US 11,535,606 B2Granted

Substituted quinoline-8-carbonitrile derivatives with androgen receptor degradation activity and uses thereof

AssigneeAccutar Biotechnology Inc.

InventorsJie Fan, Yimin Qian, Wei He, Ke Liu

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Abstract

The present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of cancer and related diseases and conditions. In some embodiments, the compounds disclosed herein exhibit androgen receptor degradation activity.

Claims34

Dependent claims

A compound of Formula (1) or a pharmaceutically acceptable salt thereof:

wherein:
X1 is CR1 or N;
X2 is CR2 or N;
X3 is CR3 or N;
X4 is CR4 or N;
each of R1, R2, R3, and R4 is independently selected from hydrogen, halogen, C1-C3alkoxy, and C1-C3haloalkyl, each of which is substituted with 0, 1, 2, or 3 RS;
each R5 is independently selected from halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, —N(R9)2, and —CN, each of which is substituted with 0, 1, 2, or 3 RS;
each R6 is independently selected from hydrogen, halogen, C1-C3alkyl, and C1-C3haloalkyl, each of which is substituted with 0, 1, 2, or 3 RS, or two R6 groups are taken together to form an oxo;
each R7 is independently selected from halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, —N(R9)2, and —CN, each of which is substituted with 0, 1, 2, or 3 RS;
each R8 is independently selected from hydrogen, hydroxyl, C1-C3alkyl, and C1-C3haloalkyl, each of which is substituted with 0, 1, 2, or 3 RS, or two R8 groups are taken together to form an oxo;
each R9 is independently selected from hydrogen, C1-C3alkyl, —C(═O)—(C1-C3alkyl), —C(═O)—O—(C1-C3alkyl), and —C(═O)—NH—(C1-C3alkyl), each of which is substituted with 0, 1, 2, or 3 RS, or two R9 groups are taken together to form a 3- to 6-membered heterocycle or heteroaryl;
each RS is independently selected from halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, —N(R9)2, and —CN;
L is a linker of 1 to 16 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(O), O, N(R9), S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R9, C2-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 RS;
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
and
o is 0, 1, 2, or 3,
wherein each hydrogen atom is independently and optionally replaced by a deuterium atom.

15 more elements

A compound selected from:

N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)oxy)benzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propoxy)propoxy)benzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)benzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)benzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butoxy)benzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentyl)oxy)benzamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)nicotinamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((1 r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)butoxy)benzamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((((1 r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)piperidin-1-yl)nicotinamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((((1 r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(ethyl)amino)methyl)piperidin-1-yl)nicotinamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((((1 r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)nicotinamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((((1 s,3s)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)nicotinamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;
N-((1 s,4s)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrazine-2-carboxamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-fluorobenzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazin-1-yl)benzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)nicotinamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrimidine-5-carboxamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrazine-2-carboxamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-fluoronicotinamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoronicotinamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(((2S)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(((2R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((2S)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((2R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((2S)-2-((dimethylamino)methyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((2R)-2-((dimethylamino)methyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((((1 r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((2-(dimethylamino)ethyl)((1 r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)amino)methyl)piperidin-1-yl)-3-fluorobenzamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(((2S)-2-((dimethylamino)methyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(((2R)-2-((dimethylamino)methyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-fluoronicotinamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide;
N-((1 r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrazine-2-carboxamide;
N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-fluoronicotinamide;
N-((1r,4S)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-((3S)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)pyrimidine-5-carboxamide;
N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-((3R)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)pyrimidine-5-carboxamide;
or a pharmaceutically acceptable salt thereof, wherein each hydrogen is independently and optionally replaced by a deuterium.

53 more elements

Dependencies are inferred from the claim text.

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