Thrombin inhibitors, formulations, and uses thereof

1. A compound according to Structure I:

or a pharmaceutically acceptable salt, solvate, or cocrystal thereof,

wherein R 1 is selected from the group consisting of hydrogen and pivaloyl.

2. A prodrug of the compound according to claim 1 according to the general Structure II:

or a pharmaceutically acceptable salt, solvate, or cocrystal thereof;

wherein R 1 is selected from the group consisting of hydrogen and pivaloyl; and

wherein R 2 is selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.

3. The prodrug of claim 2 , wherein R 2 is selected from the following group:

4. The compound according to claim 1 , wherein R 1 is pivaloyl, as Compound 1:

5. The compound according to claim 4 , wherein the compound is in crystalline form.

6. The compound according to claim 5 , wherein the crystalline form has an x-ray powder diffraction pattern comprising at least five 2θ values selected from the group consisting of 9.9°, 12.3°, 12.6°, 14.7°, 15.0°, 16.7°, 17.0°, 17.7°, 18.4°, 18.7°, 19.7°, 20.3°, 22.1°, 22.5°, 23.2°, and 24.7°, wherein each of the at least five 2θ values is within an error range of ±0.3°.

7. The compound according to claim 5 , wherein the crystalline form has an x-ray powder diffraction pattern comprising at least five 2θ values selected from the group consisting of 4.9°, 9.7°, 14.4°, 16.0°, 16.5°, 17.0°, 18.2°, 18.5°, 19.2°, 19.7°, 20.2°, 22.8°, 23.3°, 24.0°, 24.5°, and 24.8°, wherein each of the at least five 2θ values is within an error range of ±0.3°.

8. The compound according to claim 5 , wherein the crystalline form has an x-ray powder diffraction pattern comprising at least five 2θ values selected from the group consisting of 8.6°, 9.5°, 11.8°, 12.4°, 12.9°, 14.2°, 15.2°, 15.5°, 16.5°, 17.2°, 18.8°, 19.1°, 20.1°, 20.9°, and 22.9°, wherein each of the at least five 2θ values is within an error range of ±0.3°.

9. The compound according to claim 1 , wherein R 1 is hydrogen, as Compound 2:

10. The compound according to claim 1 , wherein said compound is in the form of a pharmaceutically acceptable salt.

11. The compound according to claim 10 , wherein the pharmaceutically acceptable salt has a counter-ion selected from the group consisting of sodium, potassium, calcium, L-arginine, L-lysine, meglumine, and tris(hydroxymethyl)aminomethane.

12. The compound according to claim 11 , wherein said counter-ion is tris(hydroxymethyl)aminomethane and wherein R 1 is pivaloyl.

13. The compound according to claim 12 , wherein said counter-ion is tris(hydroxymethyl)aminomethane and wherein R 1 is pivaloyl, and wherein the compound is in crystalline form having an x-ray powder diffraction pattern comprising at least five 2θ values selected from the group consisting of 6.8°, 10.0°, 13.0°, 15.1°, 16.0°, 16.5°, 18.0°, 18.4°, 19.8°, 20.5°, 20.8°, 21.2°, 21.5°, 22.8°, 23.3°, and 25.9°, wherein each of the at least five 2θ values is within an error range of ±0.3°.

14. A compound or prodrug according to claim 1 , selected from the group consisting of:

3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]acetic acid;

4-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]butanoic acid;

3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2,2-difluoropropanoic acid;

3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propenamide;

1-(2-amino-2-methylpropyl)-3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-2-one;

3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylbutanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

3-[3-(5-{[(5-chloro-1-oxo-1lambda4-thiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

(2S,3S,4S,5R,6S)-6-({3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoyl}oxy)-3,4,5-trihydroxyoxane-2-carb oxylic acid;

ethyl 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoate;

prop-2-en-1-yl 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoate; 2-(acetyloxy)ethyl;

3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoate;

1-(acetyloxy)ethyl 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoate;

({3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoyl}oxy)methyl 2,2-dimethylpropanoate;

(3,5,6-trimethylpyrazin-2-yl)methyl 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoate;

({3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoyl}oxy)methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoate;

3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl](2H4)propanoic acid;

3-{3-[5-({[5-chloro(3,4-2H2)thiophen-2-yl](2H2)methyl}amino)-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl]-2-oxo-1,2-dihydropyridin-1-yl}propanoic acid; and

3-[3-(5-{[(5-chlorothiophen-2-yl)(2H2)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid.

15. A pharmaceutical composition comprising a compound or prodrug according to claim 1 , or a pharmaceutically acceptable salt, solvate, or cocrystal thereof, and a pharmaceutically acceptable excipient.

16. A tablet comprising a pharmaceutical composition comprising Compound 1 according to claim 4 .

17. The tablet according to claim 16 , wherein Compound 1 exists as an amorphous solid in an amorphous solid dispersion.

18. The tablet according to claim 17 , wherein said amorphous solid dispersion comprises a first polymer, wherein said first polymer is a vinylpyrrolidone-vinyl acetate copolymer.

19. The tablet according to claim 18 , wherein Compound 1 and said first polymer are present in a weight ratio of 1:3.

20. The tablet according to claim 17 , further comprising at least one disintegrant, and/or at least one filler, and/or at least one lubricant or glidant, and/or an exterior layer or film.