Salts of TAM inhibitors

1. A process of preparing a salt which is N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleic acid salt, comprising reacting a compound of Formula I:

with maleic acid to form said salt.

2. The process of claim 1 , wherein about 1 equivalent of maleic acid is used based on 1 equivalent of the compound of Formula I.

3. The process of claim 1 , wherein said reacting of the compound of Formula I and maleic acid is conducted in the presence of a solvent component.

4. The process of claim 3 , wherein said solvent component comprises methanol.

5. The process of claim 3 , wherein said solvent component comprises dichloromethane.

6. The process of claim 3 , wherein said solvent component comprises methanol and dichloromethane.

7. The process of claim 6 , wherein the process further comprises removing a substantial portion of dichloromethane to precipitate said salt.

8. The process of claim 3 , wherein said process further comprises, prior to said reacting, forming a solution of the compound of Formula I in a solvent component.

9. The process of claim 8 , wherein the solution is formed by heating a slurry of the compound of Formula I in the solvent component to a temperature of from about 45° C. to about 55° C.

10. The process of claim 9 , wherein said process further comprises stirring said solution; and filtering said solution to form a filtrate prior to said reacting of the compound of Formula I with maleic acid.

11. The process of claim 10 , wherein said process further comprises adding activated carbon and silica gel to the solution after said step of heating said slurry to a temperature of from about 45° C. to about 55° C. to form a solution and before said step of stirring said solution.

12. A process of preparing a salt which is N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemi-sulfuric acid salt, comprising reacting a compound of Formula II:

with sulfuric acid to form said salt.

13. The process of claim 12 , wherein about 0.6 equivalents of sulfuric acid is used based on 1 equivalent of the compound of Formula II.

14. The process of claim 12 , wherein the process comprises:

adding the compound of Formula II to a solvent component form a solution;

adding sulfuric acid to said solution at room temperature;

concentrating the solution to form a slurry;

stirring the slurry at a temperature of from about 60° C. to about 70° C.; and

cooling the slurry to a temperature of from about 15° C. to about 25° C. to precipitate said salt.

15. The process of claim 14 , wherein the solvent component comprises methanol.

16. The process of claim 14 , wherein the solvent component comprises dichloromethane.

17. The process of claim 14 , wherein the solvent component comprises methanol and dichloromethane.

18. The process of claim 14 , wherein the sulfuric acid is about 1M in water.

19. The process of claim 12 , wherein the process comprises preparing N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo [1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1, 2,3, 4-tetrahydropyrimidine-5-carboxamide sulfuric acid salt.

20. The process of claim 19 , wherein process of preparing a salt which is N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfuric acid salt comprising reacting a compound of Formula II with about 1 equivalent of sulfuric acid based on 1 equivalent of the compound of Formula II.

21. The process of claim 19 , wherein the process for preparing N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfuric acid salt comprises:

adding the compound of Formula II to a first solvent component at room temperature to form a solution;

heating the solution to a temperature of from about 50° C. to about 60° C.;

adding sulfuric acid to said solution; and

removing solvent to precipitate the sulfuric acid salt.

22. The process of claim 21 , wherein the first solvent comprises methanol.

23. The process of claim 21 , wherein the sulfuric acid is added as a solution in water.

24. The process of claim 19 , further comprising the steps of:

adding the N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfuric acid salt to a second solvent component to form a slurry;

heating the slurry to a temperature of from about 30° C. to about 40° C.;

agitating the slurry; and

collecting the resulting hemi-sulfuric acid salt.

25. The process of claim 24 , wherein the second solvent component comprises water.

26. The process of claim 24 , further comprising preparing an amorphous form of the hemi-sulfuric acid salt, wherein the preparing an amorphous form of the hemi-sulfuric acid salt comprises the steps of:

adding the hemi-sulfuric acid salt to a third solvent component at room temperature to form a solution;

filtering the solution;

concentrating the filtrate; and

drying the resulting solid resulting in the amorphous hemi-sulfuric acid salt.

27. The process of claim 26 , wherein the third solvent component comprises acetone and methanol.

28. The process of claim 1 , wherein the salt is crystalline.

29. The process of claim 28 , wherein the salt has at least one XRPD peak, in terms of 2-theta, selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

30. The process of claim 28 , wherein the salt has at least two XRPD peaks, in terms of 2-theta, selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

31. The process of claim 28 , wherein the salt has at least three XRPD peaks, in terms of 2-theta, selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

32. The process of claim 12 , wherein the salt is crystalline.

33. The process of claim 32 , wherein the salt has at least one XRPD peak, in terms of 2-theta, selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9°.

34. The process of claim 32 , wherein the salt has at least two XRPD peaks, in terms of 2-theta, selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9°.

35. The process of claim 32 , wherein the salt has at least three XRPD peaks, in terms of 2-theta, selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9°.