Degradation of (egfr) by conjugation of egfr inhibitors with e3 ligase ligand and methods of use

A compound of Formula (I):

• or a N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof
• wherein:
• R1 is selected from —P(O)R1aR1b, —SO2R1a, —SO2—NR1aR1b or —N(R1a)—SO2R1b;
• R1a and R1b are each independently selected from hydrogen, halogen, —C1-C8alkyl or C3-C8cycloalkyl, said —C1-C8alkyl or C3-C8cycloalkyl is optionally substituted with at least one halogen;
• R2 and R3 are each independently selected from hydrogen, halogen, —C1-C8alkyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —OR2a, —SO2R2a, —SO2NR2aR2b, —C(O)R2a, —CO2R2a, —C(O)NR2aR2b, —NR2aR2b, —NR2aC(O)R2b, —NR2aCO2R2b, or —NR2aSO2R2b;
• each of —C1-C8alkyl, 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 or 6-membered unsaturated or saturated 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 occurrence, is independently hydrogen, halogen, —C1-C8alkyl, —C1-C8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, oxo (═O), —OR2a, thioxo (═S), —SR2a, —CN, —SO2R2a, —SO2NR2aR2b, —C(O)R2a, —CO2R2a, —C(O)NR2aR2b, —NR2aR2b, —NR2aCOR2b, —NR2aCO2R2b or —NR2aSO2R2b;
• each of —C1-C8alkyl, —C1-C8alkoxy, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl 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-C8alkyl, —C1-C8haloalkyl, —C2-C8alkenyl, —C2-C8alkynyl, C1-C8alkoxy-C1-C8alkyl-, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
• R2d, at each occurrence, is independently halogen, —OH, —CN, oxo (═O), —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, or 5- to 12-membered heteroaryl;
• R4 is selected from hydrogen, halogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C1-C8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —SO2R4a, —SO2NR4aR4b, —C(O)R4a, —CO2R4a, —C(O)NR4aR4b, —NR4aR4b, —NR4aCOR4b, —NR4aCO2R4b or —NR4aSO2R4b;
• each of —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C1-C8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with halogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, oxo (═O), —CN, —OR4c, —SO2R4c, —SO2NR4cR4—, —C(O)R4c, —CO2R4c, —C(O)NR4cR4d, —NR4cR4d, —NR4cCOR4d, —NR4cCO2R4d or —NR4cSO2R4d;
• R4a, R4b, R4c and R4d are each independently hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, 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-C8alkyl, —NR9aR9b, —OR9a, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, oxo (═O) or —CN;
• each of —C1-C8alkyl, 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-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl;
• each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, 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-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl;
• Z1, Z2, Z3 and Z4 are each independently selected from —CRZ, or N;
• RZ, at each occurrence, is independently selected from hydrogen, halogen, —C1-C8alkyl, —NRZaRZb, —ORZa, —SRZa, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, or CN;
• each of —C1-C8alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one RZd;
• RZc and RZd are each independently selected from hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl, each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, 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 selected from halogen, hydroxy, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, 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)—, —NRL1a—, —C3-C8cycloalkylene-, *L1—O—C C8alkylene-**L1, *L1—C1-C8alkylene-O—**L1, *L1—SO2—C1-C8alkylene-**L” *L1—C1-C8alkylene-SO2—**L1, *L1—C(O)—C1-C8alkylene-**L1, *L1—C1-C8alkylene-C(O)—**L1, *L1—NRL1a—C1-C8alkylene-**L1, *L1—C1-C8alkylene- NRL1a-**L1, *L1—NRL1a C(O)—**L1, *L1—C(O)NRL1a—**L1, —C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-, —[O(CRL1aRL1b)m4]m5
• wherein each of said —C3-C8cycloalkylene-, *L1—OC1-C8alkylene-**L1,*L1—C1-C8alkylene-O—**L1, *L1—SO2—C1-C8alkylene-**L1, *L1—C1-C8alkylene-SO2— **L1, *L1—C(O)—C1-C8alkylene-**L1, *L1—C1-C8alkylene-C(O)—**L1, *L1—NRLla—C1-C8alkylene-**L1, *L1—C1-C8alkylene-NRL1a—**L1—C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-,
• is optionally substituted with at least one RL1c;
• wherein *L1 refers to the position attached to the
• moiety, and **L1 refers to the position attached to the
• moiety;
• RL1a and RL1b are each independently selected from hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, 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 oxo (═O), halogen, hydroxy, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
• or
• two RL1c together with the 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-C8alkyl;
• L2 is selected from a single bond, —O—, —SO2—, —C(O)—, —NRL2a—, —C3-C8cycloalkylene-, *L1—O—C1-C8alkylene-**L2, *L2—C1-C8alkylene-O—**L2, *L2—SO2—C1-C8alkylene-**L2, *L2—C1-C8alkylene-SO2—**L2, *L C(O)—C1-C8alkylene-**L2, *L2—C1-C8alkylene-C(O)—**L2, *L2NRL2a—C1-C8alkylene-**L2, *L2—C1-C8alkylene-NRL2a—**L2, *L2NRL2aC(O)—**L2, *L2—C(O)NRL2a—**L2, C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-, —[O(CRL2aRL2b)m4]m5—,
• wherein each of said —C3-C8cycloalkylene-, *L2—O—C1-C8alkylene-**L2, *L2—C1-C8alkylene-O—**L2, *L2SO2—C1-C8alkylene-**L2, *L2—C1-C8alkylene-SO2—**L2, *L2—C(O)—C1-C8alkylene-**L2, *L2—C1-C8alkylene- C(O)—**L2, *L2NRL2a—C1-C8alkylene-**L2, *L2—C1-C8alkylene-NRL2a—**L2, —C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-,
• 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
• RL2a and RL2b are each independently selected from hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl, each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, 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 is independently selected from oxo (═O), halogen, hydroxy, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
• or
• two RL2c together with the 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-C8alkyl;
• L3 is selected from a single bond, —O—, —SO2—, —C(O)—, —NRL3a—, —C3-C8cycloalkylene-, *L3—O—C1-C8alkylene-**L3, *L3—C1-C8alkylene-O—**L3, *L3—SO2—C1-C8alkylene-**L3, *L3—C1-C8alkylene-SO2—**L3, *L3—C(O)—C1-C8alkylene-**L3, *L3—C1-C8alkylene-C(O)—**L3, *L3—NRL3a—C1-C8alkylene_**L3, *L3—C1-C8alkylene- NRL3a—**L3, *L3—NRL3aC(O)—**L3, *L3—C(O)NRL3a—**L3, C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-, —[O(CRL3aRL3b)m4]m5—,
• wherein each of said —C3-C8cycloalkylene-, *L3—O—C1-C8alkylene-**L3, *L3—C1-C8alkylene-O—**L3, *L3—SO2—C1-C8alkylene-**L3, *L3—C1-C8alkylene-SO2**L3, *L3—C(O)—C1-C8alkylene**L3,*L3—C1-C8alkylene- C(O)—**L3, *L3—NRL3a—C1-C8alkylene-**L3, *L3—C1-C8alkylene-NRL3a_**L3, —C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-,
• 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-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl, each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, 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 is independently selected from oxo (═O), halogen, hydroxy, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
• or
• two RL3c together with the 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, or —C1-C8alkyl;
• is selected from
• Ring A is selected from 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, aryl, or heteroaryl;
• R13, R14, R15, R16 and R17 are each independently selected from hydrogen, halogen, CN, —C1-C8alkyl, —C1-C8alkoxy, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
• said each —C1-C8alkyl, —C1-C8alkoxy, 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-C8alkyl, C1-C8alkoxy-C1-C8alkyl-, —C2-C8alkenyl, —C2-C8alkynyl, 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 —C(O)—, —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)—;
• Q1, Q2, Q3, Q4, Y1, Y2, Y3 and Y4 are each independently selected from CRa or N;
• Y5 is selected from NRa, 0 or S;
• Q5 is each independently selected from —O—, —NRa—, —CRaRb—, —S— or —C(O)—;
• P1 is a single bond, —O—, —NRa—, —CRaRb—, —S—, —SO— or —SO2—;
• at each occurrence, Ra and Rb are each independently selected from hydrogen, hydroxy, halogen, CN, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl, each of said —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, —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-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, —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-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
• m1 is 0, 1 or 2;
• 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, n7, n8 and n9 are each independently 0, 1, 2, 3 or 4.