Glucosylceramide synthase inhibitors for the treatment of diseases

1. A compound of Formula I:

wherein

R 1 is H; or R 1 and R 2 together form —OCH 2 CH 2 O—;

R 2 is C 3-6 cycloalkyloxy or 3-6 membered heterocycloalkyloxy;

R 3 is H or halogen;

R 4 is H or C 1-4 alkyl;

R 5 and R 5A are each independently H or C 1-4 alkyl;

X is N or O, and when X is N, the dashed line is a bond to form a double bond, and when X is O, the dashed line is not a bond to form a single bond;

Y is C(R 6 ) 2 or O; with the proviso that X and Y are not both O;

R 6 at each occurrence is independently H or C 1-4 alkyl;

Ring A is phenylene, naphthylene, or 5-10 membered heteroarylene;

R 7 at each occurrence is independently halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyloxy, (C 3-6 cycloalkyl)C 1-6 alkoxy, phenyl, or 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are each optionally substituted with 1, 2, or 3 R 8 ;

p is 0, 1, or 2;

R 8 at each occurrence is independently halogen, cyano, amino, C 1-6 alkylamino, C 1-6 dialkylamino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, or C 1-6 dialkylaminocarbonyl;

Ring B is a 4-6 membered heterocycloalkyl ring;

R 9 at each occurrence is independently halogen, OR 10 , or N(R 10 ) 2 ;

R 10 at each occurrence is independently H or C 1-4 alkyl;

q is 0, 1, 2, 3, or 4; and

optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein

R 1 is H; or R 1 and R 2 together form —OCH 2 CH 2 O—;

R 2 is C 3-6 cycloalkyloxy;

R 3 is H, Cl, or F;

R 4 is H or C 1-4 alkyl;

R 5 and R 5A are each independently H or C 1-4 alkyl;

X is N or O, and when X is N, the dashed line is a bond to form a double bond, and when X is O, the dashed line is not a bond to form a single bond;

Y is CH 2 , CH(C 1-4 alkyl), C(C 1-4 alkyl) 2 , or O; with the proviso that X and Y are not both O;

Ring A is phenylene, naphthylene, benzothiophenylene, indazolylene, or quinolylene;

R 7 is Cl, F, C 1-6 alkyl, (C 3-6 cycloalkyl)C 1-6 alkoxy, phenyl, or thienyl, wherein the phenyl and thienyl are each optionally substituted with R 8 ;

R 8 is Cl, F, or C 1-6 alkyl; and

optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein

R 7 at each occurrence is independently halogen, C 1-6 alkyl, phenyl, or 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are each optionally substituted with 1, 2, or 3 R 8 ; and

optionally a single stereoisomer or mixture of stereoisomers thereof and

additionally optionally a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , wherein

is selected from the group consisting of

wherein the asterix indicates the point of attachment to the rest of the molecule.

5. The compound of claim 3 , wherein Ring A is bicyclic.

6. The compound of claim 3 , wherein Ring A is phenylene, naphthylene, benzothiophenylene, indazolylene, or quinolylene.

7. The compound of claim 3 , wherein Ring A is phenylene and R 7 is phenyl or thienyl, each substituted with halogen.

8. The compound of claim 7 , wherein R 7 is phenyl substituted with Cl or F, or R 7 is thienyl substituted with Cl.

9. The compound of claim 3 , wherein the compound of Formula I is according to Formula I(a):

optionally as a single stereoisomer or mixture of stereoisomers thereof and

additionally optionally as a pharmaceutically acceptable salt thereof.

10. The compound of claim 3 , wherein the compound of Formula I is according to Formula I(b):

optionally as a single stereoisomer or mixture of stereoisomers thereof and

additionally optionally as a pharmaceutically acceptable salt thereof.

11. The compound of claim 3 , wherein the compound of Formula I is according to Formula II:

optionally as a single stereoisomer or mixture of stereoisomers thereof and additionally

optionally as a pharmaceutically acceptable salt thereof.

12. The compound of claim 3 , wherein p is 0 or 1.

13. The compound of claim 12 , wherein q is 0.

14. The compound of claim 1 , wherein the compound of Formula I is according to Formula XIII:

wherein

R 1 is H; or R 1 and R 2 together form —OCH 2 CH 2 O—;

R 2 is C 3-6 cycloalkyloxy;

R 3 is H, Cl, or F;

R 4 is H or C 1-4 alkyl;

R 5 and R 5A are each independently H or C 1-4 alkyl;

X is N or O, and when X is N, the dashed line is a bond to form a double bond, and when X is O, the dashed line is not a bond to form a single bond;

Y is CH 2 , CH(C 1-4 alkyl), C(C 1-4 alkyl) 2 , or O; with the proviso that X and Y are not both O;

Ring A is phenylene, naphthylene, benzothiophenylene, indazolylene, or quinolylene;

R 7 is Cl, F, C 1-6 alkyl, phenyl, or thienyl, where the phenyl and thienyl are each optionally substituted with R 8 ;

R 8 is Cl, F, or C 1-6 alkyl;

n is 1 or 2; and

optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

15. The compound of claim 14 , wherein the Ring A is phenylene, naphthylene or benzothiophenylene.

16. The compound of claim 1 selected from the group consisting of:

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-fluorophenyl)-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-fluorophenyl)-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-fluorophenyl-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-fluorophenyl)-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-7-(4-fluorophenyl)-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-3-(azetidin-1-yl)-1-(4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-7-(4-fluorophenyl)-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-3-(azetidin-1-yl)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxypropan-2-yl)-7-(4-fluorophenyl)-1H-benzo[d][1,2]oxazine-4-carboxamide;

7-(5-chlorothiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrolidin-1-yl)propan-2-yl)-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-3-(azetidin-1-yl)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxypropan-2-yl)-7-(5-chlorothiophen-2-yl)-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(5-chlorothiophen-2-yl)-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-3-(azetidin-1-yl) 1-(4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl-7-(5-chlorothiophen-2 yl)-1H-benzo[d][1,2]oxazine-4-carboxamide;

7-chloro-N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H-benzo[4,5]thieno[2,3-d][1,2]oxazine-4-carboxamide;

7-chloro-N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H-benzo[4,5]thieno[2,3-d][1,2]oxazine-4-carboxamide;

7-(5-chlorothiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-3-(azetidin-1-yl)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxypropan-2-yl)-7-chloro-1H-benzo[4,5]thieno[2,3-d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-7-chloro-1H-benzo[4,5]thieno[2,3-d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3 (pyrrolidin-1-yl)propan-2-yl)-7-(4-fluorophenyl)-N-methyl-1H-benzo[d][1,2]oxazine-4-carboxamide;

7-(5-chlorothiophen-2-yl)-N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrolidin-1-yl)propan-2-yl)-N-methyl-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-fluorophenyl)-N-methyl-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H-naphtho[2,3-d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-7-(4-fluorophenyl)-N-methyl-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H-naphtho[2,1-d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-fluorophenyl)-1-methyl-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-fluorophenyl)-1-methyl-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(4-cyclopropoxyphenyl)-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H-naphtho[2,1-d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-1H-naphtho[2,1-d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-10H-[1,2]oxazino[4,5-h]quinoline-7-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-8-fluoro-1H-naphtho[2,1-d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1-hydroxy-3 (pyrrolidin-1-yl)propan-2-yl)-8-fluoro-1H-naphtho[2,1-d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-8-fluoro-1H-naphtho[2,1-d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-3(azetidin-1-yl)-1-(4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-8-fluoro-1H-naphtho[2,1-d][1,2]oxazine-4-carboxamide;

8-chloro-N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H-thieno[3′,2′:3,4]benzo[1,2-d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-methyl-1,7-dihydro-[1,2]oxazino[5,4-e]indazole-4-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1-methyl-1,9-dihydro-[1,2]oxazino[4,5-g]indazole-6-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-methyl-2,9-dihydro-[1,2]oxazino[4,5-g]indazole-6-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H-[1,2]oxazino[5,4-f]quinoline-4-carboxamide;

2-chloro-N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-ylpropan-2-yl)-9H-1-thieno[2′,3′:3,4]benzo[1,2-d][1,2]oxazine-6-carboxamide;

N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-fluorophenyl)-3,4-dihydroisoquinoline-1-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1 yl)propan-2-yl)-6-(4-fluorophenyl)-N-methyl-3,4-dihydroisoquinoline-1-carboxamide;

N-((1R,2R)-3-(azetidin-1-yl)-1-(4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-6-(4-fluorophenyl)-3,4-dihydroisoquinoline-1-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl-6-(4-fluorophenyl)-3,3-dimethyl-3,4-dihydroisoquinoline-1-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-fluorophenyl)isochroman-1-carboxamide;

7-chloro-N-(1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrolidin-1-yl)propan-2-yl)-3,4-dihydro-1H-benzo[4,5]thieno[2,3-c]pyran-1-carboxamide;

8-chloro-N-((1R,2R)-1-(4-cyclopropoxyphenyl)-1 hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-1H-thieno[3′,2′:3,4]benzo[1,2-d][1,2]oxazine-4-carboxamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(cyclohexylmethoxy)-1H-benzo[d][1,2]oxazine-4-carboxamide;

N-(1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1 yl)propan-2-yl)-1-methyl-1,9-dihydro-[1,2]oxazino[4,5-g]indazole-6-carboxamide; and

2-chloro-N-((1R,2R)-1-(4-cyclopropoxy-3-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-9H-thieno[2,3′:3,4]benzo[1,2-d][1,2]oxazine-6-carboxamide; and

optionally as a single stereoisomer or mixture of stereoisomers thereof and additionally

optionally as a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising i) a compound of claim 1 optionally as a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, and ii) a pharmaceutically acceptable excipient.

18. A method of treating a disease or disorder comprising administering a compound of claim 1 or the pharmaceutical composition of claim 17 , wherein the disease or disorder is Tay Sachs, Sandhoff's, GM1 gangliosidosis, Fabry, Gaucher, Niemanns-Pick, or polycystic kidney disease.