Substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors

1. A pharmaceutical composition comprising [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

2. A pharmaceutical composition comprising [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid, and a pharmaceutically acceptable excipient.

3. A pharmaceutical composition comprising a crystalline form of [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

4. The pharmaceutical composition of claim 3 , wherein the crystalline form is characterized substantially by the following principal powder x-ray diffraction pattern peaks expressed in terms of 2⊖ as measured with a copper radiation chosen from 9.0+/−0.2°, 10.4+/−0.2°, 15.0+/−0.2°, and 21.4+/−0.2°.

5. A method of treating a disease for which an inhibitor of KHK is indicated, the method comprising the administration to a human in need thereof a therapeutically effective amount of a composition of claim 1 , wherein the disease is selected from any one or a combination of type-1 diabetes, type-2 diabetes, insulin resistance, hypertriglyceridemia, NAFLD, steatosis, NASH, NASH with fibrosis, obesity, visceral adipose dysfunction, eating disorders, and excessive sugar craving.

6. A method of treating a disease for which an inhibitor of KHK is indicated, the method comprising the administration to a human in need thereof a therapeutically effective amount of a composition of claim 2 , wherein the disease is selected from any one or a combination of type-1 diabetes, type-2 diabetes, insulin resistance, hypertriglyceridemia, NAFLD, steatosis, NASH, NASH with fibrosis, obesity, visceral adipose dysfunction, eating disorders, and excessive sugar craving.

7. A method of treating a disease for which an inhibitor of KHK is indicated, the method comprising the administration to a human in need thereof a therapeutically effective amount of a composition of claim 3 , wherein the disease is selected from any one or a combination of type-1 diabetes, type-2 diabetes, insulin resistance, hypertriglyceridemia, NAFLD, steatosis, NASH, NASH with fibrosis, obesity, visceral adipose dysfunction, eating disorders, and excessive sugar craving.

8. The method of claim 7 , wherein the crystalline form is characterized substantially by the following principal powder x-ray diffraction pattern peaks expressed in terms of 2⊖ as measured with a copper radiation chosen from 9.0+/−0.2°, 10.4+/−0.2°, 15.0+/−0.2°, and 21.4+/−0.2°.

9. A method of treating NASH with fibrosis, the method comprising the administration to a human in need thereof a therapeutically effective amount of a composition according to claim 1 .

10. A method of treating NASH with fibrosis, the method comprising the administration to a human in need thereof a therapeutically effective amount of a composition according to claim 2 .

11. A method of treating NASH with fibrosis, the method comprising the administration to a human in need thereof a therapeutically effective amount of a composition according to claim 3 .

12. The method of claim 11 wherein, wherein the crystalline form is characterized substantially by the following principal powder x-ray diffraction pattern peaks expressed in terms of 2⊖ as measured with a copper radiation chosen from 9.0+/−0.2°, 10.4+/−0.2°, 15.0+/−0.2°, and 21.4+/−0.2°.

13. The method of claim 5 , wherein the disease is NAFLD.

14. The method of claim 6 , wherein the disease is NAFLD.

15. The method of claim 7 , wherein the disease is NAFLD.

16. The method of claim 5 , wherein the disease is NASH.

17. The method of claim 6 , wherein the disease is NASH.

18. The method of claim 7 , wherein the disease is NASH.