US 12,454,521 B2
Targeted protein degradation
Andrew J. Phillips, Arlington, MA (US); Christopher G. Nasveschuk, Stoneham, MA (US); James A. Henderson, Watertown, MA (US); Katrina L. Jackson, Weston, MA (US); Minsheng He, Andover, MA (US); Yanke Liang, Belmont, MA (US); Mark E. Fitzgerald, Newton, MA (US); and Victoria Garza, Chelsea, MA (US)
Assigned to C4 Therapeutics, Inc.
Filed by C4 Therapeutics, Inc., Watertown, MA (US)
Filed on Jun. 18, 2021, as Appl. No. 17/351,935.
Application 17/351,935 is a continuation of application No. PCT/US2019/068045, filed on Dec. 20, 2019.
Claims priority of provisional application 62/783,004, filed on Dec. 20, 2018.
Prior Publication US 2022/0372016 A1, Nov. 24, 2022
Int. Cl. C07D 401/14 (2006.01); C07D 239/22 (2006.01); C07D 401/04 (2006.01); C07D 401/10 (2006.01)
CPC C07D 401/14 (2013.01) [C07D 239/22 (2013.01); C07D 401/04 (2013.01); C07D 401/10 (2013.01)] 25 Claims
 
1. A compound of Formula

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof;
wherein:
m is 1, 2, 3, or 4;
n is 1, 2, 3, 4, 5, or 6;
R1 and R2 are hydrogen;
= is a single bond;
R3 is independently at each occurrence selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C3-C6heterocycle, aryl, heteroaryl, —OR4, —N(R4)(R4′), —SR4, —C(O)R6, —S(O)R6, —S(O)2R6, F, Cl, cyano, azido, nitro, and R5;
wherein at least one of R3 is selected from R5;
R4 and R4′ are independently at each occurrence selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C3-C6heterocycle, aryl, heteroaryl, —C(O)R6, —C(S)R6, —C(═NH)R6, —S(O) R6, and —S(O)2R6;
R5 is-Linker-Targeting Ligand;
R6 is independently at each occurrence selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C3-C6heterocycle, aryl, heteroaryl, hydroxyl, C1-C6alkoxy, thio, C1-C6thioalkyl, —NH2, —NH(C1-C6alkyl, C3-C7cycloalkyl, C3-C7heterocycle, aryl, or heteroaryl), and -N(independently C1-C6alkyl, C3-C7cycloalkyl, C3-C7heterocycle, aryl, or heteroaryl)2;

OG Complex Work Unit Chemistry
XA is CH or N, wherein if XA is N then

OG Complex Work Unit Chemistry
and if XA is CH then
wherein if XA is substituted with R3, then XA is CR3;
XB is selected from NH and CH2;
wherein if XB is substituted with R3, then XB is NR3 or CHR3;
Linker is

OG Complex Work Unit Chemistry
X1 and X2 are independently selected from bond, NR4, CH2, CHR4, C(R4)2, O, and S;
R20, R21, R22, R23, and R24 are independently selected from bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO2—, —S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —CH(—O—R26)—, —CH(—NR4R4′)—, —C(—O—R26)alkyl-, —C(—NR4R4′)alkyl-, —C(R40R40)—, -alkyl(R27)-alkyl (R28)—, —C(R27R28)—, —NR4C(O)NR4—, alkene, haloalkyl, alkoxy, aryl, arylalkyl, heterocycle, heteroaryl, carbocycle;
each of which R20, R21, R22, R23, and R24 is optionally substituted with one or more, two, or three substituents selected from R101,
R101 is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2, F, Cl, CF3, NH2, NHalkyl, and N(alkyl)2, aliphatic, and heteroaliphatic;
R26 is selected from hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocyclic;
R27 and R28 are independently selected from hydrogen, alkyl, amine, or together with the carbon atom to which they are attached, form C(O), C(S), C═CH2, a C3-C6 spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O, or form a 1 or 2 carbon bridged ring;
R40 is selected at each instance from: hydrogen, alkyl, alkene, alkyne, F, Cl, hydroxyl, alkoxy, azide, amino, cyano, —NH(alkyl), —N(alkyl)2, —NHSO2(alkyl), —N(alkyl)SO2alkyl, —NHSO2(aryl, heteroaryl or heterocyclic), —N(alkyl)SO2 (aryl, heteroaryl or heterocyclic)-NHSO2alkenyl, —N(alkyl) SOzalkenyl,-NHSOzalkynyl,-N(alkyl) SOzalkynyl, haloalkyl, aryl, heteroaryl, heteroalkyl, heterocyclic, and carbocyclic; and
Targeting Ligand is a means for binding a Target Protein that mediates a disorder, wherein the Target Protein is selected from the group consisting of AKT1, ABL1, ABL2, AKT2, AP1, AP2, ASH1L, ATAD2, androgen receptor, ATF2, BMX, BCR-ABL, Bcl-2, Bcl-XL, BRPF1, CSF1R, CECR2, DDR1, DOT1L, EPHA2, EPHA3, EPHA4, EPHA7, EPHB4, EZH2, EED, EHMT1, EHMT2, estrogen receptor, FLT3, FES, FYN, FKBP, factor Xa, FLAP, GSG2, HDM2, IGF1R, INSR, IDO1, IDH1, KDM4, KDM5, KDM6, KIT, KSR1, LSD1, L3MBTL3, LCK, LYN, mPGES-1, MERTK, MEK1, MDM2, MDM4, MEN1, MTH1, MCL-1, MER, MET, MST1R, NTRK, NTRK1, NTRK2, NTRK3, PHIP, protein S100-A7, PAK1, PAK4, PPAR-gamma, PDGFR receptor, ROS1 receptor, SETD2, SETD7, SETD8, SETDB1, SMYD2, SMYD3, SUV4-20H1, Sec7, TNIK, TRIM24, TAF1, TAF1L, mTORC1, mTORC2, TANK1, TRKB, tie 2 receptor, VEGF receptor, and YES.