Substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors
Provided herein are substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.
1. 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 compound, wherein the compound is [(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 wherein the disease is selected from any one or a combination of type-1 diabetes, type-2 diabetes, insulin resistance, hypertriglyceridemia, NAFLD, steatosis, NASH, and NASH with fibrosis.
2. The method of claim 1 , wherein the compound is 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.
3. The method of claim 2 , 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°.
4. The method of claim 1 , wherein the compound is [(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.
5. The method of claim 4 , wherein the disease is type-1 diabetes.
6. The method of claim 4 , wherein the disease is type-2 diabetes.
7. The method of claim 4 , wherein the disease is insulin resistance.
8. The method of claim 4 , wherein the disease is hypertriglyceridemia.
9. The method of claim 4 , wherein the disease is NAFLD.
10. The method of claim 4 , wherein the disease is steatosis.
11. The method of claim 4 , wherein the disease is NASH.
12. The method of claim 4 , wherein the disease is NASH with fibrosis.
13. The method of claim 1 , wherein the compound is a pharmaceutically acceptable salt 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.
14. The method of claim 13 , wherein the disease is type-1 diabetes.
15. The method of claim 13 , wherein the disease is type-2 diabetes.
16. The method of claim 13 , wherein the disease is insulin resistance.
17. The method of claim 13 , wherein the disease is hypertriglyceridemia.
18. The method of claim 13 , wherein the disease is NAFLD.
19. The method of claim 13 , wherein the disease is steatosis.
20. The method of claim 13 , wherein the disease is NASH.
21. The method of claim 13 , wherein the disease is NASH with fibrosis.
22. A method of treating NASH with fibrosis, the method comprising the administration to a human in need thereof a therapeutically effective amount of a compound, wherein the compound is [(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.
23. The method of claim 22 wherein, wherein the compound is 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.
24. The method of claim 23 , 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°.