Glucosylceramide synthase inhibitors and therapeutic methods using the same

1. A compound having a structure

wherein R 1 is H or C 1-3 alkyl;

R 2 is

 and

R 3 is

wherein the fused ring B is a five- or six-membered ring, saturated or partially or fully unsaturated, comprising carbon atoms and one or two heteroatoms selected from O, S, and NR a , and wherein the phenyl ring is optionally substituted with one or two substituents selected from the group consisting of halo, C 1-3 alkyl, OR a , CO 2 R a , halomethyl, halomethoxy, cyano, nitro, and N(R a ) 2 ;

or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and R a independently is H or C 1-3 alkyl.

2. The compound of claim 1 wherein R 1 is H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , or

3. The compound of claim 1 wherein a fused B ring of R 3 is selected from the group consisting of cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, phenyl, furanyl, thienyl, 2H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 3H-pyrrolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 5H-1,2,5-oxathiazolyl, 1,3-oxathiolyl, 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, 2-pyronyl, 4-pyronyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,2-dioxinyl, 1,3-dioxinyl, 4H-1,3-oxazinyl, 2H-1,3-oxazinyl, 6H-1,2-oxazinyl, 4H-1,4-oxazinyl, 2H-1,2-oxazinyl, 1,4-oxazinyl, p-isoxazinyl, and o-isoxazinyl.

4. The compound of claim 1 wherein R 3 is

q is an integer 1 or 2, and G, independently, is O, S, or NR a .

5. The compound of claim 4 wherein R 3 is

optionally substituted with halo, C 1-3 alkyl, OR a , CO 2 R a , halomethyl, halomethoxy, cyano, nitro, or N(R a ) 2 .

6. A compound selected from the group consisting of N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)cinnamamide, N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-phenylcyclopropanecarboxamide, 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide, N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,3-dihydro-1H-indene-2-carboxamide, N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-N-methyl-3-phenylpropanamide, N-((1R,2R)-1-hydroxy-1-(2-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)octanamide, N-((1R,2R)-1-(3-(dimethylamino)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide, N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3-fluorophenyl)propanamide, N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-fluorophenyl)propanamide, N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-phenylbutanamide (mixture of diastereomers), N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(2-methoxyphenyl)propanamide, N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(phenylamino)acetamide, 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide oxylate monohydrate, and N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-phenylacetamido,

or a pharmaceutically acceptable salt thereof.

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