Salts of TAM inhibitors
The present application provides salt forms of 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 and 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, which are useful as inhibitors of TAM kinases, as well as processes and intermediates related thereto.
1. 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, wherein the salt is crystalline, and 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.
2. The salt of claim 1 that is a 1:1 stoichiometric ratio of 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 to maleic acid.
3. The salt of claim 1 that is substantially isolated.
4. The salt of claim 1 characterized by a DSC thermogram having an endothermic peak at about 211° C.
5. The salt of claim 1 having a DSC thermogram substantially as shown in FIG. 2 .
6. The salt of claim 1 having a TGA thermogram substantially as shown in FIG. 3 .
7. The salt of claim 1 having 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°.
8. The salt of claim 1 having 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°.
9. The salt of claim 1 having at least four 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°.
10. The salt of claim 1 comprising the following XRPD peaks, in terms of 2-theta: about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.
11. The salt of claim 1 having an XRPD profile substantially as shown in FIG. 1 .
12. 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, wherein the salt is crystalline, and 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°.
13. The salt of claim 12 that is a 1:0.5 stoichiometric ratio of 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 to sulfuric acid.
14. The salt of claim 12 that is substantially isolated.
15. The salt of claim 12 characterized by a DSC thermogram having an endothermic peak at about 289.4° C.
16. The salt of claim 12 having a DSC thermogram substantially as shown in FIG. 11 .
17. The salt of claim 12 having a TGA thermogram substantially as shown in FIG. 12 .
18. The salt of claim 12 having 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°.
19. The salt of claim 12 having 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°.
20. The salt of claim 12 having at least four 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°.
21. The salt of claim 12 comprising the following XRPD peaks, in terms of 2-theta: about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9°.
22. The salt of claim 12 having an XRPD profile substantially as shown in FIG. 10 .
23. A pharmaceutical composition comprising a salt of claim 1 and a pharmaceutically acceptable carrier.