Solid forms of an FGFR inhibitor and processes for preparing the same
The present disclosure relates to 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one, solid forms and polymorphs thereof, methods of preparation thereof, and intermediates in the preparation thereof, which are useful in the treatment of the FGFR-associated or mediated diseases such as cancer.
1. A method of treating cholangiocarcinoma in a patient in need thereof comprising administering to the patient a therapeutically effective amount of Compound 1 having the formula:
wherein Compound 1 is administered in a daily dose of about 5 mg to about 20 mg.
2. The method of claim 1 , wherein the cholangiocarcinoma is advanced or metastatic cholangiocarcinoma.
3. The method of claim 1 , wherein the cholangiocarcinoma is surgically unresectable.
4. The method of claim 1 , wherein the cholangiocarcinoma is intrahepatic.
5. The method of claim 1 , wherein the cholangiocarcinoma is extrahepatic.
6. The method of claim 1 , wherein the cholangiocarcinoma is hilar or perihilar.
7. The method of claim 1 , wherein the cholangiocarcinoma is distal extrahepatic.
8. The method of claim 1 , wherein the cholangiocarcinoma is characterized by FGF/FGFR genetically altered tumors.
9. The method of claim 8 , wherein the tumor exhibits FGFR2 translocations.
10. The method of claim 9 , wherein the FGFR2 translocation is selected from the group consisting of FGFR2-BICC1, FGFR2-AHCYL1, FGFR2-MACF1, and FGFR2 intron 17 rearrangement.
11. The method of claim 8 , wherein the tumor exhibits FGF/FGFR alterations other than FGFR2 translocations.
12. The method of claim 1 , wherein the cholangiocarcinoma does not exhibit FGF/FGFR genetically altered tumors.
13. The method of claim 1 , wherein the patient has failed at least one previous treatment.
14. The method of claim 13 , wherein the previous treatment is surgery or radiation therapy.
15. The method of claim 1 , wherein the patient has a history of hepatitis.
16. The method of claim 15 , wherein the hepatitis is chronic hepatitis B or hepatitis C.
17. The method of claim 1 , wherein Compound 1 is administered in a daily dose of about 10 mg to about 15 mg.
18. The method of claim 1 , wherein Compound 1 is administered in a daily dose of about 13.5 mg.
19. The method of claim 1 , wherein Compound 1 is administered as a tablet.
20. The method of claim 1 , wherein Compound 1 is administered in a daily dose of about 9 mg.
21. A method of treating cholangiocarcinoma in a patient in need thereof comprising administering to the patient a therapeutically effective amount of Compound 1 having the formula:
wherein Compound 1 is administered once daily as a tablet, and wherein the tablet comprises about 0.5 to about 10 mg of Compound 1.
22. The method of claim 21 , wherein the tablet comprises about 0.5 mg to about 5 mg of Compound 1.
23. The method of claim 21 , wherein the tablet comprises about 9 mg of Compound 1.
24. The method of claim 21 , wherein the tablet comprises about 4.5 mg of Compound 1.
25. The method of claim 21 , wherein the cholangiocarcinoma is advanced or metastatic cholangiocarcinoma.
26. The method of claim 21 , wherein the cholangiocarcinoma is surgically unresectable.
27. The method of claim 21 , wherein the cholangiocarcinoma is intrahepatic.
28. The method of claim 21 , wherein the cholangiocarcinoma is extrahepatic.
29. The method of claim 21 , wherein the cholangiocarcinoma is hilar or perihilar.
30. The method of claim 21 , wherein the cholangiocarcinoma is distal extrahepatic.
31. The method of claim 21 , wherein the cholangiocarcinoma is characterized by FGF/FGFR genetically altered tumors.
32. The method of claim 31 , wherein the tumor exhibits FGFR2 translocations.
33. The method of claim 32 , wherein the FGFR2 translocation is selected from the group consisting of FGFR2-BICC1, FGFR2-AHCYL1, FGFR2-MACF1, and FGFR2 intron 17 rearrangement.
34. The method of claim 31 , wherein the tumor exhibits FGF/FGFR alterations other than FGFR2 translocations.
35. The method of claim 21 , wherein the cholangiocarcinoma does not exhibit FGF/FGFR genetically altered tumors.
36. The method of claim 21 , wherein the patient has failed at least one previous treatment.
37. The method of claim 36 , wherein the previous treatment is surgery or radiation therapy.
38. A method of treating cholangiocarcinoma in a patient in need thereof comprising administering to the patient a therapeutically effective amount of Compound 1 having the formula:
wherein Compound 1 is administered in a 21-day dosing regimen, wherein the 21-day dosing regimen comprises:
(a) a first period wherein Compound 1 is administered once daily for 14 days; and
(b) a second period wherein Compound 1 is not administered for 7 days.
39. The method of claim 38 , wherein Compound 1 is administered in a daily dose of about 5 mg to about 20 mg during the first period.
40. The method of claim 38 , wherein Compound 1 is administered in a daily dose of about 10 mg to about 15 mg during the first period.
41. The method of claim 38 , wherein Compound 1 is administered in a daily dose of about 13.5 mg during the first period.
42. The method of claim 38 , wherein Compound 1 is administered in a daily dose of about 9 mg during the first period.
43. The method of claim 38 , wherein Compound 1 is administered as a tablet during the first period.
44. The method of claim 43 , wherein the tablet comprises about 0.5 mg to about 10 mg of Compound 1.
45. The method of claim 43 , wherein the tablet comprises about 0.5 mg to about 5 mg of Compound 1.
46. The method of claim 43 , wherein the tablet comprises about 9 mg of Compound 1.
47. The method of claim 43 , wherein the tablet comprises about 4.5 mg of Compound 1.
48. The method of claim 38 , wherein the cholangiocarcinoma is advanced or metastatic cholangiocarcinoma.
49. The method of claim 38 , wherein the cholangiocarcinoma is surgically unresectable.
50. The method of claim 38 , wherein the cholangiocarcinoma is intrahepatic.
51. The method of claim 38 , wherein the cholangiocarcinoma is extrahepatic.
52. The method of claim 38 , wherein the cholangiocarcinoma is hilar or perihilar.
53. The method of claim 38 , wherein the cholangiocarcinoma is distal extrahepatic.
54. The method of claim 38 , wherein the cholangiocarcinoma is characterized by FGF/FGFR genetically altered tumors.
55. The method of claim 54 , wherein the tumor exhibits FGFR2 translocations.
56. The method of claim 55 , wherein the FGFR2 translocation is selected from the group consisting of FGFR2-BICC1, FGFR2-AHCYL1, FGFR2-MACF1, and FGFR2 intron 17 rearrangement.
57. The method of claim 54 , wherein the tumor exhibits FGF/FGFR alterations other than FGFR2 translocations.
58. The method of claim 38 , wherein the cholangiocarcinoma does not exhibit FGF/FGFR genetically altered tumors.
59. The method of claim 38 , wherein the patient has failed at least one previous treatment.
60. The method of claim 59 , wherein the previous treatment is surgery or radiation therapy.