N-(1-hydroxy-3-(pyrrolidinyl)propan-2-yl)pyrrolidine-3-carboxamide derivatives as glucosylceramide synthase inhibitors

A compound of Formula I:

• where
• R1 is N—(R6)-azetidinyl, N—(R6)-pyrrolidinyl, or N—(R6)-piperidinyl, each of which is attached to the C(O) group by a carbon atom and is optionally substituted with hydroxy;
• R2 and R3 together with the nitrogen to which they are attached form a 4-6 membered heterocycloalkyl ring with 1 or 2 nitrogen atoms, which is optionally substituted with 1 or 2 R8;
• R4 is aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R9 groups;
• R5 is halo, hydroxy, —N3, —NH2, —NHC(O)CH3, —NH(OCH3), or —NHC(O)H and R5a is hydrogen, halo, alkyl, or deuterium;
• or R5 and R5a together with the carbon to which they are attached form C(O) or C(NOH);
• R6 is alkyl, alkoxycarbonyl, aryl, arylalkyl, arylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, or —C(O)NR6aR6b;
• wherein each aryl and heteroaryl, whether alone or as part of another group, is optionally substituted with 1 or 2 R10 groups;
• and wherein each heterocycloalkyl and cycloalkyl, whether alone or as part of another group, is optionally substituted with 1 or 2 groups independently selected from hydroxy, halo, haloalkyl, alkoxy, alkyl, alkylcarbonyl, and alkoxycarbonyl;
• R6a is hydrogen or alkyl, and R6b is aryl or heteroaryl each of which is optionally substituted with 1 or 2 halo;
• or R6a and R6b together with the nitrogen to which they are attached form a heterocycloalkyl optionally substituted with alkyl, hydroxy, alkylcarbonyl, or alkoxycarbonyl;
• each R8, when present, is independently deuterium, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl, or cycloalkyl;
• each R9, when present, is independently cyano, nitro, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, —NR11C(O)NR11aR11b, hydroxy, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyloxy, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylthio, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl;
• where the phenyl is optionally substituted with 1 or 2 R9a;
• where each heterocycloalkyl, either alone or as part of another group, is optionally substituted with 1 or 2 groups independently selected from alkyl, hydroxy, alkylcarbonyl, and alkoxycarbonyl;
• each R9a, when present, is independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino;
• each R10, when present, is independently cyano, nitro, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, alkenyl, alkynyl, —NR11C(O)NR11aR11b, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl, hydroxy, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyloxy, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylthio, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
• where each aryl or heteroaryl either alone or as part of another group, is independently optionally substituted with 1, 2 or 3 R10a;
• and each heterocycloalkyl, either alone or as part of another group, is optionally substituted with 1 or 2 groups independently selected from alkyl, hydroxy, alkylcarbonyl, and alkoxycarbonyl groups;
• each R10a, when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;
• and
• R11, R11a, and R11b are independently hydrogen, alkyl, or cycloalkyl;
• and
• optionally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.