Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
The present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R 1 , R 2 , R x , X 1 , X 2 , X 3 , n, n1, and q are as defined herein, and methods of making and using same.
1 . A compound of Formula (I):
wherein:
X 1 is C or CR 3 ;
R 3 is H or D;
is a single or double bond; when is a single bond, X 1 is CR 3 ; when is a double bond, X 1 is C;
X 2 is N and X 3 is CR 14 ; or X 2 is CR 13 and X 3 is N;
each R 1 is independently D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxyalkyl, CN, or halogen, or
two R 1 together with the carbon atoms to which they are attached form (C 3 -C 7 )cycloalkyl or a 4- to 6-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S, or
two R 1 , when on adjacent atoms, together with the atoms to which they are attached form a (C 6 -C 10 )aryl ring or a 5- or 6-membered heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N, and S;
R 2 is (C 1 -C 6 )alkyl, wherein the alkyl is optionally substituted with one or more R 4 , or
R 1 and R 2 , when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring;
each R 4 is independently selected from —C(O)OR 6 , —C(O)NR 6 R 6 , —NR 6 C(O)R 6 , halogen, —OH, —NH 2 , CN,
(C 6 -C 10 )aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, and S,
(C 3 -C 8 )cycloalkyl, and 4- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with one or more R 7 ;
each R 5 is independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy,
(C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, —OH, —NH 2 , CN,
(C 3 -C 7 )cycloalkyl, 5- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 6 -C 10 )aryl, and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or
two R 5 , when on adjacent atoms, together with the atoms to which they are attached form a (C 6 -C 10 )aryl ring or a 5- or 6-membered heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one or more R 10 , or
two R 5 , when on adjacent atoms, together with the atoms to which they are attached form a
(C 5 -C 7 )cycloalkyl ring or a 5- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S optionally substituted with one or more R 10 ;
R 6 and Re are each independently H, (C 1 -C 6 )alkyl, or (C 6 -C 10 )aryl;
each R 7 is independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy,
(C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —C(O)R 8 , —(CH 2 ) 0-3 C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —S(O) p NR 8 R 9 , —S(O) p R 12 , (C 1 -C 6 )hydroxyalkyl, halogen, —OH, —O(CH 2 ) 1-3 CN, —NH 2 , CN, —O(CH 2 ) 0-3 (C 6 -C 10 )aryl, adamantyl, —O(CH 2 ) 0-3 -5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 6 -C 10 )aryl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 3 -C 7 )cycloalkyl, and 5- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one or more R 11 , and the aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more substituents each independently selected from halogen,
(C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkoxy, or
two R 7 together with the carbon atom to which they are attached form a ═(O), or
two R 7 , when on adjacent atoms, together with the atoms to which they are attached form a (C 6 -C 10 )aryl ring or a 5- or 6-membered heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one or more R 10 , or two R 7 together with the atoms to which they are attached form a (C 5 -C 7 )cycloalkyl ring or a 5- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one or more R 10 ;
R 8 and R 9 are each independently H or (C 1 -C 6 )alkyl;
each R 10 is independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, —OH, —NH 2 , and CN, or two R 10 together with the carbon atom to which they are attached form a ═(O);
each R 11 is independently selected from CN, (C 1 -C 6 )alkoxy, (C 6 -C 10 )aryl, and 5- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl and heterocycloalkyl are optionally substituted with one or more substituents each independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, —OH, —NH 2 , and CN;
R 12 is (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 6 -C 10 )aryl, or 5- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S;
R 13 is H, halogen, —OH, or —NH 2 ;
R 14 is H, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )hydroxyalkyl, halogen, —OH, —NH 2 , —NO 2 , or CN;
R x is H or D;
p is 0, 1, or 2;
n is 0, 1, or 2;
n1 is 1 or 2, wherein n+n1≤3; and
q is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
2 . The compound according to claim 1 , wherein R x is H.
3 . The compound according to claim 1 , wherein X 2 is N and X 3 is CR 14 .
4 . The compound according to claim 1 , wherein X 2 is CR 13 and X 3 is N.
5 . The compound according to claim 1 , having a Formula (Ic), or Formula (Id):
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 , having a Formula (Ig), or Formula (Ih):
or a pharmaceutically acceptable salt thereof.
7 . The compound according to claim 1 , wherein n is 1 or 2.
8 . The compound according to claim 7 , wherein n is 1.
9 . The compound of claim 1 , having a Formula (Ik), or Formula (Il):
or a pharmaceutically acceptable salt thereof.
10 . The compound according to claim 1 , wherein R 2 is (C 1 -C 6 )alkyl substituted with one to three R 4 .
11 . The compound according to claim 1 , wherein q is 0, 1, or 2.
12 . The compound according to claim 11 , wherein q is 0 or 1.
13 . The compound according to claim 12 , wherein q is 0.
14 . A compound selected from:
3-(2-(1-benzylpiperidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione;
3-(6-(1-benzylpiperidin-4-yl)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2,6-dione;
3-(5-(1-benzylpiperidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(5-(1-benzylpiperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-amino-5-(1-benzylpiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(5-(1-benzylpiperidin-4-yl)-6-chloro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(5-(1-benzylpiperidin-4-yl)-6-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
5-(1-benzylpiperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-carbonitrile;
3-(5-(1-benzylpiperidin-4-yl)-1-oxo-4-(trifluoromethyl)isoindolin-2-yl)piperidine-2,6-dione;
3-(5-(1-benzylpiperidin-4-yl)-4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-fluoro-1-oxo-5-(1-(pyridin-4-ylmethyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione;
3-(4-chloro-5-(1-(((1r,4r)-4-methoxycyclohexyl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(4-fluoro-5-(1-(((1r,4r)-4-methoxycyclohexyl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(4-hydroxy-5-(1-(((1r,4r)-4-methoxycyclohexyl methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; and
3-(5-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione
or a pharmaceutically acceptable salt thereof.
15 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
16 . The pharmaceutical composition according to claim 15 further comprising at least one additional pharmaceutical agent.
17 . The pharmaceutical composition according to claim 15 for use in the treatment of a disease or disorder that is affected by the reduction of IKZF2 protein levels.
18 . A method of degrading IKZF2 comprising administering to a patient in need thereof a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
19 . A method of treating a disease or disorder that is affected by the reduction of IKZF2 protein levels comprising administering to a patient in need thereof a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
20 . A method of reducing IKZF2 protein levels comprising administering to a patient in need thereof a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
21 . A method of reducing the proliferation of a cell the method comprising, contacting the cell with a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and reducing IKZF2 protein levels.
22 . A method of treating cancer, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST) comprising administering to a patient in need thereof a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
23 . The method according to claim 22 , wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
24 . A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt.
25 . The method according to claim 18 , wherein administering is performed orally, parentally, subcutaneously, by injection, or by infusion.