US 12,466,809 B2
CDK2/5 degraders and uses thereof
Nathanael Gray, Stanford, CA (US); Nicholas Kwiatkowski, Brookline, MA (US); Eric Fischer, Chestnut Hill, MA (US); Katherine Donovan, Boston, MA (US); Tinghu Zhang, Brookline, MA (US); Mingxing Teng, Boston, MA (US); and Jie Jiang, Brookline, MA (US)
Assigned to DANA-FARBER CANCER INSTITUTE, INC., Boston, MA (US)
Appl. No. 17/442,923
Filed by DANA-FARBER CANCER INSTITUTE, INC., Boston, MA (US)
PCT Filed Apr. 2, 2020, PCT No. PCT/US2020/026411
§ 371(c)(1), (2) Date Sep. 24, 2021,
PCT Pub. No. WO2020/206137, PCT Pub. Date Oct. 8, 2020.
Claims priority of provisional application 62/981,334, filed on Feb. 25, 2020.
Claims priority of provisional application 62/829,302, filed on Apr. 4, 2019.
Prior Publication US 2022/0153722 A1, May 19, 2022
Int. Cl. C07D 401/14 (2006.01); A61K 47/55 (2017.01); C07D 417/12 (2006.01)
CPC C07D 401/14 (2013.01) [A61K 47/55 (2017.08); C07D 417/12 (2013.01)] 27 Claims
 
1. A bifunctional compound having a structure represented by formula:

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wherein the CDK2/5 targeting ligand is represented by the formula (TL-1):

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wherein:
R1 represents Br or CF3;
R2 represents OR5, NHR5,

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R5 represents

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represents optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl;
R3 represents

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R4 represents H, C(O), or

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provided that when R3 represents

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 and R4 represents C(O) or

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 R3 and R4 together with the atoms to which they are bound form a 5-membered cyclic sulfonamide,
the degron is represented by formula D1 or D2:

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wherein
Y is NH or NMe; and
Z is CH2, 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)2O—, —N(R′)S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O)2N(R′)—, —N(R′)S(O)N(R′)—, C3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C1-C6 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)2O—, —N(R′)S(O)2—, —S(O)2N(R′)—, —N(R′)S(O)—, —S(O)N(R′), —N(R′)S(O)2N(R′)—, —N(R′)S(O)N(R′)—, C3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C1-C6 alkyl, wherein the one or both terminating groups may be the same or different, or a pharmaceutically acceptable salt or stereoisomer thereof.