Compositions, use, and method for CDK2-PROTACs for cancer therapy and hearing loss

1. A compound having the structure of Formula (1):

X-L-E  (1)

wherein X is a cyclin-dependent kinase 2 binding moiety;

L is a linking group selected from:

alkylene, (alkylene oxide) n -alkylene, —C(═O)-alkylene, —C(═O)-alkylene-(alkylene oxide) n -alkylene, —(C═O)-alkylene-O-alkylene, alkylene-(heteroaryl)-(alkylene oxide) m -alkylene-C(═O)—, and alkylene-(heteroaryl)-(alkylene oxide) m -alkylene;

wherein n and m are each independently an integer between 1 and 10; and

E is a ubiquitin ligase binding moiety, wherein X is selected from:

, wherein L is selected from:

wherein n is an integer between 1 and 4, m is an integer between 2 and 4, and p is an integer between 0 and 4

and

, wherein E is selected from:

wherein R 8 is selected from:

2. The compound of claim 1 , wherein X is

3. The compound of claim 1 , wherein L is selected from:

wherein p is 0, 1, 2, or 4, and

m is an integer between 2 and 4.

4. The compound of claim 1 , wherein the ubiquitin ligase is Cereblon or von Hippel-Lindau.

5. The compound of claim 1 , wherein the compound of Formula (1) is:

or a pharmaceutically acceptable salt thereof,

or a pharmaceutically acceptable salt thereof,

or a pharmaceutically acceptable salt thereof, or

or a pharmaceutical salt thereof,

wherein q is 0 or 1.

6. The compound of claim 4 , wherein the compound of Formula (1) is:

or a pharmaceutically acceptable salt thereof, wherein q is 1.

7. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.