US 2025/0026749 A1 · GLUCOSYLCERAMIDE SYNTHASE INHIBITORS

Glucosylceramide synthase inhibitors

AssigneeGenzyme Corporation

InventorsElyse BOURQUE, Mario A. CABRERA-SALAZAR, Cassandra CELATKA, Seng H. CHENG, Bradford HIRTH, Andrew GOOD, Katherine JANCSICS, John MARSHALL, Markus METZ, Ronald K. SCHEULE, Renato SKERLJ, Yibin XIANG, Zhong ZHAO, John LEONARD, Thomas NATOLI, Elina MAKINO, Herve HUSSON, Oxana BESKROVNAYA

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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, cystic disease and for the treatment of cancer.

Claims22

Dependent claims

1-248. (canceled)

A method for treating a disease or disorder mediated by glucosylceramide synthase (GCS) or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound represented by the following structural formula,

or a pharmaceutically acceptable salt thereof, wherein:
n is 1, 2 or 3;
m is 0;
p is 1;
t is 0, 1 or 2;
y is 1 or 2;
z is 0, 1 or 2;
E is O;
X1 is N;
X3 is a direct bond, O, or —NH;
X4 is a direct bond or CR4R5;
X5 is a direct bond, O, CR4R5, or (C1-C6)alkyl;
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-C9)heteroaryl or (C2-C9)heterocycloalkyl wherein A1 is 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)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 (C3-C10)cycloalkyl, (C6-C12)aryl, (C2-C9)heteroaryl, or (C2-C9)heterocycloalkyl wherein A2 is optionally substituted with one or more substituents selected from the group consisting of halo, (C1-C6)alkyl, (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, (C3-C6) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C1-C6) haloalkyl, (C2-C9)heterocycloalkyl, R8R9N—CO— wherein R1 and R9 are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl or R1 and R9 can be taken together with the nitrogen to which they are attached to form a (C2-C9)heterocycloalkyl or (C2-C9)heterocycloalkyl group optionally substituted by one to three halo groups, (C1-C6)alkylsulfonyl optionally substituted by one or two groups selected from (C1-C6)alkoxy and (C3-C10)cycloalkyl;
(C1-C6)alkyl substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl optionally substituted by (C1-C6)alkoxy;
or (C3-C10)cycloalkoxy optionally substituted by (C1-C6)alkoxy;
and
(C1-C6)alkyloxy substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl optionally substituted by (C1-C6)alkoxy;
or (C3-C10)cycloalkoxy optionally substituted by (C1-C6)alkoxy;
with the proviso that the sum of n+t+y+z is not greater than 6;
and
with the proviso that when X3 is O, or —NH, and X4 is CR4R5;
then A2 must be substituted with one or more substituents selected from the group consisting of, (C2-C9)heterocycloalkyl, R8R9N—CO— wherein R1 and R9 are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl or R8 and R9 can be taken together with the nitrogen to which they are attached to form a (C2-C9)heterocycloalkyl or (C2-C9)heterocycloalkyl group optionally substituted by one to three halo groups, (C1-C6)alkylsulfonyl optionally substituted by one or two groups selected from (C1-C6)alkoxy and (C3-C10)cycloalkyl;
(C1-C6)alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl optionally substituted by (C1-C6)alkoxy;
or (C3-C10)cycloalkoxy optionally substituted by (C1-C6)alkoxy;
or (C1-C6)alkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl optionally substituted by (C1-C6)alkoxy;
or (C3-C10)cycloalkoxy optionally substituted by (C1-C6)alkoxy.

29 more elements

A compound represented by the following structural formula,

or a pharmaceutically acceptable salt thereof, wherein:
n is 2;
m is 0;
p is 1;
t is 0;
y is 1;
z is 1;
E is O;
Xt is N;
X3 is a direct bond, O, or —NH;
X4 is a direct bond or CR4R5;
X5 is a direct bond, O, CR4R5, or (C1-C6)alkyl;
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;
or (C1-C6)alkyl optionally substituted by one to four halo or (C1-C6)alkyl;
A1 is (C2-C9)heteroaryl or (C2-C9)heterocycloalkyl, wherein A1 is 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;
wherein when A1 is (C2-C9)heteroaryl it is selected from thiazolyl, isothiazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzopyrazolyl, benzimidazolyl, or benzisoxazolyl;
wherein when A1 is (C2-C9)heterocycloalkyl it is selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, piperizin-2-onyl, piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1.0]hexanyl 2-azaspiro[4.4]nonanyl, 7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, and octahydro-1H-indolyl;
A2 is (C3-C10)cycloalkyl, (C6-C12)aryl, (C2-C9)heteroaryl, or (C2-C9)heterocycloalkyl;
wherein A2 is substituted with one or more substituents selected from the group consisting of:
halo, (C1-C6)alkylenyl, (C1-C6) alkylamino, (C1-C6)dialkylamino, O(C3-C6 cycloalkyl), (C3-C6) cycloalkoxy, (C3-C6) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylcarbonyl, (C2-C9)heterocycloalkyl;
R8R9N—CO—, wherein R1 and R9 are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl, or R1 and R9 can be taken together with the nitrogen to which they are attached to form a (C2-C9)heterocycloalkyl or (C2-C9)heterocycloalkyl group optionally substituted by one to three halo groups, or (C1-C6)alkylsulfonyl optionally substituted by one or two groups selected from (C1-C6)alkoxy and (C3-C10)cycloalkyl;
(C1-C6)alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl optionally substituted by (C1-C6)alkoxy;
or (C3-C10)cycloalkoxy optionally substituted by (C1-C6)alkoxy;
and
(C1-C6)alkyloxy substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl optionally substituted by (C1-C6)alkoxy;
or (C3-C10)cycloalkoxy optionally substituted by (C1-C6)alkoxy;
and
with the proviso that when X4 is CR4R5;
then A2 must be substituted with one or more substituents selected from the group consisting of:
(C2-C9)heterocycloalkyl, R8R9N—CO— wherein R1 and R9 are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl, or R1 and R9 can be taken together with the nitrogen to which they are attached to form a (C2-C9)heterocycloalkyl or (C2-C9)heterocycloalkyl group optionally substituted by one to three halo groups, or (C1-C6)alkylsulfonyl optionally substituted by one or two groups selected from (C1-C6)alkoxy and (C3-C10)cycloalkyl;
(C1-C6)alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl optionally substituted by (C1-C6)alkoxy;
or (C3-C10)cycloalkoxy optionally substituted by (C1-C6)alkoxy;
or (C1-C6)alkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl optionally substituted by (C1-C6)alkoxy;
or (C3-C10)cycloalkoxy optionally substituted by (C1-C6)alkoxy.

34 more elements

Dependencies are inferred from the claim text.