EGFR degraders and associated methods of use

A compound of Formula (X):

• or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, wherein:
• Cy1 is a 4- to 7-membered saturated or partially unsaturated ring comprising P═O shown in Formula (X), and 0-3 additional heteroatoms independently selected from nitrogen, oxygen or sulfur in addition to P═O;
• wherein said ring is optionally substituted with at least one substituent R1c;
• R1c is selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —OR1d, —COR1d, —CO2R1d, —CONR1dR1e, —NR1dR1e, —NR1dCOR1e or —NR1dCO2R1e, wherein each of —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R1f;
• R1d, R1e and R1f are each independently selected from hydrogen, hydroxy, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, or C3-C8cycloalkyl;
• Z5 is selected from —CR2, or N;
• Z6 is selected from —CR3, or N;
• Z7 is selected from —CR9, or N;
• Z8 is selected from —CR10, or N;
• R2 and R3 are each independently selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —OR2a, —SO2R2a, —SO2NR2aR2b, —COR2a, —CO2R2a, —CONR2aR2b, —NR2aR2b, —NR2aCOR2b, —NR2aCO2R2b, or —NR2aSO2R2b wherein each of —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R2d;
• or
• R2 and R3 together with the carbon atoms to which they are attached, form a 5-6 membered saturated or partially or completely unsaturated ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• said ring is optionally substituted with at least one substituent R2e;
• R2e, at each of its occurrences, is independently hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, —C3-C8cycloalkyl, oxo, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —SO2R2a, —SO2NR2aR2b, —COR2a, —CO2R2a, —CONR2aR2b, —NR2aR2b, —NR2aCOR2b, —NR2aCO2R2b or —NR2aSO2R2b, wherein each of —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C122aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R2d;
• R2a and R2b are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C1-8alkoxy-C1-8alkyl-, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
• or
• R2a and R2b together with the carbon atoms to which they are attached, form a 5-6 membered saturated or partially or completely unsaturated ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• said ring is optionally substituted with at least one substituent R2d;
• R2d, at each of its occurrences, is independently halogen, —OH, —C1-8alkyl, —C1-8alkoxy, C1-8alkoxy-C1-8alkyl-, oxo, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, or 5- to 12-membered heteroaryl;
• R4 is selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —SO2R4a, —SO2NR4aR4b, —COR4a, —CO2R4a, —CONR4aR4b, —NR4aR4b, —NR4aCOR4b, —NR4aCO2R4b, or —NR4aSO2R4b, wherein each of —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with halogen, —C1-8alkoxy, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, oxo, —CN, —OR4c, —SO2R4c, —SO2NR4cR4d, —COR4c, —CO2R4c, —CONR4cR4d, —NR4cR4d, —NR4cCOR4d, —NR4cCO2R4d, or —NR4cSO2R4d;
• R4a, R4b, R4c and R4d are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, or 5- to 12-membered heteroaryl;
• or
• R4 and R11 together with the carbon atoms to which they are attached, form a 5-6 membered saturated or partially or completely unsaturated ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• said ring is optionally substituted with at least one substituent R4e;
• R4c, at each of its occurrences, is independently hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, —C3-C8cycloalkyl, oxo, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —SO2R4, —SO2NR4fR4g, —COR4f, —CO2R4f, —CONR4fR4g, —NR4fR4g, —NR4fCOR4g, —NR4CO2R4g or —NR4fSO2R4g, wherein each of —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C122aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R4h;
• R4f and R4g are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C1-8alkoxy-C1-8alkyl-, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
• R4h, at each of its occurrences, is independently halogen, —OH, —C1-8alkyl, —C1-8alkoxy, C1-8alkoxy-C1-8alkyl-, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, or 5- to 12-membered heteroaryl;
• R9, R10, R11 and R12 are each independently selected from hydrogen, halogen, —C1-8 alkyl, —C2-8alkenyl, —C2-8alkynyl, —NR9aR9b, —OR9a, oxo, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, or —CN, wherein each of —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R9c;
• or
• two R12 together with the carbon atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• said ring is optionally substituted with at least one substituent R9c;
• R9a and R9b are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R9d;
• or
• R9c and R9d are each independently halogen, hydroxy, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, —CN or NR9aR9b, wherein each of said —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl is optionally substituted with at least one hydrogen, halogen, hydroxy, —C1-8alkyl, —C1-8alkoxy, —CN, —NH2 or oxo, and R9a and R9b are each independently hydrogen or C1-8alkyl;
• Z1, Z2, Z3 and Z4 are each independently selected from —CRz, or N, or wherein Z1, Z2, Z3 and Z4 are each independently —CRz;
• wherein
• RZ, at each of its occurrences, is independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —NRZaRZb, —ORZa, —SRZa, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or CN, wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one RZC;
• RZa and RZb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl, wherein each of said hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RZd;
• and
• RZc and RZd are each independently —F, —Cl, —Br, —I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl;
• RZ, at each of its occurrences, is independently selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —NRZaRZb, —ORZa, —SRZa, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, or CN, wherein each of —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one RZc, or wherein RZ, at each of its occurrences, is independently selected from hydrogen H, —CH3, —C2H5, F, —CH2F, —CHF2, —CF3, —OCH3, —OC2H5, —C3H7, —OCH2F, —OCHF2, —OCH2CF3, —OCF3, —SCF3, —CF3, cyclopropyl or —CH(OH)CH3;
• or
• when adjacent two Rz together with the carbon atoms to which they are attached, form a 5-6 membered saturated or partially or completely unsaturated ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• said ring is optionally substituted with at least one substituent RZc;
• RZa and RZb are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RZd;
• RZc and RZd are each independently halogen, hydroxy, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, C1-8alkoxy-C18alkyl-, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl;
• L1 is selected from a single bond, —O—, —SO2—, —C(O)—, —NRL1—, —C3-C8cycloalkylene-, *L1—O—C1-8alkylene-**L1, *L1-C1-8alkylene-O—**L1, *L1—SO2—C1-8alkylene-**L1, *L1-C1-8alkylene-SO2—**L1, *L1—CO—C1-8alkylene-**L1, *L1-C1-8alkylene-CO—**L1, *L1—NRL1a—C1-8alkylene-**L1, *L1—C1-8alkylene-NRL1a_**L1, *L1—NRL1aC(O)—**L1, *L1—C(O)NRL1a—**L1—C1-8alkylene-, —C2-8alkenylene-, —C2-8alkynylene-, —[O(CRL1aRL1b)m4]m5—,
• wherein each of said —C1-8alkylene, —C3-C8cycloalkylene-, *L1—O—C1-8alkylene-**L1, *L-C1-8alkylene-O—**L1, *L-SO2—C1-8alkylene-**L1, *L-C1-8alkylene-SO2—**L1, *L1CO—C1-8alkylene-** * —C1-8alkylene-CO—**L1, * —NRL1a-C1-8alkylene-**L1, * —C1-8alkylene-NRL1a, —**L1, —C1-8alkylene-, —C2-8alkenylene-, —C2-8alkynylene-,
• is optionally substituted with at least one RL1c,
• wherein *L1 refers to the position attached to
• moiety, and **L1 refers to the position attached to the
• moiety;
• RL1a and RL1b are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RL1d;
• each of said RL1c and RL1d are independently halogen, hydroxy, —C1-8alkyl, —C1-8alkoxy, C1-8alkoxy-C1-8alkyl-, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl or oxo;
• L2 is selected from a single bond, —O—, —SO2—, —CO—, —NRL2a—, —C1-8alkylene, —C3-C8cycloalkylene-, *L2—O—C1-8alkylene-**L2, *L2-C1-8alkylene-O—**L2, *L2-SO2—C1-8alkylene-**L2, *L2—C1-8alkylene-SO2—**L2, *L2—CO—C1-8alkylene-**L2, *L2—C1-8alkylene-CO—**L2, *L2—NRL2aC1-8alkylene-**L2, *L2—C1-8alkylene-NRL2a—**L2, *L2—NRL2aC(O)—**L2, *L2—C(O)NRL2a—**L2,
• wherein each of said —C1-8alkylene, —C3-C8cycloalkylene-, *L2—O—C1-8alkylene-**L2, *L2—C1-8alkylene-O—**L2, *L2-SO2—C1-8alkylene-**L2, *L2—C1-8alkylene-SO2—**L2, *L2—CO—C1-8alkylene-**L2, *L2—C1-8alkylene-CO—**L2, *L2—NRL2a—C1-8alkylene-**L2, *L2—C1-8alkylene-NRL2a, —**L2, —C1-8alkylene-, —C2-8alkenylene-, —C2-8alkynylene-,
• is optionally substituted with at least one substituent RL2c;
• wherein *L2 refers to the position attached to
• moiety, and **L2 refers to the position attached to the
• moiety;
• RL2a and RL2b are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RL2d;
• each of said RL2c and RL2d are independently halogen, hydroxy, —C1-8alkyl, —C1-8alkoxy, C1-8alkoxy-C1-8alkyl-, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl or oxo;
• L3 is selected from a single bond, —O—, —SO2—, —CO—, —NRL3a, —C1-8alkylene, —C3-C8cycloalkylene-, *L3-O—C1-8alkylene-**L3, *L3-C1-8alkylene-O—**L3, *L3-SO2—C1-8alkylene-**L3*L3-C1-8alkylene-SO2—**L3, *L3-CO—C1-8alkylene-**L3, *L3-C1-8alkylene-CO—**L3, *L3-NRL3aC1-8alkylene-**L3, *L3-C1-8alkylene-NRL3a—**L3, *L3-RL3aC(O)—**L3, *L3-C(O)NRL3a—**L3, —C1-8alkylene-, —C2-8alkenylene-, —C2-8alkynylene-, —[O(CRL3aRL3b)m4]m5—,
• wherein each of said —C1-8alkylene, —C3-C8cycloalkylene-, *L3-O—C1-8alkylene-**L3, *L3-C1-8alkylene-O—**L3, *L3-SO2—C1-8alkylene-**L3, *L3-C1-8alkylene-SO2—**L3, *L3-CO—C1-8alkylene-**L3, *L3-C1-8alkylene-CO—**L3, *L3NRL3a—C1-8alkylene-**L3, *L3-C1-8alkylene-NRL3a, —**L3, —C1-8alkylene-, —C2-8alkenylene-, —C2-8akynylene-,
• is optionally substituted with at least one substituent RL3c;
• wherein *L3 refers to the position attached to
• moiety, and **L3 refers to the position attached to the
• moiety;
• RL3a and RL3b are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RL3d;
• each of said RL3c and RL3d are independently halogen, hydroxy, —C1-8alkyl, —C1-8alkoxy, C1-8alkoxy-C1-8alkyl-, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl or oxo;
• is selected from
• Ring A is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, aryl, or heteroaryl;
• said Ring A is optionally substituted with at least one halogen, oxo, —C1-8alkyl, C1-8alkoxy-C1-8alkyl-, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
• R13 and R14 are independently selected from hydrogen, halogen, CN, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C122aryl or 5- to 12-membered heteroaryl;
• said each —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, —C1-8alkyl, C1-8alkoxy-C1-8alkyl-, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
• X1, X2, X3, X4 and X8 are each independently selected from —CRa, or N;
• X5, X6, X7 and X9 are each independently selected from —NRa—, —O—, —S— and —CRaRb—;
• X12 and X13 are each independently selected from —NRa— and —O—;
• L4, L5 and L6 are each independently selected from a single bond, —O—, —NRa—, —(CRaRb)n8—, —O(CRaRb)n8—, —NRa(CRaRb)n8— or —C(O)—;
• Y1, Y2 and Y3 are each independently selected from CRa or N;
• Ra and Rb are each independently selected from hydrogen (H, D or T), halogen, CN, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl, wherein each of said —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, halogen, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl;
• or
• Ra and Rb together with the carbon atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• said ring is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
• m1 is 0 or 1;
• m2 and m3 are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;
• m4 and m5 are each independently 0, 1, 2 or 3;
• n, n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;
• and
• n6 is 0, 1, 2, 3 or 4
• n7 is 0, 1, 2 or 3;
• n8 is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
• and optionally a deuterium substitution is on degron, and optionally the deuterium substitution is on X8.