Heteroarylquinazoline compounds as protein kinase inhibitors

A compound, or a pharmaceutically acceptable salt, an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, a polymorph, a prodrug, or an isotope variant thereof, or a mixture thereof, which has a structure of formula (X):

• wherein:
• indicates a single bond or a double bond;
• ring A is a 5- to 6-membered heteroaryl;
• alternatively selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl;
• alternatively selected from:
• A2 is CRR′ or NR″;
• A3 is CRR′ or NR4;
• A4 is CRR′ or NR″;
• or A3, A4 and substituents thereon are combined to form C6-10 aryl or 5- to 10-membered heteroaryl;
• R and R′ are independently selected from H, D, —ORO1, —NRN1RN2, C1-6 alkyl, C1-6 haloalkyl, —C0-6 alkylene-C3-7 cycloalkyl, —C0-6 alkylene-3- to 7-membered heterocyclyl, —C0-6 alkylene-C6-10 aryl and —C0-6 alkylene-5- to 10-membered heteroaryl;
• or R, R′ and the carbon atom attached thereto are combined to form C═O;
• R1 is selected from H, D, halogen, —CN, —ORa, —SRa, —NRbRc, —C(O)Ra, —C(O)ORa, —C(O)NRbRc, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl and 5- to 10-membered heteroaryl;
• wherein the C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by oxo or thioxo;
• R2 is selected from H, D, halogen, —CN, —ORa, —SRa, —NRbRc, —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C0-6 alkylene-OR5, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl and 5- to 10-membered heteroaryl;
• wherein the C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by oxo or thioxo;
• R3 is selected from C1-6 alkyl, C1-6 haloalkyl, —C0-6 alkylene-C3-7 cycloalkyl, —C0-6 alkylene-3- to 7-membered heterocyclyl, —C0-6 alkylene-C6-10 aryl and —C0-6 alkylene-5- to 10-membered heteroaryl, which may be optionally substituted by 1, 2, 3, 4 or more substituents selected from D, halogen, —C0-6 alkylene-OR5, —CN, —NR6R7, C1-6 alkyl and C1-6 haloalkyl;
• Ra is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, —C0-6 alkylene-C3-7 cycloalkyl, —C0-6 alkylene-3- to 7-membered heterocyclyl, —C0-6 alkylene-C6-10 aryl and —C0-6 alkylene-5- to 10-membered heteroaryl;
• Rb and Rc are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, —C0-6 alkylene-C3-7 cycloalkyl, —C0-6 alkylene-3- to 7-membered heterocyclyl, —C0-6 alkylene-C6-10 aryl and —C0-6 alkylene-5- to 10-membered heteroaryl;
• or Rb and Rc are taken together with the nitrogen atom to which they are attached to form 3- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl;
• RO1, RN1 and RN2 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, —C(O)Rd, —S(O)mRd, —C1-6 alkylene-OR5, —C1-6 alkylene-NR6R7, —C0-6 alkylene-C3-7 cycloalkyl, —C0-6 alkylene-3- to 7-membered heterocyclyl, —C0-6 alkylene-C6-10 aryl and —C0-6 alkylene-5- to 10-membered heteroaryl;
• or RN1 and RN2 are taken together with the nitrogen atom to which they are attached to form 3- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl, which is optionally substituted by 1, 2 or 3 R8 groups;
• R4 and R″ are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, —C(O)Rd, —S(O)mRd, —C0-6 alkylene-C3-7 cycloalkyl, —C0-6 alkylene-3- to 7-membered heterocyclyl, —C0-6 alkylene-C6-10 aryl and —C0-6 alkylene-5- to 10-membered heteroaryl;
• Rd is selected from C1-6 alkyl, C1-6 haloalkyl, —C0-6 alkylene-OR5, —C0-6 alkylene-NR6R7, —C0-6 alkylene-C3-7 cycloalkyl, —C0-6 alkylene-3- to 7-membered heterocyclyl, —C0-6 alkylene-C6-10 aryl and —C0-6 alkylene-5- to 10-membered heteroaryl;
• m is 0, 1 or 2;
• R5, R6 and R7 are independently selected from H, C1-6 alkyl and C1-6 haloalkyl;
• R8 is independently selected from H, D, halogen, —CN, -L-C3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C6-10 aryl and -L-5- to 10-membered heteroaryl;
• L is selected from a chemical bond, —C(O)—, —C(O)NH—, —C1-6 alkylene-, —C2-6 alkenylene- and —C2-6 alkynylene-;
• and
• R8 is further substituted by H, D, halogen, —CN, C1-6 alkyl or C1-6 haloalkyl.