CDK2/5 degraders and uses thereof
The present invention relates to bifunctional compounds, compositions, and methods for treating diseases or conditions mediated by dysfunctional cyclin-dependent kinase 2 (CDK2) and CDK5 activity.
1 . A bifunctional compound having a structure represented by formula:
wherein the CDK2/5 targeting ligand is represented by the formula (TL-1):
wherein:
R 1 represents Br or CF 3 ;
R 2 represents OR 5 , NHR 5 ,
R 5 represents
represents optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl;
R 3 represents
R 4 represents H, C(O), or
provided that when R 3 represents
and R 4 represents C(O) or
R 3 and R 4 together with the atoms to which they are bound form a 5-membered cyclic sulfonamide,
the degron is represented by formula D1 or D2:
wherein
Y is NH or NMe; and
Z is CH 2 , NH, O, or C≡,
and the linker is an alkylene chain which may be interrupted by, and/or terminate at either or both termini in at least one of —O—, —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the interrupting and the one or both terminating groups may be the same or different, or
the linker is a polyethylene glycol chain which may terminate at either or both termini in at least one of —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′), —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the one or both terminating groups may be the same or different, or a pharmaceutically acceptable salt or stereoisomer thereof.
2 . The bifunctional compound of claim 1 , which is represented by the formula (I-1a):
or a pharmaceutically acceptable salt or stereoisomer thereof.
3 . The bifunctional compound of claim 1 , which is represented by the formula (I-1b):
or a pharmaceutically acceptable salt or stereoisomer thereof.
4 . The bifunctional compound of claim 1 , which is represented by formula (I-1c):
or a pharmaceutically acceptable salt or stereoisomer thereof.
5 . The bifunctional compound of claim 1 , which is represented by formula (I-11):
or a pharmaceutically acceptable salt or stereoisomer thereof.
6 . The bifunctional compound of claim 1 , which is represented by formula (I-1m):
or a pharmaceutically acceptable salt or stereoisomer thereof.
7 . The bifunctional compound of claim 1 , which is represented by formula (I-1n):
or a pharmaceutically acceptable salt or stereoisomer thereof.
8 . The bifunctional compound of claim 1 , which is represented by formula (I-1o):
or a pharmaceutically acceptable salt or stereoisomer thereof.
9 . The bifunctional compound of claim 1 , which is represented by formula (I-1p):
or a pharmaceutically acceptable salt or stereoisomer thereof.
10 . The bifunctional compound of claim 1 , which is represented by formula (I-1q):
or a pharmaceutically acceptable salt or stereoisomer thereof.
11 . The bifunctional compound of claim 1 , which is represented by formula (I-1r):
or a pharmaceutically acceptable salt or stereoisomer thereof.
12 . The bifunctional compound of claim 1 , wherein the linker is an alkylene chain which may be interrupted by, and/or terminate at either or both termini in at least one of —O—, —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the interrupting and the one or both terminating groups may be the same or different.
13 . The bifunctional compound of claim 12 , wherein the linker is an alkylene chain having 1-10 alkylene units and terminating in
14 . The bifunctional compound of claim 1 , wherein the linker is a polyethylene glycol chain which may terminate at either or both termini in at least one of —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′), —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′), —N(R′)S(O) 2 N(R′), —N(R′)S(O)N(R′), C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the one or both terminating groups may be the same or different.
15 . The bifunctional compound of claim 14 , wherein the linker is a polyethylene glycol linker having 2-8 PEG units and terminating in
16 . The bifunctional compound of claim 1 , which is represented by any one of the following formulas:
or a pharmaceutically acceptable salt or stereoisomer thereof.
17 . The bifunctional compound of claim 1 , which is represented by any one of the following formulas:
or a pharmaceutically acceptable salt or stereoisomer thereof.
18 . A bifunctional compound having a structure represented by formula:
wherein the CDK2/5 targeting ligand is represented by the formula (TL-1):
wherein:
R 1 represents Br or CF 3 ;
R 2 represents OR 5 , NHR 5 ,
R 5 represents
represents optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl;
R 3 represents
R 4 represents H, C(O), or
provided that when R 3 represents
and R 4 represents C(O) or
R 3 and R 4 together with the atoms to which they are bound form a 5-membered cyclic sulfonamide,
wherein the degron is represented by any one of the structures:
wherein Y′ is a bond, NH, O or CH 2 ; or
wherein Z′ is a cyclic group; or stereoisomer thereof,
and the linker is an alkylene chain which may be interrupted by, and/or terminate at either or both termini in at least one of —O—, —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the interrupting and the one or both terminating groups may be the same or different, or
the linker is a polyethylene glycol chain which may terminate at either or both termini in at least one of —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the one or both terminating groups may be the same or different, or a pharmaceutically acceptable salt or stereoisomer thereof.
19 . The bifunctional compound of claim 18 , which is represented by any one of the following formulas:
or a pharmaceutically acceptable salt or stereoisomer thereof.
20 . The bifunctional compound of claim 18 , which is:
or a pharmaceutically acceptable salt, or stereoisomer thereof.
21 . A pharmaceutical composition, comprising a therapeutically effective amount of the bifunctional compound of claim 18 , or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
22 . A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the bifunctional compound of claim 18 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer is ovarian cancer or T-cell leukemia.
23 . The bifunctional compound of claim 1 , which is:
or a pharmaceutically acceptable salt, or stereoisomer thereof.
24 . A pharmaceutical composition, comprising a therapeutically effective amount of the bifunctional compound of claim 1 , or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
25 . A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the bifunctional compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer is ovarian cancer or T-cell leukemia.
26 . The method of claim 25 , wherein the cancer is T-cell leukemia.
27 . The method of claim 25 , wherein the cancer is ovarian cancer.