US 2020/0048266 A1 · GLUCOSYLCERAMIDE SYNTHASE INHIBITORS

Abstract

The invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment of metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, and for the treatment of cancer.

A compound represented by the following structural formula,

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
n is 1, 2 or 3;
m is 0 or 1;
p is 0 or 1;
t is 0, 1 or 2;
y is 1 or 2;
z is 0, 1 or 2;
E is S, O, NH, NOH, NNO2, NCN, NR, NOR or NSO2R;
X1 is CR1 when m is 1 or N when m is 0;
X2 is O, —NH, —CH2—, SO2, NH—SO2;CH(C1-C6) alkyl or —NR2;
X3 is O, —NH —CH2—, CO, —CH(C1-C6) alkyl, SO2NH, —CO—NH— or —NR3;
X4 is CR4R5, CH2 CR4R5 or CH2—(C1-C6) alkyl-CR4R5;
X5 is a direct bond, O, S, SO2, CR4R5;
(C1-C6)alkyl, (C1-C6)alkyloxy, (C1-C6)alkenyl, (C1-C6)alkenyloxy;
R is (C6-C12)aryl, (C2-C9)heteroaryl, (C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl;
R1 is H, CN, (C1-C6)alkylcarbonyl, or (C1-C6)alkyl;
R2 and R3 are each independently —H, (C1-C6)alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, (C1-C6)alkyl, (C6-C12)aryl, (C2-C9)heteroaryl, (C1-C6)alkyl(C6-C12)aryl, halo(C6-C12)aryl, and halo(C2-C9)heteroaryl, or optionally when X2 is —NR2 and X3 is —NR3, R2 and R3 may be taken together with the nitrogen atoms to which they are attached form a non-aromatic heterocyclic ring optionally substituted by with one or more substituents selected from halogen, (C1-C6)alkyl, (C6-C12)aryl, (C2-C9)heteroaryl, (C1-C6)alkyl(C6-C12)aryl, halo(C6-C12)aryl, and halo(C2-C9)heteroaryl;
R4 and R5 are independently selected from H, (C1-C6)alkyl, or taken together with the carbon to which they are attached to form a spiro (C3-C10)cycloalkyl ring or spiro (C3-C10)cycloalkoxy ring;
R6 is —H, halogen, —CN, (C6-C12)aryl, (C6-C12)aryloxy, (C1-C6)alkyloxy;
(C1-C6)alkyl optionally substituted by one to four halo or (C1-C6)alkyl;
A1 is (C2-C6)alkynyl;
(C3-C10)cycloalkyl, (C6-C12)aryl, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl or benzo(C2-C9)heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of halo, (C1-C6)alkyl optionally substituted by one to three halo;
(C1-C6)alkenyl, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, (C1-C6)alkoxy, nitro, CN, —OH, (C1-C6)alkyloxy optionally substituted by one to three halo;
(C1-C6)alkoxycarbonyl, and (C1-C6) alkylcarbonyl;
A2 is H, (C3-C10)cycloalkyl, (C6-C12)aryl, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl or benzo(C2-C9)heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of halo, (C1-C6)alkyl optionally substituted by one to three halo;
(C1-C6)alkylenyl, amino, (C1-C6) alkylamino, (C1-C6)dialkylamino, (C1-C6)alkoxy, O(C3-C6 cycloalkyl), (C3-C6) cycloalkoxy, nitro, CN, OH, (C1-C6)alkyloxy optionally substituted by one to three halo;
(C3-C6) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) haloalkyl;
with the proviso that the sum of n+t+y+z is not greater than 6;
with the proviso that when p is 0;
X2 is NH—SO2 and X3 is NH;
with the proviso that when n is 1;
t is 0;
y is 1;
z is 1;
X2 is NH;
E is O;
X3 is NH;
A2 is H and X5 is a direct bond;
A1 is not unsubstituted phenyl, halophenyl or isopropenyl phenyl;
with the proviso that when n is 1;
t is 0;
y is 1;
z is 1;
X2 is O;
E is O;
X3 is NH;
A1 is (C6-C12)aryl and X5 is a direct bond;
A2 is H and R4 is H then R5 is not cyclohexyl;
and
with the proviso that when n is 1;
t is 0;
y is 1;
z is 1;
X2 is NH;
E is O;
X3 is CH2;
R4 and R5 are both hydrogen;
A2 is H and X5 is a direct bond;
then A1 is not unsubstituted phenyl.

56 more elements

Glucosylceramide synthase inhibitors

Life of this patent

Glucosylceramide synthase inhibitors

Life of this patent

Abstract

Claims34