Solid state forms of mnk inhibitors

Abstract

The present disclosure relates to solid forms of a compound having the following Structure (I): or a tautomer thereof. The present disclosure is also directed to methods of making and using a compound of Structure (I).

Description

This disclosure relates to compounds having structure (I) or their tautomers in solid form. This disclosure also relates to methods for manufacturing and using compounds with structure (I). Abstract

Claims

CLAIMS1. A solid form of a compound having the following Structure (I):or a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at 2-theta angles selected from the group consisting of 5.6 ± 0.2°, 10.9 ± 0.2°,18.2 ± 0.2°, and 18.6 ± 0.2°2. The solid form of claim 1, wherein the solid form has an X-ray powder diffraction pattern with at least three peaks at 2-theta angles selected from the group consisting of 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°.

3. The solid form of claim 1, wherein the solid form has an X-ray powder diffraction pattern with peaks at 2-theta angles at 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°.

4. The solid form of claim 1, wherein the solid form has an X-ray powder diffraction pattern with peaks at 2-theta angles at 5.6 ± 0.2°, 8.0 ± 0.2°, 8.4 ± 0.2°, 9.2 ± 0.2°, 10.9 ± 0.2°,11.2 ± 0.2°, 13.2 ± 0.2°, 14.3 ± 0.2°, 15.3 ± 0.2°, 16.2 ± 0.2°, 16.5 ± 0.2°, 16.9 ± 0.2°, 17.4 ±0.2°, 18.2 ± 0.2°, 18.6 ± 0.2°, 19.9 ± 0.2°, 20.2 ± 0.2°, 20.5 ± 0.2°, 21.9 ± 0.2°, 22.3 ± 0.2°, 22.5± 0.2°, 23.3 ± 0.2°, 23.6 ± 0.2°, 24.7 ± 0.2°, 25.2 ± 0.2°, 25.8 ± 0.2°, 26.2 ± 0.2°, 27.0 ± 0.2°,27.3 ± 0.2°, 27.8 ± 0.2°, 28.5 ± 0.2°, and 28.8 ± 0.2°.

5. A solid form of a compound having the following Structure (I):or a tautomer thereof, having an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 1.

6. The solid form of any one of claims 1-5, characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset of about 89.5 °C.

7. The solid form of any one of claims 1-6, characterized by a differential scanning calorimetry thermogram comprising an exothermic peak with an onset of about 213.5 °C.

8. The solid form of any one of claims 1-7, characterized by a differential scanning calorimetry thermogram substantially in accordance with that depicted in FIG. 2.

9. A solid form of a compound having the following Structure (I):or a tautomer thereof, wherein the solid form is prepared by a process comprising steps of:(i) providing N-(6-((8"-methyl-l",5"-dioxo-l",5"-dihydro-2"H-dispiro[cyclopropane- l,l'-cyclohexane-4',3"-imidazo[l,5-a]pyridin]-6"-yl)amino)pyrimidin-4- yl)cyclopropanecarboxamide (Int-A);(ii) contacting Int-A with a hydroxide base (e.g., potassium hydroxide) in a suitable solvent (e.g., ethanol, tetrahydrofuran, and water, or a mixture thereof); and(iii) isolating the solid form of a compound having Structure (I).

10. The solid form of claim 9, further comprising a step of slurrying the solid form of a compound having Structure (I) in a suitable solvent (e.g., water).

11. The solid form of any one of claims 1-10, wherein the solid form is a hemihydrate.

12. A solid form of a compound having the following Structure (I):or a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at 2-theta angles selected from the group consisting of 19.2 ± 0.2°, 19.5 ± 0.2°, and 21.2 ± 0.2°.

13. The solid form of claim 12, wherein the solid form has an X-ray powder diffraction pattern with peaks at 2-theta angles at 19.2 ± 0.2°, 19.5 ± 0.2°, and 21.2 ± 0.2°.

14. The solid form of claim 12, wherein the solid form has an X-ray powder diffraction pattern with peaks at 2-theta angles at 8.2 ± 0.2°, 9.1 ± 0.2°, 11.4 ± 0.2°, 13.8 ± 0.2°, 14.3 ± 0.2°, 15.0 ± 0.2°, 15.5 ± 0.2°, 16.5 ± 0.2°, 17.0 ± 0.2°, 19.2 ± 0.2°, 19.5 ± 0.2°, 19.9 ± 0.2°, 21.2 ± 0.2°, 22.3 ± 0.2°, 22.7 ± 0.2°, 23.3 ± 0.2°, 23.9 ± 0.2°, 24.7 ± 0.2°, 25.3 ± 0.2°, 26.0 ± 0.2°, 26.9 ± 0.2°, 27.7 ± 0.2°, 28.5 ± 0.2°, 28.9 ± 0.2°, and 29.7 ± 0.2°.

15. A solid form of a compound having the following Structure (I):or a tautomer thereof, having an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 3.

16. The solid form of any one of claims 12-15, characterized by a differential scanning calorimetry thermogram comprising no events up to about 340 °C.

17. The solid form of any one of claims 12-15, characterized by a differential scanning calorimetry thermogram substantially in accordance with that depicted in FIG. 4.

18. A solid form of a compound having the following Structure (I):or a tautomer thereof, wherein the solid form is prepared by a process comprising steps of:(i) providing Structure (I) Pattern 3;(ii) heating Structure (I) Pattern 3 to about 250 °C under vacuum; and(iii) isolating the solid form of a compound having Structure (I).

19. The solid form of any one of claims 12-18, wherein the solid form is unsolvated.

20. An amorphous solid form of a compound having the following Structure (I):or a tautomer thereof.

21. An amorphous solid form of a compound having the following Structure (I):or a tautomer thereof, wherein the amorphous form is prepared by a process comprising steps of:(i) providing Structure (I) Pattern 3;(ii) ball milling Structure (I) Pattern 3 at a suitable frequency (e.g., 30 Hz) and for a suitable amount of time (e.g., 3 sessions of 90 min each); and(iii) isolating the amorphous form of a compound having Structure (I).

22. A crystalline solid form of a compound having the following Structure (I):or a tautomer thereof, wherein the crystalline solid form is described in the Example herein.

23. A crystalline solid form of a compound having the following Structure (I):or a tautomer thereof, wherein the crystalline solid form is prepared by a process comprising steps of:(i) providing Structure (I);(ii) contacting Structure (I) with one or more suitable solvents (e.g., n-heptane, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, 2-propanol, methyl ethyl ketone, acetone, ethanol, tert-butyl methyl ether, 2-methyl-l -propanol, cyclohexane, methanol, toluene, tetrahydrofuran, acetonitrile, water, dimethylsulfoxide, or a combination thereof); and(iii) isolating the crystalline solid form, the process optionally comprising a step of heating or cooling the mixture of Structure (I) in a suitable solvent or a solid precipitate isolated therefrom.

24. A salt form of a compound having the following Structure (I):or a tautomer thereof, wherein the salt form is formed between Structure (I) and a co-former selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, maleic acid, fumaric acid, phosphoric acid, citric acid, / ?-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, tartaric acid, succinic acid, and malic acid.

25. The salt form of claim 24, wherein the salt form is described in the Examples herein.

26. The salt form of claim 24 or 25, wherein the salt form is crystalline.

27. A salt form of a compound having the following Structure (I):or a tautomer thereof, wherein the salt form is prepared by a process comprising steps of:(i) providing Structure (I);(ii) contacting Structure (I) with a co-former selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, maleic acid, fumaric acid, phosphoric acid, citric acid, / 2-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, tartaric acid, succinic acid, and malic acid; and(iii) isolating the salt form.

28. A solid form (e.g., a crystalline or amorphous form of a free base or salt form) of a compound having the following Structure (I):or a tautomer thereof, wherein the solid form is prepared by a process described in the Examples herein.

29. A pharmaceutical composition comprising a solid form of any one of claims 1-28 and a pharmaceutically acceptable carrier or excipient.

30. The pharmaceutical composition of claim 29, formulated for oral administration.

31. The pharmaceutical composition of claim 29, in the form of a capsule.

32. The pharmaceutical composition of claim 29, in the form of a tablet.

33. A method of preparing a solid form of a compound having the following Structure (I):or a tautomer thereof, the method comprising steps of(i) providing N-(6-((8"-methyl-l",5"-dioxo-l",5"-dihydro-2"H-dispiro[cyclopropane- l,T-cyclohexane-4',3"-imidazo[l,5-a]pyridin]-6"-yl)amino)pyrimidin-4- yl)cyclopropanecarboxamide (Int-A);(ii) contacting Int-A with a hydroxide base (e g., potassium hydroxide) in a suitable solvent (e.g., ethanol, tetrahydrofuran, and water, or a mixture thereof); and(iii) isolating the solid form of a compound having Structure (I).

34. The method of claim 33, further comprising a step of slurrying the solid form of a compound having Structure (I) in a suitable solvent (e g., water).

35. A method of preparing a solid form of a compound having the following Structure (I):or a tautomer thereof, the method comprising steps of:(i) providing Structure (I) Pattern 3;(ii) heating Structure (I) Pattern 3 to about 250 °C under vacuum; and(iii) isolating the solid form of a compound having Structure (I).

36. A method of preparing an amorphous form of a compound having the following Structure (I):or a tautomer thereof, the method comprising steps of:(i) providing Structure (I) Pattern 3;(ii) ball milling Structure (I) Pattern 3 at a suitable frequency (e.g., 30 Hz) and for a suitable amount of time (e.g., 3 sessions of 90 min each); and(iii) isolating the amorphous form of a compound having Structure (I).

37. A method of preparing a crystalline solid form of a compound having the following Structure (I):or a tautomer thereof, the method comprising steps of:(i) providing Structure (I);(ii) contacting Structure (I) with one or more suitable solvents (e.g., n-heptane, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, 2-propanol, methyl ethyl ketone, acetone, ethanol, tert-butyl methyl ether, 2-methyl-l -propanol, cyclohexane, methanol, toluene, tetrahydrofuran, acetonitrile, water, dimethylsulfoxide, or a combination thereof); and(iii) isolating the crystalline solid form, the method optionally comprising a step of heating or cooling the mixture of Structure (I) in a suitable solvent or a solid precipitate isolated therefrom.

38. A method of preparing a salt form of a compound having the following Structure (I):or a tautomer thereof, the method comprising steps of(i) providing Structure (I);(ii) contacting Structure (I) with a co-former selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, maleic acid, fumaric acid, phosphoric acid, citric acid, / 2-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, tartaric acid, succinic acid, and malic acid; and(iii) isolating the salt form.

39. A method for treating, preventing, or mitigating the effects of a migraine or symptoms related to a migraine, the method comprising administering a therapeutically effective amount of the solid form of any one of claims 1-28 or a pharmaceutical composition of any one of claims 29-32.

40. A method for treating, preventing, or mitigating the effects of a disease associated with aberrant MNK activity in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a solid form of any one of claims 1-28, or a pharmaceutical composition of any one of claims 29-32.

41. A method for treating, preventing, or mitigating the effects of neuropathic pain, Lupus, viral infection-induced pain, COVTD-19 related acute respiratory distress syndrome (ARDS), nonalcoholic fatty liver disease (NAFLD), high fat diet induced obesity, Alzheimer's disease, or Fragile X syndrome in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a solid form of any one of claims 1-28, or a pharmaceutical composition of any one of claims 29-32.

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