binds to the ON form of RAS but is not a tri-complex inhibitor, such as pan-KRAS inhibitors JTX-102 and JTX-105. Pan-KRAS(ON) inhibitors with a high selectivity for the ON form may be found, for example, in WO 2025193878.

[0280] In any embodiment employing a RAS(OFF) inhibitor herein, a RAS(OFF) degrader targeting the OFF state of RAS may be employed. These degraders are known in the art, such as ASP3082 (setidegrasib; G12D) and ASP5834 (pan-KRAS). RAS degraders may be found, for example, in one or more of the following applications: WO 2025240742, WO 2025240740, WO 2025218811, WO 2025218798, WO 2025190158, WO 2025169901, WO 2025168124, WO 2025168051, WO 2025162250, WO 2025159142, WO 2025151765, WO 2025125630, WO 2025108479, WO 2025107579, WO 2025103476, WO 2025096855, WO 2025085815, WO 2025083472, WO 2025078984, WO 2025076044, WO 2025058008, WO 2025053850, WO 2025024732, WO 2025019823, WO 2025006783, WO 2025006753, WO 2024263586, WO 2024261257, WO 2024261256, WO 2024241248, WO 2024233838, WO 2024199266, WO 2024188281, WO 2024 / 159164, WO 2024152247, WO 2024149214, WO 2024131777, WO 2024120424, WO 2024119278, WO 2024118966, WO 2024118960, WO 2024083258, WO 2024083256, WO 2024055112, WO 2024054625, WO 2024050742, WO 2024044334, WO 2024040080, WO 2024034657, WO 2024034593, WO 2024034591, WO 2024034123, WO 2024029613, WO 2024020159, WO 2024019103, WO 2024017392, WO 2023215906, WO 2023185864, WO 2023171781, WO 2023141570, WO 2023138524, WO 2023130012, WO 2023116934, WO 2023099620, WO 2023081476, WO 2023077441, WO 2022260482, CN 119219669, CN 119161349, CN 118955610, CN 118772249, CN 118725012, CN 118496502, CN 118496300, CN 118126040, CN 115785199, or US 2025213706, each of which is incorporated herein by reference in its entirety. Non-limiting examples of RAS degraders include: ASP3082 (KRAS G12D); ASP4396 (KRAS G12D); BPI-585725 (G12X and WT), LT-010366 (G12D); PT0253 (G12D), RD0255359 (KRAS G12C / D / V); RP03707 (G12D), JR-9000, 356A, SH1718, IPS-06061, HDB-82.

[0281] In some embodiments, the RAS(OFF) inhibitor is a peptide-based inhibitor. Peptide-based RAS(OFF) inhibitors have been developed that target specific regions of the RAS protein, such as the Switch II region or the RAS-effector interface. Non-limiting examples include the K-Ras-binding peptide (Krpep-2d), the Ras inhibitory peptide (Rasln) and LUNA18 (NCT05012618). Peptide-based RAS(OFF) inhibitors are a class of compounds that target the RAS protein by disrupting its interaction with its downstream effectors or other signaling proteins. These inhibitors are typically designed to mimic the binding motifs of RAS-interacting proteins or other RAS effectors, such as RAF or PI3K. By binding to RAS at the same site as these effectors, peptide-based inhibitors can effectively compete with these proteins and prevent the activation of downstream signaling pathways. See, e.g., WO 2025162428, WO 2025127968, WO 2025018418, WO 2024219480, WO 2024219446, WO 2024176153, WO 2024101402, PATENT

[0282] ATTORNEY DOCKET NO. 51432-053WO2

[0283] WO 2024101386, WO 2023214576, WO 2023140329, WO 2022234853, WO 2022234852, WO 2022234851, WO 2022234639, and CN 120040551, each of which is incorporated herein by reference in its entirety.

[0284] Peptide-based RAS(OFF) inhibitors can be further classified into two main categories: those that target the RAS-effector interface, and those that target other regions of the RAS protein. Peptide-based inhibitors that target the RAS-effector interface are designed to bind to the switch regions of RAS that are critical for its interaction with downstream effectors, such as RAF or PI3K. These inhibitors typically contain amino acid residues that are similar to those found in the binding motifs of RAS-interacting proteins or effectors and are often designed to form hydrogen bonds or other interactions with key residues on the surface of RAS.

[0285] Peptide-based RAS(OFF) inhibitors that target other regions of the RAS protein are typically designed to disrupt other interactions that are critical for the activation or signaling of RAS. For example, some peptide-based inhibitors are designed to bind to the hypervariable region of RAS, which is thought to play a role in membrane localization and anchoring of the protein. By binding to this region, peptide-based inhibitors can prevent the proper localization of RAS to the plasma membrane, which is necessary for its activation and signaling.

[0286] Several common motifs have been identified as important for the binding of RAS-interacting proteins and effectors and are often used in the design of peptide-based inhibitors. One example is the RAF-binding domain (RBD), which is found in many RAS-interacting proteins and is important for the interaction of RAS with downstream effectors such as RAF. The RBD contains a conserved amino acid sequence (Arg-Xaa-Arg) that is critical for binding to RAS, and this motif has been incorporated into several peptide-based inhibitors designed to disrupt the RAS-RAF interaction. Another example is the RAS-binding domain (RBD) of PI3K, which is important for the interaction of RAS with this downstream effector. The RBD of PI3K contains several conserved amino acid residues (such as Arg-Arg-Trp) that are critical for binding to RAS, and these motifs have been used in the design of peptide-based inhibitors that target the RAS-PI3K interaction. Other common motifs used in peptide-based RAS(OFF) inhibitors include the Ras-binding domain (RBD) of other RAS-interacting proteins such as RaIGDS and SOS, as well as sequences that mimic the structure of the switch regions of RAS itself. These motifs are typically used to optimize the binding affinity and selectivity of the inhibitor for the desired target protein or interaction.

[0287] In some embodiments, the RAS(OFF) inhibitor is an antibody or antigenic binding peptide specific for RAS(OFF). Antibodies have been developed that bind to specific regions of the RAS protein, such as the Switch II region or the RAS-effector interface. For example, some antibodies have been developed that target the switch regions of RAS proteins, which are critical for the activation of these proteins and their interaction with downstream effectors. Binding of these antibodies to the switch regions can prevent the conformational changes required for RAS activation and downstream signaling. Another approach involves the use of antibodies that target RAS-interacting proteins or downstream effectors, such as RAF or PI3K. Binding of these antibodies to their target proteins can disrupt the RAS-dependent signaling pathways and inhibit the growth and survival of cancer cells. Additionally, some antibodies have been developed that can induce the internalization and degradation of RAS proteins, leading to their depletion and inhibition of downstream signaling. For example, some antibodies have been developed that recognize the unique structure of mutant RAS proteins and target them for degradation via the ubiquitin- PATENT

[0288] ATTORNEY DOCKET NO. 51432-053WO2

[0289] proteasome pathway. Non-limiting examples of KRAS(OFF)-specific inhibitory antibodies include anti-p21ser, and K27 (DARPin) (see, e.g., Khan et al, Biochim Biophys Acta Mol Cell Res. 2020 Feb;1867(2):118570). See also WO 2025206850, WO 2024136608, and WO 2024111590, each of which is incorporated herein by reference in its entirety.

[0290] Antibody-drug conjugates may also be constructed using RAS inhibitors (e.g., RAS(OFF) inhibitors), such as WO 2024189481, which is incorporated herein by reference in its entirety, including the compound structures disclosed therein.

[0291] Vaccines may also be used in combination with compounds of the present invention. Non-limiting examples include: AFNT-111 (KRAS G12V), AFNT-211 (KRAS G12V), AFNT-212 (KRAS G12D), ELI-002 (KRAS G12 / 13X), HB-700, NT-112 (KRAS G12D), and TG01 (pan-KRAS).

[0292] Other RAS modalities useful in combination with compounds of the present invention include: ADGN-123, ADGN-121 (gene editing peptide-RNA nanoparticles G12D); ADT-030 (Ras / B-catenin inhibitor); BBO-10203 (PI3Ka: RAS breaker); Bl 1701963 (Pan-KRAS: SOS1); mRNA-5671 (nucleic acid) and RO7673396 (RAS inhibitor), AZD0240 (TCR-T cell product targeting G12D), MDG2021 (TCR-T cell product targeting G12D), ADGN-121 (peptide-sgRNA nanoparticles), BION-302 (antibody based) LIB111 (antibody based), SIL-204 (ASO I siRNA-based). See, e.g., WO 2025193628.

[0293] ii) SOS1 inhibitors

[0294] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more SOS1 inhibitors. A SOS1 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a SOS1 inhibitor is one or more of RMC-5845, RMC-4948, RMC-0331, BI-1701963, BI-1918455, BI-3406, SDR5, MRTX-0902, ZG2001, and BAY-293. In some embodiments, reference to the term SOS1 inhibitor includes any such SOS1 inhibitor disclosed in any one of the following patent applications: WO 2025070947, WO 2025067316, WO 2025062157, WO 2025059046, WO 2025038785, WO 2025003694, WO 2025000265, WO 2024255827, WO 2024172632, WO 2024172631, WO 2024119028, WO 2024102952, WO 2024083257, WO 2024083255, WO 2024079252, WO 2024075070, WO 2024067744, WO 2024035921, WO 2024027762, WO 2024008185, WO 2023250165, WO 2023215257, WO 2023215256, WO 2023180345, WO 2023109929, WO 2023059597, WO 2023041049, WO 2023029833, WO 2023022497, WO 2022184116, WO 2022171184, WO 2022170952, WO 2022170917, WO 2022170802, WO 2022161461, WO 2022157629, WO 2022139304, WO 2022121813, WO 2022028506, WO 2021228028, WO 2019122129, KR 20240128541, CN 119431234, CN 119039237, CN 119039234, CN 118812510, CN 117800922, CN117143175, CN 117143176, CN 116462669, CN 116444447, CN 115806560, CN 115677702, CN 115215847, CN 115028644, CN 114685488, and CN 111393519 each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0295] iii) SHP inhibitors

[0296] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more SHP inhibitors. A SHP inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, the SHP inhibitor is an inhibitor of SHP1. In some embodiments, the SHP inhibitor is an inhibitor of SHP2. In some embodiments, the SHP1 PATENT

[0297] ATTORNEY DOCKET NO. 51432-053WO2

[0298] inhibitor is SB8091 or SB6299 aka DA-4511. In some embodiments, a SHP2 inhibitor is one or more of SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, ARRY-558, or BBP-398. In some embodiments, reference to the term SHP2 inhibitor includes any such SHP2 inhibitor disclosed in any one of the following patent applications: WO 2025075693, WO 2025019666, WO 2025011568, WO 2025011480, WO 2024258652, WO 2024193439, WO 2024175081, WO 2024147703, WO 2024125603, WO 2023282702, WO 2023280283, WO 2023280237, WO 2023018155, WO 2023011513, WO 2022271966, WO 2022271964, WO 2022271911, WO 2022259157, WO 2022242767, WO 2022241975, WO 2022237676, WO 2022237367, WO 2022237178, WO 2022235822, WO 20222084008, WO 2022135568, WO 2022063190, WO 2022043865, WO 2022042331, WO 2022033430, WO 2022017444, WO 2022007869, WO 2021259077, WO 2021249449, WO 2021249057, WO 2021244659, WO 2021218755, WO 2021176072, WO 2021171261, WO 2021149817, WO 2021148010, WO 2021147879, WO 2021143823, WO 2021143701, WO 2021143680, WO 2021281752, WO 2021121397, WO 2021119525, WO 2021115286, WO 2021110796, WO 2021088945, WO 2021073439, WO 2021061706, WO 2021061515, WO 2021043077, WO 2021033153, WO 2021028362, WO 2021033153, WO 2021028362, WO 2021018287, WO 2020259679, WO 2020249079, WO 2020210384, WO 2020201991, WO 2020181283, WO 2020177653, WO 2020165734, WO 2020165733, WO 2020165732, WO 2020156243, WO 2020156242, WO 2020108590, WO 2020104635, WO 2020094104, WO 2020094018, WO 2020081848, WO 2020073949, WO 2020073945, WO 2020072656, WO 2020065453, WO 2020065452, WO 2020063760, WO 2020061103, WO 2020061101, WO 2020033828, WO 2020033286, WO 2020022323, WO 2019233810, WO 2019213318, WO 2019183367, WO 2019183364, WO 2019182960, WO 2019167000, WO 2019165073, WO 2019158019, WO 2019152454, WO 2019051469, WO 2019051084, WO 2018218133, WO 2018172984, WO 2018160731, WO 2018136265, WO 2018136264, WO 2018130928, WO 2018129402, WO

[0299] 2018081091, WO 2018057884, WO 2018013597, WO 2017216706, WO 2017211303, WO 2017210134, WO 2017156397, WO 2017100279, WO 2017079723, WO 2017078499, WO 2016203406, WO 2016203405, WO 2016203404, WO 2016196591, WO 2016191328, WO 2015107495, WO 2015107494, WO 2015107493, WO 2014176488, WO 2014113584, CN 116332908, CN 119264153, CN 117069698, CN 117143107, CN 115677661, CN 115677660, CN 115611869, CN 115521305, CN 115490697, CN 115466273, CN 115394612, CN 115304613, CN 115304612, CN 115300513, CN 115197225, CN 114957162, CN 114920759, CN 114716448, CN 114671879, CN 114539223, CN 114524772, CN 114213417, CN 114195799, CN 114163457, CN 113896710, CN 113248521, CN 113248449, CN 113135924, CN 113024508, CN 112920131, CN 112823796, CN 112409334, CN 112402385, CN 112174935, 111848599, CN 111704611, CN 111393459, CN 111265529, CN 110143949, CN

[0300] 108113848, US 11179397, US 11044675, US 11034705, US 11033547, US 11001561, US 10988466, US 10954243, US 10934302, or US 10858359, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0301] iv) MEK inhibitors

[0302] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more MEK inhibitors. A MEK inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a MEK inhibitor is one or more of PATENT

[0303] ATTORNEY DOCKET NO. 51432-053WO2

[0304] pimasertib, IMM-1-104, selumetinib, cobimetinib (COTELLIC®), trametinib (ME KI NIST®), and binimetinib (MEKTOVI®). In some embodiments, a MEK inhibitor targets a MEK mutation that is a Class I MEK1 mutation selected from D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a Class II MEK1 mutation selected from AE51-Q58; AF53-Q58; E203K; L177M; C121S; F53L; K57E;

[0305] Q56P; and K57N. In some embodiments, reference to the term MEK inhibitor includes any such MEK inhibitor disclosed in any one of the following patent applications: WO 2022221866, WO 2022125941, WO 2022208391, WO 2022015736, WO 2022177557, WO 2021018866, WO 2021069486, WO 2021142144, WO 2021168283, WO 2021234097, WO 2019076947, WO 2018233696, WO 2016188472, WO 2014063024, WO 2013019906, WO 2011047238, WO 2007044515, US 2023032403, and CN 115813930, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0306] v) RAF inhibitors

[0307] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more RAF inhibitors. A RAF inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a RAF inhibitor is VS-6766 or BTDX-4933. In some embodiments, a RAF inhibitor is a BRAF inhibitor. BRAF inhibitors that may be used in combination with a crystalline solid form of Compound A include, for example, VS-6766, IK-595, vemurafenib, dabrafenib, and encorafenib. BRAF may comprise a Class 3 BRAF mutation. In some embodiments, the Class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581 I; D594N; D594G; D594A; D594H; F595L; G596D; G596R and A762E. In some embodiments, reference to the term RAF inhibitor includes any such RAF inhibitor disclosed in any one of the following patent applications: WO 2023076991, WO 2022226626, WO 2022226261, WO 2019084459, WO 2018203219, WO 201851306, WO 2017212442, WO 2015075483, WO 2013134243, WO 2013134298, WO 2011047238, WO 2011025965, WO 2011025947, WO 2011025951, WO 2011025940, WO

[0308] 2011025938, WO 2010065893, WO 2009016460, WO 2009130015, WO 2009111278, WO 2009111279, WO 2008028141, and WO 2006024834, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0309] vi) ERK inhibitors

[0310] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more ERK inhibitors. An ERK inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, an ERK inhibitor is an ERK1 / 2 inhibitor, such as ERAS-007. In some embodiments, an ERK inhibitor is an ERK 5 inhibitor. In some embodiments, an ERK inhibitor is one or more of ASTX-029 or I-75. In some embodiments, reference to the term ERK inhibitor includes any such ERK inhibitor disclosed in any one of the following patent applications: WO 2023076305, WO 2022259222, WO 2022221547, WO 2021110169, WO 2021110168, WO 2021252316, WO 2020102686, WO 2020228817, WO 2020107987, WO 2019233456, WO 2019233457, WO 2016025561, WO 2016192063, WO 2016106029, WO 2016106009, WO 2015051341, WO 2014124230, WO 2014052563, WO 2011041152, WO 200910550, WO 2008153858, CN114315837, PATENT

[0311] ATTORNEY DOCKET NO. 51432-053WO2

[0312] CN 115057860, CN 107973783, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0313] vii) MAPK inhibitors

[0314] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Mitogen-Activated Protein Kinase (MAPK) inhibitors. A MAPK inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a MAPK inhibitor is a p38MAPK inhibitor or a MAP3K8 inhibitor. In some embodiments, the MAPK inhibitor is one or more of Tilpisertib (GS-4875) and neflamapidmod (VX-745). In some embodiments, reference to the term MAPK inhibitor includes any such MAPK inhibitor disclosed in any one of the following patent applications: WO 2016029263, CN 114767674, CN 115850179, and CN 1743006, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0315] In some embodiments, a therapeutic agent that may be combined with a crystalline solid form of Compound A is an inhibitor of MAP2K4. A non-limiting example of a MAP2K4 inhibitor useful according to the disclosure is HRX-0233.

[0316] c) Kinase Inhibitors

[0317] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more kinase inhibitors. Tyrosine kinases and serine / threonine kinases play a crucial role in various cellular processes such as cell signaling, growth, and differentiation. Kinase inhibitors known in the art have been developed as a treatment for various types of cancer in addition to therapies for conditions such as neurodegenerative diseases, autoimmune disorders, and inflammation.

[0318] i) PKA inhibitors

[0319] In some embodiments, compositions and methods described herein may include one or more Protein Kinase A (PKA) inhibitors. A PKA inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a PKA inhibitor is H89. In some embodiments, reference to the term PKA inhibitor includes any such PKA inhibitor disclosed in any one of the following patent applications: CN 106620678 and CN 114632155, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0320] ii) FAK inhibitors

[0321] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Focal Adhesion Kinase (FAK) inhibitors. A FAK inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a FAK inhibitor is one or more of BI853520, defactinib, GSK2256098, PF-00562271, and VS-4718. In some embodiments, reference to the term FAK inhibitor includes any such FAK inhibitor disclosed in any one of the following patent applications: WO 2022152315, WO 2021098679, WO 2020135442, WO 2020191448, WO 2012022408, WO 2013134353, WO 2012110774, WO 2010062578, CN 111072571, and KR 101691536, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT

[0322] ATTORNEY DOCKET NO. 51432-053WO2

[0323] iii) ROCK inhibitors

[0324] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Rho-associated, coiled-coil containing protein kinase (ROCK) inhibitors. A ROCK inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a ROCK inhibitor is GSK269962A. In some embodiments, reference to the term ROCK inhibitor includes any such ROCK inhibitor disclosed in any one of the following patent applications: WO 2023051753, WO 2022237892, WO 2022012409, WO 2021093795, WO 2021214200, WO 2020177292, WO 202011751, WO 2019014304, WO 2019179525, WO 2019089868, WO 2019014300, WO 2018108156, WO 2018009627, WO 2018009625, WO 2018009622, WO 2017123860, WO 2017205709, WO 2016112236, WO 2014068035, WO 2013030367, WO 2012146724, WO 2012067965, WO 2011107608, CN 108129453, CN 108191821, CN 110917352, CN 108558823, CN108047193, CN107973777, CN108047197, CN108129448, CN 115869304, and GB202214708, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0325] iv) MSK1 inhibitors

[0326] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Mitogen- and stress-activated kinase (MSK1) inhibitors. A MSK1 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a MSK1 inhibitor is one or more of SB-747651 A, SB 747651 A, Ro 320432, CGP 57380, GSK2830371, SR1664, LY-3214996, PFI-4, MSC-2363318A, and AS601245.

[0327] v) RSK inhibitors

[0328] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more ribosomal S6 kinase (RSK) inhibitors. A RSK1 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a RSK inhibitor is one or more of BI-D1870, LJH685, SL0101-1, FMK, BRD7389, BIX 02565, LJI308, LJI308-S, LJI308-1, and LJH685-S. In some embodiments, a RSK inhibitor is PMD-026. In some embodiments, reference to the term RSK inhibitor includes any such RSK inhibitor disclosed in any one of the following patent applications: WO 2021249558, WO 2020165646, WO 2017141116, and CN 113801139, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0329] vi) ALK inhibitors

[0330] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Anaplastic Lymphoma Kinase (ALK) inhibitors. An ALK inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, an ALK inhibitor is one or more of Crizotinib (Xalkori), Ceritinib (Zykadia), Alectinib (Alecensa), Brigatinib (Alunbrig), Lorlatinib (Lorbrena), Ensartinib (X-396), TAE684, ASP3026, TPX-0131, LDK378 (Ceritinib analog), CEP-37440; 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113.

[0331] Additional examples of ALK kinase inhibitors are described in examples 3-39 of W005016894. In some PATENT

[0332] ATTORNEY DOCKET NO. 51432-053WO2

[0333] embodiments, reference to the term ALK inhibitor includes any such ALK inhibitor disclosed in any one of the following patent applications: WO 2019142095, WO 2019179482, WO 2018130928, WO 2018127184, WO 2017101803, WO 2016192132, WO 2014100431, WO 2012082972, CN 111138492, CN 110526914, CN 109836415, CN 105801603, CN107987056, and CN 105878248, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0334] d) Receptor tyrosine kinase inhibitors

[0335] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more receptor tyrosine kinase inhibitors. A receptor tyrosine kinase (RTK) inhibitor is a type of molecule (e.g., small molecule, antibody, and nucleic acid) that binds to and blocks the activity of receptor tyrosine kinases or their ligands. RTKs are proteins found on the surface of cells that play a critical role in cell signaling and growth and have been developed as therapeutics for a range of diseases, including cancer, diabetes, and autoimmune disorders. In some embodiments, a therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0336] i) EGFR inhibitors

[0337] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more EGFR inhibitors. An EGFR inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotide or siRNA. Useful antibody inhibitors of EGFR include cetuximab (ERBITUX®), panitumumab (VECTIBIX®), zalutumumab, nimotuzumab, and matuzumab. Further antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Nonlimiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res.

[0338] 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8): 1935-40; and Yang et al., Cancer Res.1999, 59:1236-1243. The EGFR inhibitor can be monoclonal antibody Mab E7.6.3 (Yang, 1999 supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0339] Small molecule antagonists of EGFR include gefitinib (IRESSA®), Lazertinib, erlotinib (TARCEVA®), and lapatinib (TYKERB®). See, e.g., Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (TAGRISSO®). In some embodiments, an EGFR inhibitor is one or more of cetuximab, gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif). Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. An EGFR inhibitor may be ERAS-801. In some embodiments, an EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4). In some embodiments, the EGFR inhibitor may be bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, ruxolitinib, sunitinib, vemurafenib, abrocitinib, asciminib, futibatinib, ibrutinib, imatinib, pacritinib, or sorafenib. In some embodiments, reference to the PATENT

[0340] ATTORNEY DOCKET NO. 51432-053WO2

[0341] term EGFR inhibitor includes any such EGFR inhibitor disclosed in any one of the following patent applications: WO 2023041071, WO 2023049312, WO 2023020600, WO 2023284747, WO 2022206797, WO 2022258977, WO 2022033416, WO 2022033410, WO 2022105908, WO 2022100641, WO 2022014639, WO 2022007841, WO 2021018009, WO 2021057882, WO 2021252661, WO 2021018003, WO 2021073498, WO 2021238827, WO 2020254547, WO 2020216371, WO 2020147838, WO 2020207483, WO 2020254572, WO 2020001350, WO 2021001351, WO 2019164948, WO 2019218958, WO 2019046775, WO 2019015655, WO 2018121758, WO 2018218963, WO 2017220007, WO 2017205459, WO 2017161937, WO 2016192609, WO 199633980, WO 199630347, WO 199730034, WO 199730044, WO 199738994, WO 199749688, WO 199802434, WO 199738983, WO 199519774, WO 199519970, WO 199713771, WO 199802437, WO 199802438, WO 199732881, WO 199833798, WO 199732880, WO 199732880, WO 199702266, WO 199727199, WO 199807726, WO 1997 / 34895, WO 199631510, WO 199814449, WO 199814450, WO 199814451, WO 199509847, WO 199719065, WO 199817662, WO 199935146, WO 199935132, WO 199907701, WO 199220642, DE 19629652, EP 682027, EP 837063, EP 0787772, EP 0520722, EP 0566226, CN 115960018, CN 110283162, CN 114044774, CN111973601, CN 111973602, and CN113896744, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0342] ii) HER2 inhibitors

[0343] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more HER2 inhibitors. A HER2 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, an HER2 inhibitor is one or more of tucatinib, rastuzumab (Herceptin™), pertuzumab (Perjeta™), lapatinib (Tykerb™), ado-trastuzumab emtansine (Kadcyla™), and neratinib (Nerlynx™). Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (HERCEPTIN®) and pertuzumab (PERJETA®); small molecule tyrosine kinase inhibitors such as gefitinib (IRESSA®), erlotinib (TARCEVA®), pilitinib, CP-654577, CP-724714, canertinib (Cl 1033), HKI-272, lapatinib (GW-572016; TYKERB®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW2992, ARRY-334543, and JNJ-26483327. In some embodiments, reference to the term HER2 inhibitor includes any such HER2 inhibitor disclosed in any one of the following patent applications: WO 2021156178, WO 2021156180, WO 2021213800, WO 2021088987, WO 2013561183, and WO 2013056108, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0344] iii) MET inhibitors

[0345] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more MET inhibitors. A MET inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a MET inhibitor is one or more of Crizotinib (Xalkori™), Cabozantinib (Cometriq, Cabometyx™), Capmatinib (Tabrecta™), Tepotinib (Tepmetko™), Savolitinib (Volitinib™), Onartuzumab (MetMab™), Foretinib (GSK1363089), MGCD-265 (Amuvatinib), SU11274, and SU5416. In some embodiments, reference to the term MET inhibitor includes any such MET inhibitor disclosed in any one of the following patent applications: WO PATENT

[0346] ATTORNEY DOCKET NO. 51432-053WO2

[0347] 2022226168, WO 2021222045, WO 2020047184, WO 2020015744, WO 2020244654, WO 2020156453, WO 2019206268, WO 2018077227, WO 2017012539, WO 2016015653, WO 2016012963, WO 2012015677, WO 2011162835, WO 2010089507, WO 2009091374, WO 2009056692, WO 2008051547, WO 2007130468, US 2012237524, CN 103497177, CN 107311983, CN 107382968, CN 110218191, and TW201331206, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0348] iv) AXL inhibitors

[0349] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more AXL inhibitors. An AXL inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. AXL is a receptor tyrosine kinase that belongs to the TAM family of receptors, which also includes TYRO3 and MERTK. In some embodiments, an AXL inhibitor is one or more of bemcentib, BGB324, R428, SGI-7079, TP-0903, BMS-777607, UNC2025, and TP-0903. In some embodiments, reference to the term AXL inhibitor includes any such AXL inhibitor disclosed in any one of the following patent applications: WO 2023045816, WO 2022237843, WO 2022246179, WO 2021012717, WO 2021088787, WO 2021067772, WO 2021239133, WO 2021204713, WO 2020238802, WO 2019039525, WO 2019101178, WO 2019074116, WO 2017146236, WO 2016097918, WO 2015012298, WO 2010005876, WO 2010083465, CN 115073367, and JP 2022171109, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0350] v) IGFR inhibitors

[0351] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more insulin-like growth factor receptor 1 (IGF-1R) inhibitors. An IGFR inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. IGFR inhibitors have been developed to target the IGFR receptor, which plays a critical role in cancer progression and metastasis. In some embodiments, an IGFR inhibitor is one or more of linsitinib, AXL1717, OSI-906 (Linsitinib), BMS-754807, Bl 836845, AZ12253801, PQIP (Pyrrolo[1,2-a]quinoxaline), and NVP-AEW541. In some embodiments, reference to the term IGFR inhibitor includes any such IGFR inhibitor disclosed in any one of the following patent applications: WO 2022115946, WO 2022217923, WO 2021203861, WO 2021246413, WO 2020116398, WO 2019046600, WO 2018195250, WO 2018221521, WO 2018204872, WO 2017072196, WO 2016173682, WO 2015162291, WO 2015162292, WO 2010066868, WO 2006069202, and CN 112125916, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0352] vi) RET inhibitors

[0353] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Rearranged during transfection (RET) inhibitors. An RET inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. RET plays a critical role in various cellular processes, including cell growth, differentiation, survival, and migration. RET is activated by binding of its ligands, such as glial cell line-derived neurotrophic factor (GDNF) family ligands, which PATENT

[0354] ATTORNEY DOCKET NO. 51432-053WO2

[0355] leads to the activation of downstream signaling pathways that promote these cellular processes. In some embodiments, a RET inhibitor is one or more of pralsetinib, selpercatinib (LOXO-292), BLU-667, RXDX-105, TPX-0046, GSK3179106, molidustat (BAY 85-3934), and RPI-1 (Retrophin). In some embodiments, reference to the term RET inhibitor includes any such RET inhibitor disclosed in any one of the following patent applications: WO 2021211380, WO 2021057963, WO 2021043209, WO 2021222017, WO 2020035065, WO 2020114487, WO 2020200314, WO 2020200316, WO 2020114494, WO 2018071447, WO 2018213329, WO 2017079140, WO 2014050781, CN 113943285, CN 113683610, CN 113683611, CN 113620944, CN 113620945, CN 113527291, CN 113527292, CN 113527290, CN 113135896, CN 111057075, CN111233899, and CN111362923, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0356] vii) ROS1 inhibitors

[0357] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more c-ros oncogene 1 (ROS1) inhibitors. A ROS1 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. ROS1 is a receptor tyrosine kinase that belongs to the insulin receptor family and plays a role in various cellular processes, including cell growth, differentiation, survival, and migration. In some embodiments, a ROS1 inhibitor is one or more of taletrectinib, DS-6051b, TPX-0131, GZD824, and PF-06463922. In some embodiments, reference to the term ROS1 inhibitor includes any such ROS1 inhibitor disclosed in any one of the following patent applications: WO 2021098703, WO 2020024825, and US 2017079972, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0358] viii) PDGFR inhibitors

[0359] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more platelet-derived growth factor receptor (PDGFR) inhibitors. A PDGFR inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. PDGFR is a family of receptor tyrosine kinases that consists of two members, PDGFRa and PDGFRp. They are activated by binding to their ligands, such as platelet-derived growth factor (PDGF), which leads to the activation of downstream signaling pathways that promote cell growth, proliferation, and survival. In some embodiments, a PDGFR inhibitor is one or more of CP-673451, imatinib, nintedanib (Ofev™), sunitinib (Sutent™), pazopanib (Votrient™), regorafenib (Stivarga™), and dasatinib (Sprycel™).

[0360] ix) FGF inhibitors

[0361] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with fibroblast growth factor (FGF) inhibitors. An FGF inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. FGFRs are a family of receptor tyrosine kinases that consists of four members, FGFR1-4. FGFRs are activated by binding to their ligands, fibroblast growth factors (FGFs), which leads to the activation of downstream signaling pathways that promote cell growth, differentiation, and survival. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR2. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR4. In some embodiments, an FGFR inhibitor is PATENT

[0362] ATTORNEY DOCKET NO. 51432-053WO2

[0363] one or more of futibatinib (TAK-659), erdafitinib (Balversa™), infigratinib (Truseltiq™), Debio 1347, and rogaratinib (BAY 1163877). In some embodiments, reference to the term FGFR inhibitor includes any such FGFR inhibitor disclosed in any one of the following patent applications: WO 2022033472, WO 2022152274, WO 2022166469, WO 2022206939, WO 2021037219, WO 2021089005, WO 2021113462, WO 2020185532, WO 2019213544, WO 2020164603, WO 2019154364, WO 2019034076, WO 2019213506, WO 2019223766, WO 2018028438, WO 2018153373, WO 2018121650, WO 2018010514, WO 2017028816, WO 2017118438, WO 2016134320, WO 2015008844, WO 2014172644, WO 2014007951, WO 2013179033, WO 2013087578, WO 2012047699, CN 105906630, CN 115869315, CN 115141176, CN 115043832, and CN 115028634, each of which is incorporated herein by reference in its entirety. In some embodiments, the FGF pathway inhibitor targets an FGF ligand. Such FGF pathway inhibitors include FGF ligand traps and antibodies. Non-limiting examples include FP-1039, an FGF ligand trap consisting of the extracellular domain of FGFR1 fused to the Fc portion of human IgG1, designed to sequester FGF ligands and inhibit FGF signaling, and MFGR1877S, a monoclonal antibody targeting FGF ligands, designed to block FGF-mediated signaling, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0364] x) VEGF inhibitors

[0365] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more vascular endothelial growth factor (VEGF) signaling inhibitors. VEGF (vascular endothelial growth factor) signaling inhibitors are a class of drugs that target the signaling pathway mediated by VEGF and its receptors. VEGF plays a critical role in angiogenesis, the process of forming new blood vessels from existing ones, and it is overexpressed in many types of cancer, making it an attractive target for cancer therapy. A VEGF inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, the VEGF inhibitor is an antibody or antigen binding regions that specifically bind VEGF (e.g., bevacizumab), or soluble VEGF receptors or a ligand binding region thereof) such as VEGF-TRAP™, and anti- VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind thereto). In some embodiments, the VEGF inhibitor is one or more of bevacizumab, aflibercept, ramucirumab, sorafenib, sunitinib, and pazopanib.

[0366] e) PI3K / mTOR pathway inhibitors

[0367] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more inhibitors of the PI3K-AKT-TOR signaling pathway. The PI3K-AKT-mTOR signaling pathway is a critical intracellular pathway that regulates a wide range of cellular processes including cell growth, proliferation, metabolism, and survival. The pathway is initiated when growth factors, such as insulin or IGF-1, bind to cell surface receptors and activate phosphoinositide 3-kinase (PI3K). Activated PI3K then phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to produce phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates AKT. Activated AKT then phosphorylates a variety of downstream targets including the tuberous sclerosis complex (TSC1 / TSC2), leading to the activation of mTOR (mammalian target of rapamycin) complex 1 (mTORCI). Activated mTORCI promotes protein synthesis and cell growth by phosphorylating key regulators of translation initiation such as S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). PATENT

[0368] ATTORNEY DOCKET NO. 51432-053WO2

[0369] i) PI3K inhibitors

[0370] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more PI3K inhibitors. A PI3K inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. A PI3K inhibitor useful in a combination of the disclosure may be a PI3Ka: RAS breaker, such as BBO-10203. PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs described in WO 2006044453; 4-[2-(1H-lndazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO 2009036082 and WO 2009055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO 2006122806); (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO 2008070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl] phenol hydrochloride (available from Axon Medchem); PIK75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1 -methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem); AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2, 4-dione (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrirnidin-4-one (available from Axon Medchem); XL-765; and XL-147. Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136. In some embodiments, the PI3K inhibitor is alpelisib or copanlisib. In some embodiments, reference to the term PI3K inhibitor includes any such PI3K inhibitor disclosed in any one of the following patent applications WO 2025072451 A1, WO 2025061125 A1, WO 2025051235 A1, WO 2025045106 A1, WO 2025040167 A1, WO 2025036439 A1, WO 2025038698 A1, WO 2025038395 A1, WO 2025034858 A1, WO 2025034849 A1, WO 2025029683 A1, WO 2025016314 A1, WO 2025003330 A1, WO 2025007074 A1, WO 2025002179 A1, WO 2024260464 A1, WO 2024229121 A1, WO 2024222894 A1, WO 2024215799 A1, WO 2024192309 A1, WO 2024183806 A1, WO 2024182404 A1, WO 2024182447 A1, each of which is incorporated herein by reference in its entirety.

[0371] ii) AKT inhibitors

[0372] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more AKT inhibitors. An AKT inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. AKT inhibitors include, but are not limited to, ipatasertib, GSK-2141795, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); Akt-1-1,2 (inhibits Akl and 2) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05 / 011700); indole-3-carbinol and derivatives thereof (e.g., U. S. Pat. No. 6,656,963; Sarkarand Li J Nutr. 2004, 134(12 Suppl):3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res. 2004, 10(15):5242-52); phosphatidylinositol ether lipid analogues (e.g., Gills and PATENT

[0373] ATTORNEY DOCKET NO. 51432-053WO2

[0374] Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9). The PI3K / AKT inhibitor may include, but is not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758-1784. For example, the PI3K / AKT inhibitor may be selected from one or more of NVP-BEZ235; BGT226;

[0375] XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; and GSK2126458.

[0376] iii) mTOR inhibitors

[0377] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more mTOR inhibitors. A mTOR inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, e.g., PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and derivatives thereof, including temsirolimus (TORISEL®); everolimus (AFINITOR®; WO 199409010); ridaforolimus (also known as deforolimus or AP23573); rapalogs, e.g., as disclosed in WO 199802441 and WO 200114387, e.g.

[0378] AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolyt)-rapamycin (also called ABT578); 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanycin; derivatives disclosed in WO 2005005434; derivatives disclosed in U. S. Patent Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and in WO 1994090101, WO 199205179, WO 1993111130, WO 199402136, WO 199402485, WO 199514023, WO 199402136, WO 199516691, WO 199641807, WO 199641807, and WO 2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO 2005016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, e.g., WO 2018204416, WO 2019212990 and WO 2019212991), such as RMC-5552.

[0379] iv) MNK inhibitors

[0380] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more mitogen-activated protein kinase-interacting kinase (MNK) inhibitors. A MNK inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. MNK proteins are activated downstream of the mitogen-activated protein kinase (MAPK) signaling pathway, which plays a critical role in the regulation of cellular proliferation, differentiation, and survival. MNKs phosphorylate elF4E, a key component of the eukaryotic translation initiation complex, which enhances the translation of specific mRNAs, including those encoding proteins involved in cell cycle regulation and oncogenesis. In some embodiments, a MNK inhibitor is one or more tomivosertib (eFT508), CGP57380, and SEL201. In some embodiments, reference to the term MNK inhibitor includes any such MNK inhibitor disclosed in any one of the following patent applications: WO 2021098691, WO 2020108619, WO 2020086713, WO 2018152117, WO 2018228275, WO 2015200481, and CN115583942, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0381] v) elF4 inhibitors

[0382] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more eukaryotic initiation factor 4A (elF4A) inhibitors. An elF4A inhibitor may be administered or formulated in combination with a crystalline solid PATENT

[0383] ATTORNEY DOCKET NO. 51432-053WO2

[0384] form of Compound A and / or any additional therapeutic agent described herein. elF4A is a critical component of the eukaryotic translation initiation complex, where it functions as an RNA helicase to unwind the secondary structure of mRNA and facilitate ribosome binding. elF4A is required for the translation of many cancer-associated genes, making it an attractive therapeutic target for cancer treatment. In some embodiments, an elF4A inhibitor is one or more zotatifin (eFT226), silvestrol, pateamine A, and rocaglates. In some embodiments, reference to the term elF4A inhibitor includes any such elF4A inhibitor disclosed in any one of the following patent applications: WO 2023034813, WO 2021195128, and WO 2017091585, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0385] In some embodiments, compositions and methods described herein may include one or more eukaryotic initiation factor 4G (elF4G) inhibitors. An elF4G inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. elF4G family includes several proteins that are involved in the initiation of protein translation. elF4G serves as a scaffold for other proteins, including elF4E and elF4A, to form the elF4F complex, which is responsible for binding to the 5’ cap of mRNA and unwinding the secondary structure of the mRNA to allow ribosomal scanning and translation initiation. In some embodiments, an elF4G inhibitor is one or more pateamine A, and hippuristanol.

[0386] f) DNA Damage Response Inhibitors

[0387] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more DNA damage response (DDR) inhibitors. The DDR pathway is a critical cellular pathway that is activated in response to DNA damage and is essential for maintaining genomic stability, thereby preventing the development of cancer. However, cancer cells often have defects in the DDR pathway, which makes them more sensitive to DDR inhibitors. DDR inhibitors have shown promise in preclinical studies as potential cancer therapeutics, particularly in combination with other agents. i) Wee1 inhibitors

[0388] In some embodiments, compositions and methods described herein may include one or more Wee1 inhibitors. A Wee1 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. Wee1 is a kinase that plays a critical role in regulating the cell cycle by inhibiting the activity of cyclin-dependent kinases (CDKs) and preventing the progression of cells through the G2 / M checkpoint. Wee1 is overexpressed in several cancer types and has been implicated in tumor growth and survival. In some embodiments, a Wee1 inhibitor is one or more of imp7068, adavosertib, or ZNL-02-096. In some embodiments, reference to the term Wee1 inhibitor includes any such Wee1 inhibitor disclosed in any one of the following patent applications: WO 2022011391, WO 2022247641, WO 2021043152, WO 2020221358, WO 2020083404, WO 2020192581, WO 2019085933, WO 2018133829, WO 2015115355, WO 2015183776, WO 2014085216, and CN 114831993, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0389] ii) CHK inhibitors

[0390] In some embodiments, compositions methods described herein may include one or more checkpoint kinase (CHK) inhibitors. A CHK inhibitor may be administered or formulated in combination PATENT

[0391] ATTORNEY DOCKET NO. 51432-053WO2

[0392] with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. CHK1 kinase is a critical regulator of the cell cycle and the DNA damage response pathway. In some embodiments, the CHK inhibitor is a CHK1 inhibitor. In some embodiments, a CHK inhibitor is a CHK2 inhibitor. In some embodiments, a CHK1 inhibitor is one or more BBI-355, rabusertib, LY2606368, LY2880070, GDC-0575, MK-8776, BEBT-260, and PEP07. In some embodiments, reference to the term CHK1 inhibitor includes any such CHK1 inhibitor disclosed in any one of the following patent applications: WO 2024196923, WO 2024211271, WO 2024211270, WO 2024118564, WO 2023230477, WO 2022251502, WO 2021113661, WO 2021104461, WO 2019012030, WO 2010118390, WO 2008067027, WO 2002070494, CN119661557, and TW202126818, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0393] iii) ATM inhibitors

[0394] In some embodiments, compositions and methods described herein may include one or more ataxia telangiectasia mutated (ATM) inhibitors. An ATM inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. ATM plays a role in regulating the replication stress response and maintaining genomic stability. In some embodiments, an ATM inhibitor is one or more lartesertib, AZD1390, AZD0156, KU-60019, M4076, M3541, WSD-0628, ZN-B-2262, SYH2051, and VE-821. In some embodiments, reference to the term ATM inhibitor includes any such ATM inhibitor disclosed in any one of the following patent applications: WO 2024189299, WO 2022058351, WO 2021197339, WO 2021098734, WO 2021260580, WO 2020193660, WO 2020063855, WO 2016155884, WO 2007026157, WO 2006085067, US 2016113935, CN 116440082, CN 117180432 and CN 115105596 each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0395] iv) ATR inhibitors

[0396] In some embodiments, compositions and methods described herein may include one or more ataxia telangiectasia and Rad3-related (ATR) inhibitors. An ATR inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, an ATR inhibitor is one or more berzosertib, gartisertib, camonsertib, ceralaertib, VE-821, RP-3500, AZ20, VX-970, abd110, VX-803, and elimusertib (BAY 1895344). In some embodiments, reference to the term ATR inhibitor includes any such ATR inhibitor disclosed in any one of the following patent applications: WO 2025019344, WO 2025019346, WO 2023138343, WO 2023126823, WO 2023109883, WO 2023016529, WO 2022237875, WO 2022268025, WO 2021012049, WO 2021023272, WO 2021260579, WO 2021228758, WO 2019050889, WO 2019154365, WO 2019036641, WO 2019133711, WO 2017059357, WO 2013049859, WO 2007046426, WO 2007015632, and CN113797341, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0397] v) PARP inhibitors

[0398] In some embodiments, compositions and methods described herein may include one or more Poly(ADP-ribose) polymerase (PARP) inhibitors. A PARP inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent PATENT

[0399] ATTORNEY DOCKET NO. 51432-053WO2

[0400] described herein. There are 17 PARP (aka tankyrase) family members that have been identified. PARP enzymes play a critical role in DNA damage repair, particularly in the repair of single-strand DNA breaks. PARP inhibitors block the activity of PARP enzymes, leading to the accumulation of DNA damage and ultimately cell death. In some embodiments, a PARP inhibitor is one or more olaparib, rucaparib, niraparib, and veliparib (ABT-888). In some embodiments, reference to the term PARP inhibitor includes any such PARP inhibitor disclosed in any one of the following patent applications: WO 2025024581, WO 2025037273, WO 2025061057, WO 2024256377, WO 2024255782, WO 2023051812, WO 2023051807, WO 2023051716, WO 2023278592, WO 2022228387, WO 2022022664, WO 2022000946, WO 2022222921, WO 2021163530, WO 2020122034, WO 2020239097, WO 2020142583, WO 2020156577, WO 2020098774, WO 2020196712, WO 2019200382, WO 2018125961, WO 2018205938, WO 2018192576, WO 2018218025, WO 2017032289, WO 2017177838, WO 2017029601, WO 2017088723, WO 2016155655, WO 2015154630, WO 2013097225, WO 2012130166, WO 2011006794, WO 2009046205, WO 2009063244, WO 2008084261, WO 2007138351, WO 2006110816, WO 2005053662, WO 2005012524, CN113698356, CN 113603647, CN 115073544, CN 108938634, CN 104887680, CN 110343088, CN108976236, CN 117069731, CN 119185316, CN 119112794, and CN 107629071, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0401] vi) DNA-PK inhibitors

[0402] In some embodiments, compositions and methods described herein may include one or more DNA-dependent protein kinase (DNA-PK) inhibitors. A DNA-PK inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. DNA-PK is a serine / threonine protein kinase that plays a crucial role in DNA repair and maintenance of genome stability. In some embodiments, a DNA-PK inhibitor is one or more NU7441, AZD7648, VX-984, peposertib (M3814), and CC-115. In some embodiments, reference to the term DNA-PK inhibitor includes any such DNA-PK inhibitor disclosed in any one of the following patent applications: WO 2025023957, WO 2023220418, WO 2023215991, WO 2023165603, WO 2022187965, WO 2021197159, WO 2021260583, WO 2021204111, WO 2021104277, WO 2021098813, WO 2021022078, WO 2020259613, WO 2019143678, WO 2019143675, WO 2019201283, WO 2015058031, WO 2014159690, WO 2012028233, WO 2009010761, WO 2006032869, WO 2006109084, CN 112574179, CN 112300132, CN 115322209, and CN 112300126, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0403] g) Cell Cycle Inhibitors

[0404] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more cell cycle inhibitors. Cell cycle inhibitors target specific proteins involved in regulating the cell cycle, which is the process by which a cell divides and replicates its DNA. Nonlimiting examples cell cycle proteins include cyclin-dependent kinase (CDK), aurora kinase, and polo-like kinase (PLK). CDKs are a family of kinases that are involved in regulating the cell cycle. CDK inhibitors block the activity of these kinases, leading to cell cycle arrest and / or apoptosis. Aurora kinases are a family of serine / threonine kinases that play a critical role in regulating mitosis. Aurora kinase inhibitors block the activity of these kinases, leading to mitotic arrest and cell death. PLKs are a family of PATENT

[0405] ATTORNEY DOCKET NO. 51432-053WO2

[0406] serine / threonine kinases that are involved in regulating multiple stages of the cell cycle. PLK inhibitors block the activity of these kinases, leading to cell cycle arrest and / or apoptosis.

[0407] i) CDK inhibitors

[0408] In certain embodiments, a cell cycle inhibitor is a cyclin-dependent kinase (CDK) inhibitor. Cyclin-dependent kinases are a family of protein kinases that regulate cell division and proliferation. Cell cycle progression is controlled by cyclins and their associated cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4 and CDK6, while other CDKs such as CDK7, CDK8 and CDK9 are critical to transcription. CDK binding to cyclins forms heterodimeric complexes that phosphorylate their substrates on serine and threonine residues, which in turn initiates events required for cell-cycle transcription and progression. In some embodiments, a CDK inhibitor is a CDK2 inhibitor. In some embodiments, a CDK inhibitor is a CDK4 / 6 inhibitor. In some embodiments, a CDK inhibitor is a CDK7 inhibitor. In some embodiments, a CDK inhibitor is a CDK9 inhibitor. In some embodiments, a CDK inhibitor is one or more palbociclib, ribociclib, abemaciclib, and trilaciclib. In some embodiments, a CDK inhibitor is one or more of tagtociclib (PF-07104091), seliciclib, voruciclib (P1446A-05), BLU-222, dinaciclib, AT-7519, RGB286638, and AZD4573.

[0409] In some embodiments, reference to the term CDK inhibitor includes any such CDK inhibitor disclosed in any one of the following patent applications: WO 2025040170, WO 2025060620, WO 2024238574, WO 2024027825, WO 2024048541, WO 2022166793, WO 2022187611, WO 2022130304, WO 2021227906, WO 2021057867, WO 2020207260, WO 2020138370, WO 2020125513, WO 2020093011, WO 2020148635, WO 2020215156, WO 2020052627, WO 2017177837, WO 2017162215, WO 2017177836, WO 2017172826, WO 2016193939, WO 2016014904, WO 2016015598, WO 2016015605, WO 2015181737, WO 2012061156 A1, WO 2012038411, WO 2010020675, WO 2010125004, WO 2007139732, WO 2006024945, CN 114478529, CN 108794496, CN 105294737, CN107652284, KR 20180106188, and US 2017152269, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0410] ii) Aurora kinase inhibitors

[0411] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more aurora kinase inhibitors. An aurora kinase inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. Aurora kinases are a family of serine / threonine kinases that play a critical role in regulating cell division and maintaining genomic stability. The Aurora kinase family consists of three members: Aurora A, Aurora B, and Aurora C. In some embodiments, an aurora kinase inhibitor is one or more palbociclib, ribociclib, and abemaciclib. In some embodiments, an aurora kinase inhibitor is one or more of alisertib, danusertib, barasertib, and MLN8237. In some embodiments, reference to the term aurora kinase inhibitor includes any such aurora kinase inhibitor disclosed in any one of the following patent applications: WO 2021110009, WO 2021008338, WO 2020112514, WO 2019129234, WO 2016077161, WO 2013143466, WO 2011103089, WO 2010081881, WO 2010133794, WO 2009134658, WO 2008001886, WO 2007095124, WO 2007003596, WO 2006129064, CN 114276227, CN 108078991, CN 106543155, CN 104211692, and CN 104098551, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT

[0412] ATTORNEY DOCKET NO. 51432-053WO2

[0413] iii) PLK inhibitors

[0414] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more polo-like kinase (PLK) inhibitors. A PLK inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. PLKs are a family of serine / threonine kinases that play a crucial role in regulating cell division, DNA damage response, mitotic progression, and consists of four members: PLK1, PLK2, PLK3, and PLK4. In some embodiments, a PLK inhibitor is one or more of volasertib, onvansertib, Bl 2536, and GSK461364. In some embodiments, reference to the term PLK inhibitor includes any such PLK inhibitor disclosed in any one of the following patent applications: WO 2011012534 A1, WO 2010065134, WO 2009130453, WO 2009042806, WO 2004043936, WO 2007030361, WO 2006021547, CN 115804777, and EP 2325185, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0415] iv) Kinesin superfamily of microtubule motor protein inhibitors

[0416] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Kinesin spindle protein (KSP) inhibitors. In some embodiments, compositions described herein may include one or more Kinesin family (KIF) inhibitors. In some embodiments, a KSP inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. KSP and KIF are a subset of the kinesin superfamily of microtubule motor proteins. KSP, also known as Eg5, is a member of the kinesin superfamily of motor proteins that plays a critical role in mitotic spindle formation and cell division. KSP inhibitors selectively target rapidly dividing cancer cells by disrupting spindle formation and inducing mitotic arrest. In some embodiments, a KSP inhibitor is one or more of SB743921, monastrol, S-Trityl-L-cysteine (STLC), and filanesib (ARRY-520). In some embodiments, a KIF inhibitor is an inhibitor of a Kinesin-8 family microtubule motor protein. In some embodiments, the kinesin-8 family protein is KIF18A. In some embodiments, a KIF inhibitor is one or more of AMG650, BTB-1, K03861, and SJ000291942. In some embodiments, reference to the term kinesin superfamily of microtubule motor protein inhibitor includes any such kinesin superfamily of microtubule motor protein inhibitor disclosed in any one of the following patent applications: WO 2015114854, WO 2015114855, WO 2010084186, WO 2006101761, WO 2006110390, WO 2006044825, WO 2006078574, WO 2005060654, WO 2004092147, WO 2004037171, WO 2004058700, WO 2003050064, WO 2003105855, WO 2022037665, WO 2018114804, WO 2017162663, WO 2016207089, WO 2012073375, JP 2014162787, JP 2019189590, JP2013166713, and KR 20220145566, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0417] v) DYRK1 inhibitors

[0418] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Dual-specificity tyrosine phosphorylation-regulated kinase 1 (DYRK1) inhibitors. A DYRK1 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. DYRK1 is a member of the DYRK (dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases. It plays essential roles in various cellular processes, including cell cycle PATENT

[0419] ATTORNEY DOCKET NO. 51432-053WO2

[0420] regulation, neuronal development, and transcriptional control. In some embodiments, a DYRK1 inhibitor is one or more of harmine, INDY, D4476, and AZ191. In some embodiments, reference to the term DYRK1 inhibitor includes any such DYRK1 inhibitor disclosed in any one of the following patent applications: WO 2023277331 A1, WO 2023140846 A1, WO 2017181087 A1, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0421] h) Anti-Apoptotic Protein Inhibitors

[0422] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more anti-apoptotic protein inhibitors. In some embodiments, an anti-apoptotic protein inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. Anti-apoptotic inhibitors target proteins that play a role in preventing apoptosis, a form of programmed cell death. Apoptosis is a critical mechanism for eliminating damaged or unwanted cells. Anti-apoptotic proteins are a family of proteins that inhibit the apoptotic pathway, thereby preventing cell death. There are several known classes of anti-apoptotic inhibitors, including Bcl-2 inhibitors, XIAP inhibitors, survivin inhibitors, Mcl-1 inhibitors, and FLIP inhibitors. These inhibitors work by binding to specific anti-apoptotic proteins and preventing their activity, thereby promoting cell death in cancer cells. In some embodiments, compositions described herein may include one or more anti-apoptotic protein inhibitors. An anti-apoptotic protein inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, the anti-apoptotic protein inhibitor includes a MCL-1 inhibitor. Non-limiting examples of MCL-1 inhibitors include, AMG-176, MIK665, and S63845. The myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT-263. In some embodiments, the anti-apoptotic protein inhibitor includes a BCL protein inhibitor. Examples of BCL protein inhibitors include but are not limited to Venetoclax (Venclexta), Navitoclax (ABT-263), A-1331852, S63845, and AT-101.

[0423] I) Autophagy Inhibitors

[0424] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more autophagy inhibitors. In some embodiments, an autophagy inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. Autophagy inhibitors include, but are not limited to chloroquine, 3- methyladenine, hydroxychloroquine (Plaquenil™), spautin-1, SAR405, bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, autophagy-suppressive algal toxins which inhibit protein phosphatases of type 2A or type 1, analogues of cAMP, and drugs which elevate cAMP levels such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense or siRNA that inhibits expression of proteins including but not limited to ATG5 (which are implicated in autophagy), may also be used. In some embodiments, the one or more additional therapies include an autophagy inhibitor.

[0425] i) ULK inhibitors

[0426] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Unc-51-like kinase (ULK) inhibitors. An ULK PATENT

[0427] ATTORNEY DOCKET NO. 51432-053WO2

[0428] inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a ULK inhibitor is a ULK1 / 2 inhibitor. In some embodiments, an ULK inhibitor is one or more of ULK-101, MRT68921, SBI-0206965, MRT67307, MRT68920, MRT68922, MRT199665, LY3009120, and Dorsomorphin.

[0429] ii) VPS inhibitors

[0430] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Vacuolar protein sorting protein (VPS) inhibitors. A VPS inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. VPS (proteins are a family of proteins that play a critical role in the process of autophagy by regulating the formation and function of autophagosomes, structures that engulf and transport cellular components to lysosomes for degradation. Dysregulation of VPS proteins has been implicated in various diseases, including cancer, neurodegenerative disorders, and infectious diseases. In some embodiments, a VPS inhibitor is a VPS34 inhibitor. In some embodiments, a VPS inhibitor is one or more of PIK-III, VPS34-IN1, SAR405, Spautin- 1, and NSC185058.

[0431] iii) Macropinocytosis inhibitors

[0432] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more macropinocytosis inhibitors. A macropinocytosis inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. Macropinocytosis inhibitors are compounds that can block or reduce the process of macropinocytosis. In some embodiments, a macropinocytosis inhibitor is one or more of EIPA (ethylisopropylamiloride), Wortmannin, Amiloride, Apilimod, Dyngo-4a, and Latrunculin B.

[0433] j) WNT / beta-catenin Pathway Inhibitors

[0434] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more WNT / beta-catenin pathway inhibitors. In some embodiments, a WNT / beta-catenin pathway inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. The WNT / beta-catenin pathway is an important signaling pathway that plays a crucial role in development, tissue homeostasis, and disease. Dysregulation of this pathway has been implicated in various cancers, making it an attractive target for cancer therapy. WNT / beta-catenin pathway inhibitors target various components of the pathway, including WNT ligands, receptors, and downstream effectors.

[0435] i) β-catenin inhibitors

[0436] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A and one or more beta-catenin inhibitors. A beta-catenin inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. Beta-catenin is a protein that plays an important role in the WNT signaling pathway, which regulates various cellular processes including cell proliferation, differentiation, and migration. In normal cells, beta-catenin levels are tightly regulated by a destruction complex, which marks beta-catenin for degradation. However, in many cancer cells, the destruction complex is impaired, leading to the accumulation of beta-catenin in the nucleus and the activation of target genes involved in tumor growth and metastasis. In some embodiments, a WNT / beta-catenin PATENT

[0437] ATTORNEY DOCKET NO. 51432-053WO2

[0438] inhibitor is one or more of FOG-001, OMP-131 R10, Foxy-5, LGK974, RXC004, ETC-159, OMP-54F28, Niclosamide, OMP-18R5, OTSA-101, BNC101, DKN-01, Sulindac, Pyrvinium, E7449, BC2059, PRI-724, SM08502, IWP1, IWP2, IWP3, IWP4, IWP12, IWP L6, C59, GNF-6231, GNF-1331, DK-520, DK-419, lgG-2919, Fz7-21, RHPD-P1, SRI37892, 1094-0205, 2124-0331, 3235-0367, NSC36784, NSC654259, lgG-2919, Salinomycin, BMD4702, 3289-8625, J01-017a, FJ9, KY-02061, KY-02327, NSC668036, Peptide Pen-N3, SSTC3, CCT031374, TCS 183, XAV939, AZ1366, G007-LK, MSC2504877, G244-LM, IWR-1, JW74, JW55, K-756, NVP-TNKS656, MN-64, RK-287107, WIKI4, KY1220, KYA1797K, MSAB, PKF115-584, CGP049090, AV-65, PNU-74654, Windorphen, IQ-1 tegavivant, foscenvivant, PNPB-29, ZW4864, SAH-BCL9, Carnosic acid, xStAx-VHL, NRX-252114, Septuximab vedotin, PF-06647020, LGR5-mc-vc-PAB-MMAE, LGR5-NMS818, CWP232291, PRI-724 (also known as ICG-001), C-82, and BC2059. In some embodiments, reference to the term beta-catenin inhibitor includes any such beta-catenin inhibitor disclosed in any one of the following patent applications: CN 104388427 and CN 103830211, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0439] ii) PORCN inhibitors

[0440] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Porcupine (PORCN) inhibitors. A PORCN inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. PORCN is a membrane-bound O-acyltransferase enzyme that plays a critical role in the WNT signaling pathway by mediating the palmitoylation of WNT ligands. This palmitoylation is essential for the secretion and signaling activity of WNT proteins. Inhibition of PORCN leads to reduced WNT signaling activity. In some embodiments, a PORCN inhibitor is one or more of LGK974 (WNT974), ETC-1922159, CGX1321, and CWP232291. iii) GSK3 inhibitors

[0441] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Glycogen synthase kinase (GSK3) inhibitors. A GSK3 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. The GSK3 family consists of two closely related serine / threonine kinases: GSK3a and GSK3p. These kinases are involved in numerous cellular processes, including glycogen metabolism, cell cycle regulation, and Wnt signaling. GSK inhibitors have been investigated as potential therapeutics for various diseases, including cancer, diabetes, Alzheimer's disease, and bipolar disorder. In some embodiments, a GSK3 inhibitor is one or more of Tideglusib, laduviglusib, LiCI (Lithium chloride), CHIR99021, SB216763, AZD1080, and LY2090314. In some embodiments, reference to the term GSK3 inhibitor includes any such GSK3 inhibitor disclosed in any one of the following patent applications: WO 2017153834, WO 2014059383, WO 2010012398, WO 2009017455, WO 2003037891, CN 107151235, and CN 102258783, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0442] iv) CLK inhibitors

[0443] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Cdc2-like kinase (CLK) inhibitors. A CLK inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A PATENT

[0444] ATTORNEY DOCKET NO. 51432-053WO2

[0445] and / or any additional therapeutic agent described herein. CLKs (Cdc2-like kinases) are a family of serine / threonine kinases that play a crucial role in pre-mRNA splicing, specifically in the regulation of alternative splicing. There are four members of the CLK family: CLK1, CLK2, CLK3, and CLK4. The CLK family of kinases have been shown to be involved in several diseases, including cancer, neurodegenerative disorders, and viral infections. In some embodiments, a CLK inhibitor is a CLK 2 inhibitor. In some embodiments, a CLK2 inhibitor is one or more of Lorecivivint, SM08502, SM04690, TG003, KH-CB19, Cmpd-1, T3.5, and CX-4945. In some embodiments, reference to the term CLK inhibitor includes any such CLK inhibitor disclosed in WO 2020006115, which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0446] k) JAK / STAT Pathway Inhibitors

[0447] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more JAK / STAT pathway inhibitors. In some embodiments, a JAK / STAT pathway inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. The Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway is a signaling pathway involved in many cellular processes, including immune response, cell growth, and differentiation. Dysregulation of this pathway has been linked to various diseases, including inflammatory disorders, cancer, and autoimmune diseases. Inhibitors of the JAK / STAT pathway can be used for the treatment of these diseases. In some embodiments, a JAK / STAT pathway inhibitor is an inhibitor of JAK1, JAK2 and / or JAK3. In some embodiments, a JAK inhibitor is one or more of Ruxolitinib (JAKAFI®), Pacritinib, Fedratinib, Tofacitinib (XELJANZ®), Abrocitinib, Filgotinib, Oclacitinib, Peficitinib, Upadacitinib, Deucravacitinib, Delgocitinib, and Baricitinib (OLUMIANT®). In some embodiments, reference to the term JAK inhibitor includes any such JAK inhibitor disclosed in any one of the following patent applications: WO 2023011301, WO 2023201044, WO 2022143629, WO 2022251434, WO 2022067106, WO 2022033551, WO 2021244323, WO 2021238817, WO 2021238818, WO 2021178991, WO 2021136345, WO 2021190647, WO 2020219639, WO 2020182159, WO 2020155931, WO 2020038457, WO 2020219524, WO 2020173400, WO 2018204233, WO 2018204238, WO 2018169875, WO 2018117152, WO 2017215630, WO 2016070697, WO 2016027195, CN 117815195, CN117815367, and CN 115969796, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0448] In some embodiments, the JAK / STAT pathway inhibitor is a STAT inhibitor. In some embodiments, the STAT inhibitor is an inhibitor of STAT3 and / or STAT5. In some embodiments, the STAT inhibitor is a STAT3 degrader. In some embodiments, the STAT3 degrader is KT-333. In some embodiments, the STAT inhibitor is one or more of TTI-101, C-188-9, WP1066, VVD-130850, LLL12B, STA-21, SD-36, Stattic, S3I-201, OPB-31121, KT-333, and Napabucasin (BBI608). In some embodiments, reference to the term STAT inhibitor includes any such STAT inhibitor disclosed in any one of the following patent applications: WO 2024030628, WO 2023164680, WO 2023192960, WO 2023133336, W02020206424, WO 2023107706, WO 2021150543, WO 2008151037, and CN 109288845, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT

[0449] ATTORNEY DOCKET NO. 51432-053WO2

[0450] I) Epigenetic Modulators

[0451] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more epigenetic modulators. Epigenetic modulators are a class of therapeutics that target enzymes responsible for modifying the structure and function of chromatin, the complex of DNA and proteins that make up chromosomes. These enzymes, including histone deacetylases (HDACs), histone methyltransferases (HMTs), and DNA methyltransferases (DNMTs), play critical roles in gene expression and regulation by modifying the packaging of DNA and affecting how it is read and transcribed. Epigenetic modulators work by altering the activity of these enzymes, either by inhibiting or enhancing their function, to regulate gene expression in specific ways. By targeting specific epigenetic modifications, such as acetylation, methylation, and DNA methylation, these therapies have the potential to treat a wide range of diseases, including cancer, inflammatory disorders, and neurological disorders.

[0452] i) HDAC inhibitors

[0453] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more histone deacetylase (HDAC) inhibitors. A HDAC inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. There are several classes of HDACs, including class I, class Ila, class lib, class III, and class IV. Class I HDACs are further divided into HDAC1, HDAC2, HDAC3, and HDAC8, while class Ila HDACs include HDAC4, HDAC5, HDAC7, and HDAC9. Class lib HDACs consist of HDAC6 and HDAC10, and class III HDACs are known as sirtuins. HDAC inhibitors can target different classes of HDACs, and their specific effects on gene expression can vary depending on which HDACs they target. In some embodiments, a HDAC inhibitor is one or more of Vorinostat (Zolinza™), Romidepsin (Istodax™), Belinostat (Beleodaq™), Panobinostat (Farydak™), Entinostat (MS-275), Valproic acid (Depakene™), Trichostatin A (TSA), Sodium butyrate, and Mocetinostat (MGCD0103). Non-limiting examples of HDAC inhibitors include trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and Panobinostat. In some embodiments, reference to the term HDAC inhibitor includes any such HDAC inhibitor disclosed in any one of the following patent applications: WO 2022110958, WO 2021252628, WO 2019204550, WO 2018178060, WO 2016126724, WO 2014143666, WO 2013041480, and WO 2006120456, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0454] ii) BET inhibitors

[0455] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more bromodomain and extra-terminal protein (BET) inhibitors. A BET inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. BET (bromodomain and extra-terminal) proteins are a family of epigenetic reader proteins that recognize and bind to acetylated lysine residues on histones, leading to chromatin remodeling and gene expression regulation. There are four BET proteins in humans: BRD2, BRD3, BRD4, and BRDT. BET inhibitors specifically target the bromodomains of BET proteins, inhibiting their binding to acetylated lysine residues on histones and leading to alterations in gene expression. BET inhibitors are useful in the treatment of cancer and other diseases characterized by dysregulated gene expression. In some embodiments, a BET inhibitor is one or more of JQ1, 1-BET762, OTX015, RVX-208, and CPI-0610. In some embodiments, reference to the PATENT

[0456] ATTORNEY DOCKET NO. 51432-053WO2

[0457] term BET inhibitor includes any such BET inhibitor disclosed in any one of the following patent applications: WO 2022046682, WO 2022182857, WO 2021107657, WO 2021107656, WO 2020221006, WO 2020053660, WO 2018097977, WO 2017222977, WO 2017142881, WO 2015075665, WO 2015011084, and CN 113264930, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0458] iii) EZH2 inhibitors

[0459] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Enhancer of Zeste Homolog 2 (EZH2) inhibitors. An EZH2 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. EZH2 is a histone-lysine N-methyltransferase that is a member of the Polycomb repressive complex 2 (PRC2) family. EZH2 plays a crucial role in gene expression regulation, specifically by catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), leading to transcriptional repression of target genes. EZH2 has been found to be overexpressed in several types of cancers and is associated with tumor progression and poor prognosis. In some embodiments, an EZH2 inhibitor is one or more of Tazemetostat, GSK2816126, and CPI-1205 (lirametostat). In some embodiments, reference to the term EZH2 inhibitor includes any such EZH2 inhibitor disclosed in any one of the following patent applications: WO 2023030299, WO 2022179584, WO 2020224607, WO 2021243060, WO 2021086069, WO 2019206155, WO 2018133795, WO 2018137639, WO 2017184999, WO 2017218953, WO 2016201328, WO 2015195848, WO 2013155317, WO 2013138361, and CN 114621191, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0460] iv) Co-REST inhibitors

[0461] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Co-REST inhibitors. A Co-REST inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. Co-REST is a transcriptional co-repressor protein that interacts with a variety of transcription factors to regulate gene expression. Co-REST acts by recruiting histone deacetylases (HDACs) to chromatin, leading to the repression of gene expression. Inhibition of Co-REST has been proposed as a potential therapeutic strategy for the treatment of various diseases, including neurodegenerative disorders and cancer. In some embodiments, a co-REST inhibitor is one or more of Nocodazole, NSC 1892, and Anacardic acid.

[0462] v) EP300

[0463] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more E1A-binding protein p300 (EP300) inhibitors. An EP300 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. EP300 is a transcriptional coactivator involved in the regulation of numerous cellular processes, including chromatin remodeling, DNA damage response, and cell cycle progression. EP300 acts as a histone acetyltransferase, catalyzing the transfer of acetyl groups to lysine residues on histone proteins, which leads to changes in chromatin structure and gene expression. EP300 activity has been implicated in diseases, such as cancer, PATENT

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[0465] cardiovascular and neurological disorders. In some embodiments, an EP300 inhibitor is one or more of C646, A-485, NU9056, and L002. In some embodiments, reference to the term EP300 inhibitor includes any such EP300 inhibitor disclosed in any one of the following patent applications: WO 2021213521 and WO 2016044694, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0466] vi) LSD1

[0467] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Lysine-specific demethylase 1 (LSD1) inhibitors. A LSD1 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. LSD1 is an enzyme that plays a crucial role in regulating gene expression through histone modification. It specifically removes the methyl group from lysine 4 on histone 3, leading to gene repression. Dysregulation of LSD1 has been associated with various diseases including cancer and neurodegenerative disorders. In some embodiments, a LSD1 inhibitor is one or more of GSK2879552, IMG-7289, ORY-1001, IMG-8419, SP-2577, CC-90011, HCI-2509, and INCB059872. In some embodiments, reference to the term LSD1 inhibitor includes any such LSD1 inhibitor disclosed in any one of the following patent applications: WO 2021095840, WO 2021175079, WO 2021058024, WO 2020047198, WO 2020052649, WO 2020015745, WO 2020052647, WO 2018137644, WO 2017184934, WO 2017027678, WO 2017116558, WO 2017149463, WO 2016161282, WO 2015123465, WO 2015123424, WO 2013057322, WO 2013057320, WO 2012135113, CN 114805261, CN 111072610 CN107174584, CN 110478352, CN 106432248, and CN 106045881, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0468] vii) PRMT5

[0469] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Protein arginine methyltransferase 5 (PRMT5) inhibitors. A PRMT5 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. PRMT5 is a member of the PRMT family, which catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the nitrogen atoms of arginine residues in target proteins. PRMT5 is involved in various biological processes, including gene expression regulation, signal transduction, and DNA repair. In some embodiments, a PRMT5 inhibitor is one or more of TNG908, TNG462, AMG193, GSK591, EPZ015666, TC-E 5003, and MS023. In some embodiments, reference to the term PRMT5 inhibitor includes any such PRMT5 inhibitor disclosed in any one of the following patent applications: WO 2023001133, WO 2022206964, WO 2022153161, WO 2021068953, WO 2021088992, WO 2020259478, WO 2020205660, WO 2020250123, WO 2020033288, WO 2019102494, WO 2019112719, WO 2019180631, WO 2018065365, WO 2017153186, WO 2017212385, WO 2017032840, WO 2016022605, WO2014100695, WO 2014145214, WO 2014100719, CN 111825656, CN 114558014, CN 11304554, and CN 112778275, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0470] viii) MAT2A

[0471] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more methionine adenosyltransferase 2A (MAT2A) PATENT

[0472] ATTORNEY DOCKET NO. 51432-053WO2

[0473] inhibitors. A MAT2A inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. MAT2A is an enzyme that catalyzes the production of S-adenosylmethionine (SAM), which is an important cofactor in many biological processes, including DNA methylation, protein methylation, and polyamine synthesis. Elevated MAT2A expression has been associated with various cancers. In some embodiments, a MAT2A inhibitor is one or more of cycloleucine and 2-hydroxy-4-methylthiobutanoic acid. In some embodiments, reference to the term MAT2A inhibitor includes any such MAT2A inhibitor disclosed in any one of the following patent applications: WO 2022256808, WO 2022256806, WO 2019191470, and CN 115716831, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0474] ix) DOT1 L

[0475] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Disruptor of Telomeric silencing 1 -like (DOT1L) inhibitors. A DOT1L inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. DOT 1 L is a histone methyltransferase enzyme that catalyzes the methylation of lysine 79 on histone H3. This modification is associated with transcriptional elongation and is important for the maintenance of gene expression programs. The DOT1L family includes enzymes that are involved in epigenetic regulation and transcriptional control, and their dysregulation has been linked to various diseases, including cancer. In some embodiments, a DOT1L inhibitor is one or more of EPZ-5676 (pinometostat) and EPZ-004777. In some embodiments, reference to the term DOT1 L inhibitor includes any such DOT1L inhibitor disclosed in any one of the following patent applications: WO 2016090271, WO 2014100662, and CN 108997480, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0476] x) UBA1

[0477] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more ubiquitin-activating enzyme inhibitors (e.g., a UBA1 inhibitor). A UBA1 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. UBA1, also known as ubiquitin-activating enzyme 1, is a key enzyme involved in the ubiquitination process, a fundamental cellular mechanism for protein degradation and regulation. Ubiquitination involves the covalent attachment of ubiquitin molecules to target proteins, marking them for degradation by the proteasome or modulating their activity, localization, or interactions within the cell. Several inhibitors have been developed to modulate UBA1 activity, with the aim of disrupting ubiquitination-mediated processes in diseased cells. These inhibitors include but are not limited to adenosine-based inhibitors which typically compete with ATP for binding to the active site of UBA1, thereby preventing the activation of ubiquitin (e.g., PYR-41 and MLN7243); covalent inhibitors which form irreversible bonds with specific amino acid residues in the active site of UBA1, leading to inhibition of its activity (e.g., TAK-243 (formerly known as MLN4924)); allosteric inhibitors which bind to sites on UBA1 distinct from the active site, inducing conformational changes that inhibit its catalytic activity (e.g., compound 2i); and fragment-based inhibitors which are designed based on smaller molecular fragments that bind to UBA1. In some embodiments, a UBA1 inhibitor is one or more of PYR-41, MLN7243, and TAK-243. In some embodiments, reference to PATENT

[0478] ATTORNEY DOCKET NO. 51432-053WO2

[0479] the term UBA1 inhibitor includes any such UBA1 inhibitor disclosed in any one of the following patent applications: WO 2016069393 A1, WO 2016069392 A1, and JP 2013237627 A2, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0480] m) Ribonucleotide reductase inhibitors

[0481] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more ribonucleotide reductase inhibitors (RNRi). RNR inhibitors are a class of compounds that inhibit the enzyme ribonucleotide reductase, which is essential for DNA synthesis and repair. RNR catalyzes the conversion of ribonucleotides (RNA building blocks) into deoxyribonucleotides (DNA building blocks), providing the necessary precursors for DNA replication and repair in proliferating cells. By inhibiting RNR, these compounds effectively limit the production of deoxyribonucleotides, thereby preventing DNA synthesis and halting the proliferation of rapidly dividing cells, such as cancer cells.

[0482] RNR is composed of two subunits: the R1 large subunit (containing the catalytic site) and the R2 small subunit (containing a di-iron center critical for enzymatic activity). RRIs typically act by binding to either the active site on the R1 subunit or the iron-oxygen complex in the R2 subunit, leading to the inhibition of the enzyme's activity. In some embodiments, a RNR inhibitor is a nucleoside analog inhibitor, an iron chelator, or an allosteric inhibitor. In some embodiments, a RNR inhibitor useful according to the present disclosure include but are not limited to one or more of hydroxyurea, triapine, didox, GTI-2040, CPI-613 (devimistat), and clofarabine. In some embodiments, reference to the term RNR inhibitor includes any such RNR inhibitor disclosed in any one of the following patent applications: WO 2025049814, WO 2022059691, WO 2022059692, WO 2021034776, WO 2019106579, WO 2014205179, WO 2013105088, WO 199312782, US 5,071,835, US 5,405,850, US 4,814,432, and WO 199518815 each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0483] n) Additional Therapeutic Agents Useful for Combination Therapy

[0484] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Farnesyl transferase inhibitors. A farnesyl transferase inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. Farnesyl transferase inhibitors (FTIs) are a class of drugs that target the farnesyl transferase enzyme, which plays a role in a process called protein prenylation. Protein prenylation is an important step in the process of activating certain proteins involved in signal transduction, cell growth, and differentiation. In some embodiments, a farnesyl transferase inhibitor is one or more of tipifarnib, lonafarnib, and rilapladib. In some embodiments, reference to the term farnesyl transferase inhibitor includes any such farnesyl transferase inhibitor disclosed in any one of the following patent applications: WO 2010057028, WO 2007042465, WO 200136395, WO 200064891, WO 200042849, WO 199938862, WO 199928315, WO 199829390, WO 199426723, CN 107312000, CN 107365310, KR 100375421, KR 100388790, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT

[0485] ATTORNEY DOCKET NO. 51432-053WO2

[0486] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more casein kinase inhibitors. In some embodiments, a casein inhibitor is, SR-3029, a potent and ATP competitive CK1δ and CK1ε inhibitor.

[0487] In some embodiments, compositions and methods described herein may include one or more FLT3 inhibitors in combination with a crystalline solid form of Compound A disclosed herein. FLT3 (Fms-like tyrosine kinase 3), also known as CD135, is a receptor tyrosine kinase (RTK) that plays a crucial role in regulating hematopoiesis, the process by which blood cells are formed. It is primarily expressed on hematopoietic stem cells (HSCs) and progenitor cells in the bone marrow, where it controls cell proliferation, survival, and differentiation. In some embodiments, a FLT3 inhibitor includes, but are not limited to, midostaurin, gilteritinib, sorafenib, quizartinib, crenolanib, ponatinib and quizartinib.

[0488] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more one or more TGFp pathway inhibitors. In some embodiments, compositions and methods described herein may include one or more TGFp inhibitors. A TGFp inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. TGFp (transforming growth factor beta) is a multifunctional cytokine involved in various cellular processes, including cell growth, differentiation, apoptosis, and immune response. Dysregulation of the TGFp signaling pathway has been implicated in various diseases, including cancer, fibrosis, and autoimmune disorders. In some embodiments, a TGFp inhibitor is one or more of galunisertib (LY2157299), and vactosertib (TEW-7197). In some embodiments, a TGFp inhibitor is one or more of Galunisertib, LY2157299, Fresolimumab, Lerdelimumab, Trabedersen, curcumin, resveratrol and small interfering RNA (siRNA) to silence TGFp receptor expression. In some embodiments, reference to the term TGFp inhibitor includes any such TGFp inhibitor disclosed in any one of the following patent applications: WO 2023043473, WO 2020104648, WO 2020128850, WO 2016140884, WO 2007018818, WO 2004024159, WO 200226935, WO 2002062753, WO 2002062776, and JP 2012087076, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0489] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more HSP90 inhibitors. A HSP90 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. HSP90, also known as heat shock protein 90, is a molecular chaperone that plays a critical role in regulating the folding, stability, and activity of a large number of client proteins involved in various cellular processes, including cell cycle progression, signal transduction, and apoptosis. In some embodiments, a HSP90 inhibitor is one or more of Geldanamycin and its derivatives (e.g., 17-AAG, 17-DMAG), KOS 953, Radicicol and its derivatives (e.g., PU-H71), SNX-2112, Ganetespib, AT13387, Onalespib, Luminespib, and KW-2478. In some embodiments, reference to the term HSP90 inhibitor includes any such HSP90 inhibitor disclosed in any one of the following patent applications: WO 2021137665, WO 2018200534, WO 2017151425, WO 2015200514, WO 2013053833, WO 2013009657, WO 2013119985, WO 2012138894, WO 2011044394, WO 2009097578, WO 2008115719, CN 105237533, and CN 104030904, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT

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[0491] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Glutathione peroxidase 4 (GPX4) inhibitors. A GPX4 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. GPX4 is an antioxidant enzyme that plays a critical role in protecting cells against oxidative stress-induced cell death. GPX4 catalyzes the reduction of lipid hydroperoxides to their corresponding alcohols and acts as a regulator of ferroptosis, a form of regulated cell death driven by lipid peroxidation. In some embodiments, a GPX4 inhibitor is one or more of RSL3, ML162, DPI7, FINO2, MCB-613, CBS9106, ML210, ODSH, and TLN232. In some embodiments, reference to the term GPX4 inhibitor includes any such GPX4 inhibitor disclosed in any one of the following patent applications: WO 2021132592, US 2021244715, and KR 20220115536, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0492] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more NRF2 inhibitors. A NRF2 inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. NRF2 is a transcription factor that regulates the expression of genes involved in the cellular antioxidant response, detoxification, and other cyto protective pathways. It plays a critical role in cellular defense mechanisms against oxidative stress and other forms of cellular damage. In some embodiments, a NRF2 inhibitor is one or more of ML385, Brusatol, CDDO-Im, RTA-408, and trigonelline. In some embodiments, reference to the term NRF2 inhibitor includes any such NRF2 inhibitor disclosed in any one of the following patent applications: WO 2023051088, WO 2021202720, KR 2022013610, and CN 107519168, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0493] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more TEA domain (TEAD) inhibitors. A TEAD inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. TEAD is a family of transcription factors that play a key role in regulating gene expression during embryonic development and tissue homeostasis. The four members of the TEAD family (TEAD1-4) are transcriptional co-activators that bind to DNA through their conserved TEA domain and interact with other transcription factors to activate the expression of target genes. In some embodiments, a TEAD inhibitor is one or more of VT3989, VT-107, a pan-TEAD, VT-104, Verteporfin, CA3, IAG933, K-975, IK-595, and Statins (see, e.g., Chapeau, Emilie and Schmelzle, Tobias (2023) IAG933, an oral selective YAP1-TAZ / pan-TEAD protein-protein interaction inhibitor (PPIi) with pre-clinical activity in monotherapy and combinations with MAPK inhibitors. Nature cancer). In some embodiments, reference to the term TEAD inhibitor includes any such TEAD inhibitor disclosed in any one of the following patent applications: WO 2023280254, WO 2023031781, WO 2022258040, WO 2020070181 WO 2018185266, and WO 2017064277, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0494] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more NOTCH / Gamma secretase inhibitors. A PATENT

[0495] ATTORNEY DOCKET NO. 51432-053WO2

[0496] NOTCH / Gamma secretase inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. In some embodiments, a NOTCH / Gamma secretase inhibitor is nirogacestat. In some embodiments, reference to the term NOTCH / Gamma secretase inhibitor includes any such NOTCH / Gamma secretase inhibitor disclosed in any one of the following patent applications: WO 2020208572, WO 2017200969, WO 2014047390, WO 2014047372, WO 2011041336, WO 2010090954, WO 2009008980, WO 2009087130, WO 2007110335, CN 103664904, CN 105560244, and KR 20200077480, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0497] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Hedgehog inhibitors. A hedgehog inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. The hedgehog (Hh) family of proteins are secreted signaling molecules that play a crucial role in embryonic development and tissue homeostasis in adults. The Hh signaling pathway is involved in regulating cell growth, differentiation, and survival. In some embodiments, a hedgehog inhibitor is one or more of Vismodegib (Erivedge), Sonidegib (Odomzo), and Glasdegib (Daurismo). In some embodiments, reference to the term hedgehog inhibitor includes any such hedgehog inhibitor disclosed in any one of the following patent applications: WO 2011063309, and CN 107163028, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0498] Compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more NFkB pathway inhibitors. An NFkB inhibitor may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. NF-kappa B (NFKB) is a family of transcription factors involved in regulating various cellular processes, including inflammation, immunity, cell survival, and proliferation. Non-limiting examples of NFkB inhibitors include Bortezomib (Velcade), Curcumin, Parthenolide, IKK inhibitors (e.g., IKK-16, BAY 11-7082), Resveratrol, Andrographolide and Proteasome inhibitors (e.g., MG132, lactacystin).

[0499] In some embodiments, the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence or severity of side effects of treatment. For example, in some embodiments, a crystalline solid form of Compound A can also be used in combination with a therapeutic agent that treats nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0500] In some embodiments, the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies includes a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). In some embodiments, the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy) and a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). PATENT

[0501] ATTORNEY DOCKET NO. 51432-053WO2

[0502] Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and T cell adoptive transfer (ACT) therapy.

[0503] In some embodiments, a crystalline solid form of Compound A may be used as an adjuvant therapy after surgery. In some embodiments, a crystalline solid form of Compound A may be used as a neo-adjuvant therapy prior to surgery.

[0504] Radiation therapy may be used for inhibiting abnormal cell growth or treating a hyperproliferative disorder, such as cancer, in a subject (e.g., mammal (e.g., human)). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered through one of several methods, or a combination of methods, including, without limitation, external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachy therapy. The term "brachy therapy," as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended, without limitation, to include exposure to radioactive isotopes (e.g., At-211, 1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present disclosure include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as 1-125, 1-131, Yb-169, lr-192 as a solid source, 1-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, or Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive micro spheres.

[0505] In some embodiments, a crystalline solid form of Compound A can render abnormal cells more sensitive to treatment with radiation for purposes of killing or inhibiting the growth of such cells.

[0506] Accordingly, this disclosure further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a crystalline solid form of Compound A, which amount is effective to sensitize abnormal cells to treatment with radiation. The amount of the compound in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein. In some embodiments, a crystalline solid form of Compound A may be used as an adjuvant therapy after radiation therapy or as a neo-adjuvant therapy prior to radiation therapy.

[0507] In some embodiments, the non-drug treatment is a T cell adoptive transfer (ACT) therapy. In some embodiments, the T cell is an activated T cell. The T cell may be modified to express a chimeric antigen receptor (CAR). CAR modified T (CAR-T) cells can be generated by any method known in the art. For example, the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present disclosure, any number of T cell lines available in the art may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, PATENT

[0508] ATTORNEY DOCKET NO. 51432-053WO2

[0509] for example, in U. S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466;

[0510] 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041.

[0511] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more Claudin-18 targeting agents. A Claudin-18 targeting agents may be administered or formulated in combination with a crystalline solid form of Compound A and / or any additional therapeutic agent described herein. Claudin-18 (e.g., claudin 18.2; CLDN18.2) has become a promising target for the treatment of patients with digestive malignancies, such as gastric cancer (GC), gastroesophageal junction (GEJ) cancer, esophageal cancer, and pancreatic cancer, because of its limited expression in healthy tissues and abnormal overexpression in a range of malignancies. Multiple clinical trials of CLDN18.2-targeted therapies, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies, are ongoing, with some showing promising early results. Malignant transformation of gastric epithelial tissue leads to disruption of cell polarity and then to exposure of CLDN18.2 epitopes on the cell surface. Although targeted monoclonal antibodies are largely unable to access CLDN18.2 located in tight-junction supramolecular complexes in normal tissue, the perturbations in cell polarity that expose CLDN18.2 epitopes may theoretically enable CLDN18.2 targeted agents to bind to CLDN18.2 in malignant tissues with minimal off-target effects, making CLDN18.2 an attractive target for therapy. In some embodiments, a Claudin-18 targeting agent is one or more of Zolbetuximab, ASKB589, Osemitamab (TST001), PT886 (a bispecific antibody that targets CLDN18.2 and CD47), TJ-CD4B, CMG901 (an ADC that is composed of an antiCLDN18.2 monoclonal antibody joined to a cytotoxic payload, monomethyl auristatin E), and CT041 (autologous T cells genetically engineered to express a CLDN18.2-targeted CAR). In some embodiments, reference to the term Claudin-18 targeting agent includes any such Claudin-18 targeting agent disclosed in any one of the following patent applications: WO 2024081544, WO 2024131683, WO 2024137619, WO 2024140670, WO 2024136594, WO 2023034922, WO 2023046202, WO 2022203090, WO 2022133169, WO 2022100613, WO 2022256449, WO 2022136642, WO 2021155380, WO 2021129765, WO 2021011885, WO 2021058000, WO 2021218874, WO 2021027850, WO 2020156554, WO 2020025792, WO 2020114480, WO 2020211792, WO 2020239005, WO 2019219089, WO 2018157147, WO 2018108106, WO 2016166122, WO 2014146778, CN 118290582, CN118203658, and CN 118286201, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference.

[0512] In some embodiments, a therapeutic agent for combination therapy may be a steroid.

[0513] Accordingly, in some embodiments, the one or more additional therapies includes a steroid. Suitable steroids may include, but are not limited to, 21 -acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, PATENT

[0514] ATTORNEY DOCKET NO. 51432-053WO2

[0515] prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof.

[0516] Further examples of therapeutic agents that may be used in combination therapy with a crystalline solid form of Compound A include compounds described in the following patents: U. S. Patent Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and International Patent Applications WO 200137820, WO 200132651, WO 200268406, WO 200266470, WO 200255501, WO 200405279, WO 200407481, WO 200407458, WO 200409784, WO 200259110, WO 199945009, WO 2000 / 59509, WO 199961422, WO 200012089, and WO 200002871.

[0517] An additional therapeutic agent may be a biologic (e.g., cytokine (e.g., interferon or an interleukin such as IL-2)) used in treatment of cancer or symptoms associated therewith. In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer. Also included are antibody-drug conjugates.

[0518] An additional therapeutic agent may be an immune modulatory agent. For example, an additional therapeutic agent may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with the ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion a protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / lg fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, A2bR, A2aR / A2bR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as, e.g., avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene) or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including, without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514Z MEDI0680, BMS936559, MEDI4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002. Non-limiting examples of immune modulatory agent includes targets identified in Table 1. PATENT

[0519] ATTORNEY DOCKET NO. 51432-053WO2

[0520] Table 1: Exemplary Immune Modulatory Targets

[0521] Target Biological Function Target Biological Function A2aR, A2bR or both

[0522] CTLA-4 Inhibitory Receptor Inhibitory Receptor A2aR / A2bR

[0523] PD-1 Inhibitory Receptor CD73 Inhibitory Receptor PD-L1 Ligand for PD-1 CD39 Inhibitory Receptor LAG-3 Inhibitory Receptor PVRIG Inhibitory Receptor B7.1 Costimulatory Molecule IDO Inhibitory enzyme B7-H3 Inhibitory Ligand CSF1R Inhibitory Receptor B7-H4 Inhibitory Ligand LIF Inhibitory Cytokine TIM3 Inhibitory Receptor CD47 Inhibitory Receptor VISTA Inhibitory Receptor SIRPa Inhibitory Receptor CD137 Costimulatory Molecule IL-2 Effector Cytokines OX-40 Costimulatory Receptor IL-15 Effector Cytokines CD40 agonist Costimulatory Molecule IL-12 Effector Cytokines CD40 agonist + FLT3

[0524] Costimulatory Molecule TREM2 Receptor ligand

[0525] CD27 Costimulatory Receptor TGFb Multifunctional Cytokine CCR4 Costimulatory Receptor CD73 / TGFb trap Multifunctional Cytokine TCR-T cells directed

[0526] to KRASMUT,

[0527] GITR Costimulatory Receptor Cell therapy mesothelin, or

[0528] PRAME

[0529] mRNA cancer

[0530] NKG2D Activating Receptor vaccines vaccines

[0531] Bi-specific T-cell KIR Costimulatory Receptor BiTEs

[0532] engager Dual EP2 / EP4

[0533] NKG2A Inhibitory Receptor E-prostanoid receptor inhibitor

[0534] ENPP1 Inhibitory Receptor Gamma delta T Cells Cell therapy TIGIT Inhibitory Receptor NK cells Cell therapy

[0535]

[0536] CTLA4, cytotoxic T-lymphocyte-associated antigen 4; LAG3, lymphocyte activation gene 3; PD- 1, programmed cell death protein 1; PD-L1, PD-1 ligand; TIM3, T cell membrane protein 3; VISTA, V- domain immunoglobulin (Ig)-containing suppressor of T-cell activation; KIR, killer IgG-like receptor, APC (Antigen Presenting Cells); TREM2 (Triggering receptor expressed on myeloid cells 2); TGF-b (Transforming growth factor beta)

[0537] In some embodiments, compositions and methods described herein may include a crystalline solid form of Compound A in combination with one or more immune checkpoint inhibitor (ICI). An immune checkpoint inhibitor may be administered or formulated in combination with a compound as described herein. PATENT

[0538] ATTORNEY DOCKET NO. 51432-053WO2

[0539] Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system, which, under normal physiological conditions are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues to minimize collateral tissue damage in response to pathogenic infection. However, the expression of immune checkpoint proteins is often dysregulated by tumors as an important immune resistance and escape mechanism.

[0540] Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Thus, inhibition of these pathways has been used to activate therapeutic anti-tumor immunity. For example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with inhibitors of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD-1), indicate broad and diverse opportunities to enhance anti-tumor immunity with the potential to produce durable clinical responses.

[0541] T cell activation through blockade of immune checkpoints has been a major focus of efforts to therapeutically manipulate endogenous anti-tumor immunity, owing to the capacity of T cells for the selective recognition of peptides derived from proteins in all cellular compartments; their capacity to directly recognize and kill antigen-expressing cells (by CD8+ effector T cells; also known as cytotoxic T lymphocytes (CTLs)); and their ability to orchestrate diverse immune responses (by CD4+ helper T cells), which integrate adaptive and innate effector mechanisms. Thus, agonists of co-stimulatory receptors or antagonists of inhibitory signals, both of which result in the amplification of antigen-specific T cell responses, are currently agents of interest in clinical testing.

[0542] ICIs approved or in development include, but are not limited to, YERVOY® (ipilimumab), OPDIVO® (nivolumab), KEYTRUDA® (pembrolizumab), tremelimumab, galiximab, MDX-1106, BMS-936558, MEDI4736, MPDL3280A, MEDI6469, BMS-986016, BMS-663513, PF-05082566, IPH2101, KW-0761, CDX-1127, CP-870, CP-893, GSK2831781, MSB0010718C, MK3475, CT-011, AMP-224, MDX-1105, IMP321, and MGA271, as well as numerous other antibodies or fusion proteins directed to the immune checkpoint proteins noted in Table 1. Common immune checkpoint proteins that may be targeted by ICIs include, but are not limited to B7.1, B7-H3, LAG3, CD137, KIR, CCR4, CD27, 0X40, GITR, CD40, CTLA4, PD-1, and PD-L1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of a target selected from the group comprising or consisting of programmed cell death protein- 1, ligand of PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and ITIM domain (TIGIT), B7 homolog 3 protein (B7-H3), B- and T-lymphocyte attenuator (BTLA), Sialic acid binding Ig-like lectin 15 (Siglec-15), cytokine-inducible SH2-containing protein (CISH), and combination thereof.

[0543] In some embodiments, the ICI therapy is selected from one or more of anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-LAG3, anti-B7.1, anti-B7H3, anti-B7H4, anti-TIM3, anti- VISTA, anti-CD137, anti-OX40, anti-CD40, anti-CD27, anti-CCR4, anti-GITR, anti-NKG2D, and anti-KIR. In some embodiments, the ICI therapy is an antibody (e.g., a monoclonal antibody selective for any of the targets in Table 1). In some embodiments the ICI is an anti-PD-1 antibody. The antibody may be, e.g., humanized or fully human.

[0544] In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts PATENT

[0545] ATTORNEY DOCKET NO. 51432-053WO2

[0546] with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with the ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion a protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / lg fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as, e.g., avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (also known as tislelizumab; BeiGene & Celgene) ora checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including, without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDI4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0547] In some embodiments, the immune checkpoint inhibitor is an inhibitor of programmed cell death protein- 1 (PD-1) or an inhibitor of the ligand of PD-1 (PDL-1).

[0548] Programmed cell death protein-1 is herein interchangeably referred to as PD-1, PD1, PDCD1, PDCD-1, SLEB2, SLE1 and CD279.

[0549] In humans, PD-1 typically has the sequence as disclosed in UniProtKB Ref. Q15116, incorporated herein by reference.

[0550] Programmed death-ligand 1 is herein interchangeably referred to as PDL-1, PD-LI, PDL1, PDCD1 L1, PDCD1 LG1, CD274, B7-H1, B7-H, B7H1.

[0551] In humans, PD-L1 typically has the sequence as disclosed in UniProtKB Ref. Q9NZQ7, incorporated herein by reference.

[0552] In some embodiments, the anti-PD1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, sasanlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS-010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, orXmAb20717.

[0553] In some embodiments, the PD-1 inhibitor is a bispecific antibody specific for PD-1 and VEGF. In some embodiments, the bispecific antibody is ivonescimab (SMT112).

[0554] In some embodiments, the anti-PDL1 antibody is atezolizumab, avelumab, durvalumab, envafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-07Z.

[0555] An additional therapeutic agent may be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A or OMP-313M32 (etigilimab).

[0556] In some embodiments, the combination therapy includes a crystalline solid form of Compound A and an anti-CCR8 antibody. In an embodiment, the anti-CCR8 antibody is an afucosylated antibody. In an embodiment, the anti-CCR8 antibody is a depleting antibody. In an embodiment, the anti-CCR8 antibody PATENT

[0557] ATTORNEY DOCKET NO. 51432-053WO2

[0558] has ADCC activity. In an embodiment, the anti-CCR8 antibody is a neutralizing antibody. In an embodiment, the anti-CCR8 antibody is not a neutralizing antibody. In an embodiment, the anti-CCR8 antibody is BMS-986340. In an embodiment, the anti-CCR8 antibody is GS-1811. In an embodiment, the anti-CCR8 antibody is ABBV-514. In an embodiment, the anti-CCR8 antibody is LM-108. In an embodiment, the anti-CCR8 antibody is S-531011. In an embodiment, the anti-CCR8 antibody is BAY3375968. In an embodiment, the anti-CCR8 antibody is SRFI 14. In an embodiment, the anti-CCR8 antibody is CM369. In an embodiment, the anti-CCR8 antibody is ZL-1218. In an embodiment, the anti-CCR8 antibody is IPG0521. In an embodiment, the anti-CCR8 antibody is an anti-CCR8 antibody disclosed in WO 2025076288, WO 2022256563, W02022004760, WO2022136649, WO 2021142002, WO 2021194942, WO 2021260206, WO 2021260208, WO 2021260210, WO 2021260209, WO 2021152186, WO 2020138489, and WO 2018181425 which are incorporated herein by reference including the structures disclosed therein.

[0559] In some embodiments, the combination therapy includes a crystalline solid form of Compound A and a cancer vaccine composition. In some embodiments, the cancer vaccine composition is ELI-002 2P, ELI-002 7P, HB-700, mRNA-4157, mRNA-5671, BNT111, GVAX Pancreas, IMA901, DCVax, SOT101, Sipuleucel-T, PROSTVAC-VF orTG01.

[0560] In some embodiments, the combination therapy includes a crystalline solid form of Compound A and an additional therapy or therapeutic agent selected from group consisting of RAS pathway targeted therapeutic agents, kinase-targeted therapeutics, mTORCI inhibitors or degraders, YAP inhibitors or degraders, proteasome inhibitors or degraders, HSP90 inhibitors or degraders, farnesyl transferase inhibitors or degraders, PTEN inhibitors or degraders, signal transduction pathway inhibitors or degraders, checkpoint inhibitors, modulators of the apoptosis pathway, chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, radiotherapy, and combinations thereof.

[0561] An additional therapeutic agent may be an agent that treats cancer or symptoms associated therewith (e.g., a cytotoxic agent, non-peptide small molecules, or other compound useful in the treatment of cancer or symptoms associated therewith, collectively, an “anti-cancer agent”). Anti-cancer agents can be, e.g., chemotherapeutics or targeted therapy agents.

[0562] Anti-cancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Further anti-cancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, the one or more additional therapies includes two or more anti-cancer agents. The two or more anti-cancer agents can be used in a cocktail to be administered in combination or administered separately. Suitable dosing regimens of combination anti-cancer agents are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0563] Other non-limiting examples of anti-cancer agents include GLEEVEC® (Imatinib Mesylate); KYPROLIS® (carfilzomib); VELCADE® (bortezomib); CASODEX (bicalutamide); IRESSA® (gefitin ib); alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, PATENT

[0564] ATTORNEY DOCKET NO. 51432-053WO2

[0565] improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, such as calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Inti. Ed Engl.

[0566] 33:183-186 (1994)); dynemicin such as dynemicin A; bisphosphonates such as clodronate; an esperamicin; neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes such as T- 2 toxin, verracurin A, roridin A and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (" Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel), ABRAXANE® (cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel), and TAXOTERE® (doxetaxel); chloranbucil; tamoxifen (Nolvadex™); raloxifene; aromatase inhibiting 4(5)-imidazoles; 4-hydroxytamoxifen; trioxifene; keoxifene; LY 117018; onapristone; toremifene (FARESTON®); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil;

[0567] GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; PATENT

[0568] ATTORNEY DOCKET NO. 51432-053WO2

[0569] ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicins; capecitabine (e.g., XELODA®); and pharmaceutically acceptable salts of any of the above.

[0570] Additional non-limiting examples of anti-cancer agents include trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), cetuximab (ERBITUX®), rituximab (RITUXAN®), TAXOL®, ARIMIDEX®, ABVD, avicine, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastics (e.g., cell-cycle nonspecific antineoplastic agents, and other antineoplastics described herein), antitumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0571] Further non-limiting examples of anti-cancer agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelaamine and thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites such as folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, DNA binding agents (e.g., ZALYPSIS®), PI3K inhibitors such as PI3K delta inhibitor (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitor (e.g., CAL-130), copanlisib, alpelisib and idelalisib; multi-kinase inhibitor (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormone agonists such as leutinizing hormone releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide and triptorelin), BAFF-neutralizing antibody (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CSI (e.g., elotuzumab, PI3K / Akt inhibitors (e.g., perifosine), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targeting agents (e.g., MKC-3946), and cFMS inhibitors (e.g., ARRY-382). PATENT

[0572] ATTORNEY DOCKET NO. 51432-053WO2

[0573] In some embodiments, an anti-cancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, NAVELBINE®, sorafenib, or any analog or derivative variant of the foregoing. In some embodiments, the anti-cancer agent is JAB-3312.

[0574] In some embodiments, an anti-cancer agent is a PD-1 or PD-L1 antagonist.

[0575] In some embodiments, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immune modulatory therapies, such as an immune checkpoint inhibitor. In some embodiments, a therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0576] In some embodiments, the additional therapeutic agent is selected from the group consisting of a MEK inhibitor, a HER2 inhibitor, a SHP2 inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, a SOS1 inhibitor, and a PD-L1 inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of a MEK inhibitor, a SHP2 inhibitor, and a PD-L1 inhibitor. See, e.g., Hallin et al., Cancer Discovery, DOI: 10.1158 / 2159-8290 (October 28, 2019) and Canon et al., Nature, 575:217 (2019). In some embodiments, a RAS(ON) inhibitor of the present disclosure is used in combination with a MEK inhibitor and a SOS1 inhibitor. In some embodiments, a RAS(ON) inhibitor of the present disclosure is used in combination with a PD-L1 inhibitor and a SOS1 inhibitor. In some embodiments, a RAS(ON) inhibitor of the present disclosure is used in combination with a PD-L1 inhibitor and a SHP2 inhibitor. In some embodiments, a RAS(ON) inhibitor of the present disclosure is used in combination with a MEK inhibitor and a SHP2 inhibitor. In some embodiments, the cancer is colorectal cancer, and the treatment comprises administration of a Ras inhibitor of the present disclosure in combination with a second or third therapeutic agent.

[0577] Proteasome inhibitors include, but are not limited to, carfilzomib (KYPROLIS®), bortezomib (VELCADE®), and oprozomib.

[0578] Immune therapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T-cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1, anti-PD-L1, anti-CTLA4, anti-LAG3, and anti-OX40 agents).

[0579] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that adjust immune responses) containing an imide group. The I MiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0580] Exemplary anti-PD-1 antibodies and methods fortheir use are described by Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO 2006121168 A1), as well as described elsewhere herein.

[0581] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as, a GITR fusion protein described in U. S. Pat. No. 6,111,090,, U. S. Pat. No. 8,586,023, WO 2010003118 and WO 2011090754; or an anti-GITR antibody described, e.g., in U. S. Pat. No. 7,025,962, EP 1947183, U. S. Pat. No. 7,812,135, U. S. Pat. No. 8,388,967, U. S. Pat. No. 8,591,886, U. S. Pat. No. 7,618,632, EP 1866339, and WO 2011028683, WO 2013039954, WO 2005007190, WO 2007133822, WO 2005055808, WO 199940196, WO 200103720, WO 199920758, WO 2006083289, WO 2005115451, and WO 2011051726.

[0582] Another example of a therapeutic agent that may be used in combination with a crystalline solid form of Compound A is an anti-angiogenic agent. Anti-angiogenic agents are inclusive of, but not limited PATENT

[0583] ATTORNEY DOCKET NO. 51432-053WO2

[0584] to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof. An anti-angiogenic agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or arrest cell growth. In some embodiments, the one or more additional therapies include an anti-angiogenic agent.

[0585] Anti-angiogenic agents can be MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 199633172, WO 199627583, WO 199807697, WO 199803516, WO 199834918, WO 199834915, WO 199833768, WO 199830566, WO 199005719, WO 199952910, WO 199952889, WO 199929667, WO 1999007675, EP 0606046, EP 0780386, EP 1786785, EP 1181017, EP 0818442, EP 1004578, and US 20090012085, and U. S. Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 or AMP-9 relative to the other matrix- metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP- 8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO 32-3555, and RS 13-0830.

[0586] Further anti-angiogenic agents include KDR (kinase domain receptor) inhibitory agents (e.g., antibodies and antigen binding regions that specifically bind to the kinase domain receptor), EGFR inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto) such as VECTIBIX® (panitumumab), erlotinib (TARCEVA®), anti-Angl and anti-Ang2 agents (e.g., antibodies or antigen binding regions specifically binding thereto or to their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US 20030162712; US 6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; see US 6,727,225), ADAM distintegrin domain to antagonize the binding of integrin to its ligands (US 20020042368), specifically binding anti-eph receptor or anti-ephrin antibodies or antigen binding regions (U. S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and patent family members thereof), and anti-PDGF-BB antagonists (e.g., specifically binding antibodies or antigen binding regions) as well as antibodies or antigen binding regions specifically binding to PDGF-BB ligands, and PDGFR kinase inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, US 5712291); ilomastat, (Arriva, USA, US5892112); emaxanib, (Pfizer, USA, US 5792783); vatalanib, (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); alpha-0148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands), DACantiangiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); fibrinogen-E fragment (BioActa, UK); angiogenic inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, PATENT

[0587] ATTORNEY DOCKET NO. 51432-053WO2

[0588] USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); maspin (Sosei, Japan); 2-methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610); platelet factor 4 (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); bevacizumab (pINN) (Genentech, USA); angiogenic inhibitors (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); MAb, alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and Medlmmune, USA); enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived antiangiogenic (XOMA, USA); PI 88 (Progen, Australia); cilengitide (Merck KGaA, German; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292, (Telios, USA); Endostatin (Boston Childrens Hospital, USA); ATN 161 (Attenuon, USA); 2-methoxyestradiol (Boston Childrens Hospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (Angiogene Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitors, (EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA); xanthorrhizol, (Yonsei University, South Korea); vaccine, gene-based, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University of California at San Diego, USA); PX 478, (ProIX, USA); METASTATIN, (EntreMed, USA); troponin I, (Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE, USA); o-guanidines, (Dimensional Pharmaceuticals, USA); motuporamine C, (British Columbia University, Canada); CDP 791, (Celltech Group, UK); atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna, Canada); vaccine, angiogenic, (EntreMed, USA); urokinase plasminogen activator inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA); HIF-lalfa inhibitors, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA); KR 31372, (Korea Research Institute of Chemical Technology, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery, Japan); drug delivery system, intraocular, 2-methoxyestradiol; anginex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor-alpha inhibitors; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518, (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, alpha5 beta (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK, and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA) CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); irsogladine, (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); squalamine, (Genaera, USA); RPI 4610 (Sirna, USA); heparanase inhibitors (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); PATENT

[0589] ATTORNEY DOCKET NO. 51432-053WO2

[0590] VGA 1102 (Taisho, Japan); VE-cadherin-2 antagonists(lmClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligands (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0591] Further examples of therapeutic agents that may be used in combination with a crystalline solid form of Compound A include agents (e.g., antibodies, antigen binding regions, or soluble receptors) that specifically bind and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as Scatter Factor), and antibodies or antigen binding regions that specifically bind its receptor, c-Met.

[0592] Another example of a therapeutic agent that may be used in combination with a crystalline solid form of Compound A is an anti-neoplastic agent. In some embodiments, the one or more additional therapies include an anti-neoplastic agent. Non-limiting examples of anti-neoplastic agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa, interferon alfa, natural, interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-NI, interferon alfa-n3, interferon alfacon-1, interferon alpha, natural, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, natural interferon gamma- la, interferon gamma-lb, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis stimulating protein, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 PATENT

[0593] ATTORNEY DOCKET NO. 51432-053WO2

[0594] (Dendreon), decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techni clone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium p...

Claims

PATENTATTORNEY DOCKET NO. 51432-053WO2Claims1. A crystalline solid form of Compound A:Compound A2. The crystalline solid form of claim 1, wherein the crystalline solid form is a Compound A solvate.

3. The crystalline solid form of claim 2, wherein the Compound A solvate is substantially crystalline.

4. The crystalline solid form of claim 2 or 3, wherein the Compound A solvate comprises Compound A and a solvent comprising acetone, isopropyl acetate, heptane, anisole, methyl t-butyl ether, ethyl acetate or a combination thereof.

5. The crystalline solid form of any one of claims 1 to 4, wherein the crystalline solid form of Compound A is selected from Form 1, Form 2, Form 3, Form 4, and Form 5.

6. The crystalline solid form of claim 1 or 5, wherein the crystalline solid form is Form 1.

7. The crystalline solid form of claim 6, wherein Form 1 has at least one peak at diffraction angle 20 (°) selected from 8.2 ± 0.5, 23.9 ± 0.5, 24.7 ± 0.5, 25.2 ± 0.5, 26.1 ± 0.5, 28.3 ± 0.5, 30.8 ± 0.5, 32.9 ± 0.5, and 35.7 ± 0.5.

8. The crystalline solid form of claim 6, wherein Form 1 has at least one peak at diffraction angle 20 (°) selected from 8.2 ± 0.5, 23.9 ± 0.5, and 24.7 ± 0.5.

9. The crystalline solid form of claim 6, wherein Form 1 has at least one peak at diffraction angle 20 (°) selected from 8.2 ± 0.5, 14.3 ± 0.5, 14.4 ± 0.5, 18.0 ± 0.5, 18.7 ± 0.5, 21.6 ± 0.5, 22.2 ± 0.5, 24.6 ± 0.5, and 28.6 ± 0.5.PATENTATTORNEY DOCKET NO. 51432-053WO210. The crystalline solid form of claim 6, wherein Form 1 has at least 10 peaks at diffraction angles 20 (°) selected from 8.2 ± 0.5, 14.3 ± 0.5, 14.4 ± 0.5, 18.0 ± 0.5, 18.7 ± 0.5, 21.6 ± 0.5, 22.2 ± 0.5, 24.6 ± 0.5, 28.6 ± 0.5, 23.9 ± 0.5, 24.7 ± 0.5, 25.2 ± 0.5, 26.1 ± 0.5, 28.3 ± 0.5, 30.8 ± 0.5, 32.9 ± 0.5, and 35.7 ± 0.5.

11. The crystalline solid form of any one of claims 6 to 10, characterized by an endothermic peak with an onset temperature at about 163.2 °C in a differential scanning calorimetry (DSC) thermogram.

12. The crystalline solid form of claim 1 or 5, wherein the crystalline solid form is Form 2.

13. The crystalline solid form of claim 12, wherein Form 2 has at least one peak at diffraction angle 20 (°) selected from 3.3 ± 0.5, 4.3 ± 0.5, 10.1 ± 0.5, 13.1 ± 0.5, 13.8 ± 0.5, 16.6 ± 0.5, 17.7 ± 0.5, 19.2 ± 0.5, 19.9 ± 0.5, 20.1 ± 0.5, 20.2 ± 0.5, 20.3 ± 0.5, 22.3 ± 0.5, and 23.5 ± 0.5, 24.2 ± 0.5, 24.9 ± 0.5, 25.5 ± 0.5, 27.0 ± 0.5, 27.7 ± 0.5, 28.2 ± 0.5, 31.0 ± 0.5, and 36.7 ± 0.5.

14. The crystalline solid form of claim 12, wherein Form 2 has at least ten peaks at diffraction angles 20 (°) selected from 3.3 ± 0.5, 4.3 ± 0.5, 10.1 ± 0.5, 13.1 ± 0.5, 13.8 ± 0.5, 16.6 ± 0.5, 17.7 ± 0.5, 19.2 ± 0.5, 19.9 ± 0.5, 20.1 ± 0.5, 20.2 ± 0.5, 20.3 ± 0.5, 22.3 ± 0.5, and 23.5 ± 0.5, 24.2 ± 0.5, 24.9 ± 0.5, 25.5 ± 0.5, 27.0 ± 0.5, 27.7 ± 0.5, 28.2 ± 0.5, 31.0 ± 0.5, and 36.7 ± 0.5.

15. The crystalline solid form of claim 12, wherein Form 2 has at least one peak at diffraction angle 20 (°) of 10.1 ± 0.5, 16.6 ± 0.5, and 22.3 ± 0.5.

16. The crystalline solid form of any one of claims 12 to 15, characterized by an endothermic peak with an onset temperature at about 56.7 °C in a DSC thermogram.

17. The crystalline solid form of claim 1 or 5, wherein the crystalline solid form is Form 3.

18. The crystalline solid form of claim 17, wherein Form 3 has at least one peak at diffraction angle 20 (°) selected from 7.0 ± 0.5, 7.8 ± 0.5, 7.9 ± 0.5, 10.0 ± 0.5, 12.7 ± 0.5, 14.6 ± 0.5, 17.6 ± 0.5, 19.1 ± 0.5, 25.3 ± 0.5, and 28.5 ± 0.5.

19. The crystalline solid form of claim 17, wherein Form 3 has at least one peak at diffraction angle 20 (°) of 7.8 ± 0.5, 14.6 ± 0.5, and 19.1 ± 0.5.

20. The crystalline solid form of claim 17, wherein Form 3 has at least one peak at diffraction angle 20 (°) of 7.8 ± 0.5, 8.5 ± 0.5, 11.3 ± 0.5, 12.4 ± 0.5, 15.0 ± 0.5, 15.9 ± 0.5, 17.2 ± 0.5, 18.9 ± 0.5, 19.3 ± 0.5, 19.6 ± 0.5, 19.7 ± 0.5, 21.4 ± 0.5, 22.9 ± 0.5, 23.0 ± 0.5, 25.7 ± 0.5, and 28.0 ± 0.5.PATENTATTORNEY DOCKET NO. 51432-053WO221. The crystalline solid form of claim 17, wherein Form 3 has at least ten peaks at diffraction angles 20 (°) of 7.0 ± 0.5, 7.8 ± 0.5, 7.9 ± 0.5, 8.5 ± 0.5, 10.0 ± 0.5, 11.3 ± 0.5, 12.4 ± 0.5, 12.7 ± 0.5, 14.6 ± 0.5, 15.0 ± 0.5, 15.9 ± 0.5, 17.2 ± 0.5, 17.6 ± 0.5, 18.9 ± 0.5, 19.1 ± 0.5, 19.3 ± 0.5, 19.6 ± 0.5, 19.7 ± 0.5, 21.4 ± 0.5, 22.9 ± 0.5, 23.0 ± 0.5, 25.3 ± 0.5, 25.7 ± 0.5, 28.0 ± 0.5, and 28.5 ± 0.5.

22. The crystalline solid form of any one of claims 17 to 21, characterized by an endothermic peak with an onset temperature at about 155.6 °C in a DSC thermogram.

23. The crystalline solid form of claim 1 or 5, wherein the crystalline solid form is Form 4.

24. The crystalline solid form of claim 23, wherein Form 4 has at least one peak at diffraction angle 20 (°) of 3.8 ± 0.5, 4.9 ± 0.5, 5.3 ± 0.5, 6.2 ± 0.5, and 12.1 ± 0.5.

25. The crystalline solid form of claim 23, wherein Form 4 has at least one peak at diffraction angle 20 (°) of 4.9 ± 0.5, 5.3 ± 0.5, and 6.2 ± 0.5.

26. The crystalline solid form of claim 23 having at least one peak at diffraction angle 20 (°) of 5.7 ± 0.5, 8.2 ± 0.5, 11.1 ± 0.5, 12.2 ± 0.5, and 28.8 ± 0.5.

27. The crystalline solid form of claim 23 having at least four peaks at diffraction angle 20 (°) of 3.8 ± 0.5, 4.9 ± 0.5, 5.3 ± 0.5, 6.2 ± 0.5, and 12.1 ± 0.5, 5.7 ± 0.5, 8.2 ± 0.5, 11.1 ± 0.5, 12.2 ± 0.5, and 28.8 ± 0.5.

28. The crystalline solid form of any one of claims 23 to 27, characterized by a first endothermic peak with an onset temperature at about 124.1 °C and a second endothermic peak with an onset temperature at about 157.0 °C in a DSC thermogram.

29. The crystalline solid form of claim 1 or 5, wherein the crystalline solid form is Form 5.

30. The crystalline solid form of claim 29, wherein Form 5 has at least one peak at diffraction angle 20 (°) of 7.3 ± 0.5, 8.2 ± 0.5, 8.6 ± 0.5, 13.0 ± 0.5, 23.3 ± 0.5, and 24.8 ± 0.5.

31. The crystalline solid form of claim 29, wherein Form 5 has at least one peak at diffraction angle 20 (°) of 8.2 ± 0.5, 8.6 ± 0.5, and 23.3 ± 0.5.

32. The crystalline solid form of claim 29, wherein Form 5 has at least four peaks at diffraction angle 20 (°) of 7.3 ± 0.5, 8.2 ± 0.5, 8.6 ± 0.5, 13.0 ± 0.5, 23.3 ± 0.5, and 24.8 ± 0.5.

33. The crystalline solid form of any one of claims 29 to 32, characterized by an endothermic peak with an onset temperature at about 158.6°C in a DSC thermogram.PATENTATTORNEY DOCKET NO. 51432-053WO234. A pharmaceutical composition comprising the crystalline form of Compound A of any one of claims 1 to 33 and a pharmaceutically acceptable carrier or excipient.

35. A pharmaceutically acceptable salt of Compound A selected from the group consisting of a citrate salt of Compound A, a maleate salt of Compound A, a fumarate salt of Compound A, a malate salt of Compound A, a nicotinate salt of Compound A, a phosphate salt of Compound A, a tartrate salt of Compound A, and a benzoate salt of Compound A.

36. A pharmaceutical composition comprising the pharmaceutically acceptable salt of Compound A of claim 35 and a pharmaceutically acceptable carrier or excipient.

37. A method of making the crystalline solid form of any one of claims 1 to 33, the method comprising preparing a slurry of Compound A in a suitable solvent or buffer to precipitate crystalline solid forms, isolating the crystalline solid form from the slurry, and drying the crystalline solid form.

38. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline solid form of any one of claims 1 to 33 or the pharmaceutically acceptable salt of claim 34, or the pharmaceutical composition of claim 34 or 36.

39. The method of claim 38, wherein the cancer comprises a KRAS G13C mutation.

40. A method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of the crystalline solid form of any one of claims 1 to 33 or the pharmaceutically acceptable salt of claim 34, or the pharmaceutical composition of claim 34 or 36.

41. The method of claim 40, wherein the Ras protein is KRAS comprising a G13C mutation.

42. An amorphous solid form of Compound A:Compound A

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