Crystal morphology of KRAS G12C inhibitors
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- MIRATI THERAPEUTICS INC
- Filing Date
- 2026-02-26
- Publication Date
- 2026-06-09
Smart Images
Figure 2026094278000017 
Figure 2026094278000018 
Figure 2026094278000019
Abstract
Claims
1. Crystalline form of 2-[(2S-4-[7-(8-chloro-1-naphthyl)-2-[[(2S-1-methylpyrrolidine-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-4-yl]-1-(2-fluoropropanenoyl)piperazine-2-yl]acetonitrile.
2. The crystal morphology according to claim 1, wherein the crystal morphology is morphology A having an X-ray powder diffraction pattern that includes at least one peak at °2θ selected from 8.6±0.2, 14.6±0.2, 16.9±0.2, and 18.3±0.
2.
3. The crystal morphology according to claim 1, wherein the crystal morphology is morphology A having an X-ray powder diffraction pattern that includes two or more peaks at °2θ of 8.6±0.2, 14.6±0.2, 16.9±0.2 and 18.3±0.
2.
4. The crystal morphology according to claim 1, wherein the crystal morphology is morphology A having an X-ray powder diffraction pattern with peaks at 8.6±0.2, 14.6±0.2, 16.9±0.2 and 18.3±0.2°2θ.
5. The crystal morphology according to claim 3, wherein morphology A has an X-ray powder diffraction pattern that includes peaks at °2θ of 5.8±0.2, 8.6±0.2, 12.3±0.2, 13.0±0.2, 14.2±0.2, 14.6±0.2, 16.0±0.2, 16.9±0.2, 18.1±0.2, 18.3±0.2, 20.4±0.2, 21.2±0.2, 23.9±0.2 and 25.5±0.
2.
6. The crystal form according to claim 1, wherein the crystal form is substantially form A having the XRPD pattern shown in Figure 1A or Figure 1B.
7. The crystal morphology according to claim 2, characterized in that morphology A has an endothermic peak that starts at approximately 107°C, as determined by differential scanning calorimetry.
8. The crystal morphology according to claim 2, characterized in that morphology A has an endothermic peak that starts at approximately 119°C, as determined by differential scanning calorimetry.
9. The crystal morphology according to claim 2, wherein morphology A substantially has the DSC thermogram shown in Figure 2.
10. The crystal morphology according to claim 9, wherein morphology A has an X-ray powder diffraction pattern that includes at least one peak at °2θ selected from 8.6±0.2, 14.6±0.2, 16.9±0.2, and 18.3±0.
2.
11. The crystal morphology according to claim 9, wherein morphology A has an X-ray powder diffraction pattern that includes at least one peak at °2θ selected from 5.8±0.2, 8.6±0.2, 12.3±0.2, 13.0±0.2, 14.2±0.2, 14.6±0.2, 16.0±0.2, 16.9±0.2, 18.1±0.2, 18.3±0.2, 20.4±0.2, 21.2±0.2, 23.9±0.2, and 25.5±0.
2.
12. The crystal morphology according to claim 2, wherein morphology A substantially has the DSC thermogram shown in Figure 11.
13. The crystal morphology according to claim 12, wherein morphology A has an X-ray powder diffraction pattern that includes at least one peak at °2θ selected from 5.8±0.2, 8.6±0.2, 12.3±0.2, 13.0±0.2, 14.2±0.2, 14.6±0.2, 16.0±0.2, 16.9±0.2, 18.1±0.2, 18.3±0.2, 20.4±0.2, 21.2±0.2, 23.9±0.2, and 25.5±0.
2.
14. The crystal morphology according to claim 1, wherein the crystal morphology is substantially morphology A having the thermogravimetric analysis ("TGA") profile shown in Figure 3.
15. The crystal morphology according to claim 1, wherein the crystal morphology is morphology A, which, when measured by TGA, has a negligible weight loss until the start of decomposition at approximately 200°C.
16. The crystal morphology according to claim 14 or 15, wherein morphology A has an X-ray powder diffraction pattern that includes at least one peak at °2θ selected from 5.8±0.2, 8.6±0.2, 12.3±0.2, 13.0±0.2, 14.2±0.2, 14.6±0.2, 16.0±0.2, 16.9±0.2, 18.1±0.2, 18.3±0.2, 20.4±0.2, 21.2±0.2, 23.9±0.2, and 25.5±0.
2.
17. The crystal morphology according to claim 1, wherein the crystal morphology is morphology A, which has an observed weight increase of about 0.1% at 40% RH to 0.6% at 90% RH and is completely lost upon desorption to 0% RH.
18. The crystal morphology according to claim 1, wherein the crystal morphology is substantially morphology A having a dynamic vapor deposition ("DVS") isotherm shown in Figure 4.
19. The crystal morphology according to claim 17 or 18, wherein morphology A has an X-ray powder diffraction pattern that includes at least one peak at °2θ selected from 5.8±0.2, 8.6±0.2, 12.3±0.2, 13.0±0.2, 14.2±0.2, 14.6±0.2, 16.0±0.2, 16.9±0.2, 18.1±0.2, 18.3±0.2, 20.4±0.2, 21.2±0.2, 23.9±0.2, and 25.5±0.
2.
20. The crystal morphology according to claim 1, wherein the crystal morphology is morphology B having an X-ray powder diffraction pattern that includes at least one peak at °2θ selected from 16.7±0.2, 17.5±0.2, and 18.8±0.
2.
21. The crystal morphology according to claim 20, wherein morphology B has an X-ray powder diffraction pattern including peaks at °2θ of 16.7±0.2, 17.5±0.2, and 18.8±0.
2.
22. The crystal morphology according to claim 20, wherein morphology B has an X-ray powder diffraction pattern including two or more peaks at °2θ of 5.8±0.2, 13.3±0.2, 13.9±0.2, 14.2±0.2, 15.6±0.2, 15.9±0.2, 16.7±0.2, 17.5±0.2, 17.9±0.2, 18.1±0.2, 18.8±0.2, 19.5±0.2, 19.9±0.2, 21.4±0.2, 21.8±0.2, 23.1±0.2, 23.7±0.2 and 24.7±0.
2.
23. The crystal morphology according to claim 20, wherein morphology B has an X-ray powder diffraction pattern including peaks at °2θ of 5.8±0.2, 13.3±0.2, 13.9±0.2, 14.2±0.2, 15.6±0.2, 15.9±0.2, 16.7±0.2, 17.5±0.2, 17.9±0.2, 18.1±0.2, 18.8±0.2, 19.5±0.2, 19.9±0.2, 21.4±0.2, 21.8±0.2, 23.1±0.2, 23.7±0.2 and 24.7±0.
2.
24. The crystal form according to claim 1, wherein the crystal form is substantially form B having the XRPD pattern shown in Figure 5A or Figure 5B.
25. The crystal morphology according to claim 20, characterized in that morphology B has an endothermic peak that starts at approximately 109°C by DSC.
26. The crystal morphology according to claim 20, characterized in that morphology B has an endothermic peak that starts at approximately 122°C by DSC.
27. The crystal morphology according to claim 20, wherein morphology B substantially has the DSC thermogram shown in Figure 6 or Figure 12.
28. The crystalline morphology according to any one of claims 25 to 27, wherein morphology B has an X-ray powder diffraction pattern including at least one peak at °2θ selected from 5.8±0.2, 13.3±0.2, 13.9±0.2, 14.2±0.2, 15.6±0.2, 15.9±0.2, 16.7±0.2, 17.5±0.2, 17.9±0.2, 18.1±0.2, 18.8±0.2, 19.5±0.2, 19.9±0.2, 21.4±0.2, 21.8±0.2, 23.1±0.2, 23.7±0.2, and 24.7±0.
2.
29. The crystal form according to claim 1, wherein the crystal form is substantially form B having the TGA profile shown in Figure 7.
30. The crystal form B according to claim 1, characterized in that the crystal form has a weight loss of 0.6% at 25 to 150°C when measured by TGA, and does not undergo any further events until the decomposition initiation point at approximately 200°C.
31. The crystal morphology according to claim 29 or 30, wherein morphology B has an X-ray powder diffraction pattern that includes at least one peak at °2θ selected from 5.8±0.2, 13.3±0.2, 13.9±0.2, 14.2±0.2, 15.6±0.2, 15.9±0.2, 16.7±0.2, 17.5±0.2, 17.9±0.2, 18.1±0.2, 18.8±0.2, 19.5±0.2, 19.9±0.2, 21.4±0.2, 21.8±0.2, 23.1±0.2, 23.7±0.2, and 24.7±0.
2.
32. The crystal form B according to claim 1, characterized in that the crystal form has a weight increase of approximately 0.6% at 60% RH to 2.9% at 70% RH, and further increases to 2.5% at 90% RH, as measured by DVS.
33. The crystal morphology according to claim 1, wherein the crystal morphology is substantially morphology B having DVS isotherms as shown in Figure 8.
34. The crystal morphology according to claim 32 or 33, wherein morphology B has an X-ray powder diffraction pattern that includes at least one peak at °2θ selected from 5.8±0.2, 13.3±0.2, 13.9±0.2, 14.2±0.2, 15.6±0.2, 15.9±0.2, 16.7±0.2, 17.5±0.2, 17.9±0.2, 18.1±0.2, 18.8±0.2, 19.5±0.2, 19.9±0.2, 21.4±0.2, 21.8±0.2, 23.1±0.2, 23.7±0.2, and 24.7±0.
2.
35. The crystal morphology according to claim 1, wherein the crystal morphology is morphology C having an X-ray powder diffraction pattern that includes at least one peak at a °2θ value selected from 16.4 ± 0.2 and 19.7 ± 0.
2.
36. The crystal morphology according to claim 1, wherein the crystal morphology is morphology C having an X-ray powder diffraction pattern that includes peaks at °2θ values of 16.4 ± 0.2 and 19.7 ± 0.
2.
37. The crystal morphology according to claim 35, wherein morphology C has an X-ray powder diffraction pattern that includes two or more peaks at °2θ values of 5.7±0.2, 13.3±0.2, 13.9±0.2, 14.2±0.2, 15.5±0.2, 16.4±0.2, 17.8±0.2, 18.0±0.2, 19.7±0.2, 23.2±0.2, 23.7±0.2, 24.4±0.2 and 26.7±0.
2.
38. The crystal morphology according to claim 35, wherein morphology C has an X-ray powder diffraction pattern that includes peaks at °2θ values of 5.7±0.2, 13.3±0.2, 13.9±0.2, 14.2±0.2, 15.5±0.2, 16.4±0.2, 17.8±0.2, 18.0±0.2, 19.7±0.2, 23.2±0.2, 23.7±0.2, 24.4±0.2 and 26.7±0.
2.
39. The crystal morphology according to claim 1, wherein the crystal morphology is substantially morphology C having the XRPD pattern shown in Figure 9.
40. The crystal morphology according to claim 35, characterized in that morphology C has a broad endothermic peak with a maximum peak value at approximately 73°C and an endothermic peak that begins at approximately 118°C, as determined by differential scanning calorimetry.
41. The crystal morphology according to claim 35, wherein morphology C substantially has the DSC thermogram shown in Figure 10.
42. The crystal morphology according to claim 41, wherein morphology C has an X-ray powder diffraction pattern that includes at least one peak at a °2θ value selected from 5.7±0.2, 13.3±0.2, 13.9±0.2, 14.2±0.2, 15.5±0.2, 16.4±0.2, 17.8±0.2, 18.0±0.2, 19.7±0.2, 23.2±0.2, 23.7±0.2, 24.4±0.2, and 26.7±0.
2.
43. The crystal morphology according to claim 1, wherein the crystal morphology is substantially morphology C having the TGA profile shown in Figure 10.
44. The crystal form according to claim 1, wherein the crystal form C is characterized by having a stepwise mass loss of about 1.2% from about 45°C to about 86°C until decomposition begins at about 260°C, as measured by TGA.
45. The crystal morphology according to claim 43 or 44, having an X-ray powder diffraction pattern that includes at least one peak at a °2θ value selected from 5.7±0.2, 13.3±0.2, 13.9±0.2, 14.2±0.2, 15.5±0.2, 16.4±0.2, 17.8±0.2, 18.0±0.2, 19.7±0.2, 23.2±0.2, 23.7±0.2, 24.4±0.2, and 26.7±0.
2.
46. The crystal morphology according to claim 1, wherein the crystal morphology is morphology D having an X-ray powder diffraction pattern with a peak at a °2θ value of 4.4 ± 0.
2.
47. The crystal morphology according to claim 1, wherein the crystal morphology is morphology D having an X-ray powder diffraction pattern that includes two or more peaks at °2θ values of 4.4±0.2, 13.6±0.2, 13.8±0.2, 15.2±0.2, 16.3±0.2, 17.7±0.2, 18.0±0.2, 20.9±0.2, 22.6±0.2, 23.0±0.2 and 27.6±0.
2.
48. The crystal morphology according to claim 1, wherein the crystal morphology is morphology D having an X-ray powder diffraction pattern that includes peaks at °2θ values of 4.4±0.2, 13.6±0.2, 13.8±0.2, 15.2±0.2, 16.3±0.2, 17.7±0.2, 18.0±0.2, 20.9±0.2, 22.6±0.2, 23.0±0.2, and 27.6±0.
2.
49. The crystal morphology according to claim 1, wherein the crystal morphology is substantially morphology D having the XRPD pattern shown in Figure 13.
50. The crystal morphology according to claim 46, characterized in that morphology D has two broad endothermic peaks having maximum peak values at approximately 84°C and 110°C, as determined by differential scanning calorimetry.
51. The crystal morphology according to claim 46, wherein morphology D substantially has the DSC thermogram shown in Figure 14.
52. The crystal morphology according to claim 51, wherein morphology D has an X-ray powder diffraction pattern that includes at least one peak at a °2θ value selected from 4.4±0.2, 13.6±0.2, 13.8±0.2, 15.2±0.2, 16.3±0.2, 17.7±0.2, 18.0±0.2, 20.9±0.2, 22.6±0.2, 23.0±0.2, and 27.6±0.
2.
53. The crystal morphology according to claim 1, wherein the crystal morphology is substantially morphology D having the TGA profile shown in Figure 14.
54. The crystal morphology according to claim 1, wherein the crystal morphology is morphology D, characterized in that, when measured by TGA, it has a stepwise mass loss of about 4.3% from about 45°C to about 116°C until the start of decomposition at about 260°C.
55. The crystal morphology according to claim 53 or 54, wherein morphology D has an X-ray powder diffraction pattern that includes at least one peak at a °2θ value selected from 4.4±0.2, 13.6±0.2, 13.8±0.2, 15.2±0.2, 16.3±0.2, 17.7±0.2, 18.0±0.2, 20.9±0.2, 22.6±0.2, 23.0±0.2, and 27.6±0.
2.
56. The crystal morphology according to claim 1, wherein the crystal morphology is morphology E having an X-ray powder diffraction pattern that includes at least one peak at a °2θ value selected from 5.2 ± 0.2 and 10.2 ± 0.
2.
57. The crystal morphology according to claim 1, wherein the crystal morphology is morphology E having an X-ray powder diffraction pattern with peaks at °2θ values of 5.2 ± 0.2 and 10.2 ± 0.
2.
58. The crystal morphology according to claim 1, wherein the crystal morphology is morphology E having an X-ray powder diffraction pattern that includes two or more peaks at °2θ values of 5.2±0.2, 10.2±0.2, 11.8±0.2, 13.5±0.2, 14.3±0.2, 16.9±0.2, 17.7±0.2, 20.3±0.2, 20.5±0.2 and 21.9±0.
2.
59. The crystal morphology according to claim 1, wherein the crystal morphology is morphology E having an X-ray powder diffraction pattern that includes peaks at °2θ values of 5.2±0.2, 10.2±0.2, 11.8±0.2, 13.5±0.2, 14.3±0.2, 16.9±0.2, 17.7±0.2, 20.3±0.2, 20.5±0.2 and 21.9±0.
2.
60. The crystal morphology according to claim 1, wherein morphology E substantially has the XRPD pattern shown in Figure 15.
61. The crystal morphology according to claim 56, characterized in that morphology E has an endothermic peak starting point at approximately 99°C as determined by differential scanning calorimetry.
62. The crystal morphology according to claim 56, wherein morphology E substantially has the DSC thermogram shown in Figure 16.
63. The crystal morphology according to claim 62, wherein morphology E has an X-ray powder diffraction pattern that includes at least one peak at a °2θ value selected from 5.2±0.2, 10.2±0.2, 11.8±0.2, 13.5±0.2, 14.3±0.2, 16.9±0.2, 17.7±0.2, 20.3±0.2, 20.5±0.2, and 21.9±0.
2.
64. The crystal morphology according to claim 1, wherein the crystal morphology is substantially morphology E having the TGA profile shown in Figure 17.
65. The crystal form according to claim 1, wherein the crystal form E is characterized in that, when measured by TGA, it has a negligible mass loss of crystal form E up to about 94°C until the start of decomposition at about 240°C.
66. The crystal morphology according to claim 64 or 65, wherein morphology E has an X-ray powder diffraction pattern that includes at least one peak at a °2θ value selected from 5.2±0.2, 10.2±0.2, 11.8±0.2, 13.5±0.2, 14.3±0.2, 16.9±0.2, 17.7±0.2, 20.3±0.2, 20.5±0.2, and 21.9±0.
2.
67. The crystal morphology according to claim 1, wherein the crystal morphology is characterized by having a stepwise weight increase of 1.2% from 5% to 95% RH when measured by DVS.
68. The crystal morphology according to claim 1, wherein the crystal morphology is substantially morphology E having DVS isotherms as shown in Figure 18.
69. The crystal morphology according to claim 67 or 68, wherein morphology E has an X-ray powder diffraction pattern that includes at least one peak at °2θ selected from 5.2±0.2, 10.2±0.2, 11.8±0.2, 13.5±0.2, 14.3±0.2, 16.9±0.2, 17.7±0.2, 20.3±0.2, 20.5±0.2, and 21.9±0.
2.
70. The crystalline form according to any one of claims 1 to 69, wherein the crystalline form substantially does not contain residual organic solvents.
71. The crystalline form according to any one of claims 1 to 69, wherein the crystalline form is a hydrate.
72. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form A of 2-[(2S-4-[7-(8-chloro-1-naphthyl)-2-[[(2S-1-methylpyrrolidine-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-4-yl]-1-(2-fluoropropa-2-enoyl)piperazine-2-yl]acetonitrile according to any one of claims 2 to 19.
73. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form B of 2-[(2S-4-[7-(8-chloro-1-naphthyl)-2-[[(2S-1-methylpyrrolidine-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-4-yl]-1-(2-fluoropropa-2-enoyl)piperazine-2-yl]acetonitrile according to any one of claims 20 to 34.
74. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form C of 2-[(2S-4-[7-(8-chloro-1-naphthyl)-2-[[(2S-1-methylpyrrolidine-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-4-yl]-1-(2-fluoropropa-2-enoyl)piperazine-2-yl]acetonitrile according to any one of claims 35 to 45.
75. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form D of 2-[(2S-4-[7-(8-chloro-1-naphthyl)-2-[[(2S-1-methylpyrrolidine-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-4-yl]-1-(2-fluoropropa-2-enoyl)piperazine-2-yl]acetonitrile according to any one of claims 46 to 55.
76. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form E of 2-[(2S-4-[7-(8-chloro-1-naphthyl)-2-[[(2S-1-methylpyrrolidine-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-4-yl]-1-(2-fluoropropa-2-enoyl)piperazine-2-yl]acetonitrile according to any one of claims 56 to 69.
77. A pharmaceutical composition comprising a mixture of one or more crystalline forms A, B, C, D, and E of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidine-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-4-yl]-1-(2-fluoropropa-2-enoyl)piperazine-2-yl]acetonitrile in a therapeutically effective amount.
78. A pharmaceutical composition comprising a mixture of one or more forms of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidine-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-4-yl]-1-(2-fluoropropa-2-enoyl)piperazine-2-yl]acetonitrile in a therapeutically effective amount, wherein the form is selected from amorphous, form A, form B, form C, form D and form E.
79. The pharmaceutical composition according to any one of claims 72 to 78, further comprising at least one pharmaceutically acceptable excipient and / or diluent.
80. A method for inhibiting KRas G12C activity in cells, comprising contacting cells in which inhibition of KRas G12C activity is desired, with a therapeutically effective amount of the crystalline form described in any one of claims 1 to 71, either alone or in combination with one or more pharmaceutically acceptable excipients and / or diluents.
81. A method for treating cancer in a subject requiring cancer treatment, comprising administering to the subject a therapeutically effective amount of the crystalline form described in any one of claims 1 to 71, either alone or in combination with one or more pharmaceutically acceptable excipients and / or diluents.
82. The method according to claim 81, wherein the therapeutically effective dose of the crystalline form of the KRas G12C inhibitor is about 0.01 to 100 mg / kg per day.
83. The method according to claim 81, wherein the therapeutically effective dose of the crystalline form of the KRas G12C inhibitor is about 0.1 to 50 mg / kg per day.
84. The aforementioned cancers include: cardiac sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma, mesothelioma; Gastrointestinal tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenocarcinoma, chorioadenoma, hamartoma, leiomyoma); urogenital tract: kidney ( Adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, fetal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, mammary fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampulla carcinoma, cholangiocarcinoma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticuloma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondroma exostosoma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecological system: Uterus (endometrial cancer (serous cystadenoma, mucinous cystadenoma, unclassified cancer), granulosa-enveloplastic cell carcinoma) The method according to claim 81, comprising: tumors, Sertoli-Leydig cell tumors, undifferentiated germ cell tumors, malignant teratomas; vulvas (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); blood system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, spinal dysplasia syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands: neuroblastoma.
85. The method according to claim 81, wherein the cancer is a KRas G12C-related cancer.
86. The method according to claim 81, wherein the cancer is non-small cell lung cancer.
87. The method according to claim 81, wherein the subject is an adult patient.
88. The method according to claim 81, wherein the subject is a pediatric patient.
89. (a) Dissolve 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidine-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-4-yl]-1-(2-fluoropropa-2-enoyl)piperazine-2-yl]acetonitrile in isopropanol / heptane (80 / 20 v / v) at approximately 60°C, (b) A step of cooling the solution to about 45°C over a period of about 15 minutes, (c) A step of adding a seed slurry of form B to the solution to prepare a slurry of form B, (d) The step of holding the slurry of form B at 45°C, then cooling it to 30°C, then cooling it to 20°C, (e) A crystalline form of form B according to claim 1, obtained by a process comprising the steps of (e) recovering the solid and drying it.
90. (a) A step of dissolving 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidine-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-4-yl]-1-(2-fluoropropanenoyl)piperazine-2-yl]acetonitrile in isopropanol at approximately 50°C, (b) The step of cooling the solution at a rate of approximately 0.5°C / min to approximately 5°C to obtain a suspension of crystalline particles, (c) A crystalline form of form B according to claim 1, obtained by a process comprising the step of removing the particles from the suspension.