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US 2022/0009935 A1Published application
Inhibitors of gli1 as therapeutic agents
AssigneeNew York University
InventorsWilliam J. GREENLEE, John VAN DRIE, Xinyan HUANG, James SALZER, Nadim SHOHDY
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Abstract
This disclosure relates to compounds, pharmaceutical compositions comprising them, and methods of using the compounds and compositions for treating diseases related to glioma-associated oncogene (Gli) expression. More particularly, this disclosure relates to bicyclic compounds and pharmaceutical compositions thereof, methods of inhibiting Gli expression with these compounds, and methods of treating diseases related to Gli expression.
Claims21
A compound of the formula (I):
- or a pharmaceutically acceptable salt thereof, wherein
- m is an integer 1 or 2;
- n is an integer 1 or 2;
- p is an integer 0, 1, or 2;
- R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocyclyl, hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), —OH, and oxetanyl;
- R2 is C1-C6 alkyl;
- ring A represents an aryl optionally substituted with one or more R3, heteroaryl optionally substituted with one or more R3, or C4-C8 cycloalkyl optionally substituted with one or more R3;
- and
- ring B and ring C form a bicyclic heteroaryl, bicyclic heterocyclyl, or bicyclic cycloalkyl moiety, each optionally substituted with one or more R4;
- wherein
- each R3 is independently selected from halogen, —NO2, —CN, C1-C6 alkyl optionally substituted with one or more R5, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), amino(C1-C6 alkyl), —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CO2H, —CO2(C1-C6 alkyl), —SO2R7, —SO2OR7, —SO2N(R7)2, cyclopropylethynyl, aryl optionally substituted with one or more R6, heteroaryl optionally substituted with one or more R6, heterocyclyl optionally substituted with one or more R6, and C3-C8 cycloalkyl optionally substituted with one or more R6;
- each R4 is independently selected from halogen, —NO2, —CN, C1-C6 alkyl optionally substituted with one or more R5, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), amino(C1-C6 alkyl), —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CO2H, —CO2(C1-C6 alkyl), —SO2R7, —SO2OR7, —SO2N(R7)2, cyclopropylethynyl, aryl optionally substituted with one or more R6, heteroaryl optionally substituted with one or more R6, heterocyclyl optionally substituted with one or more R6, C3-C8 cycloalkyl optionally substituted with one or more R6, aryloxy optionally substituted with one or more R6, heteroaryloxy optionally substituted with one or more R6, heterocyclyloxy optionally substituted with one or more R6, cycloalkyloxy optionally substituted with one or more R6, 2-hydroxy-3-methoxypropoxy, (2-methoxyethoxy)methyl, and 2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy;
- or two R4 groups when attached to the same carbon atom form ═O;
- each R5 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkoxy), alkoxy(C1-C5 alkoxy), —SO2R7, —SO2OR7, and —SO2N(R7)2;
- each R6 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
- and
- each R7 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, or tolyl.
14 more elements
A compound of the formula (II):
- or a pharmaceutically acceptable salt thereof, wherein
- t is an integer 1, 2, or 3;
- q is an integer 0, 1, or 2;
- R11 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocyclyl, hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), —OH, and oxetanyl;
- R12 is C1-C6 alkyl;
- ring X represents an aryl optionally substituted with one or more R13, heteroaryl optionally substituted with one or more R13, or C4-C8 cycloalkyl optionally substituted with one or more R13;
- and
- ring Y and ring Z form a bicyclic heteroaryl or bicyclic heterocyclyl moiety, each optionally substituted with one or more R14;
- wherein
- each R13 is independently selected from halogen, —NO2, —CN, C1-C6 alkyl optionally substituted with one or more R15, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), amino(C1-C6 alkyl), —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CO2H, —CO2(C1-C6 alkyl), —SO2R17, —SO2OR17, —SO2N(R17)2, cyclopropylethynyl, aryl optionally substituted with one or more R16, heteroaryl optionally substituted with one or more R16, heterocyclyl optionally substituted with one or more R16, and C3-C8 cycloalkyl optionally substituted with one or more R16;
- each R14 is independently selected from halogen, —NO2, —CN, C1-C6 alkyl optionally substituted with one or more R15, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), amino(C1-C6 alkyl), —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CO2H, —CO2(C1-C6 alkyl), —SO2R17, —SO2OR17, —SO2N(R17)2, cyclopropylethynyl, aryl optionally substituted with one or more R16, heteroaryl optionally substituted with one or more R16, heterocyclyl optionally substituted with one or more R16, C3-C8 cycloalkyl optionally substituted with one or more R16, aryloxy optionally substituted with one or more R16, heteroaryloxy optionally substituted with one or more R16, heterocyclyloxy optionally substituted with one or more R16, cycloalkyloxy optionally substituted with one or more R16, 2-hydroxy-3-methoxypropoxy, (2-methoxyethoxy)methyl, and 2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy;
- or two R14 groups when attached to the same carbon atom form ═O;
- each R15 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkoxy), —SO2R17, —SO2OR7, and —SO2N(R17)2;
- each R16 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
- and
- each R17 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, or tolyl.
13 more elements
(canceled)
(canceled)
Dependencies are inferred from the claim text.