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 mammal in need thereof a therapeutically effective amount of a compound, wherein the compound is [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-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 combination of T1D, T2D, insulin resistance, hypertriglyceridemia, NAFLD, steatosis, and NASH.
2. The method of claim 1 , wherein the compound is
or pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the compound is [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.
4. The method of claim 1 , wherein the compound is a sodium salt form of [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-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 compound is a crystalline sodium salt form of [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.
6. The method of claim 5 , wherein the crystalline form of the compound is characterized substantially by the following principal powder x-ray diffraction pattern peaks expressed in terms of 2θ as measured with a copper radiation chosen from 5.9, 11.5, 11.8, 13.3, and 21.5+/−0.2°.
7. The method of claim 1 , wherein the disease is T2D.
8. The method of claim 1 , wherein the disease is insulin resistance.
9. The method of claim 1 , wherein the disease is hypertriglyceridemia.
10. The method of claim 1 , wherein the disease is NAFLD.
11. The method of claim 1 , wherein the disease is steatosis.
12. The method of claim 1 , wherein the disease is NASH.