IP Library › Granted Patent US 12,252,486
Granted Patent B2
US 12,252,486 · App. 17/612,717 · Granted Mar 18, 2025

Solid state forms

Inventors: Mary Chaves (Arlington, MA); Ron C. Kelly (Westlake Village, CA); Prashant Agarwal (Chelsea, MA); Stephan D. Parent (West Lafayette, IN); Darren Leonard Reid (Belmont, MA); Roman Shimanovich (Brighton, MA)
Assignee: Amgen Inc.
C07D471/04A61P35/00C07B2200/13
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Quick Facts
Patent No.
US 12,252,486
App. No.
17/612,717
Granted
Mar 18, 2025
Kind
B2
Abstract

The present invention provides a crystalline form and stable salts of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one, including several hydrochloride salt forms, phosphate salt form, mesylate salt form, and solid state forms thereof, pharmaceutical compositions, and methods of treating a disease mediated by KRAS G12C inhibition.

Claims (54)

1. A compound, wherein the compound is a crystalline hydrochloride salt of the M atropisomer of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2 (1H)-one.

2. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern substantially as shown in FIG. 1 as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

3. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising, at least five peaks selected from 6.6, 8.9, 10.9, 13.7, 14.2, 15.1, 18.0, 19.0, and 21.1±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

4. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising peaks at 8.9, 10.9, and 14.2±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

5. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern substantially as shown in FIG. 4 as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

6. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising at least seven peaks selected from 6.0, 6.3, 8.2, 10.6, 11.2, 12.7, 13.6, 14.3, 16.1, 16.5, 17.2, 21.4, and 21.6±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

7. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising peaks at 6.3, 8.2, 10.6, and 16.1±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

8. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern substantially as shown in FIG. 7 as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

9. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising at least seven peaks selected from 6.4, 8.4, 11.0, 11.2, 12.7, 13.6, 13.9, 15.0, 15.6, 16.6, 16.7, 16.8, and 21.2±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

10. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising peaks at 6.4, 8.4, 11.0, and 15.6±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

11. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern substantially as shown in FIG. 10 as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

12. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising at least five peaks, selected from 5.6, 6.5, 8.5, 11.3, 12.8, 13.6, 14.0, 14.1, 15.0, 16.7, 17.8, and 18.4±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

13. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising peaks at 5.6, 6.5, and 8.5±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

14. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern substantially as shown in FIG. 13 as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

15. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising at least seven peaks selected from 6.0, 7.9, 9.1, 9.9, 12.0, 12.4, 12.7, 13.2, 13.8, 14.7, 15.4, 15.7, and 18.9±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

16. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising peaks at 7.9, 9.9, 13.8, and 15.7±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

17. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern substantially as shown in FIG. 16 as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

18. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising at least five peaks selected from 6.0, 7.7, 10.0, 12.1, 12.5, 13.7, 14.5, 15.2, 15.9, 18.1, 19.0, and 20.9±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

19. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising peaks at 7.7, 10.0, and 15.9±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

20. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern substantially as shown in FIG. 19 as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

21. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising at least seven peaks selected from 6.0, 7.8, 9.0, 9.9, 12.0, 12.6, 13.2, 13.8, 14.6, 15.4, 15.8, 15.9, 18.9, 20.1, 20.6, and 20.9±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

22. The compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising peaks at 7.8, 9.9, 13.2, and 14.6±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

23. A compound, wherein the compound is a crystalline phosphate salt of the M atropisomer of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2 (1H)-one.

24. The compound of claim 23 , wherein the compound is characterized by an x-ray powder diffraction pattern substantially as shown in FIG. 22 as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

25. The compound of claim 23 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising at least seven peaks selected from 6.0, 8.7, 10.9, 11.8, 13.7, 14.5, 15.1, 17.2, 19.1, 19.6, 21.4, 24.0, 25.6, 26.3, 26.7, and 27.4±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

26. The compound of claim 23 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising peaks at 8.7, 13.7, 14.5, 17.2 and 19.1±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

27. A compound, wherein the compound is a crystalline mesylate salt of the M atropisomer of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2 (1H)-one.

28. The compound of claim 27 , wherein the compound is characterized by an x-ray powder diffraction pattern substantially as shown in FIG. 25 as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

29. The compound of claim 27 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising at least seven peaks selected from 7.6, 9.8, 14.6, 15.2, 15.8, 19.0, 19.6, 20.5, and 23.2±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

30. The compound of claim 27 , wherein the compound is characterized by an x-ray powder diffraction pattern comprising peaks at 7.6, 9.8, 15.8, 19.6 and 20.5±0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

31. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

32. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable excipient.

33. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable excipient.

34. A pharmaceutical composition comprising the compound of claim 10 and a pharmaceutically acceptable excipient.

35. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable excipient.

36. A pharmaceutical composition comprising the compound of claim 16 and a pharmaceutically acceptable excipient.

37. A pharmaceutical composition comprising the compound of claim 19 and a pharmaceutically acceptable excipient.

38. A pharmaceutical composition comprising the compound of claim 22 and a pharmaceutically acceptable excipient.

39. A pharmaceutical composition comprising the compound of claim 23 and a pharmaceutically acceptable excipient.

40. A pharmaceutical composition comprising the compound of claim 26 and a pharmaceutically acceptable excipient.

41. A pharmaceutical composition comprising the compound of claim 27 and a pharmaceutically acceptable excipient.

42. A pharmaceutical composition comprising the compound of claim 30 and a pharmaceutically acceptable excipient.

43. A method of treating a cancer having a KRAS G12C mutation in a human patient in need thereof, the method comprising administering to the human patient a therapeutically effective amount of the compound of claim 1 , wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, endometrial cancer, pancreatic cancer, skin cancer, gastric cancer, nasal cavity cancer, bile duct cancer, or brain tumor.

44. The method of claim 43 , wherein the cancer is non-small cell lung cancer.

45. The method of claim 43 , wherein the cancer is colorectal cancer.

46. The method of claim 43 , wherein the cancer is pancreatic cancer.

47. A method of treating a cancer having a KRAS G12C mutation in a human patient in need thereof, the method comprising administering to the human patient a therapeutically effective amount of the compound of claim 23 , wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, endometrial cancer, pancreatic cancer, skin cancer, gastric cancer, nasal cavity cancer, bile duct cancer, or brain tumor.

48. The method of claim 47 , wherein the cancer is non-small cell lung cancer.

49. The method of claim 47 , wherein the cancer is colorectal cancer.

50. The method of claim 47 , wherein the cancer is pancreatic cancer.

51. A method of treating a cancer having a KRAS G12C mutation in a human patient in need thereof, the method comprising administering to the human patient a therapeutically effective amount of the compound of claim 27 , wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, endometrial cancer, pancreatic cancer, skin cancer, gastric cancer, nasal cavity cancer, bile duct cancer, or brain tumor.

52. The method of claim 51 , wherein the cancer is non-small cell lung cancer.

53. The method of claim 51 , wherein the cancer is colorectal cancer.

54. The method of claim 51 , wherein the cancer is pancreatic cancer.

Assignments (4)
CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE AMGEN INC. PREVIOUSLY RECORDED ON REEL 61503 FRAME 348. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Feb 5, 2025
From: PARENT, STEPHAN D.
To: ALBANY MOLECULAR RESEARCH INC. (AMRI)
Reel/Frame 070126/0356 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 21, 2022
From: PARENT, STEPHAN D.
To: AMGEN INC.
Reel/Frame 061503/0348 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 21, 2022
From: CHAVES, MARY; KELLY, RON C.; AGARWAL, PRASHANT; REID, DARREN LEONARD; SHIMANOVICH, ROMAN
To: AMGEN INC.
Reel/Frame 061503/0352 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 21, 2022
From: ALBANY MOLECULAR RESEARCH INC.
To: INC., AMGEN
Reel/Frame 061503/0362 →
Continuity (2)
Provisional Application 62851049 · May 21, 2019
Related Publication 20220235045A1 · Jul 28, 2022
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