Indoline compounds and derivatives as egfr inhibitors

A compound of Formula (I):

• or an N-oxide thereof or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or prodrug thereof, wherein:
• X1 is a single bond, NR4, O, S, S(O), S(O)2 or CH2;
• Z1 is N or CR9, Z2 is N or CR10, Z3 is N or CR11, Z4 is N or CR12;
• R1 is —S(O)R1a, —S(O)2R1a, —C(O)R1a, —P(O)R1aR1b or
• R1a and R1b are each independently H, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —OR1d, —CH2CONR1dR1e, —CH2CH2CONR1dR1e, —CH2CH2CH2CONR1dR1e, —NR1dR1e, —CH2NR1dR1e, —CH2CH2NR1dR1e, —CH2CH2CH2NR1dR1e or —NR1dCOR1e, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R1f;
• R1d and R1e are each independently hydrogen, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
• or
• R1d and R1e together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R1f;
• R1f, at each of its occurrence, is independently hydrogen, halogen, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (═O), —CN, —OR1g, —COR1g, —CO2R1g, —CONR1gR1h, —NR1gR1h, —NR1gCOR1h or —NR1gCO2R1h;
• or
• two R1f together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent hydrogen, halogen, hydroxyl, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo or —CN;
• R1g and R1h are each independently hydrogen, halogen, hydroxyl, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
• R2, R3a, R3b and R3c are each hydrogen, halogen, —C1-8alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, oxo (=O), —OR2a, —COR2a, —CO2R2a, —CONR2aR2b, —NR2aR2b, —NR2aCOR2b or —NR2aCO2R2b, wherein each of said —C1-8alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R2c;
• or
• R2 and R3a together with the atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R2c;
• or
• when m≥2, two germinal R2 together with the atom to which they are attached, form a 3- to 12-membered spiro ring, or two R2 together with the atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R2c;
• or
• R3a and R3b, or R3b and R3c, together with the atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R2c;
• R2a and R2b are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C1-8alkoxy-C1-8alkyl-, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C1-8alkoxy-C1-8alkyl-, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R2c;
• R2c, at each of its occurrence, is independently halogen, amino, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), —CN, —OR2d, —COR2d, —CO2R2, —CONR2dR2e, —NR2dR2e, —NR2dCOR2e or —NR2dCO2R2e;
• R2d and R2e are each independently hydrogen, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
• R4 and R7 are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl or cycloalkyl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl or cycloalkyl is optionally substituted with at least one substituent R4a;
• R4a is independently hydrogen, halogen, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, —CN or —OR4b;
• R4b is hydrogen, —C1-8alkyl, -haloC1-8alkyl, C1-8alkoxy-C1-8alkyl- or —C3-6cycloalkyl;
• R5 and R6 are independently hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —OR5a, —COR5a, —CO2Ra, —CONR5aR5b, —NR5aR5b or —NR5aCOR5b, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R5c;
• R5a are R5b are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C1-8alkoxy-C1-8alkyl-, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C1-8alkoxy-C1-8alkyl-, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R5c;
• R5c, at each occurrence, is independently halogen, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
• or R5 and R6, together with the atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, sulfur and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R56;
• R56 is hydrogen, halogen, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C3-6cycloalkyl, 3- to 8-membered heterocyclyl, —C6-12aryl, 3- to 8-membered heteroaryl, C1-8alkoxy-C1-8alkyl-, oxo (=O), —CN, —OR56a, —COR56a, —CO2R56a, —CONR56aR56b, —NR56aR56b or —NR56aCOR56b;
• R56a and R56b are each independently hydrogen, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C1-8alkoxy-C1-8alkyl-, cycloalkyl, heterocyclyl, aryl or heteroaryl;
• R8 is halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR8a or —NR5aR5b, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R8c;
• R8a and R8b are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C1-8alkoxy-C1-8alkyl-, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C1-8alkoxy-C1-8alkyl-, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R1d;
• or
• R8a and R8b, together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R8d;
• R8c is independently hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), —CN, —OR8f;
• —COR8f, —CO2R8f, —CONR8fR8g, —NR8fR8g or —NR8fCOR8g, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one R8e;
• or
• two R8c together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one R8e;
• R8d and R8e are each independently hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), —CN, —OR8h, —COR8h, —CO2R8h, —CONR8hR8i, —NR8hR8i or —NR8hCOR8i, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, —C1-8alkoxy or C1-8alkoxy-C1-8alkyl-;
• or
• two R8e together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, —C1-8alkoxy or C1-8alkoxy-C1-8alkyl-;
• R8f, R8g, R8h and R8i are each independently hydrogen, —C1-8alkyl, -haloC1-8alkyl, C1-8alkoxy-C1-8alkyl-, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
• R9, R10, R11 and R12 are each independently hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, —C6-12aryl, heteroaryl, —CN, —OR9d, —CH2CONR9dR9e, —CH2CH2CONR9dR9e, —CH2CH2CH2CONR9dR9e, —NR9dR9e, —CH2NR9dR9e, —CH2CH2NR9dR9e, —CH2CH2CH2NR9dR9e or —NR9dCOR9e, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R9f;
• or
• R9 and R11, or R10 and R12, together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R9f;
• R9d and R9e are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one halogen, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, —C1-8alkoxy or C1-8alkoxy-C1-8alkyl-;
• or
• R9d and R9e together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R9f;
• R9f, at each of its occurrence, is independently hydrogen, halogen, -haloC1-8alkyl, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, aryl, heteroaryl, oxo (=O), —CN, —OR9g, —COR9g, —CO2R9g, —CONR9gR9h, —NR9gR9h, —NR9gCOR9h or —NR9gCO2R9h;
• or
• two R9f together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one halogen, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, —C1-8alkoxy or C1-8alkoxy-C1-8alkyl-;
• R9g and R9h are each independently hydrogen, halogen, hydroxyl, —C1-8alkyl, -haloC1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
• n is 0, 1, 2 or 3;
• and
• m is 0, 1, 2, 3 or 4.