US2023135173A1PendingUtilityA1
Novel substituted quinoline-8-carbonitrile derivatives having androgen receptor degradation activity and uses thereof
Est. expirySep 23, 2039(~13.2 yrs left)· nominal 20-yr term from priority
C07D 403/14A61P 35/00C07D 401/14A61K 31/506A61K 31/4709A61K 31/496A61K 31/501
75
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Claims
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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (1) or a pharmaceutically acceptable salt thereof:
wherein:
X 1 is CR 1 or N;
X 2 is CR 2 or N;
X 3 is CR 3 or N;
X 4 is CR 4 or N;
each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, halogen, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl, each of which is substituted with 0, 1, 2, or 3 R S ;
each R 5 is independently selected from halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, —N(R 9 ) 2 , and —CN, each of which is substituted with 0, 1, 2, or 3 R S ;
each R 6 is independently selected from hydrogen, halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl, each of which is substituted with 0, 1, 2, or 3 R S , or two R 6 groups are taken together to form an oxo;
each R 7 is independently selected from halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, —N(R 9 ) 2 , and —CN, each of which is substituted with 0, 1, 2, or 3 R S ;
each R 8 is independently selected from hydrogen, hydroxyl, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl, each of which is substituted with 0, 1, 2, or 3 R S , or two R 8 groups are taken together to form an oxo;
each R 9 is independently selected from hydrogen, C 1 -C 3 alkyl, —C(═O)—(C 1 -C 3 alkyl), —C(═O)—O—(C 1 -C 3 alkyl), and —C(═O)—NH—(C 1 -C 3 alkyl), each of which is substituted with 0, 1, 2, or 3 R S , or two R 9 groups are taken together to form a 3- to 6-membered heterocycle or heteroaryl;
each R S is independently selected from halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, —N(R 9 ) 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(R 9 ), S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R 9 , C 2 -alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R S ;
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.
2 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X 1 is N.
3 . The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 , wherein X 2 is N.
4 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X 1 and X 2 are each N.
5 . The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 , wherein X 2 is CR 2 , X 3 is CR 3 , and X 4 is CR 4 .
6 . The compound or pharmaceutically acceptable salt thereof according to claim 5 , wherein R 2 , R 3 , and R 4 are each independently selected from H and F.
7 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , and X 4 is CR 4 .
8 . The compound or pharmaceutically acceptable salt thereof according to claim 7 , wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from H and F.
9 . The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8 , wherein R 1 is F.
10 . The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8 , wherein R 2 is F.
11 . The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8 , wherein R 3 is F.
12 . The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8 , wherein R 4 is F.
13 . The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8 , wherein R 1 and R 3 are each F.
14 . The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8 , wherein R 3 and R 4 are each F.
15 . The compound or pharmaceutically acceptable salt thereof according to claim 9 , wherein R 2 , R 3 , and R 4 are each H.
16 . The compound or pharmaceutically acceptable salt thereof according to claim 10 , wherein R 1 , R 3 , and R 4 are each H.
17 . The compound or pharmaceutically acceptable salt thereof according to claim 11 , wherein R 1 , R 2 , and R 4 are each H.
18 . The compound or pharmaceutically acceptable salt thereof according to claim 12 , wherein R 1 , R 2 , and R 3 are each H.
19 . The compound or pharmaceutically acceptable salt thereof according to claim 13 , wherein R 2 and R 4 are each H.
20 . The compound or pharmaceutically acceptable salt thereof according to claim 14 , wherein R 1 and R 2 are each H.
21 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the
group is selected from
22 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21 , wherein each R 5 is independently selected from halogen, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl.
23 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22 , wherein each R 5 is independently selected from —Cl, —OCH 3 , and —CF 3 .
24 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 , wherein m is 0 or 1.
25 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 24 , wherein m is 0.
26 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 25 , wherein m is 1.
27 . The compound or pharmaceutically acceptable salt according to any one of claims 1 to 26 , wherein o is 0.
28 . The compound or pharmaceutically acceptable salt according to any one of claims 1 to 26 , wherein o is 1.
29 . The compound or pharmaceutically acceptable salt according to any one of claims 1 to 23 , wherein m and o are each 0.
30 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 29 , wherein each R 6 is independently selected from H and C 1 -C 3 alkyl.
31 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 30 , wherein each R 6 is independently selected from H and —CH 3 .
32 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31 , wherein the two R 6 groups attached to the same carbon are identical.
33 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31 , wherein each R 6 is identical.
34 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31 , wherein each R 6 is different.
35 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 34 , wherein the
group is selected from
36 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 34 , wherein the
group is selected from
37 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 36 , wherein each R 7 is independently selected from halogen, hydroxyl, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
38 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 37 , wherein each R 7 is independently selected from halogen, hydroxyl, —CH 3 , and —CF 3 .
39 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 38 , wherein each R 7 is independently selected from F, hydroxyl, —CH 3 , and —CF 3 .
40 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 39 , wherein each R 7 is independently F.
41 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 37 , wherein n is 0.
42 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 37 , wherein n is 1.
43 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42 , wherein each R 8 is hydrogen or two R 8 groups are taken together to form an oxo.
44 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42 , wherein each R 8 is hydrogen.
45 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42 , wherein two R 8 groups are taken together to form an oxo.
46 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 45 , wherein each R 9 is independently selected from hydrogen, C 1 -C 3 alkyl, and —C(═O)—C 1 -C 3 alkyl.
47 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 46 , wherein each R 9 is independently selected from hydrogen and C 1 -C 3 alkyl.
48 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 47 , wherein each R 9 is independently selected from hydrogen, —CH 3 , —CH 2 CH 3 , and —CH(CH 3 ) 2 .
49 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 36 , wherein the
group is selected from
50 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 49 , wherein L is a linker of 1 to 12 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(═O), O, N(R 9 ), S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R 9 , C 2 -alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R S .
51 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 50 , wherein L is a linker of 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(═O), O, N(R 9 ), S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R 9 , C 2 -alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R S .
52 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 51 , wherein L is a linker of 1 to 8 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(═O), O, N(R 9 ), S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R 9 , C 2 -alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R S .
53 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 52 , wherein L is a linker of 1 to 6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(═O), O, N(R 9 ), S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R 9 , C 2 -alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R S .
54 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 53 , wherein one or more carbon atoms of linker L are optionally replaced by C(═O), O, N(R 9 ), S, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R 9 , C 2 -alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R S .
55 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 54 , wherein one or more carbon atoms of linker L are optionally replaced by O, N(R 9 ), cycloalkyl, or heterocycle, wherein the R 9 , cycloalkyl, and heterocycle are each independently substituted with 0, 1, 2, or 3 R S .
56 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 55 , wherein at least one carbon atom of linker L is replaced by a heterocycle, which is substituted with 0, 1, 2, or 3 R S .
57 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 55 , wherein at least two carbon atoms of linker L are replaced by a heterocycle, each of which is substituted with 0, 1, 2, or 3 R S .
58 . The compound or pharmaceutically acceptable salt thereof according to claim 56 or 57 , wherein the heterocycle is selected from piperidine and piperazine, each of which is substituted with 0, 1, 2, or 3 R S .
59 . The compound or pharmaceutically acceptable salt thereof according to claim 56 or 57 , wherein the heterocycle is selected from
60 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 49 , wherein L is selected from:
61 . The compound according to claim 1 , wherein the compound is chosen from:
1
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-((5-
((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)
oxy)pentyl)oxy)benzamide;
2
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-
(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)
oxy)propoxy)propoxy)benzamide;
3
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-
(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
ethoxy)benzamide
4
N-((1r,3r)-3-((8-oyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-
(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
propoxy)benzamide
5
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
butoxy)benzamide
6
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-((5-
(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
pentyl)oxy)benzamide
7
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
nicotinamide
8
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
(((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)
oxy)cyclobutyl)(methyl)amino)butoxy)benzamide
9
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)
oxy)cyclobutyl)(methyl)amino)methyl)piperidin-1-yl)nicotinamide
10
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-,3-dioxoisoindolin-5-yl)
oxy)cyclobutyl)(ethyl)amino)methyl)piperidin-1-yl)nicotinamide
11
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)
oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)nicotinamide
12
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((((1s,3s)-3-((2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)
oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)nicotinamide
13
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)nicotinamide
14
N-((1S,3S)-3-((8-cyanoquinolin-5-yl)oxy)-2,2-dimethylcyclobutyl)-6-(4-((4-(2-
(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)nicotinamide
15
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)cyclobutyl)-6-(4-((4-(2-(2,6-
dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)
nicotinamide
16
N-((1s,3s)-3-((8-cyanoquinolin-5-yl)oxy)cyclobutyl)-6-(4-((4-(2-(2,6-
dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)
nicotinamide
17
N-((1S,3R)-3-((8-cyanoquinolin-5-yl)oxy)-2,2-dimethylcyclobutyl)-6-(4-((4-(2-
(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)nicotinamide
18
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-
((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)pyrimidine-5-carboxamide
19
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)pyridazine-3-carboxamide
20
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-
((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)pyrazine-2-carboxamide
21
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)benzamide
22
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)-3-fluorobenzamide
23
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
ethyl)piperazin-1-yl)-3-fluorobenzamide
24
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
ethyl)piperidin-1-yl)-3-fluorobenzamide
25
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
ethyl)piperidin-1-yl)nicotinamide
26
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-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
27
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-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
28
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
(2-(4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
ethyl)piperidin-1-yl)-5-fluoronicotinamide
29
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)nicotinamide
30
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-
((4-(2-((S)-2,6-dioxopipendin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)pyrimidine-5-carboxamide
31
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((4-(2-((S)-2,6-dioxopipendin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)pyridazine-3-carboxamide
32
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
((4-(2-((S)-2,6-dioxopipendin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)-3-fluorobenzamide
33
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((4-(2-((S)-2,6-dioxopipendin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)nicotinamide
34
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-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
35
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-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
36
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)nicotinamide
37
N-((1r,3S)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
(((2S)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-
methylpiperazin-1-yl)methyl)piperidin-1-yl)nicotinamide
38
N-((1r,3R)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
(((2R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-
methylpiperazin-1-yl)methyl)piperidin-1-yl)nicotinamide
39
N-((1r,3S)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
(((2S)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-
methylpiperazin-1-yl)methyl)piperidin-1-yl)benzamide
40
N-((1r,3R)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
(((2R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-
methylpiperazin-1-yl)methyl)piperidin-1-yl)benzamide
41
N-((1r,3R)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
(((2R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-
methylpiperazin-1-yl)methyl)piperidin-1-yl)benzamide
42
N-((1r,3R)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-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
43
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
ethyl)piperidin-1-yl)benzamide
44
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)
oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)pyridazine-3-
carboxamide
45
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
(((2-(dimethylamino)ethyl)((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-
dioxoisoindolin-5-yl)oxy)cyclobutyl)amino)methyl)piperidin-1-yl)-3-
fluorobenzamide
46
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-
((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)-5-fluoronicotinamide
47
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)benzamide
48
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-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
49
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)benzamide
50
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-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
51
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)-3-fluorobenzamide
52
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-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
53
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)
methyl)piperidin-1-yl)-3-fluorobenzamide
54
N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-
((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)
oxy)cyclobutyl)(ethyl)amino)methyl)piperidin-1-yl)benzamide
or a pharmaceutically acceptable salt thereof, wherein each hydrogen is independently and optionally replaced by a deuterium.
62 . A pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 61 and a pharmaceutically acceptable carrier.
63 . The pharmaceutical composition according to claim 62 , wherein the compound or pharmaceutically acceptable salt thereof is present in a therapeutically effective amount.
64 . A method of treating cancer in a subject in need thereof, comprising administering to said subject a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 or 63 .
65 . The method according to claim 64 , wherein the cancer is selected from prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, cervical cancer, uterine cancer, ovarian cancer, and breast cancer.
66 . The method according to claim 64 or 65 , wherein the cancer is prostate cancer.
67 . The method according to any one of claims 64 to 66 , wherein the cancer is androgen receptor positive.
68 . The method according to any one of claims 64 to 67 , wherein the subject has been previously treated with an anti-cancer agent.
69 . The method according to claim 68 , wherein the anti-cancer agent is enzalutamide, apalutamide, bicalutamide, darolutamide, flutamide, abiraterone, or a combination of any of the foregoing.
70 . The method according to claim 69 , wherein the anti-cancer agent is enzalutamide.
71 . A use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 or 63 for treating cancer.
72 . The use according to claim 71 , wherein the cancer is selected from prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, cervical cancer, uterine cancer, ovarian cancer, and breast cancer.
73 . The method according to claim 71 or 72 , wherein the cancer is prostate cancer.
74 . The method according to any one of claims 71 to 73 , wherein the cancer is androgen receptor positive.
75 . A use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 or 63 in the manufacture of a medicament.
76 . The use according to claim 75 , wherein the medicament is for the treatment of a cancer selected from prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, cervical cancer, uterine cancer, ovarian cancer, and breast cancer.
77 . The use according to claim 76 , wherein the cancer is prostate cancer.
78 . The use according to claim 76 or 77 , wherein the cancer is androgen receptor positive.
79 . A method of inhibiting cell growth, comprising contacting a cell with a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 or 63 .
80 . The method according to claim 79 , wherein the cell is a cancer cell.
81 . The method according to claim 80 , wherein the cancer cell is a prostate cancer cell.
82 . The method according to any one of claims 79 to 81 , wherein the cell is androgen receptor positive.
83 . The compound of Formula (1) according to claim 1 , wherein the compound is a compound of Formula (1A)Join the waitlist — get patent alerts
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