C3-carbon linked glutarimide degronimers for target protein degradation

A compound of Formula:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• W1 is C═O;
• W2 is C═O;
• X is NH;
• n is 0, 1, 2, or 3;
• is a single or double bond;
• R6 is selected from:
• Y is independently selected from N, CH, and CR11, wherein 0, 1, or 2 instances of Y are selected to be N;
• R7, R8, and R15 are independently selected from hydrogen, alkyl, heterocyclic, carbocyclic, aryl, heteroaryl, hydroxyl, halo, azide, CN—, alkoxy, amine, —NHalkyl, and Nalkyl2;
• or R7 and R8 together with the carbon to which they are attached form a 3-, 4-, 5-, or 6-membered spiro-carbocycle, or a 4-, 5-, or 6-membered spiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O;
• or R15 and R7 form a 3, 4, 5, or 6 carbon fused ring;
• or R15 and R5 form a 3, 4, 5, or 6 carbon fused ring wherein R5 is on the carbon alpha to R15 or a 1, 2, 3, or 4 carbon bridged ring wherein R5 is not on the carbon alpha to R15;
• R5 is selected at each instance from:
• alkyl, alkene, alkyne, heterocyclic, aryl, heteroaryl, halogen, hydroxyl, alkoxy, azide, amino, —NH(alkyl), —N(alkyl)2, —NHSO2(alkyl), —N(alkyl)SO2(alkyl), —NHSO2aryl, —N(alkyl)SO2aryl, —NHSO2alkenyl, —N(alkyl)SO2alkenyl, —NHSO2alkynyl, —N(alkyl)SO2alkynyl, and halo(alkyl);
• or two R5 substituents together with the carbon atom(s) to which they are bound can form a 3, 4, 5 or 6 membered ring;
• R10 is a linker-targeting ligand;
• linker is selected from:
• wherein:
• X1 and X2 are independently selected from the group consisting of bond, NH, NR25, CH2, CHR25, C(R25)2, O, and S;
• R20, R21, R22, R23, and R24 are independently selected from the group consisting of heteroarylalkyl, aryl, arylalkyl, heterocycle, heteroaryl, carbocycle, bond, alkyl, —C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —SO2—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —CH(—O—R26)—, —CH(—NHR25)—, —CH(—NH2)—, —CH(—NR252)—, —C(—O—R26)alkyl-, -alkyl(R27)-alkyl(R28)—, —C(R27R28)—, —NHC(O)NH—, —N(R25)C(O)N(R25)—, —N(H)C(O)N(R25)—, polyethylene glycol, alkene, haloalkyl, alkoxy, and alkyne, each of which is optionally substituted with one or more substituents independently selected from R101;
• R25 is selected at each instance from the group consisting of alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, and alkynyl;
• R26 is hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, or heterocyclic;
• R27 and R28 are independently selected from the group consisting of hydrogen, alkyl, and amine, or together with the carbon atom to which they are attached, form C(O), C═CH2, a C3-C6 spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
• R101 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, —COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, and N(alkyl)2;
• R11 is selected at each instance from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, hydroxyl, heterocyclic, heteroalkyl, carbocyclic, alkoxy, aryl, heteroaryl, alkylamino, alkylhydroxyl, —NHalkyl, —Nalkyl2, amino, cyano, nitro, thioalkyl, thiol, and haloalkyl;
• targeting ligand is a means for binding the targeted protein that mediates a disorder;
• wherein the targeted protein selected from the group consisting of AKT1, AXL, ABL, ABL1, ABL2, AKT2, AP1, AP2, ASH1L, ATAD2, androgen receptor, ATF2, BMX, BCR-ABL, Bcl-2, Bel-XL, BAZ2A, BAZ2B, BRPF1, BMX, CSF1R, CECR2, cathepsin, cyclin dependent kinase, DDR1, DOT1L, dihydrofolate reductase, EPHA2, EPHA3, EPHA4, EPHA7, EPHB4, EZH2, EED, EHMT1, EHMT2, estrogen receptor, FLT3, FES, FYN, FKBP, fatty acid binding protein, factor Xa, FLAP, GSG2, HIV integrase, HIV reverse transcriptase, HIV protease, HCV protease, HDM2, HBV, HCK, histone deacetylase, histone acetyltransferase, heat shock protein, IGF1R, INSR, IDO1, IDH1, ITK, KIT, KSR1, kringle domain V, 4BVV, kallikrein 7, KSR receptor, lactoylglutathione lyase, L3MBTL3, lysine-specific histone demethylase, lysine methyltransferase, LCK, LYN, mPGES-1, MERTK, MEK1, MDM2, MDM4, MEN1, MTH1, MCL-1, MER, MET, mast/stem cell growth factor receptor, MST1R, NTRK, NTRK1, NTRK2, NTRK3, PDZ, phospholipase A2 domain, PB1, PHIP, protein S100-A7, PAK1, PAK4, PPAR-gamma, PDGFR receptor, PNET, ROS1 receptor, RCC receptor, RAML receptor, SETD2, SETD7, SETD8, SETDB1, SMYD2, SMYD3, SUV4-20H1, saposin-B, Sec7, SH2 domain, SEGA receptor, TNIK, TRIM24, TAF1, TAF1L, mTORC1, mTORC2, TANK1, TRKB, tie 2 receptor, TEC, SF6D, U09-CX-5279, VEGF receptor, and YES.