Solid state forms

Abstract

The present invention provides crystalline and amorphous forms of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propane)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenyl)-1-piperyl)pyrido[2,3-d]pyrimidin-2(1H)-one, including several anhydrous, hydrated and solvated forms, as well as their solid forms, pharmaceutical compositions, and methods for treating diseases mediated by KRAS G12C inhibition.

Description

[Technical Field] The present invention provides crystalline forms (including anhydrous, hydrated, and several solvated crystalline forms) of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propane)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenyl)-1-piperyl)pyrido[2,3-d]pyrimidin-2(1H)-one (hereinafter referred to as "Compound 1"), as well as its physical form, pharmaceutical composition, and method for treating diseases mediated by KRAS G12C inhibition. [Previous Technology] Compound 1 is a selective inhibitor of KRAS G12C and can be used to treat cancers, including lung cancer (e.g., non-small cell lung cancer (NSCLC)), pancreatic cancer, and colorectal cancer. Compound 1 is disclosed in U.S. Patent Application Publication No. 2018 / 0334454 A1, published on November 22, 2018. Many compounds can exist in different crystalline or polymorphic forms, which exhibit different physical, chemical, and spectroscopic properties. For example, some polymorphs of a compound may be more soluble in a particular solvent, more fluid, or more compressible than other polymorphs. See, for example, P. DiMartino et al., J. Thermal Anal., 48:447-458 (1997). In the case of pharmaceuticals, some solid forms may have higher bioavailability than others, while others may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a regulatory perspective, as pharmaceuticals are only approved by agencies such as the U.S. Food and Drug Administration if they meet stringent purity and characterization standards. In fact, regulatory approval of one polymorph of a compound (which exhibits certain solubility and physicochemical (including spectroscopic) properties) does not usually imply easy approval of other polymorphs of the same compound. In the pharmaceutical field, it is known that the polymorphism of a compound affects, for example, the solubility, stability, flowability, fractability, and compressibility of the compound, as well as the safety and efficacy of pharmaceutical products containing it. See, for example, Knapman, K. Modern Drug Discoveries, 2000, 53. Therefore, discovering new polymorphs of drugs can offer a variety of advantages. This invention provides novel polycrystalline forms of compound 1 (including anhydrous, hydrated, and several crystalline forms of solvates), as well as their physical forms, pharmaceutical compositions, and methods for treating diseases mediated by KRAS G12C inhibition. The novel polycrystalline forms can be further developed into formulations for treating such chronic diseases, and can generate numerous formulation, manufacturing, and therapeutic benefits. [Summary of the Invention] This invention provides crystalline and amorphous forms (including several anhydrous, hydrated and solvated forms) of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propane)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenyl)-1-piperyl)pyrido[2,3-d]pyrimidin-2(1H)-one, as well as their solid forms, pharmaceutical compositions, and methods for treating diseases mediated by KRAS G12C inhibition.

Implementation Method

Claims

1. A compound, wherein the compound is in the crystalline form of the M configuration isomer of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propyl)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenyl)-1-piperyl)pyridino[2,3-d]pyrimidin-2(1H)-one (compound 1), wherein the compound is characterized by at least one of the following: (a) a powder X-ray diffraction pattern containing peaks at 2θ degrees of 8.8, 10.8, 13.6, 14.2, and 19.0 ± 0.2, measured by X-ray wavelength of 1.54 Å; or (b) a 19F solid-state NMR containing peaks at about -109 and -120 ppm.

2. The compound of claim 1, wherein X-ray powder diffraction is measured using an X-ray wavelength of 1.54 Å, and the compound is characterized by X-ray powder diffraction patterns containing peaks at 2θ degrees of 8.8, 10.8, 13.6, 14.2, and 19.0 ± 0.

2.

3. The compound of claim 1, wherein the compound is characterized by 19F solid-state NMR, the 19F solid-state NMR containing peaks at about -109 and -120 ppm.

4. The compound of claim 1, wherein the compound is characterized by 19F solid-state NMR, the 19F solid-state NMR containing peaks at about -49, -60, -79, -90, -109, -120, -138, -150, -168 and -179 ppm.

5. The compound of claim 1, wherein the compound is characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic start at 293 °C.

6. The compound of claim 1, wherein the compound is characterized by a thermogravimetric analysis (TGA) heatmap that includes a 0.2% weight loss when heated from 25°C to 275°C.

7. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 6, and a pharmaceutically acceptable excipient.

8. The pharmaceutical composition as claimed in item 7, wherein the pharmaceutical composition is a dosage form for oral administration.

9. The pharmaceutical composition as claimed in item 8, wherein the dosage form is a solid dosage form.

10. The pharmaceutical composition of claim 9, wherein the solid dosage form is a tablet.

11. Use of a compound as claimed in any one of claims 1 to 6, for the preparation of a medicament for treating cancers with KRAS G12C mutations.

12. As claimed in claim 11, wherein the cancer with the KRAS G12C mutation is non-small cell lung cancer, small intestinal cancer, appendiceal cancer, colorectal cancer, endometrial cancer, pancreatic cancer, skin cancer, gastric cancer, nasal cancer, or bile duct cancer.

13. As claimed in claim 12, wherein the cancer with the KRAS G12C mutation is non-small cell lung cancer.

14. As claimed in claim 12, wherein the cancer with the KRAS G12C mutation is pancreatic cancer.

15. As claimed in claim 12, wherein the cancer with the KRAS G12C mutation is colorectal cancer.

16. The use as claimed in any of claims 12 to 15, wherein the compound is administered at a total daily dose of 5 mg to 1000 mg.

17. The use of any of claims 12 to 15, wherein the compound is administered to an adult.

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