Glucosylceramide synthase inhibitors
The invention relates to inhibitors of glucosylceramide synthase (GCS) of the Formula I: represented by the following structural formula or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein, useful for the treatment of metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, cystic disease and for the treatment of cancer.
1. A compound represented by the following structural formula,
or a pharmaceutically acceptable salt thereof, wherein:
n is 1;
m is 1;
p is 1;
t is 0;
y is 1;
z is 1;
E is O;
X t is CR 1 and X 1 is directly bonded to X 2 ;
X 2 is O or —NH;
X 3 is —NH;
X 4 is a direct bond or CR 4 R 5 ;
X 5 is a direct bond or O;
R 1 is H or (C 1 -C 6 )alkyl;
R 4 and R 5 are independently selected from H, (C 1 -C 6 )alkyl, or taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring;
R 6 is H;
A 1 is (C 6 -C 12 )aryl, or (C 2 -C 9 )heteroaryl selected from isothiazolyl, furanyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, and benzisoxazolyl; and
A 2 is selected from (C 6 -C 12 )aryl or (C 2 -C 9 )heteroaryl; wherein A 2 is substituted with one or more substituents selected from the group consisting of:
halo;
R 8 R 9 N—CO—, wherein R 8 and R 9 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, or R 8 and R 9 can be taken together with the nitrogen to which they are attached to form a (C 2 -C 9 )heterocycloalkyl;
(C 1 -C 6 )alkyl substituted by one to four substituents selected from the group consisting of hydroxy, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy; and
(C 1 -C 6 )alkyloxy substituted by one to four substituents selected from the group consisting of halo, cyano, and (C 1 -C 6 )alkoxy;
with the proviso that when X 4 is CR 4 R 5 ; then A 2 must be substituted with one or more substituents selected from the group consisting of:
R 8 R 9 N—CO— wherein R 8 and R 9 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, or R 8 and R 9 can be taken together with the nitrogen to which they are attached to form a (C 2 -C 9 )heterocycloalkyl;
(C 1 -C 6 )alkyl substituted by one to four substituents selected from the group consisting of hydroxy, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy; and
(C 1 -C 6 )alkyloxy substituted by one to four substituents selected from the group consisting of cyano, and (C 1 -C 6 )alkoxy; and
with the proviso that the compound is not quinuclidin-3-yl (2-(4′-(2-methoxyethoxy) [1,1′-biphenyl]-4-yl)propan-2-yl)carbamate.
2. The compound of claim 1 , wherein X 4 is a direct bond.
3. The compound of claim 1 , wherein m is 1, E is O, X 2 is O, and X 3 is NH.
4. The compound of claim 1 , wherein A 2 is (C 6 -C 12 )aryl.
5. The compound of claim 1 , wherein R 1 is hydrogen or methyl.
6. A pharmaceutical composition comprising a compound according to claim 1 , and at least one pharmaceutically acceptable carrier.
7. The compound of claim 1 , wherein A 1 is (C 2 -C 9 )heteroaryl selected from isothiazolyl, furanyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, and benzisoxazolyl.