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OwnerGrazia Piizzi, Eugene L. Piatnitski Chekler +8inventors
InventorsGrazia Piizzi, Eugene L. Piatnitski Chekler, Jonathan Barry Hurov, Alexandra Lantermann, Kiley Marie Couto, Hua Xu, Sourav Sarkar, Bruce Allen Lefker, Ralph P. Robinson, Volodymyr Kysil
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Provided herein are compounds (e.g., compounds of Formulae (A-I), (B-I), (C-I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, pharmaceutical compositions thereof, and kits comprising the same. The compounds provided herein are degraders of GRK2 proteins and are therefore useful for, e.g., treating and/or preventing diseases (e.g., cancer) in a subject, for inhibiting tumor growth in a subject, for inhibiting the activity of GRK2 and/or degrading a GRK2 protein in vitro or in vivo, etc. In certain embodiments, the compounds provided herein are selective for GRK2. Also provided herein are methods and synthetic intermediates useful in the preparation of compounds described herein.
A compound of Formula (A-I):
A compound of Formula (B-I):
A compound of Formula (C-I):
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein X1 is N.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein X2 is CR3.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein R1 is C1-6 alkyl.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein R2 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein R4 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein each instance of R3 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein m is 0.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein n is 0.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein R7 and R8 are hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein R13 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein R13 is C1-6 alkyl.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein R14 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein G1 is CR15.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein G2, G3, G4, and G5 are independently CR16 or CH.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein R15 is selected from halogen, C1-6 haloalkyl, and —O—C1-6 alkyl.
The compound of any one of the preceding claims, wherein R13 and R15 are joined together to form:
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein p is 0.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein Q1, Q2, Q3, and Q4 are independently CRA1 or CH.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein s is 0.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RA5 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RA6 and RA7 are hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein r is 0.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RB2 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RB3 C1-6 alkyl.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RB4 is hydrogen
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RB5 is hydrogen
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RB7 is C1-6 alkyl.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RB8 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RB9 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RB9 is C1-6 alkyl.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RB10 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein q is 0.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein v2 is 0.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein y is 0.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein z is 0.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RCb is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RCd is C3-8 carbocyclyl.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RCe is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RCf is C1-6 alkyl.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RCg is C1-6 alkyl.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RCh is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein Z1 is —O—.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein Z2 is —NRA11— or —NRN—.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein RA11 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein Z2 is —O—.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein L1 is optionally substituted C1-40 alkylene or optionally substituted C1-40 heteroalkylene.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein L1 is optionally substituted C1-40 alkylene or optionally substituted C1-40 heteroalkylene, interrupted with at least one instance of optionally substituted triazolylene.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein L1 is of one of the following formulae:
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein L2 is optionally substituted C1-C30 alkylene or optionally substituted C1-C30 heteroalkylene.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein L2 is optionally substituted C1-C30 alkylene or optionally substituted C1-C30 heteroalkylene, interrupted with at least one instance of optionally substituted triazolylene.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein L2 is of one of the following formulae:
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, wherein at least one instance of RN is hydrogen.
A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient.
A method of treating a proliferative disease in a subject comprising administering to the subject a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.
A method of inhibiting tumor growth in a subject comprising administering to the subject a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.
A method of treating a cardiovascular disease in a subject comprising administering to the subject a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.
A method of treating a GRK2-related disease in a subject comprising administering to the subject a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.
A method of inhibiting the activity of GRK2 in a subject or biological sample comprising administering to the subject or contacting the biological sample with a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.
A method of degrading a GRK2 protein in a subject or biological sample comprising administering to the subject or contacting the biological sample with a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.
The method of any one of the preceding claims, wherein the subject is a human.
A compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, for use in a method of any one of the preceding claims.
Use of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament.
A kit comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof;
Dependencies are inferred from the claim text.