Solid form of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-D][1,3]oxazin-2-one

Abstract

To provide physically and chemically stable solid forms of a compound A having advantageous solubility and pharmacokinetic properties.SOLUTION: Solid forms includes: 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one (compound A); and a dihydroxybenzoic acid selected from 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. Pharmaceutical compositions including the solid forms, methods for using the solid forms in treating cancer patients, and methods of making the solid forms are also provided.SELECTED DRAWING: None

Description

[Background technology]

[0001] IDH1 and IDH2 catalyze the conversion of isocitrate to α-ketoglutarate, which is converted to nicotinamide adenine dinucleotide phosphate (NADP + ) to NADPH (Megias-Vericat J, et al., Blood Lymph. Cancer: Targets and Therapy 2019;9:19-32).

[0002] De novo mutations in IDH1, for example at IDH1 amino acid residue R132, contribute to tumorigenesis in several types of cancer, including solid tumor cancers and hematological malignancies (Badur MG, et al., Cell Reports 2018;25:1680). IDH1 mutations can result in high levels of 2-hydroxyglutarate (2-HG), which inhibits cell differentiation, and inhibitors of mutant IDH1 can reduce 2-HG levels, which promotes cell differentiation (Molenaar RJ, et al., Oncogene 2018;37:1949-1960). Mutations also occur in IDH2, for example, at amino acid residues R140 and R172 (Yang H, et al., Clin. Cancer. Res. 2012; 18: 5562-5571; Mondesir J, et al., J. Blood Med. 2016; 7: 171-180).

[0003] Certain mutant IDH1 and IDH2 inhibitors are disclosed in WO2018 / 111707A1 and include 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one ("Compound A"), which has the following structure: [ka]

[0004] Compound A is currently in Phase 1 trials for advanced hematological malignancies (NCT04603001) and advanced solid tumors (NCT04521686). Certain preclinical studies have determined that Compound A is more soluble in acidic environments than in neutral environments, and drug absorption may be adversely affected by elevated gastric pH. As a result, Phase 1 trials impose certain restrictions on patients' food intake and the use of gastric acid reducing agents. The trials restrict food intake to at least 2 hours before and at least 1 hour after administration of Compound A. If concomitant use of H2 blockers or antacids is required, they must be administered at least 2 hours before or after administration of Compound A. Additionally, concomitant use of proton pump inhibitors (PPIs) is prohibited due to their long pharmacodynamic half-lives, and patients must discontinue PPIs at least 1 week prior to the first dose of Compound A. Thus, there is a need for a physically and chemically stable solid form of Compound A that provides consistent exposure across patient populations and offers more flexible dosing, such as with concomitant food consumption or co-administration of gastric acid reducing agents (e.g., H2 blockers, antacids, or PPIs). [Brief description of the drawings]

[0005] [Figure 1] FIG. 1 is an XRPD pattern of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I. [Diagram 2] Solid-state NMR spectrum of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I. [Diagram 3]Figure 2 is the XRPD pattern of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form II acetone solvate. [Figure 4] Figure 2 is the XRPD pattern of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form III. [Diagram 5] Figure 2 is the XRPD pattern of amorphous 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). [Figure 6] FIG. 1 shows the mean observed plasma concentrations (± standard deviation) of Compound A over time when administered as Compound A crystalline free base (in capsules) versus Compound A digentisate Form I (in tablet formulation) in healthy adult subjects under fasting conditions. [Figure 7] FIG. 1 shows the mean observed plasma concentrations (± standard deviation) of Compound A over time when administered as Compound A digentisate Form I (in a tablet formulation) in healthy adult subjects under fasted versus fed conditions. [Figure 8] FIG. 1 shows the mean observed plasma concentrations (± standard deviation) of Compound A over time when administered as Compound A digentisate Form I (in a tablet formulation) in healthy adult subjects under fasting conditions and following multiple oral doses of esomeprazole. [Figure 9] FIG. 1 shows the mean observed plasma concentrations (± standard deviation) of Compound A over time when administered as Compound A digentisate Form I (in a tablet formulation) in healthy adult subjects under fed conditions and following multiple oral doses of esomeprazole.

[0006] The present invention provides physically and chemically stable solid forms of Compound A with advantageous solubility and pharmacokinetic properties. Solid forms may provide consistent exposure across a patient population and more flexible dosing, such as with concurrent food consumption or co-administration of gastric acid reducing agents (e.g., H2 blockers, antacids, or PPIs).

[0007] The solid form comprises 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and a dihydroxybenzoic acid selected from 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. In one embodiment, the 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and the dihydroxybenzoic acid are in a molar ratio of about 1:2. In another embodiment, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and dihydroxybenzoic acid are in a molar ratio of 1:2.

[0008] In one aspect, the solid form comprises 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,5-dihydroxybenzoic acid. In one embodiment, the 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,5-dihydroxybenzoic acid are in a molar ratio of about 1:2. In another embodiment, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,5-dihydroxybenzoic acid are in a 1:2 molar ratio, as defined herein for 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino] amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), or 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido￥[4,5-d]￥[1,3]oxazin-2-one, bis(2,5-dihydroxybenzoic acid), which can be represented by the following structure: [ka]

[0009] In another embodiment, the solid form comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,5-dihydroxybenzoic acid is a crystalline solid. In another embodiment, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,5-dihydroxybenzoic acid are in a molar ratio of about 1:2 in the crystalline solid. In another embodiment, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,5-dihydroxybenzoic acid are in a 1:2 molar ratio in the crystalline solid, as referred to herein in the crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one. This is referred to as crystalline bis(2,5-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), or crystalline bis(2,5-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one.

[0010] In another embodiment, the solid form is an anhydrous, non-solvated crystalline solid referred to herein as crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I, or crystalline bis(2,5-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one Form I, or Compound A digentisate Form I.

[0011] In one embodiment, Form I is characterized by an X-ray powder diffraction pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 9.0°±0.2° combined with at least one peak selected from 7.2°±0.2°, 9.5°±0.2°, 10.9°±0.2°, 11.7°±0.2°, 14.5°±0.2°, 15.7°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 19.2°±0.2°, 20.8°±0.2°, 24.1°±0.2°, 24.7°±0.2°, and 25.8°±0.2°. In another embodiment, Form I is characterized by an X-ray powder diffraction pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 9.0°±0.2° combined with at least one peak selected from 7.2°±0.2°, 9.5°±0.2°, and 11.7°±0.2°.

[0012] In another embodiment, Form I is 5.1, 5.9, 8.2, 12.8, 23.9, 32.1, 39.0, 41.9, 44.1, 49.6, 52.7, 63.1, 68.1, 102.7, 114.0, 115.9, 117.6, 118.0, 119.0, 119.3, 120.1, 122.4, 126.7, 127.1, 127.6, Contains at least one peak referenced to the upfield resonance of adamantane (d=29.5 ppm) at 128.4, 129.2, 130.3, 133.9, 141.0, 145.2, 149.4, 150.8, 153.0, 155.1, 159.8, 166.3, 174.2, or 175.2 ppm (each ±0.2 ppm) 13 In another embodiment, Form I is characterized by a C solid-state NMR (100.6 MHz) spectrum. In another embodiment, Form I contains at least one peak referenced to the upfield resonance of adamantane (d=29.5 ppm) at 12.8, 23.9, 41.9, 68.1, 149.4, or 155.1 ppm (each ±0.2 ppm). 13 In another embodiment, Form I is characterized by a C solid-state NMR (100.6 MHz) spectrum. In another embodiment, Form I contains peaks referenced to the upfield resonance of adamantane (d=29.5 ppm) at 12.8, 23.9, 41.9, 68.1, 149.4, and 155.1 ppm (each ±0.2 ppm). 13 It is characterized by C solid-state NMR (100.6 MHz) spectrum.

[0013] In another embodiment, the solid form is a crystalline solid isostructural solvate referred to herein as crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form II, or crystalline bis(2,5-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one Form II. In one embodiment, Form II is an isostructural solvate of acetone or methyl ethyl ketone (MEK). In another embodiment, Form II is an acetone solvate. In another embodiment, Form II is a MEK solvate. In one embodiment, Form II is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-theta of 6.5°±0.2° combined with at least one peak selected from 4.9°±0.2°, 7.5°±0.2°, 8.2°±0.2°, 9.9°±0.2°, 12.0°±0.2°, 12.7°±0.2°, 14.8°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 16.0°±0.2°, 17.0°±0.2°, 17.4°±0.2°, and 19.6°±0.2°. In another embodiment, Form II is characterized by an X-ray powder diffraction pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 6.5°±0.2° combined with at least one peak selected from 4.9°±0.2°, 8.2°±0.2°, and 12.7°±0.2°.

[0014] In another embodiment, the solid form is an anhydrous, non-solvated crystalline solid referred to herein as 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form III, or crystalline bis(2,5-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one Form III.

[0015] In one embodiment, Form III is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-theta of 5.5°±0.2° combined with at least one peak selected from 8.5°±0.2°, 11.0°±0.2°, 11.9°±0.2°, 12.4°±0.2°, 14.0°±0.2°, 14.3°±0.2°, 16.3°±0.2°, 16.6°±0.2°, 17.0°±0.2°, and 19.1°±0.2°. In another embodiment, Form III is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-theta of 5.5°±0.2° combined with at least one peak selected from 8.5°±0.2°, 11.0°±0.2°, and 11.9°±0.2°.

[0016] In another embodiment, the solid form is an amorphous solid referred to herein as amorphous 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), or amorphous bis(2,5-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one.

[0017] In another aspect, the solid form comprises 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,4-dihydroxybenzoic acid. In one embodiment, the 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,4-dihydroxybenzoic acid are in a molar ratio of about 1:2. In another embodiment, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,4-dihydroxybenzoic acid are in a 1:2 molar ratio, as used herein, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,4-dihydroxybenzoic acid are in a 1:2 molar ratio, as used herein, 2,4-dihydroxybenzoic acid (1:2), or bis(2,4-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one, which can be represented by the following structure: [ka]

[0018] In another embodiment, the solid form comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,4-dihydroxybenzoic acid is a crystalline solid. In another embodiment, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,4-dihydroxybenzoic acid are in a molar ratio of about 1:2 in the crystalline solid. In another embodiment, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,4-dihydroxybenzoic acid are in a 1:2 molar ratio in the crystalline solid, as referred to herein in the crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one. This is referred to as crystalline bis(2,4-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid (1:2), or crystalline bis(2,4-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one.

[0019] In another aspect, the solid form comprises 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,3-dihydroxybenzoic acid. In one embodiment, the 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,3-dihydroxybenzoic acid are in a molar ratio of about 1:2. In another embodiment, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,3-dihydroxybenzoic acid are in a 1:2 molar ratio, as used herein, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,3-dihydroxybenzoic acid are in a 1:2 molar ratio, as used herein, 2,3-dihydroxybenzoic acid (1:2), or bis(2,3-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one, which can be represented by the following structure: [ka]

[0020] In another embodiment, the solid form comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,3-dihydroxybenzoic acid is a crystalline solid. In another embodiment, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,3-dihydroxybenzoic acid are in a molar ratio of about 1:2 in the crystalline solid. In another embodiment, 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,3-dihydroxybenzoic acid are in a 1:2 molar ratio in the crystalline solid, as referred to herein in the crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one. This is referred to as crystalline bis(2,3-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid (1:2), or crystalline bis(2,3-dihydroxybenzoic acid) 7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one.

[0021] In another embodiment, the solid form comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,3-dihydroxybenzoic acid exhibits the following peaks: 7.5°±0.2°, 8.9°±0.2°, 9.3°±0.2°, 10.9°±0.2°, 12.3°±0.2°, 14. The crystalline solid is characterized by an X-ray powder diffraction (XRPD) pattern using CuKa radiation having a peak at a diffraction angle 2-theta of 11.5°±0.2° combined with at least one peak selected from 0°±0.2°, 15.0°±0.2°, 16.6°±0.2°, 17.3°±0.2°, 18.7°±0.2°, 21.1°±0.2°, 23.7°±0.2°, 24.6°±0.2°, and 25.8°±0.2°. In another embodiment, the crystalline solid is characterized by an XRPD pattern using CuKa radiation having a peak at a diffraction angle 2-theta of 11.5°±0.2° combined with at least one peak selected from 8.9°±0.2°, 15.0°±0.2°, and 24.6°±0.2°.

[0022] Further provided is a process for preparing the solid form described herein.The process includes providing a solution containing 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, a dihydroxybenzoic acid selected from 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid, and a solvent, and precipitating a solid form, preferably a crystalline solid form as described herein, from the solution.

[0023] In one aspect, the process includes providing a solution comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid, and a solvent; and extracting from the solution a solid form, preferably a mixture of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,5-dihydroxybenzoic acid, as described herein. and precipitating a crystalline solid form comprising, preferably, crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), more preferably, crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I. In one embodiment, the solvent is acetonitrile, ethyl acetate, isopropyl alcohol, or water. In one embodiment, the solvent is acetonitrile. In another embodiment, the solution is heated to above room temperature, preferably to about 70° C., prior to precipitation. In another embodiment, at least two equivalents of 2,5-dihydroxybenzoic acid are used relative to 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one. In another embodiment, the solvent is acetonitrile and the solution is heated to above room temperature, preferably to about 70° C., prior to precipitation.In another embodiment, the solvent is acetonitrile and at least two equivalents of 2,5-dihydroxybenzoic acid are used for 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one. In another embodiment, the solution is heated to a temperature above room temperature, preferably about 70° C., prior to precipitation and at least two equivalents of 2,5-dihydroxybenzoic acid are used for 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one. In another embodiment, the solvent is acetonitrile, the solution is heated to above room temperature, preferably about 70° C., prior to precipitation, and at least two equivalents of 2,5-dihydroxybenzoic acid are used relative to 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one.

[0024] In another aspect, the process includes providing a solution comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid, and a solvent; and extracting from the solution a solid form, preferably 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, as described herein. and precipitating a crystalline solid form comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid, preferably crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid (1:2). In one embodiment, the solvent is acetonitrile, ethyl acetate, isopropyl alcohol, or water. In one embodiment, the solvent is acetonitrile. In another embodiment, the solution is heated to a temperature above room temperature, preferably about 70° C., prior to precipitation. In another embodiment, at least two equivalents of 2,4-dihydroxybenzoic acid are used for 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one. In another embodiment, the solvent is acetonitrile and the solution is heated to a temperature above room temperature, preferably about 70° C., prior to precipitation. In another embodiment, the solvent is acetonitrile and at least two equivalents of 2,4-dihydroxybenzoic acid are used for 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one.In another embodiment, the solution is heated to above room temperature, preferably about 70° C., prior to precipitation and at least two equivalents of 2,4-dihydroxybenzoic acid are used relative to 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one. In another embodiment, the solvent is acetonitrile, the solution is heated to above room temperature, preferably to about 70° C., prior to precipitation, and at least two equivalents of 2,4-dihydroxybenzoic acid are used relative to 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one.

[0025] In another aspect, the process includes providing a solution comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid, and a solvent; and extracting from the solution a solid form, preferably 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, as described herein. and precipitating a crystalline solid form comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid, preferably crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid (1:2). In one embodiment, the solvent is acetonitrile, ethyl acetate, isopropyl alcohol, or water. In one embodiment, the solvent is acetonitrile. In another embodiment, the solution is heated to a temperature above room temperature, preferably about 70° C., prior to precipitation. In another embodiment, at least two equivalents of 2,3-dihydroxybenzoic acid are used for 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one. In another embodiment, the solvent is acetonitrile and the solution is heated to a temperature above room temperature, preferably about 70° C., prior to precipitation. In another embodiment, the solvent is acetonitrile and at least two equivalents of 2,3-dihydroxybenzoic acid are used for 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one.In another embodiment, the solution is heated to above room temperature, preferably about 70° C., prior to precipitation and at least two equivalents of 2,3-dihydroxybenzoic acid are used relative to 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one. In another embodiment, the solvent is acetonitrile, the solution is heated to above room temperature, preferably about 70° C., prior to precipitation, and at least two equivalents of 2,3-dihydroxybenzoic acid are used relative to 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one.

[0026] Further provided is a pharmaceutical composition comprising the solid form described herein and pharma- ceutically acceptable carrier, diluent or excipient.The solid form can be formulated as a pharmaceutical composition that can be administered by various routes.In one embodiment, such a composition is formulated for oral administration.Pharmaceutical compositions and the process for preparing them are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy (A.Gennaro, et al., eds., 21st ed., Mack Publishing Co., 2005)).

[0027] In one aspect, the pharmaceutical composition comprises a solid form comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,5-dihydroxybenzoic acid, as described herein, and a pharma- ceutically acceptable carrier, diluent, or excipient. In one embodiment, the pharmaceutical composition comprises 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), as described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, or sodium stearyl fumarate. In one embodiment, the pharmaceutical composition comprises 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), as described herein, microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate. In one embodiment, the pharmaceutical composition comprises crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), as described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, or sodium stearyl fumarate.In one embodiment, the pharmaceutical composition comprises crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), as described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate. In one embodiment, the pharmaceutical composition comprises crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I described herein and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, or sodium stearyl fumarate. In one embodiment, the pharmaceutical composition comprises crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0028] In another aspect, the pharmaceutical composition comprises a solid form comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,4-dihydroxybenzoic acid, as described herein, and a pharma- ceutically acceptable carrier, diluent, or excipient. In one embodiment, the pharmaceutical composition comprises 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid (1:2), as described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, or sodium stearyl fumarate. In one embodiment, the pharmaceutical composition comprises 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid (1:2), as described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate. In one embodiment, the pharmaceutical composition comprises crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid (1:2), as described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, or sodium stearyl fumarate.In one embodiment, the pharmaceutical composition comprises crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid (1:2), as described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0029] In another aspect, the pharmaceutical composition comprises a solid form comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,3-dihydroxybenzoic acid, as described herein, and a pharma- ceutically acceptable carrier, diluent, or excipient. In one embodiment, the pharmaceutical composition comprises 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid (1:2), as described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, or sodium stearyl fumarate. In one embodiment, the pharmaceutical composition comprises 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid (1:2), as described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate. In one embodiment, the pharmaceutical composition comprises crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid (1:2), as described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, or sodium stearyl fumarate.In one embodiment, the pharmaceutical composition comprises crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid (1:2), as described herein, and microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0030] Further provided is a combination comprising the solid form described herein and one or more therapeutic agents.The solid form and one or more other therapeutic agents can be administered simultaneously, separately, or as a sequential combination.The solid form and one or more other therapeutic agents can be administered, for example, as separate pharmaceutical compositions for simultaneous, separate, or sequential administration, or as part of a single pharmaceutical composition that includes pharmaceutically acceptable carriers, diluents, or excipients.

[0031] In one embodiment, the combination comprises a solid form as described herein and an antimetabolite, a hypomethylating agent, a Bcl-2 inhibitor, a mutant Flt3 inhibitor, or a deoxyadenosine analog and a platinum agent.Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0032] In one embodiment, the combination comprises a solid form as described herein and an antimetabolite, or a pharmaceutically acceptable salt thereof. In one embodiment, the antimetabolite is cytarabine, 5-fluorouracil (5-FU), 6-mercaptourine (6-MP), capecitabine, floxuridine, fludarabine, gemcitabine, hydroxycarbamide, methotrexate, pemetrexed, or phototrexate, or a pharmaceutically acceptable salt of any one of them. In another embodiment, the antimetabolite is cytarabine, or a pharmaceutically acceptable salt thereof. In another embodiment, the antimetabolite is cytarabine. Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0033] In another embodiment, the combination comprises a solid form described herein and a hypomethylating agent, or a pharma- ceutically acceptable salt thereof. In another embodiment, the hypomethylating agent is azacitidine (5-azacytidine), 5-aza-2'-deoxycytidine (decitabine), guadecitabine (SGI-110), 5-fluoro-2'-deoxycytidine, zebularine, CP-4200, RG108, or nanaomycin A, or a pharma- ceutically acceptable salt of any one of them. In another embodiment, the hypomethylating agent is azacitidine, or a pharma- ceutically acceptable salt thereof. Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0034] In another embodiment, the combination comprises a solid form as described herein and a Bcl-2 inhibitor, or a pharma- ceutically acceptable salt thereof. In another embodiment, the Bcl-2 inhibitor is venetoclax, obatoclax, or navitoclax, or a pharma- ceutically acceptable salt of any one of them. In another embodiment, the Bcl-2 inhibitor is venetoclax, or a pharma- ceutically acceptable salt thereof. In another embodiment, the Bcl-2 inhibitor is venetoclax. Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0035] In another embodiment, the combination comprises a solid form as described herein, a hypomethylating agent, or a pharma- ceutically acceptable salt thereof, and a Bcl-2 inhibitor, or a pharma- ceutically acceptable salt thereof. In another embodiment, the hypomethylating agent is azacitidine and the Bcl-2 inhibitor is venetoclax. Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0036] In another embodiment, the combination comprises the solid form described herein and mutant Flt3 inhibitor, or its pharmaceutically acceptable salt.In another embodiment, the mutant Flt3 inhibitor is midostaurin, gilteritinib, quizartinib (AC220), sorafenib, sunitinib, lestaurtinib, or crenolanib, or any one of them pharmaceutically acceptable salt.In another embodiment, the mutant Flt3 inhibitor is midostaurin, or its pharmaceutically acceptable salt.In another embodiment, the mutant Flt3 inhibitor is midostaurin. Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0037] In another embodiment, the combination comprises a solid form described herein and a deoxyadenosine analog and a platinum agent. In another embodiment, the deoxyadenosine analog is cytarabine or gemcitabine, or a pharmaceutically acceptable salt thereof. In another embodiment, the deoxyadenosine analog is gemcitabine, or a pharmaceutically acceptable salt thereof. In another embodiment, the deoxyadenosine analog is gemcitabine. In another embodiment, the platinum agent is cisplatin, carboplatin, or oxaliplatin. In another embodiment, the platinum agent is cisplatin. In another embodiment, the deoxyadenosine analog is gemcitabine and the platinum agent is cisplatin. Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0038] Further provided is a method for treating cancer in a patient expressing an IDH mutation by administering a therapeutically effective amount of the solid form described herein to a patient in need of treatment.Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0039] Further provided is the solid form described herein for use in treating cancer in patients expressing IDH mutation.Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2).More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0040] Further provided is the use of the solid form described herein for the manufacture of a medicament for the treatment of cancer in patients expressing IDH mutation.Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2).More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0041] In one embodiment of the method of treatment or solid form for use, the IDH mutation is an IDH1 mutation or an IDH2 mutation.

[0042] In another embodiment of the method of treatment or solid form for use, the IDH mutation is an IDH1 mutation. In another embodiment of the method of treatment or solid form for use, the IDH1 mutation is an IDH1 R132 mutation. In another embodiment of the method of treatment or solid form for use, the IDH1 R132 mutation is R132C, R132G, R132H, R132L, or R132S. In another embodiment of the method of treatment or solid form for use, the IDH1 R132 mutation is R132C. In another embodiment of the method of treatment or solid form for use, the IDH1 R132 mutation is R132G. In another embodiment of the method of treatment or solid form for use, the IDH1 R132 mutation is R132H. In another embodiment of the method of treatment or solid form for use, the IDH1 R132 mutation is R132L. In another embodiment of the method of treatment or solid form for use, the IDH1 R132 mutation is R132S.

[0043] In another embodiment of the method of treatment or solid form for use, the IDH mutation is an IDH2 mutation. In another embodiment of the method of treatment or solid form for use, the IDH2 mutation is an IDH2 R140 mutation or an IDH2 R172 mutation. In another embodiment of the method of treatment or solid form for use, the IDH2 mutation is an IDH2 R140 mutation. In another embodiment of the method of treatment or solid form for use, the IDH2 R140 mutation is R140Q, R140L, or R140W. In another embodiment of the method of treatment or solid form for use, the IDH2 R140 mutation is R140Q. In another embodiment of the method of treatment or solid form for use, the IDH2 R140 mutation is R140L. In another embodiment of the method of treatment or solid form for use, the IDH2 R140 mutation is R140W. In another embodiment of the method of treatment or solid form for use, the IDH2 mutation is an IDH2 R172 mutation. In another embodiment of the method of treatment or solid form for use, the IDH2 R172 mutation is R172K, R172M, R172G, R172S, or R172W. In another embodiment of the method of treatment or solid form for use, the IDH2 R172 mutation is R172K. In another embodiment of the method of treatment or solid form for use, the IDH2 R172 mutation is R172M. In another embodiment of the method of treatment or solid form for use, the IDH2 R172 mutation is R172G. In another embodiment of the method of treatment or solid form for use, the IDH2 R172 mutation is R172S. In another embodiment of the method of treatment or solid form for use, the IDH2 R172 mutation is R172W.

[0044] In one embodiment of the method of treatment or solid form for use, the cancer is solid tumor cancer. In another embodiment of the method of treatment or solid form for use, the solid tumor cancer is cholangiocarcinoma, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder cancer, colorectal cancer, lung cancer, or undifferentiated sinonasal carcinoma. In another embodiment of the method of treatment or solid form for use, the cancer is non-small cell lung cancer. In another embodiment of the method of treatment or solid form for use, the solid tumor cancer is cholangiocarcinoma.

[0045] In one embodiment of the method of treatment or solid form for use, the cancer is hematological malignancy.In another embodiment of the method of treatment or solid form for use, the hematological malignancy is acute myeloid leukemia, myelodysplastic syndrome myeloproliferative neoplasm, angioimmunoblastic T-cell lymphoma, T-cell acute lymphoblastic leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, or chronic myelogenous leukemia.In another embodiment of the method of treatment or solid form for use, the hematological malignancy is acute myeloid leukemia.

[0046] In one embodiment of the method of treatment or solid form for use, the cancer is glioma, glioblastoma, glioblastoma multiforme, astrocytoma, oligodendroglioma, paraganglioma, fibrosarcoma, angioimmunoblastic T-cell lymphoma (AITL), myelodysplastic syndrome (MDS), B-cell acute lymphoblastic leukemia (B-ALL), thyroid cancer, colorectal cancer, acute myeloid leukemia (AML), melanoma, prostate cancer, chondrosarcoma, or cholangiocarcinoma.

[0047] In another embodiment of the method of treatment or solid form for use, the patient is identified as having an IDH1 mutation, for example, an IDH1 R132 mutation. In another embodiment of the method of treatment or solid form for use, the patient is identified as having an IDH2 mutation, for example, an IDH2 R140 or R172 mutation.

[0048] In another embodiment of the therapeutic method or solid form for use, the patient is identified as having an IDH mutation in blood, bone marrow, lymph nodes, lymph, blood cells, bone marrow cells, lymph node cells, or lymph cells. In another embodiment of the therapeutic method or solid form for use, the cancer is a hematological malignancy and the patient is identified as having an IDH mutation in blood, bone marrow, lymph nodes, or lymph.

[0049] In another embodiment of the method of treatment or solid form for use, the patient is identified as having IDH mutation in tissue.In another embodiment of the method of treatment or solid form for use, the patient is identified as having IDH mutation in solid tumor tissue.In another embodiment of the method of treatment or solid form for use, the cancer is solid tumor cancer, and the patient is identified as having IDH1 mutation in solid tumor tissue.

[0050] In another embodiment of the method of treatment or solid form for use, the cancer is a frontline cancer. In another embodiment of the method of treatment or solid form for use, the frontline cancer is a solid tumor cancer. In another embodiment of the method of treatment or solid form for use, the frontline cancer is a hematological malignancy. In another embodiment of the method of treatment or solid form for use, the frontline hematological malignancy is frontline AML.

[0051] In another embodiment of the method of treatment or solid form for use, the cancer is a recurrent cancer. In another embodiment of the method of treatment or solid form for use, the recurrent cancer is a solid tumor cancer. In another embodiment of the method of treatment or solid form for use, the recurrent cancer is a hematological malignancy. In another embodiment of the method of treatment or solid form for use, the recurrent hematological malignancy is recurrent AML.

[0052] In another embodiment of the method of treatment or solid form for use, the cancer is a refractory cancer. In another embodiment of the method of treatment or solid form for use, the refractory cancer is a solid tumor cancer. In another embodiment of the method of treatment or solid form for use, the refractory cancer is a hematological malignancy. In another embodiment of the method of treatment or solid form for use, the refractory hematological malignancy is a refractory AML.

[0053] In another embodiment of the method of treatment or solid form for use, the cancer is an aggressive cancer. In another embodiment of the method of treatment or solid form for use, the aggressive cancer is an aggressive solid tumor cancer. In another embodiment of the method of treatment or solid form for use, the aggressive cancer is an aggressive hematological malignancy. In another embodiment of the method of treatment or solid form for use, the aggressive hematological malignancy is an aggressive AML. In another embodiment of the method of treatment or solid form for use, the AML is acute promyelocytic leukemia.

[0054] In another embodiment of the method of treatment or solid form for use, the solid form is administered with or without food.In another embodiment of the method of treatment or solid form for use, the solid form is administered with food.Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0055] In another embodiment of the method of treatment or solid form for use, food is consumed prior to administration of the solid form (e.g., within 2 hours prior to administration). In another embodiment of the method of treatment or solid form for use, food is consumed within 2 hours prior to administration of the solid form. In another embodiment of the method of treatment or solid form for use, food is consumed within 1 hour prior to administration of the solid form. In another embodiment of the method of treatment or solid form for use, food is consumed within 0.5 hours prior to administration of the solid form. Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0056] In another embodiment of the method of treatment or solid form for use, food is consumed after administration of the solid form (e.g., within 1 hour after administration). In another embodiment of the method of treatment or solid form for use, food is consumed within 1 hour after administration of the solid form. In another embodiment of the method of treatment or solid form for use, food is consumed within 0.5 hours after administration of the solid form. Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0057] In another embodiment of the method of treatment or solid form for use, the solid form is administered with or without a gastric acid reducing agent (e.g., H2 blocker, antacid, or PPI).Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0058] In another embodiment of the method of treatment or solid form for use, the solid form is administered with or without an H2 blocker (e.g., famotidine, nizatidine, cimetidine, or ranitidine). In another embodiment of the method of treatment or solid form for use, the solid form is administered with an H2 blocker. In another embodiment of the method of treatment or solid form for use, the H2 blocker is administered within 2 hours before or after administration of the solid form. In another embodiment of the method of treatment or solid form for use, the H2 blocker is administered within 1 hour before or after administration of the solid form. In another embodiment of the method of treatment or solid form for use, the H2 blocker is administered within 0.5 hours before or after administration of the solid form. Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0059] In another embodiment of the method of treatment or solid form for use, the solid form is administered with or without an antacid (e.g., aluminum hydroxide / magnesium hydroxide / simethicone or calcium carbonate). In another embodiment of the method of treatment or solid form for use, the solid form is administered with an antacid. In another embodiment of the method of treatment or solid form for use, the antacid is administered within 2 hours before or after administration of the solid form. In another embodiment of the method of treatment or solid form for use, the antacid is administered within 1 hour before or after administration of the solid form. In another embodiment of the method of treatment or solid form for use, the antacid is administered within 0.5 hours before or after administration of the solid form. Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0060] In another embodiment of the method of treatment or solid form for use, the solid form is administered with or without a PPI (e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole sodium, or rabeprazole). In another embodiment of the method of treatment or solid form for use, the PPI is administered within 2 hours before or after administration of the solid form. In another embodiment of the method of treatment or solid form for use, the PPI is administered within 1 hour before or after administration of the solid form. In another embodiment of the method of treatment or solid form for use, the PPI is administered within 0.5 hours before or after administration of the solid form. Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0061] In another embodiment of the method of treatment or solid form for use, the solid form is administered simultaneously, separately, or sequentially with a gastric acid reducing agent (e.g., H2 blocker, antacid, or PPI).Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0062] In another embodiment of the method of treatment or solid form for use, the solid form is administered simultaneously, separately, or sequentially with an H2 blocker (e.g., famotidine, nizatidine, cimetidine, or ranitidine).Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0063] In another embodiment of the method of treatment or solid form for use, the solid form is administered simultaneously, separately, or sequentially with an antacid (e.g., aluminum hydroxide / magnesium hydroxide / simethicone or calcium carbonate).Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0064] In another embodiment of the method of treatment or solid form for use, the solid form is administered simultaneously, separately, or sequentially with a PPI (e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole sodium, or rabeprazole).Preferably, the solid form is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). More preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2). Even more preferably, the solid form is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0065] Various aspects of the invention are described in the following numbered sections.

[0066] Item 1. A solid form of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and a dihydroxybenzoic acid selected from 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid.

[0067] Item 2. The solid form of item 1, wherein the solid form is a crystalline solid form.

[0068] Item 3. The solid form of item 1 or 2, wherein 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and dihydroxybenzoic acid are in a molar ratio of about 1:2.

[0069] Item 4. The solid form of any one of items 1 to 3, wherein 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and dihydroxybenzoic acid are in a molar ratio of 1:2.

[0070] Item 5. The solid form of any one of items 1 to 4, which is a crystalline solid form of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,5-dihydroxybenzoic acid.

[0071] Section 6.7. A solid form of any one of sections 1-5, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having at least one peak at a diffraction angle 2-theta of 2°, 9.0°, 9.5°, 10.9°, 11.7°, 14.5°, 15.7°, 16.8°, 17.2°, 19.2°, 20.8°, 24.1°, 24.7°, or 25.8° (each, ±0.2°).

[0072] 7. The solid form of any one of paragraphs 1-6, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 9.0° combined with at least one peak selected from 7.2°, 9.5°, 10.9°, 11.7°, 14.5°, 15.7°, 16.8°, 17.2°, 19.2°, 20.8°, 24.1°, 24.7°, or 25.8° (each ±0.2°).

[0073] Item 8. The solid form of any one of items 1-7, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 9.0°±0.2° combined with at least one peak selected from 7.2°±0.2°, 9.5°±0.2°, and 11.7°±0.2°.

[0074] Item 9. A solid form of any one of items 1-8, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having at least peaks at diffraction angles 2-theta of 7.2°, 9.0°, 9.5°, 10.9°, 11.7°, 14.5°, 15.7°, 16.8°, 17.2°, 19.2°, 20.8°, 24.1°, 24.7°, and 25.8° (each ±0.2°).

[0075] Sections 10.5.1, 5.9, 8.2, 12.8, 23.9, 32.1, 39.0, 41.9, 44.1, 49.6, 52.7, 63.1, 68.1, 102.7 , 114.0, 115.9, 117.6, 118.0, 119.0, 119.3, 120.1, 122.4, 126.7, 127.1, 127.6, 128. Contains at least one peak referenced to the upfield resonance of adamantane (d = 29.5 ppm) at 4, 129.2, 130.3, 133.9, 141.0, 145.2, 149.4, 150.8, 153.0, 155.1, 159.8, 166.3, 174.2, or 175.2 ppm (each ±0.2 ppm). 13 A solid form of any one of items 1 to 9, characterized by a C solid state NMR (100.6 MHz) spectrum.

[0076] 11.12. Contains at least one peak referenced to the upfield resonance of adamantane (d = 29.5 ppm) at 8, 23.9, 41.9, 68.1, 149.4, or 155.1 ppm (respectively, ±0.2 ppm) 13 A solid form of any one of items 1 to 10, characterized by a C solid state NMR (100.6 MHz) spectrum.

[0077] Item 12.12.8, including peaks at 23.9, 41.9, 68.1, 149.4, and 155.1 ppm (each ±0.2 ppm) referenced to the upfield resonance of adamantane (d = 29.5 ppm) 13 A solid form of any one of items 1 to 11, characterized by a C solid state NMR (100.6 MHz) spectrum.

[0078] Sections 13.5.1, 5.9, 8.2, 12.8, 23.9, 32.1, 39.0, 41.9, 44.1, 49.6, 52.7, 63.1, 68.1, 102 .7, 114.0, 115.9, 117.6, 118.0, 119.0, 119.3, 120.1, 122.4, 126.7, 127.1, 127.6, Includes peaks at 128.4, 129.2, 130.3, 133.9, 141.0, 145.2, 149.4, 150.8, 153.0, 155.1, 159.8, 166.3, 174.2, and 175.2 ppm (each ±0.2 ppm) referenced to the upfield resonance of adamantane (d = 29.5 ppm). 13 A solid form of any one of items 1 to 12, characterized by a C solid state NMR (100.6 MHz) spectrum.

[0079] Item 14. The solid form of any one of items 1 to 4, which is a crystalline solid form of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,4-dihydroxybenzoic acid.

[0080] Item 15. The solid form of any one of items 1 to 4, which is a crystalline solid form of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one and 2,3-dihydroxybenzoic acid.

[0081] Item 16. A solid form of any one of items 1-4 or 15, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having at least one peak at a diffraction angle 2-theta of 7.5°±0.2°, 8.9°±0.2°, 9.3°±0.2°, 10.9°±0.2°, 11.5°±0.2°, 12.3°±0.2°, 14.0°±0.2°, 15.0°±0.2°, 16.6°±0.2°, 17.3°±0.2°, 18.7°±0.2°, 21.1°±0.2°, 23.7°±0.2°, 24.6°±0.2°, or 25.8°±0.2°.

[0082] Item 17. The solid form of any one of items 1-4, 15, or 16, characterized by an X-ray powder diffraction (XRPD) pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 11.5°±0.2° combined with at least one peak selected from 7.5°±0.2°, 8.9°±0.2°, 9.3°±0.2°, 10.9°±0.2°, 12.3°±0.2°, 14.0°±0.2°, 15.0°±0.2°, 16.6°±0.2°, 17.3°±0.2°, 18.7°±0.2°, 21.1°±0.2°, 23.7°±0.2°, 24.6°±0.2°, and 25.8°±0.2°.

[0083] Item 18. A solid form of any one of items 1-4, or items 15-17, characterized by an X-ray powder diffraction (XRPD) pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 11.5°±0.2° combined with at least one peak selected from 8.9°±0.2°, 15.0°±0.2°, and 24.6°±0.2°.

[0084] Item 19. A solid form of any one of items 1-4 or 15-18, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having at least peaks at diffraction angles 2-theta of 7.5°±0.2°, 8.9°±0.2°, 9.3°±0.2°, 10.9°±0.2°, 11.5°±0.2°, 12.3°±0.2°, 14.0°±0.2°, 15.0°±0.2°, 16.6°±0.2°, 17.3°±0.2°, 18.7°±0.2°, 21.1°±0.2°, 23.7°±0.2°, 24.6°±0.2°, and 25.8°±0.2°.

[0085] Item 20. 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), in solid form.

[0086] Item 21. 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid (1:2), solid form.

[0087] Item 22. 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid (1:2), in solid form.

[0088] Item 23. Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), solid form.

[0089] Item 24. Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid (1:2), solid form.

[0090] Item 25. Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid (1:2), solid form.

[0091] Item 26. A pharmaceutical composition comprising the solid form of any one of items 1 to 25 or items 86 to 113, and a pharma- ceutically acceptable carrier, diluent, or excipient.

[0092] Item 27. The pharmaceutical composition of Item 26, formulated for oral administration.

[0093] Item 28. The pharmaceutical composition of item 26 or 27, wherein the pharma- ceutically acceptable carrier, diluent, or excipient comprises microcrystalline cellulose, mannitol, polyvinylpyrrolidone vinyl acetate, croscarmellose sodium, colloidal silicon dioxide, or sodium stearyl fumarate.

[0094] Item 29. A combination of the solid form of any one of items 1 to 25 or items 86 to 113 with one or more therapeutic agents selected from antimetabolites, hypomethylating agents, Bcl-2 inhibitors, mutant Flt3 inhibitors, and deoxyadenosine analogs, and platinum agents.

[0095] Item 30. The combination of item 29, wherein the one or more therapeutic agents are a deoxyadenosine analogue and a platinum agent.

[0096] Item 31. The combination of item 30, wherein the deoxyadenosine analog is gemcitabine.

[0097] Item 32. The combination of item 30, wherein the platinum agent is cisplatin.

[0098] Item 33. The combination of item 30, wherein the deoxyadenosine analogue is gemcitabine and the platinum agent is cisplatin.

[0099] Clause 34. A method for treating cancer in a patient expressing an IDH mutation, comprising administering to a patient in need thereof a therapeutically effective amount of any one of the solid forms of clauses 1-25 or clauses 86-113, any one of the pharmaceutical compositions of clauses 26-28, or any one of the combinations of clauses 29-33.

[0100] Item 35. The method of item 34, wherein the IDH mutation is an IDH1 mutation.

[0101] Item 36. The method of item 35, wherein the IDH1 mutation is an IDH1 R132 mutation.

[0102] Item 37. The method of item 34, wherein the IDH mutation is an IDH2 mutation.

[0103] Item 38. The method of item 37, wherein the IDH2 mutation is an IDH2 R140 mutation.

[0104] Item 39. The method of item 37, wherein the IDH2 mutation is an IDH2 R172 mutation.

[0105] Item 40. The method of any one of items 34 to 39, wherein the cancer is a solid tumor cancer.

[0106] Clause 41. The method of clause 40, wherein the solid tumor cancer is cholangiocarcinoma, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder cancer, colorectal cancer, lung cancer, or paranasal sinus undifferentiated carcinoma.

[0107] Item 42. The method according to Item 41, wherein the solid tumor cancer is bile duct cancer.

[0108] Item 43. The method of any one of items 34 to 39, wherein the cancer is a hematological malignancy.

[0109] Clause 44. The method of clause 43, wherein the hematological malignancy is acute myeloid leukemia, myelodysplastic syndrome myeloproliferative neoplasm, angioimmunoblastic T-cell lymphoma, T-cell acute lymphoblastic leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, or chronic myeloid leukemia.

[0110] Item 45. The method of item 44, wherein the hematological malignancy is acute myeloid leukemia.

[0111] Item 46. Any one of the methods of items 34 to 45, wherein the solid form of any one of items 1 to 25 or items 86 to 113, the pharmaceutical composition of any one of items 26 to 28, or the combination of any one of items 29 to 33 is administered with or without food.

[0112] Item 47. The method of any one of items 34 to 46, wherein the food can be consumed before (e.g., within 2 hours before) or after (e.g., within 1 hour after) administration of any one of the solid forms of items 1 to 25 or 86 to 113, any one of the pharmaceutical compositions of items 26 to 28, or any one of the combinations of items 29 to 33.

[0113] Item 48. Any one of the methods of items 34 to 47, wherein the solid form of any one of items 1 to 25 or items 86 to 113, the pharmaceutical composition of any one of items 26 to 28, or the combination of any one of items 29 to 33 is administered with or without a gastric acid reducing agent (e.g., an H2 blocker, an antacid, or a PPI).

[0114] Item 49. Any one of the methods of items 34 to 47, wherein the solid form of any one of items 1 to 25 or items 86 to 113, the pharmaceutical composition of any one of items 26 to 28, or the combination of any one of items 29 to 33 is administered with or without an H2 blocker (e.g., famotidine, nizatidine, cimetidine, or ranitidine).

[0115] Item 50. The method of any one of items 34 to 47, wherein the solid form of any one of items 1 to 25 or items 86 to 113, the pharmaceutical composition of any one of items 26 to 28, or the combination of any one of items 29 to 33 is administered with or without an antacid (e.g., aluminum hydroxide / magnesium hydroxide / simethicone or calcium carbonate).

[0116] Item 51. Any one of the methods of items 34 to 47, wherein the solid form of any one of items 1 to 25 or items 86 to 113, the pharmaceutical composition of any one of items 26 to 28, or the combination of any one of items 29 to 33 is administered with or without a PPI (e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole sodium, or rabeprazole).

[0117] Item 52. Any one of the methods of items 34 to 47, wherein the solid form of any one of items 1 to 25 or items 86 to 113, the pharmaceutical composition of any one of items 26 to 28, or the combination of any one of items 29 to 33 is administered simultaneously, separately, or sequentially with a gastric acid reducing agent (e.g., an H2 blocker, an antacid, or a PPI).

[0118] Item 53. A solid form of any one of items 1 to 25 or items 86 to 113, a pharmaceutical composition of any one of items 26 to 28, or a combination of any one of items 29 to 33 for use in therapy.

[0119] Clause 54. A solid form of any one of clauses 1 to 25 or clauses 86 to 113, a pharmaceutical composition of any one of clauses 26 to 28, or a combination of any one of clauses 29 to 33 for use in treating cancer in patients expressing an IDH mutation.

[0120] Clause 55. A solid form for use according to clause 54, wherein the IDH mutation is an IDH1 mutation.

[0121] Clause 56. A solid form for use according to clause 55, wherein the IDH1 mutation is an IDH1 R132 mutation.

[0122] Clause 57. A solid form for use according to clause 54, wherein the IDH mutation is an IDH2 mutation.

[0123] Clause 58. A solid form for use according to clause 57, wherein the IDH2 mutation is an IDH2 R140 mutation.

[0124] Clause 59. A solid form for use according to clause 57, wherein the IDH2 mutation is an IDH2 R172 mutation.

[0125] Item 60. A solid form for use according to any one of items 54 to 59, wherein the cancer is a solid tumor cancer.

[0126] Clause 61. A solid form for use according to clause 60, wherein the solid tumour cancer is cholangiocarcinoma, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder cancer, colorectal cancer, lung cancer or paranasal sinus undifferentiated carcinoma.

[0127] Item 62. A solid form for use according to item 61, wherein the solid tumor cancer is bile duct cancer.

[0128] Item 63. A solid form for use according to any one of items 54 to 59, wherein the cancer is a hematological malignancy.

[0129] Clause 64. A solid form for use according to clause 63, wherein the hematological malignancy is acute myeloid leukemia, myelodysplastic syndrome myeloproliferative neoplasm, angioimmunoblastic T-cell lymphoma, T-cell acute lymphoblastic leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, or chronic myeloid leukemia.

[0130] Clause 65. A solid form for use according to clause 64, wherein the hematological malignancy is acute myeloid leukemia.

[0131] Clause 66. Use of any one of the solid forms of clauses 1 to 25 or clauses 86 to 113, any one of the pharmaceutical compositions of clauses 26 to 28, or any one of the combinations of clauses 29 to 33 in the manufacture of a medicament for treating cancer in a patient expressing an IDH mutation.

[0132] Clause 67. The use of the solid form of clause 66, wherein the IDH mutation is an IDH1 mutation.

[0133] Item 68. The use of the solid form of item 67, wherein the IDH1 mutation is an IDH1 R132 mutation.

[0134] Clause 69. The use of the solid form of clause 66, wherein the IDH mutation is an IDH2 mutation.

[0135] Item 70. The use of the solid form of Item 69, wherein the IDH2 mutation is an IDH2 R140 mutation.

[0136] Item 71. The use of the solid form of Item 69, wherein the IDH2 mutation is an IDH2 R172 mutation.

[0137] Item 72. The use of any one of the solid forms of items 66 to 71, wherein the cancer is a solid tumor cancer.

[0138] Clause 73. The use of the solid form of clause 72, wherein the solid tumor cancer is cholangiocarcinoma, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder cancer, colorectal cancer, lung cancer, or paranasal sinus undifferentiated carcinoma.

[0139] Item 74. The use of the solid form of item 73, wherein the solid tumor cancer is bile duct cancer.

[0140] Item 75. The use of a solid form of any one of items 66 to 71, wherein the cancer is a hematological malignancy.

[0141] Item 76. The use of the solid form of item 75, wherein the hematological malignancy is acute myeloid leukemia, myelodysplastic syndrome myeloproliferative neoplasm, angioimmunoblastic T-cell lymphoma, T-cell acute lymphoblastic leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, or chronic myeloid leukemia.

[0142] Item 77. The use of the solid form of item 76, wherein the hematological malignancy is acute myeloid leukemia.

[0143] Item 78. A process for preparing the solid form of any one of items 1 to 25, comprising providing a solution comprising 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, a dihydroxybenzoic acid selected from 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid, and a solvent, and precipitating the solid form from the solution.

[0144] Item 79. The process of item 78, wherein the solvent is acetonitrile.

[0145] Item 80. The process of paragraphs 78 or 79, wherein the solution is heated to a temperature above room temperature, preferably to about 70° C., prior to precipitation.

[0146] Item 81. The process of any one of items 78 to 80, wherein at least two equivalents of dihydroxybenzoic acid are used relative to 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one.

[0147] Item 82. The solid form of any one of items 1 to 25 produced by a process comprising providing a solution of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, a dihydroxybenzoic acid selected from 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid, and a solvent, and precipitating the solid form from the solution.

[0148] Item 83. The solid form of item 82, wherein the solvent is acetonitrile.

[0149] Item 84. The solid form of item 82 or 83, wherein the solution is heated to a temperature above room temperature, preferably to about 70° C., prior to precipitation.

[0150] Item 85. Any one of items 82 to 84, wherein at least two equivalents of dihydroxybenzoic acid are used relative to 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one.

[0151] Item 86. A solid form which is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I.

[0152] Item 87. Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), (i) an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-theta of 7.2°±0.2°, 9.0°±0.2°, 9.5°±0.2°, 10.9°±0.2°, 11.7°±0.2°, 14.5°±0.2°, 15.7°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 19.2°±0.2°, 20.8°±0.2°, 24.1°±0.2°, 24.7°±0.2°, or 25.8°±0.2°; or (ii) 5.1, 5.9, 8.2, 12.8, 23.9, 32.1, 39.0, 41.9, 44.1, 49.6, 52.7, 63.1, 68.1, 102.7 , 114.0, 115.9, 117.6, 118.0, 119.0, 119.3, 120.1, 122.4, 126.7, 127.1, 127.6, 128.4 , containing at least one peak referenced to the upfield resonance of adamantane (d = 29.5 ppm) at 129.2, 130.3, 133.9, 141.0, 145.2, 149.4, 150.8, 153.0, 155.1, 159.8, 166.3, 174.2, or 175.2 ppm (each ±0.2 ppm). 13 A solid form characterized by at least one of the following: C solid state NMR (100.6 MHz) spectra.

[0153] Item 88. A solid form of item 86 or 87 characterized by an X-ray powder diffraction pattern using Cu Ka radiation having at least one peak at a diffraction angle 2-theta of 7.2°, 9.0°, 9.5°, 10.9°, 11.7°, 14.5°, 15.7°, 16.8°, 17.2°, 19.2°, 20.8°, 24.1°, 24.7°, or 25.8° (respectively, ±0.2°).

[0154] Item 89. The solid form of any one of items 86 to 88, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 9.0° combined with at least one peak selected from 7.2°, 9.5°, 10.9°, 11.7°, 14.5°, 15.7°, 16.8°, 17.2°, 19.2°, 20.8°, 24.1°, 24.7°, or 25.8° (each ±0.2°).

[0155] Item 90. The solid form of any one of items 86 to 89, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-theta of 9.0°±0.2° combined with at least one peak selected from 7.2°±0.2°, 9.5°±0.2°, and 11.7°±0.2°.

[0156] Item 91. The solid form of any one of items 86-90, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having at least peaks at diffraction angles 2-theta of 7.2°, 9.0°, 9.5°, 10.9°, 11.7°, 14.5°, 15.7°, 16.8°, 17.2°, 19.2°, 20.8°, 24.1°, 24.7°, and 25.8° (each ±0.2°).

[0157] Item 92. The solid form of item 86, having an X-ray powder diffraction pattern substantially as shown in FIG.

[0158] Section 93.5.1, 5.9, 8.2, 12.8, 23.9, 32.1, 39.0, 41.9, 44.1, 49.6, 52.7, 63.1, 68.1, 102.7 , 114.0, 115.9, 117.6, 118.0, 119.0, 119.3, 120.1, 122.4, 126.7, 127.1, 127.6, 128. Contains at least one peak referenced to the upfield resonance of adamantane (d = 29.5 ppm) at 4, 129.2, 130.3, 133.9, 141.0, 145.2, 149.4, 150.8, 153.0, 155.1, 159.8, 166.3, 174.2, or 175.2 ppm (each ±0.2 ppm). 13 8. The solid form of any one of claims 86 to 92, characterized by a C solid state NMR (100.6 MHz) spectrum.

[0159] Contains at least one peak referenced to the upfield resonance of adamantane (d = 29.5 ppm) at terms 94.12.8, 23.9, 41.9, 68.1, 149.4, or 155.1 ppm (respectively, ±0.2 ppm). 13 86. The solid form of any one of claims 86 to 93, characterized by a C solid state NMR (100.6 MHz) spectrum.

[0160] Term 95. Contains peaks at 12.8, 23.9, 41.9, 68.1, 149.4, and 155.1 ppm (each ±0.2 ppm) referenced to the upfield resonance of adamantane (d = 29.5 ppm). 13 86. The solid form of any one of claims 86 to 94, characterized by a C solid state NMR (100.6 MHz) spectrum.

[0161] Sections 96.5.1, 5.9, 8.2, 12.8, 23.9, 32.1, 39.0, 41.9, 44.1, 49.6, 52.7, 63.1, 68.1, 102 .7, 114.0, 115.9, 117.6, 118.0, 119.0, 119.3, 120.1, 122.4, 126.7, 127.1, 127.6, Includes peaks at 128.4, 129.2, 130.3, 133.9, 141.0, 145.2, 149.4, 150.8, 153.0, 155.1, 159.8, 166.3, 174.2, and 175.2 ppm (each ±0.2 ppm) referenced to the upfield resonance of adamantane (d = 29.5 ppm). 13 86. The solid form of any one of claims 86 to 95, characterized by a C solid state NMR (100.6 MHz) spectrum.

[0162] Item 97. Substantially as shown in FIG. 13 86. The solid form of any one of claims 86 to 92, having a C solid state NMR spectrum.

[0163] Item 98. A solid form which is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form II.

[0164] Item 99. A solid form which is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form II acetone solvate.

[0165] Item 100. A solid form of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form II MEK solvate.

[0166] Item 101. The solid form of any one of items 98 to 100, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having at least one peak at a diffraction angle 2-theta of 4.9°, 6.5°, 7.5°, 8.2°, 9.9°, 12.0°, 12.7°, 14.8°, 15.0°, 15.4°, 16.0°, 17.0°, 17.4°, or 19.6° (each, ±0.2°).

[0167] Item 102. The solid form of any one of items 98 to 101, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 6.5° combined with at least one peak selected from 4.9°, 7.5°, 8.2°, 9.9°, 12.0°, 12.7°, 14.8°, 15.0°, 15.4°, 16.0°, 17.0°, 17.4°, and 19.6° (each ±0.2°).

[0168] Item 103. The solid form of any one of items 98 to 102, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 6.5° combined with at least one peak selected from 4.9°, 8.2°, and 12.7° (each ±0.2°).

[0169] Item 104. The solid form of any one of items 98 to 103, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having at least peaks at diffraction angles 2-theta of 4.9°, 6.5°, 7.5°, 8.2°, 9.9°, 12.0°, 12.7°, 14.8°, 15.0°, 15.4°, 16.0°, 17.0°, 17.4°, and 19.6° (each ±0.2°).

[0170] Item 105. The solid form of item 98 having an X-ray powder diffraction pattern substantially as shown in FIG.

[0171] Item 106. A solid form which is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form III.

[0172] Item 107. The solid form of item 106, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having at least one peak at a diffraction angle 2-theta of 5.5°, 8.5°, 11.0°, 11.9°, 12.4°, 14.0°, 14.3°, 16.3°, 16.6°, 17.0°, or 19.1° (each ±0.2°).

[0173] Item 108. The solid form of items 106 or 107, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 5.5°±0.2° combined with at least one peak selected from 8.5°, 11.0°, 11.9°, 12.4°, 14.0°, 14.3°, 16.3°, 16.6°, 17.0°, and 19.1° (each ±0.2°).

[0174] Item 109. The solid form of any one of items 106 to 108, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having a peak at a diffraction angle 2-theta of 5.5° combined with at least one peak selected from 8.5°, 11.0°, and 11.9° (each ±0.2°).

[0175] Item 110. A solid form of any one of items 106 to 109, characterized by an X-ray powder diffraction pattern using Cu Ka radiation having at least peaks at diffraction angles 2-theta of 5.5°, 8.5°, 11.0°, 11.9°, 12.4°, 14.0°, 14.3°, 16.3°, 16.6°, 17.0°, and 19.1° (each ±0.2°).

[0176] Item 111. The solid form of item 106, having an X-ray powder diffraction pattern substantially as shown in FIG.

[0177] Item 112. Amorphous 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), solid form.

[0178] Item 113. The solid form of item 112, having an X-ray powder diffraction pattern substantially as shown in FIG.

[0179] The term "about" means plus or minus 10% of the recited numerical value.

[0180] The terms "acute myeloid leukemia," "acute myelogenous leukemia," and "acute nonlymphocytic leukemia" are synonymous.

[0181] The term "aggressive cancer" refers to cancer that has spread to lymph nodes or other tissues other than where the cancer began. For example, aggressive AML is AML that has spread to tissues other than the blood or bone marrow.

[0182] The term "anhydrous crystalline solid" refers to a crystalline solid that does not have water associated in the crystal lattice. Anhydrous crystalline solids may still contain residual water that is not part of the crystal structure but may be adsorbed on the surface or absorbed into disordered regions of the crystal.

[0183] The term "anhydrous nonsolvated crystalline solid" refers to a crystalline solid that does not have water or organic solvents associated in the crystalline lattice. Anhydrous nonsolvated crystalline solids may still contain residual water or organic solvents that are not part of the crystal structure but may be adsorbed on the surface or absorbed into disordered regions of the crystal.

[0184] The term "cancer" refers to or describes a physiological condition in a patient that is typically characterized by uncontrolled cell growth. This definition includes benign and malignant cancers.

[0185] The term "crystalline solid isostructural solvate" refers to a crystalline solid that is capable of associating different organic solvents in the crystal lattice without significant distortion of the crystal lattice structure.

[0186] The term "crystalline solid solvate" refers to a crystalline solid having an organic solvent associated in the crystalline lattice.

[0187] The term "frontline cancer" means that the human cancer patient has not received treatment for the cancer being treated.

[0188] The term "gentisic acid" refers to 2,5-dihydroxybenzoic acid, which can be represented by the following structure: [ka]

[0189] The term "hematological malignancy" relates to cancer originating in the blood, bone marrow, lymph nodes, or lymphatic fluid.

[0190] The term "IDH1 R132 mutation" refers to an IDH1 mutation at amino acid residue 132 in a subject's IDH1 enzyme, eg, as determined in a subject's nucleic acid (eg, DNA).

[0191] The term "IDH2 R140 mutation" refers to an IDH2 mutation at amino acid residue 140 in a subject's IDH2 enzyme, eg, as determined in a subject's nucleic acid (eg, DNA).

[0192] The term "IDH2 R172 mutation" refers to an IDH2 mutation at amino acid residue 172 in a subject's IDH2 enzyme, eg, as determined in a subject's nucleic acid (eg, DNA).

[0193] The term "identified as having an IDH1 R132 mutation" means that nucleic acid (e.g., DNA) from a subject's tissue or cells (e.g., circulating tumor cells) has been analyzed to determine whether the subject has an IDH2 R132 mutation. For example, the subject's blood cells, bone marrow cells, blood cells, bone marrow, or solid tissues have been analyzed for an IDH1 R132 mutation.

[0194] The term "identified as having an IDH2 R140 mutation" means that nucleic acid (e.g., DNA) from a tissue or cell of a subject has been analyzed to determine whether the subject has an IDH2 R140 mutation. For example, the blood cells, bone marrow cells, blood cells, bone marrow, or solid tissue of a subject have been analyzed for an IDH2 R140 mutation.

[0195] The term "identified as having an IDH2 R172 mutation" means that nucleic acid (e.g., DNA) from a tissue or cell of a subject has been analyzed to determine whether the subject has an IDH2 R172 mutation. For example, the blood cells, bone marrow cells, blood cells, bone marrow, or solid tissue of a subject have been analyzed for an IDH2 R172 mutation.

[0196] The term "nonsolvated crystalline solid" refers to a crystalline solid that does not have organic solvent associated in the crystal lattice. Nonsolvated crystalline solids may still contain residual organic solvent that is not part of the crystal structure but may be adsorbed on the surface or absorbed into disordered regions of the crystal.

[0197] The term "patient" means a mammal, including, but not limited to, a human. Humans are the preferred patient.

[0198] The term "pharmaceutically acceptable carrier, diluent, or excipient" refers to a medium generally accepted in the art for the delivery of a biologically active agent to a mammal, e.g., a human.

[0199] The term "pharmaceutically acceptable salt(s)" refers to relatively non-toxic inorganic and organic salt(s) of a therapeutic agent (SM Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol 66, No. 1, January 1977).

[0200] The term "refractory cancer" refers to cancers that have been treated but in which the human cancer patient has failed to respond to the treatment.

[0201] The term "recurrent cancer" means that a human cancer patient has responded to treatment for a period of time, but the cancer has returned.

[0202] The term "solid tumor cancer" means that the cancer originates in tissue that is not the blood, bone marrow, lymph nodes, or lymphatic fluid.

[0203] The term "solid tumor tissue" refers to tissue that is not blood tissue. Non-limiting examples of solid tissue are bile duct tissue, pancreatic tissue, head tissue, neck tissue, liver tissue, skin tissue, astrocyte tissue, oligodendrocyte tissue, glial tissue, brain tissue, bladder tissue, colorectal tissue, lung tissue, and sinonasal undifferentiated carcinoma tissue.

[0204] The term "therapeutically effective amount" refers to the amount of solid form described herein administered to a subject that will induce the subject's biological or medical response or the desired therapeutic effect on the subject. Therapeutically effective amount can be easily determined by the attending physician who is skilled in the art by using known techniques and observing the results obtained under similar circumstances. In determining the effective amount for a subject, many factors are considered by the attending physician, including, but not limited to, the size, age, and general health of the individual subject; the specific disease or disorder involved; the degree or severity of the involvement of the disease or disorder; the response of the individual subject; the specific compound administered; the method of administration; the bioavailability characteristics of the preparation administered; the selected dosing schedule; the use of concomitant drugs; and other relevant circumstances.

[0205] The terms "treatment," "treat," "treating," and the like are meant to include slowing, halting, or reversing the progression of cancer. These terms also include alleviating, ameliorating, mitigating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the cancer is not actually eliminated or the progression of the cancer itself is not slowed, halted, or reversed.

[0206] The following examples are provided to illustrate the invention and are not intended to limit it in any way.

[0207] XRPD patterns of the crystalline solids of Examples 2 and 7 are obtained on a Bruker D8 Endeavor X-ray powder diffractometer equipped with a CuKα (1.5418 Å) source and a Linxeye detector, operating at 40 kV and 40 mA. Samples are scanned from 4 to 42 2θ°, using a primary slit aperture of 0.3°, and a particle size distribution (PSD) aperture of 3.9°, with a step size of 0.009 2θ° and a scan rate of 0.5 sec / step. Dry powders are loaded into a quartz sample holder, and a glass slide is used to obtain a smooth surface. Diffraction patterns of the crystalline forms are collected at ambient temperature and relative humidity. Crystalline peak positions are determined in MDI-Jade after shifting the entire pattern based on an internal NIST675 standard with peaks at 8.853 and 26.774 2θ°.

[0208] XRPD patterns of the crystalline solids of Examples 3 and 4 are obtained on a PANalytical X'Pert PRO MPD or Empyrean diffractometer using an incident beam of Cu radiation generated with an Optix long fine focus source. An elliptical tilted multilayer mirror was used to focus Cu Kα (1.5418 Å) X-ray radiation through the specimen onto the detector. Prior to analysis, a silicon specimen (NIST SRM 640f) is analyzed to verify that the position of the observed Si(111) peak is consistent with the NIST certified position. The specimen is sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, short anti-scatter extensions, and an anti-scatter knife edge are used to minimize background generated by air. Soller slits of the incident and diffracted beams are used to minimize spread from axial divergence. Diffraction patterns are collected using a scanning position sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v.5.5. Crystalline peak positions are determined with MDI-Jade v7.9.9.

[0209] For all XRPD examples in this document, it is well known in the art of crystallography that for any given crystalline form, the relative intensities of the diffraction peaks may vary due to preferred orientations resulting from factors such as crystal morphology and crystal habit. When preferred orientation effects are present, the peak intensities change, but the characteristic peak positions of the polymorph do not. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the art of crystallography that for any given crystalline form, the angular peak positions may vary slightly. For example, peak positions may vary due to variations in the temperature at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the case of the present invention, the variation in peak positions of ±0.2 2θ° is estimated to account for these potential variations without precluding unambiguous identification of the indicated crystalline form. Confirmation of the crystalline form may be based on any unique combination of prominent peaks.

[0210] Solid-state NMR (ssNMR) was obtained on a Bruker Avance III HD equipped with a Bruker Ultrashield 400WB Plus magnet operating at a frequency of 100.6 MHz. The probe used is a Bruker MAS 4 BL CP BB DVT NP / H. Acquisition parameters were as follows: 7776 scans, 34 ms acquisition time, 4.2 s interpulse delay, 10 kHz magic angle spinning (MAS) frequency, 1.5 ms contact time, and SPINAL64 decoupling scheme. Data were externally referenced to adamantane at 29.5 ppm.

[0211] Combined TGA / DSC analysis is performed using a Mettler Toledo TGA / DSC3+ analyzer. Temperature and enthalpy adjustments are made using phenyl salicylate, indium, tin, and zinc, then verified with indium. The balance is verified with calcium oxalate. The sample is placed in an aluminum pan. The pan is hermetically sealed, the lid is drilled, and then inserted into the TG furnace. A weighing aluminum pan configured as the sample pan is placed on the reference platform. The furnace is heated under nitrogen.

[0212] Example 1 Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one The title compound may be prepared as described in WO / 18 / 111707.

[0213] Example 2 Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I [ka] 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one (17.9 g, 35.5 mmol) is suspended in acetonitrile (250 mL) at 70 °C with stirring at 700 rpm. 2,5-Dihydroxybenzoic acid (12.05 g, 78.1 mmol) is added to the solution. The reaction mixture becomes a clear solution before a white solid precipitates. The heat source is removed and the mixture is stirred at room temperature, becoming an off-white solid slurry. The solid is isolated by filtration under vacuum, rinsed with acetonitrile (50 mL), dried under vacuum and nitrogen for 15 minutes, and then dried in a vacuum oven at 60° C. overnight to give the title compound (27.3 g, 94.7% yield). 13 C solid-state NMR (100.6MHz) δ175.2, 174.2, 166.3, 159.8, 155.1, 153.0, 150.8, 149.4, 145.2, 141.0, 133.9, 130.3, 129.2, 128.4, 127.6, 127.1, 126.7, 122.4, 120.1, 119.3, 119.0, 118.0, 117.6, 115.9, 114.0, 102.7, 68.1, 63.1, 52.7, 49.6, 44.1, 41.9, 39.0, 32.1, 23.9, 12.8, 8.2, 5.9, 5.1ppm.

[0214] XRPD A prepared sample of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I is characterized by an XRPD pattern using CuKα radiation having the diffraction peaks (2-theta values) set out in Table 1 below, in particular having a peak at 9.0 combined with one or more peaks selected from 7.2, 9.5, and 11.7, with a diffraction angle tolerance of 0.2 degrees. [Table 1]

[0215] Single crystal structure analysis A 12.0 mg prepared sample of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I was placed in a vial and dissolved in ethanol (1 ml). The vial opening was sealed with aluminum foil and pierced once. The sample was kept at 10°C and allowed to evaporate almost completely over a period of 12 days after which the appropriate crystals were isolated. Dimensions: 0.25 x 0.05 x 0.02 mm 3 A colorless needle with approximate dimensions of is attached to the polymer loop in random orientation. Preliminary examination and data collection are performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus sealed X-ray tube (Cu Kαλ=1.54184 Å) and a Dectris Pilatus3 R 200K hybrid pixel array detector. The cell constant and orientation matrix for data collection are obtained from a least-squares refinement using set angles of 10655 reflections in the range 4.2920°<θ<75.6600°. The space group is determined to be C2 (International Table Number 5) by the program CRYSALISPRO. Data are collected at room temperature up to a maximum diffraction angle (2θ) of 151.682°.

[0216] The structure of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I is determined to be an anhydrous, nonsolvated crystalline solid consisting of one 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one dication and two gentisate anions in the asymmetric unit. The absolute configuration was determined from the crystal structure and the molecule is found to bond in the S configuration at both chiral centers.

[0217] TGA Analyze a prepared sample of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I by thermogravimetric analysis (TGA). Form I exhibits a weight loss of 0.6% between 45 and 100 °C, likely due to loss of moisture, consistent with the anhydrous form.

[0218] Example 3 Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form II acetone solvate Example 2 (52 mg, 0.064 mmol) is suspended in acetone (4 mL) and heated to 55 °C to form a clear solution. Filter the solution through a 0.2 µm nylon syringe filter and quickly cool the solution to 0 °C and observe for precipitation. Store the material at 10-25 °C for 7 days and isolate the solid wet by vacuum filtration.

[0219] XRPD A prepared sample of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form II acetone solvate is characterized by an XRPD pattern using CuKα radiation having the diffraction peaks (2 theta values) set forth in Table 2 below, in particular having a peak of 6.5 combined with one or more peaks selected from the group consisting of 4.9, 8.2, and 12.7, with a diffraction angle tolerance of 0.2 degrees. [Table 2]

[0220] TGA A prepared sample of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form II acetone solvate is analyzed by thermogravimetric analysis (TGA). Form II acetone solvate exhibits a weight loss of approximately 7.1% between 37 and 140 °C, corresponding to approximately 1.1 moles of acetone.

[0221] Example 4 Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form III Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form II acetone solvate is dried under vacuum at 45° C. for 1 day.

[0222] XRPD A prepared sample of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form III is characterized by an XRPD pattern using CuKα radiation having the diffraction peaks (2-theta values) set forth in Table 3 below, in particular having a peak at 5.5 combined with one or more peaks selected from the group consisting of 8.5, 11.0, and 11.9, with a diffraction angle tolerance of 0.2 degrees. [Table 3]

[0223] TGA Analyze a prepared sample of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form III by thermogravimetric analysis (TGA). Form III exhibits a weight loss of 0.6% between 47 and 150 °C, consistent with the anhydrous form.

[0224] Example 5 Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form II MEK solvate Example 2 is stirred in methyl ethyl ketone (MEK) at room temperature for 1 day. The resulting precipitated solid is collected by filtration through a 0.22 μm nylon centrifuge filter to give the title compound.

[0225] Example 6 Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form III The crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form II MEK solvate is dried under vacuum at 75° C. for 5 hours to provide the title compound.

[0226] Example 7 Amorphous 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) (approximately 340 mg, 0.44 mmol) is dissolved in a minimum amount of EtOH to dissolve the material, evaporate to dryness at 55° C., and dry under vacuum at room temperature for 1 day to give the title compound as amorphous.

[0227] Example 8 Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid (1:2) [ka] 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one (1.205 g, 2.45 mmol) is suspended in acetonitrile (20 mL) at 70° C. with stirring at 700 rpm. 2,3-Dihydroxybenzoic acid (0.832 g, 5.4 mmol) is added to the solution, dissolving the solids to give a clear, light pink solution. The mixture is syringe filtered, the heat source is removed, and the mixture is stirred and allowed to cool to room temperature to give a solid slurry. The white solid is isolated by filtration under vacuum, rinsed with acetonitrile (5 mL), dried under vacuum and nitrogen for 15 minutes, then dried in a vacuum oven at 60° C. overnight to give the title compound.

[0228] XRPD A prepared sample of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid (1:2) is characterized by an XRPD pattern using CuKα radiation having the diffraction peaks (2 theta values) set out in Table 4 below, in particular having a peak at 11.5 combined with one or more peaks selected from 8.9, 15.0, and 24.6, with a diffraction angle tolerance of 0.2 degrees. [Table 4]

[0229] Example 9 Crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid (1:2) [ka] 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one (approximately 0.150 g, 2.45 mmol) is added to a saturated solution of 2,4-dihydroxybenzoic acid in acetonitrile (5 mL) at 60° C. The solid dissolves into a light brown solution, then a white solid precipitates. The white solid is isolated by filtration under vacuum, rinsed with acetonitrile (3 mL), and dried under vacuum and nitrogen for 15 minutes to give the title compound.

[0230] Example 10 No-sink dissolution test Non-sink dissolution is performed by adding the test composition to a solution of 0.01N HCl pH 2 (e.g., in a centrifuge tube) and analyzing by HPLC for 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one solution concentration at about time zero, 20, and 40 minutes. After about 40 minutes, a solution of fasted state simulated intestinal fluid (FaSSIF) pH 6.5 containing 0.224% by weight bile salts is added to the pH 2 solution. 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one concentrations are monitored by HPLC at approximately 50, 70, 90, and 120 minutes from time zero. At each time point, samples are centrifuged at 18,500 g force for 3 minutes to remove undissolved solids from the samples. For analysis, supernatant samples (100 μL) are diluted 5-fold using 1:1 acetonitrile / H2O and analyzed. Non-sink dissolution tests are completed at room temperature. See Table 5 below. [Table 5]

[0231] Table 5 shows the increased solution concentration of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one at 70 minutes at high pH provided by TC2, TC3, and TC4 compared to TC1.

[0232] Example 11 Pharmacokinetic study in dogs Pharmacokinetic (PK) studies are conducted to evaluate the pharmacokinetic performance of formulations containing crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I and formulations containing crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one.

[0233] Male beagle dogs will be administered a single 5 mg / kg or 50 mg oral gavage dose of each formulation. Within each study, a crossover design will be used with eight fasted dogs in each period in which one formulation will be tested, with a 4-7 day washout period in between.

[0234] The studies are performed under conditions of high gastric pH or under conditions that mimic the normal human gastric pH environment: two studies include famotidine to mimic patients taking acid reducers, and one study uses pentagastrin to mimic the normal human gastric pH environment or does not include a PPI.

[0235] Blood samples (approximately 1 mL, jugular vein) from each group are collected at 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after dosing. Plasma is collected from the blood samples, diluted with water:phosphate (75:25) to a plasma ratio of 100:1, and stored frozen until analyzed. For example, add 10.0 μL of water:phosphate (75:25) to whole blood (1000 μL) before collecting plasma.

[0236] Plasma concentrations of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one are measured using a validated LC-MS / MS assay using the following conditions: the instrument autosampler is a Shimadzu SIL20AC, the liquid chromatography pump is a Shimadzu LC20AD pump, the liquid chromatography controller is a Shimadzu CBM10A controller, and the mass spectrometer is a Sciex API 5000. The liquid chromatography uses a mobile phase A of 1M ammonium formate in water and a mobile phase B of 1M ammonium formate in 50% acetonitrile and 50% methanol on a Halo 5 C18, 20x2.1 mm column at ambient temperature with a flow rate of 1.5 mL / min.

[0237] Pharmacokinetic parameters are reported to three significant figures, except for values ​​for time, which are reported to two decimal places. Noncompartmental plasma pharmacokinetic parameters are calculated using Watson (version 7.5). Plasma concentrations of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one below the lower limit of quantification (1 ng / mL or 1.98 nM) are assigned a value of zero.

[0238] Pharmacokinetic study 1 Formulation 1. A suspension of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I is prepared as follows: Weigh crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I into a preparation vessel. The vehicle, 0.5% (w / v) methylcellulose A4M in purified water, is slowly added while pasting with a spatula to prepare a suspension (5 mg of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one / mL suspension). Continue pasting and stirring with a spatula until the mixture is well dispersed. The mixture is then stirred with a magnetic stir bar and stir plate to ensure the formulation is homogenous.

[0239] Comparative Formulation 1. A suspension of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one is prepared as follows: Weigh crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one into a preparation vessel. The vehicle, 0.5% (w / v) methylcellulose A4M in purified water, is added slowly while pasting with a spatula to prepare a suspension (5 mg of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one active ingredient / mL suspension). Continue pasting and stirring with a spatula until the mixture is well dispersed. The mixture is then stirred with a magnetic stir bar and stir plate to ensure the formulation is homogenous.

[0240] Study 1. Fasted dogs are administered famotidine tablets (40 mg / animal) by oral gavage. Water (5-10 mL) is used ad libitum to facilitate swallowing of the famotidine tablets. Approximately 1 hour later, dogs are administered Formulation 1 or Comparative Formulation 1 by oral gavage. Water (approximately 15 mL) is flushed through the gavage tube before withdrawing it after administration of Formulation 1 or Comparative Formulation 1. The dose level of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one active ingredient is 5 mg / kg. At selected time points, whole blood (approximately 1 mL) is drawn from the jugular vein and added to tubes (Covidien Monoject 2 mL, Cat. No. 8881311149 and Greiner Bio-One 2 mL, Cat. No. 454222) pre-coated with the anticoagulant tripotassium ethylenediaminetetraacetate (K3EDTA). Within the study, a crossover design with eight fasted dogs is used with one formulation tested in each period, and a seven day washout period in between. Samples are collected for each formulation tested at the following time points: 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose. [Table 6]

[0241] Table 6 shows that dogs had increased exposure to 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one via administration of Formulation 1 when pretreated with famotidine. max and AUC 0-24 The exposure levels of the comparative formulations were approximately 10-fold and 4-fold higher than that of the comparative formulation 1, as measured by both serotonin and serotonin concentrations.

[0242] Pharmacokinetic study 2 Formulation 2. A tablet containing crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I is prepared as follows. Tablets are prepared by blending crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I with microcrystalline cellulose (MCC), mannitol, croscarmellose sodium, silicon dioxide, and sodium stearyl fumarate. After blending, the powder is compressed into slugs and milled to create free-flowing granules. The granules are blended with croscarmellose sodium, silicon dioxide, and sodium stearyl fumarate to create the final blend. Tablets (containing 25 mg of active ingredient) are made from the final blend by compressing 11 / 32 inch standard concave round tablets to approximately 8 kP hardness. See Table 7 below for tablet formulation. [Table 7]

[0243] Comparative Formulation 2. Capsules containing crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one are prepared as follows: Neat crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one powder is filled into size #3 hypromellose opaque white capsule shells at a strength of 25 mg active ingredient per capsule.

[0244] Study 2. Dogs are administered famotidine (40 mg) tablets by oral gavage. Approximately 1 hour later, dogs are administered formulation 2 or comparative formulation 2 by oral gavage, followed by water (5-10 mL) flushing to ensure swallowing. The dose level is 50 mg of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one using two tablets. Whole blood (approximately 1 mL) is collected from the jugular vein and added to tubes (Greiner Bio-One 2 mL, catalog number 454428) pre-coated with the anticoagulant dipotassium ethylenediaminetetraacetate (K2-EDTA). Within the study, a crossover design was used with 8 fasted dogs in each period testing one formulation with a 4 day washout period in between. Samples are collected for each formulation tested at the following time points: 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose. [Table 8]

[0245] Table 8 shows that formulation 2 has an AUC 0-24 This shows that the exposure level is approximately four times that of Comparative Formulation 2, as measured by

[0246] Test 3: Pentagastrin (6 μg / kg) at a dose volume of 0.06 mL / kg is administered by intramuscular injection in dogs approximately 30 minutes prior to dosing with Formulation 2 or Comparative Formulation 2. Formulation 2 and Comparative Formulation 2 are added by oral gavage followed by water (5-10 mL) flush to ensure swallowing. The dose level is 50 mg of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one. Whole blood (approximately 1 mL) is collected from the jugular vein and added to tubes (Covidien Monoject 2 mL, catalog number 8881311149) pre-coated with the anticoagulant K3EDTA and pre-spiked with 25% phosphoric acid (10 μL). Within the study, a crossover design with 8 fasted dogs is used with one formulation tested in each period and a 5-day washout period in between. Samples are collected at the following time points: 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose. [Table 9]

[0247] AUC under acidic conditions 0-24 Table 9 shows that Comparative Formulation 2 and Formulation 2 have more comparable exposure levels compared to exposure at high pH as measured by pH 7.0 and indicates that the lower exposure of 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one crystalline free base in famotidine pretreated dogs (Tables 6 and 8) is due to gastric pH dependent solubility.

[0248] Example 12 An Open-Label, Randomized, Crossover Study to Evaluate the Effects of Food and Proton Pump Inhibitors on the Single-Dose Pharmacokinetics of Crystalline 7-[[(1S)-1-[4-[(1S)-2-Cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2) Form I in Healthy Adult Subjects

[0249] Test Rationale The aqueous solubility of Compound A is pH dependent, therefore gastrointestinal (GI) pH modification may affect the solubility and subsequent oral absorption of Compound A from the GI tract. The primary objectives of the study were to evaluate and compare the single-dose PK of Compound A when administered as Compound A crystalline free base (in capsules) versus Compound A digentisate Form I (in tablet formulation) in healthy adult subjects under fasting conditions, to evaluate the effect of a standard low-fat meal on the single-dose PK of Compound A when administered as Compound A digentisate Form I (in tablet formulation) in healthy adult subjects, and to evaluate the effect of gastric pH modification by a PPI (esomeprazole) on the single-dose PK of Compound A when administered as Compound A digentisate Form I (in tablet formulation) under fasting or fed conditions in healthy adult subjects.

[0250] Study design This is a Phase 1, open-label study in four groups of healthy adult subjects. Groups 1 and 2 have a randomized, two-way crossover design, and groups 3 and 4 have a fixed sequence design. The groups can be dosed in any order.

[0251] Group 1: Tablet vs. Capsule Comparison Group (Fasting State) In Group 1, a single oral dose of Compound A is administered on days 1 and 4 via a capsule containing Compound A crystalline free base or a tablet containing Compound A digentisate Form I. According to a randomization scheme, subjects are randomly assigned to one of two treatment sequences (AB or BA).

[0252] Treatment Sequence AB: On Day 1 (Period 1), a single oral dose of 300 mg Compound A (4 x 75 mg capsules) is administered in the morning, fasted for at least 10 hours before and 4 hours after dosing (Treatment A). On Day 4 (Period 2), a single oral dose of 300 mg Compound A (4 x 75 mg capsules) is administered in the morning, fasted for at least 10 hours before and 4 hours after dosing (Treatment B), at the same time of day (± 1 hour) as the actual Day 1 Compound A dose.

[0253] Treatment sequence BA: On Day 1 (Period 1), a single oral dose of 300 mg Compound A (4 x 75 mg tablets) is administered in the morning, fasted for at least 10 hours before and 4 hours after dosing (Treatment B). On Day 4 (Period 2), a single oral dose of 300 mg Compound A (4 x 75 mg capsules) is administered in the morning, fasted for at least 10 hours before and 4 hours after dosing (Treatment A), at the same time of day (± 1 hour) as the actual Day 1 Compound A dose.

[0254] Group 2: Food effect comparison group (tablet formulation) In Group 2, a single oral dose of Compound A is administered under fasted and fed conditions on days 1 and 4 via a tablet containing Compound A digentisate Form I. According to a randomization scheme, subjects are randomly assigned to one of two treatment sequences (BC or CB).

[0255] Treatment Sequence BC: On Day 1 (Period 1), a single oral dose of 300 mg Compound A (4 x 75 mg tablets) is administered in the morning, fasted for at least 10 hours before and 4 hours after dosing (Treatment B). On Day 4 (Period 2), a single oral dose of 300 mg Compound A (4 x 75 mg tablets) is administered in the morning, approximately 30 minutes after starting a standard low-fat meal (Treatment C), at the same time of day (± 1 hour) as the actual Day 1 Compound A dose.

[0256] Treatment Sequence CB: On Day 1 (Period 1), a single oral dose of 300 mg Compound A (4 x 75 mg tablets) is administered in the morning, approximately 30 minutes after starting a standard low-fat meal (Treatment C). On Day 4 (Period 2), a single oral dose of 300 mg Compound A (4 x 75 mg capsules) is administered in the morning, fasted for at least 10 hours before and 4 hours after dosing (Treatment B), at the same time of day (± 1 hour) as the actual Day 1 Compound A administration.

[0257] Group 3: pH-effect fasting group (tablet formulation) In Group 3, a single oral dose of Compound A is administered under fasting conditions in Period 1 via a tablet containing Compound A digentisate Form I. In Period 2, a single oral dose of Compound A via a tablet containing Compound A digentisate Form I is administered simultaneously under fasting conditions after multiple oral doses of esomeprazole.

[0258] Period 1 (Treatment B): A single oral dose of 300 mg of Compound A (4 x 75 mg tablets) is administered in the morning, with the subject fasting for at least 10 hours prior to dosing and 4 hours after dosing.

[0259] Period 2 (Treatment D): A single oral dose of 400 mg esomeprazole (1 x 40 mg capsule) is administered QD in the morning on days 4-8, after fasting for at least 8 hours prior to esomeprazole administration, followed by a standard low-fat meal 1 hour after dosing. On day 9, subjects receive a single oral dose of 40 mg esomeprazole (1 x 40 mg capsule) followed immediately by a single oral dose of 300 mg Compound A (4 x 75 mg tablets) in the morning, after fasting for at least 10 hours prior to and 4 hours after esomeprazole and Compound A co-administration, at the same time of day (± 1 hour) as the actual day 1 Compound A administration.

[0260] Group 4: pH effect feeding group (tablet formulation) In Group 4, a single oral dose of Compound A is administered under fed conditions in Period 1 via a tablet containing Compound A digentisate Form I. In Period 2, a single oral dose of Compound A via a tablet containing Compound A digentisate Form I is administered under fed conditions after multiple oral doses of esomeprazole.

[0261] Period 1 (Treatment C): A single oral dose of 300 mg of Compound A (4×75 mg tablets) is administered on the morning of Day 1, approximately 30 minutes after the start of a standard low-fat meal.

[0262] Period 2 (Treatment E): A single oral dose of 400 mg esomeprazole (1 x 40 mg capsule) is administered QD in the morning on days 4-8 after at least 8 hours of fasting prior to esomeprazole administration, followed by a standard low-fat meal 1 hour after administration. On day 9, subjects receive a single oral dose of 40 mg esomeprazole followed immediately by a single oral dose of 300 mg Compound A (4 x 75 mg tablets) in the morning, approximately 30 minutes after starting a standard low-fat meal, at the same time of day (± 1 hour) as the actual day 1 Compound A administration.

[0263] There is a three-day washout period between the two doses of Compound A administered to subjects in Groups 1 and 2, and between the first dose of Compound A administered on day 1 and the first dose of esomeprazole administered to subjects in Groups 3 and 4.

[0264] All study drugs will be administered orally in approximately 240 mL of water. If necessary, an additional 100 mL of water may be administered.

[0265] A standard low-fat meal should be consumed entirely within 30 minutes. A standard low-fat meal is: 400-500 total calories, 11-14 grams of fat, 25% calories from fat.

[0266] Serial PK blood samples for analysis of Compound A plasma concentrations are collected pre-dose through 48 hours post-dose of Compound A for each treatment period in each of the four treatment groups. In addition, urine is collected pre-dose through 24 hours post-dose of Period 1 of Group 3 for analysis of Compound A urinary concentrations. Samples collected for analysis of Compound A plasma and urinary concentrations may be stored and analyzed for subsequent exploratory analyses, such as quantification of Compound A metabolites.

[0267] Whenever possible, the following PK parameters are calculated for each subject based on the plasma concentrations of Compound A (as appropriate): AUC from 0 to 24 hours post-dose (AUC0-24), calculated by the linear trapezoidal rule for increasing and decreasing concentrations, AUC from 0 to 48 hours post-dose (AUC0-48, if possible), calculated by the linear trapezoidal rule for increasing and decreasing concentrations, AUC from 0 hours to the last measurable concentration (AUC0-t), calculated using the linear trapezoidal rule for increasing and decreasing concentrations, extrapolated AUC from 0 hours to infinity (AUC0-inf), extrapolated percentage of AUC0-inf (%AUCextrap), Cmax, time to Cmax (tmax), apparent terminal elimination rate constant (λZ), apparent total body clearance (CL / F), apparent plasma terminal elimination half-life (t1 / 2), and apparent volume of distribution at terminal time (VZ / F). λZ and t1 / 2 are calculated by linear least squares regression analysis using the maximum number of points in the terminal log-linear phase (e.g., 3 or more nonzero plasma concentrations). Individual subject measurements and summary statistics (e.g., group means, standard deviations, coefficients of variation, ranges) are reported.

[0268] Whenever possible, the following PK parameters will be calculated for each subject in Period 1 of Group 3 based on urinary concentrations of Compound A (as appropriate): amount of drug excreted in urine (Ae), percentage of the dose excreted unchanged in urine (Fe), and renal clearance (CLR).

[0269] Capsule Formulation: Capsules containing crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one are prepared as follows: Neat crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one powder is filled into size #0 light blue hypromellose capsule shells at a strength of 75 mg active ingredient per capsule.

[0270] Tablet formulation. Tablets containing Compound A digentisate Form I are prepared as follows. The tablets are prepared by blending crystalline Compound A digentisate Form I with microcrystalline cellulose (MCC), mannitol, poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP VA), croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate. After blending, the powder is dry granulated and milled to make free-flowing granules. The granules are blended with croscarmellose sodium, talc, colloidal silicon dioxide, and sodium stearyl fumarate to make the final blend. Tablets (containing 15 mg, 25 mg, 75 mg, or 150 mg of active ingredient) are made from the final blend by compression. Finally, the tablets are superficially coated using a conventional pan coating procedure. See Table 10 below for tablet formulation. [Table 10]

[0271] Test results Group 1: Tablet vs. Capsule Comparison Group (Fasting State) As shown in Table 11 and FIG. 6, the capsule and tablet formulations provide comparable relative bioavailability in healthy volunteers (n=14). [Table 11]

[0272] Group 2: Food effect comparison group (tablet formulation) As shown in Table 12 and FIG. 7, the tablet formulations provide comparable relative bioavailability in healthy volunteers (n=14) under fed and fasted conditions. [Table 12]

[0273] Group 3: pH-effect fasting group (tablet formulation) As shown in Table 13 and FIG. 8, the tablet formulations alone and with esomeprazole (PPI) provide comparable relative bioavailability in healthy volunteers (n=14) under fasting conditions. [Table 13]

[0274] Group 4: pH effect feeding group (tablet formulation) As shown in Table 14 and FIG. 9, the tablet formulations alone and with esomeprazole (PPI) provide comparable relative bioavailability in healthy volunteers (n=14) under fed conditions. [Table 14]

[0275] Test Conclusion Food effect. Data from healthy volunteers given Compound A digentisate Form I in a tablet formulation with a low-fat meal shows no effect of food on Compound A exposure. Thus, Compound A digentisate Form I in a tablet formulation can be given with or without food.

[0276] pH effect. Data from healthy volunteers given Compound A digentisate Form I in a tablet formulation in the fasted or fed state shows no effect of proton pump inhibitors (PPIs) on Compound A exposure. Thus, Compound A digentisate Form I in a tablet formulation can be given in the fasted or fed state with or without a PPI and an antacid.

Claims

1. A solid form which is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2).

2. A solid form which is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), (i) an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-theta of 7.2°±0.2°, 9.0°±0.2°, 9.5°±0.2°, 10.9°±0.2°, 11.7°±0.2°, 14.5°±0.2°, 15.7°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 19.2°±0.2°, 20.8°±0.2°, 24.1°±0.2°, 24.7°±0.2°, or 25.8°±0.2°; or (ii) 5.1, 5.9, 8.2, 12.8, 23.9, 32.1, 39.0, 41.9, 44.1, 49.6, 52.7, 63.1, 68.1, 102.7 , 114.0, 115.9, 117.6, 118.0, 119.0, 119.3, 120.1, 122.4, 126.7, 127.1, 127.6, 128.4 , 129.2, 130.3, 133.9, 141.0, 145.2, 149.4, 150.8, 153.0, 155.1, 159.8, 166.3, 174.2, or 175.2 ppm (each ±0.2 ppm) and containing at least one peak referenced to the upfield resonance of adamantane (d=29.5 ppm). １３ A solid form characterized by at least one of the following: C solid state NMR (100.6 MHz) spectrum.

3. 3. The solid form of claim 2, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-theta of 9.0°±0.2° combined with at least one peak selected from 7.2°±0.2°, 9.5°±0.2°, and 11.7°±0.2°.

4. Contains peaks referenced to the upfield resonance of adamantane (d=29.5 ppm) at 12.8, 23.9, 41.9, 68.1, 149.4, and 155.1 ppm (each ±0.2 ppm). １３ 3. The solid form of claim 2, characterized by a C solid state NMR (100.6 MHz) spectrum.

5. having at least one peak at a diffraction angle 2-theta of 4.9°±0.2°, 6.5°±0.2°, 7.5°±0.2°, 8.2°±0.2°, 9.9°±0.2°, 12.0°±0.2°, 12.7°±0.2°, 14.8°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 16.0°±0.2°, 17.0°±0.2°, 17.4°±0.2°, or 19.6°±0.2° A solid form of crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), characterized by an X-ray powder diffraction pattern using CuKa radiation.

6. 6. The solid form of claim 5, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-theta of 6.5° combined with at least one peak selected from 4.9°, 8.2°, and 12.7° (each ±0.2°).

7. X-rays using CuKa radiation having at least one peak at a diffraction angle 2-theta of 5.5°±0.2°, 8.5°±0.2°, 11.0°±0.2°, 11.9°±0.2°, 12.4°±0.2°, 14.0°±0.2°, 14.3°±0.2°, 16.3°±0.2°, 16.6°±0.2°, 17.0°±0.2°, or 19.1°±0.2° A solid form which is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2), characterized by a powder diffraction pattern.

8. 8. The solid form of claim 7, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-theta of 5.5°±0.2° combined with at least one peak selected from 8.5°±0.2°, 11.0°±0.2°, and 11.9°±0.2°.

9. A solid form which is amorphous 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,5-dihydroxybenzoic acid (1:2).

10. A solid form which is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,4-dihydroxybenzoic acid (1:2).

11. A solid form which is crystalline 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enoylpiperazin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one, 2,3-dihydroxybenzoic acid (1:2).

12. 12. The solid form of claim 11, characterized by an X-ray powder diffraction (XRPD) pattern using CuKa radiation having a peak at a diffraction angle 2-theta of 11.5°±0.2° combined with at least one peak selected from 8.9°±0.2°, 15.0°±0.2°, and 24.6°±0.2°.

13. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 12.

14. 14. The pharmaceutical composition of claim 13 for treating cancer in a patient expressing an IDH mutation.

15. 15. The pharmaceutical composition of claim 14, wherein the IDH mutation is an IDH1 mutation.

16. 16. The pharmaceutical composition of claim 15, wherein the IDH1 mutation is an IDH1 R132 mutation.

17. 15. The pharmaceutical composition of claim 14, wherein the IDH mutation is an IDH2 mutation.

18. 18. The pharmaceutical composition of claim 17, wherein the IDH2 mutation is an IDH2 R140 mutation.

19. 18. The pharmaceutical composition of claim 17, wherein the IDH2 mutation is an IDH2 R172 mutation.

20. The pharmaceutical composition of claim 14, wherein the cancer is a solid tumor cancer.

21. 21. The pharmaceutical composition of claim 20, wherein the solid tumor cancer is cholangiocarcinoma, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder cancer, colorectal cancer, lung cancer, or paranasal sinus undifferentiated carcinoma.

22. The pharmaceutical composition of claim 20, wherein the solid tumor cancer is cholangiocarcinoma.

23. 15. The pharmaceutical composition of claim 14, wherein the cancer is a hematological malignancy.

24. 24. The pharmaceutical composition of claim 23, wherein the hematological malignancy is acute myeloid leukemia, myelodysplastic syndrome myeloproliferative neoplasm, angioimmunoblastic T-cell lymphoma, T-cell acute lymphoblastic leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, or chronic myeloid leukemia.

25. 24. The pharmaceutical composition of claim 23, wherein the hematological malignancy is acute myeloid leukemia.

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