Diacylglycerol acyl transferase 2 inhibitor
Described herein are compounds of Formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are defined herein, their use as diacylglycerol acyltransferase 2 (DGAT2) inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat, for example, NASH.
1. A compound of Formula (I)
wherein
R 1 is H or fluoro;
R 2 , R 3 , R 4 and R 5 are each independently selected from H, and (C 1 -C 3 )fluoroalkyl and
R 6 , R 7 , R 8 , and R 9 are each independently selected from H, fluoro, and (C 1 -C 3 )fluoroalkyl; and
wherein 1 or 2 of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are other than H;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 2 , R 3 , R 4 and R 5 are each independently selected from H and (C 1 )fluoroalkyl and R 6 , R 7 , R 8 , and R 9 are each independently selected from H, (C 1 )fluoroalkyl, and fluoro; wherein 1 or 2 of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are other than H; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are H; and R 8 and R 9 are independently selected from H, (C 1 )fluoroalkyl and fluoro; wherein at least one of R 8 , and R 9 are (C 1 )fluoroalkyl or fluoro; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 8 , and R 9 are H; and R 6 and R 7 are each independently selected from H, (C 1 )fluoroalkyl and fluoro wherein at least one of R 6 and R 7 are (C 1 )fluoroalkyl or fluoro; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 9 are H; and R 7 and R 8 are each independently selected from H, (C 1 )fluoroalkyl and fluoro wherein at least one of R 7 and R 8 are (C 1 )fluoroalkyl or fluoro; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 are H; and R 7 is (C 1 )fluoroalkyl or fluoro; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 are H; and R 7 is fluoro; or a pharmaceutically acceptable salt thereof.
8. A compound selected from the group consisting of:
2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4S)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide;
2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3S,5S)-5-fluoropiperidin-3-yl)pyrimidine-5-carboxamide;
2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4S)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide;
2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4R)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide;
2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4R)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; and
2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3S,5S)-5-fluoropiperidin-3-yl)pyrimidine-5-carboxamide
or a pharmaceutically acceptable salt thereof.
9. The compound
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 9 wherein the compound is 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3S,5S)-5-fluoropiperidin-3-yl)pyrimidine-5-carboxamide.
11. The compound of claim 9 wherein the compound is 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3S,5S)-5-fluoropiperidin-3-yl)pyrimidine-5-carboxamide hydrochloride.
12. The compound of claim 9 wherein the compound is 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3S,5S)-5-fluoropiperidin-3-yl)pyrimidine-5-carboxamide tosylate.
13. The compound of claim 1 wherein the compound is 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(5-fluoropiperidin-3-yl)pyrimidine-5-carboxamide.
14. A method of treating fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis or nonalcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of claim 9 or a pharmaceutically acceptable salt of said compound.
15. The method as recited in claim 14 wherein nonalcoholic steatohepatitis is treated.
16. The method as recited in claim 14 wherein nonalcoholic fatty liver disease is treated.
17. The method as recited in claim 14 wherein nonalcoholic steatohepatitis with liver fibrosis is treated.
18. A method of treating hypertriglyceridemia, atherosclerosis, myocardial infarction, dyslipidemia, coronary heart disease, hyper apo B lipoproteinemia, ischemic stroke, type 2 diabetes mellitus, glycemic control in patients with type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, insulin resistance, impaired glucose metabolism, comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of claim 9 or a pharmaceutically acceptable salt thereof.
19. The method as recited in claim 18 wherein hypertriglyceridemia is treated.
20. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 9 or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
21. A pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising:
a first compound, said first compound being a compound of claim 9 , or a pharmaceutically acceptable salt of said compound;
a second compound, said second compound being an anti-diabetic agent; a non-alcoholic steatohepatitis treatment agent, a non-alcoholic fatty liver disease treatment agent, a cholesterol or lipid lowering agent, or an anti-heart failure treatment agent and
a pharmaceutical carrier, vehicle or diluent.
22. The pharmaceutical combination composition as recited in claim 21 wherein said non-alcoholic steatohepatitis treatment agent or non-alcoholic fatty liver disease treatment agent is an ACC inhibitor, a KHK inhibitor, a BCKDK inhibitor, an FXR agonist, metformin, an incretin analog, or a GLP-1 receptor agonist.
23. The pharmaceutical combination composition as recited in claim 21 wherein said non-alcoholic steatohepatitis treatment agent or non-alcoholic fatty liver disease treatment agent is 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid; [(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; 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid; 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; or 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof.
24. The pharmaceutical combination composition as recited in claim 21 wherein said anti-diabetic agent is an SGLT-2 inhibitor, a BCKDK inhibitor, metformin, an incretin analog, an incretin receptor modulator, a DPP-4 inhibitor, or a PPAR agonist.
25. The pharmaceutical combination composition as recited in claim 24 wherein said anti-diabetic agent is metfomin, sitagliptin, ertuglifozin, 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.
26. The pharmaceutical combination composition as recited in claim 21 wherein said anti-heart failure agent or cholesterol or lipid lowering agent is an ACE inhibitor, an angiotensin receptor blocker, a BCKDK inhibitor, an angiotensin receptor blocker-neprilysin inhibitor, a beta adrenergic receptor blocker, a calcium channel blocker, a fibrate, an HMG CoA reductase inhibitor or a vasodilator.
27. A crystal comprising a compound having the structure:
or a pharmaceutically acceptable salt thereof.
28. The crystal of claim 27 wherein the crystal comprises a p-toluenesulfonate salt of the compound.
29. The crystal of claim 27 having a powder x-ray diffraction pattern comprising 2-theta values of (CuKα radiation, wavelength of 1.54056 Å) 7.2±0.2, 14.5±0.2, 15.8±0.2, and 27.7±0.2.
30. The crystal of claim 28 having a powder x-ray diffraction pattern comprising 2-theta values of (CuKα radiation, wavelength of 1.54056 Å) 3.8±0.2, 7.7±0.2, 8.8±0.2, 22.4±0.2, and 24.6±0.2.