Glucosylceramide synthase inhibitors and therapeutic methods using the same

1. A compound having a structure

wherein R 1 , independently, is selected from the group consisting of halo, C 1-3 alkyl, C 1-3 alkyl substituted with one to five fluoro atoms, OC 1-3 alkyl, OC 1-3 alkyl substituted with one to five fluoro atoms, cyclopropyl, CH 2 cyclopropyl, Ocyclopropyl, and OCH 2 cyclopropyl;

NR 2 R 2′ is selected from the group consisting of 1-pyrrolidinyl, 3-fluoro-1-pyrrolidinyl, 1-morpholinyl, 1-azetidinyl, and 1-pyrrolidinyl-3-one;

R 3 is H, F, or Cl;

G is (CH 2 ) n ;

m is 1 or 2; and

n is 1 or 2,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 1 , independently is —OCH 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —F, —CF 3

3. The compound of claim 1 , wherein m is 2, and R 1 is F and —OCH 3 .

4. The compound of claim 1 , wherein R 3 is H.

5. The compound of claim 1 wherein —NR 2 R 2′ is

6. The compound of claim 1 wherein

is

7. The compound of claim 1 selected from the group consisting of 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(3-fluoro-4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(3-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(2-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(4-fluoro-3-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1,2,3,4-tetrahydronaphthalen-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(trifluoromethoxy)phenyl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(trifluoromethyl)phenyl)propan-2-yl)acetamide; N-((1R,2R)-1-(4-(difluoromethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2,3-dihydro-1H-inden-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(4-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; N-((1R,2R)-1-(4-(cyclopropylmethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2,3-dihydro-1H-inden-2-yl)acetamide; and 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or vehicle.

9. A method of treating a disease or condition wherein inhibition of GCS provides a benefit comprising administering a therapeutically effective amount of a compound of claim 1 to an individual in need thereof, wherein the disease or condition is a Gaucher disease, Fabry disease, Sandhoff disease, Tay-Sachs disease, Parkinson's disease, type 2 diabetes, hypertrophy or hyperplasia associated with diabetic neuropathy, an elevated plasma TNF-α level, an elevated blood glucose level, an elevated glycated hemoglobin level, a glomerular disease, lupus, a disorder involving cell growth, a disorder involving cell division, a collagen vascular disease, atherosclerosis, renal hypertrophy in a diabetic individual, a growth of arterial epithelial cells, an infection, a tumor, and an autosomal dominant or recessive form of a polycystic kidney disease.

10. The method of claim 9 wherein the Gaucher disease is type I, type II, or type III Gaucher disease, and the glomerular disease is selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis, and membranous nephropathy.

11. A method of inhibiting glucosylceramide synthase or lowering a glycosphinolipid concentration in an individual in need thereof comprising administering a therapeutically effective amount of a compound of claim 1 to the individual.