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CN115803326A - EGFR inhibitor, preparation method and pharmaceutical application thereof - Google Patents

EGFR inhibitor, preparation method and pharmaceutical application thereof Download PDF

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CN115803326A
CN115803326A CN202180049014.0A CN202180049014A CN115803326A CN 115803326 A CN115803326 A CN 115803326A CN 202180049014 A CN202180049014 A CN 202180049014A CN 115803326 A CN115803326 A CN 115803326A
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deuterium
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CN115803326B (en
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邓海兵
杨飞
喻红平
陈椎
徐耀昌
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Abbisko Therapeutics Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

Relates to an EGFR inhibitor having a structure shown in a formula (I), a preparation method thereof, a pharmaceutical composition containing the same, and application thereof as an EGFR inhibitor and application thereof in treating and/or preventing cancers, tumors or metastatic diseases at least partially related to insertion or deletion mutation of EGFR exon 20, particularly application in treating hyperproliferative diseases and cell death disorder-inducing diseases. Wherein each substituent group of the formula (I) is defined as the specification.

Description

PCT国内申请，说明书已公开。PCT domestic application, specification has been published.

Claims (20)

  1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021132029-APPB-100001
    wherein, X 1 And X 2 Each independently is CR 7 Or N; y is CR 8 Or N; z is NR 9 Or O;
    ring a is a 3-12 membered nitrogen containing heterocyclyl group, preferably selected from the group consisting of:
    Figure PCTCN2021132029-APPB-100002
    Figure PCTCN2021132029-APPB-100003
    each R 1 Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C(O)R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (= NR) 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 and-C 0-8 alkyl-N (R) 13 )-C(O)R 12 ；
    Each R 2 Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (= NR) 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 and-C 0-8 alkyl-N (R) 13 )-C(O)R 12 Or, when n is more than or equal to 2, two adjacent R 2 Together with the directly attached portion thereof form a C 4-8 Cycloalkyl or 5-8 membered heterocyclyl;
    R 3 and R 4 Each independently selected from hydrogenDeuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;
    R 5 selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -C (O) OR 11 、-C(O)R 12 、-C(O)-NR 13 R 14 and-C 0-4 alkyl-NR 13 R 14 ；
    R 7 Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (= NR) 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 and-C 0-8 alkyl-N (R) 13 )-C(O)R 12 ；
    R 6 And R 8 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 10 、-C 0-4 alkyl-O-R 11 、-C 0-4 alkyl-C (O) OR 11 、-C 0-4 alkyl-C (O) R 12 、-C 0-4 alkyl-O-C (O) R 12 、-C 0-4 alkyl-NR 13 R 14 、-C 0-4 alkyl-C (= NR) 13 )R 12 、-C 0-4 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-4 alkyl-C (O) NR 13 R 14 and-C 0-4 alkyl-N (R) 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (= NR) 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 and-C 0-8 alkyl-N (R) 13 )-C(O)R 12 Provided that when ring A is
    Figure PCTCN2021132029-APPB-100004
    When R is 8 Not being unsubstituted or halogen-substituted C 1-4 An alkoxy group;
    R 9 selected from hydrogen, deuterium, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl and 3-12 membered heterocyclyl;
    each R 10 Independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and-NR 13 R 14 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, = O, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 13 R 14 Substituted with a substituent of (a);
    each R 11 Independently selected from hydrogen, deuterium, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, = O, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 13 R 14 Substituted with the substituent(s);
    each R 12 Independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 13 R 14 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, = O, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 13 R 14 Substituted with the substituent(s);
    each R 13 And R 14 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-10 Alkanoyl, which radicals are independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, = O, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Substituted by alkanoyl group;
    or, R 13 And R 14 Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said 4-10 membered heterocyclyl or 5-10 membered heteroaryl being optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, = O, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Substituted by alkanoyl group;
    m is 0, 1,2, 3 or 4;
    n is 0, 1,2, 3 or 4; and is
    Each r is independently 0, 1 or 2.
  2. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is 1 Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 10 、-C 0-4 alkyl-O-R 11 、-C 0-4 alkyl-C (O) OR 11 、-C 0-4 alkyl-C (O) R 12 、-C 0-4 alkyl-O-C (O) R 12 、-C 0-4 alkyl-NR 13 R 14 、-C 0-4 alkyl-C (= NR) 13 )R 12 、-C 0-4 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-4 alkyl-C (O) NR 13 R 14 and-C 0-4 alkyl-N (R) 13 )-C(O)R 12 ；
    R 2 Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 10 、-C 0-4 alkyl-O-R 11 、-C 0-4 alkyl-C (O) OR 11 、-C 0-4 alkyl-C (O) R 12 、-C 0-4 alkyl-O-C (O) R 12 、-C 0-4 alkyl-NR 13 R 14 、-C 0-4 alkyl-C (= NR) 13 )R 12 、-C 0-4 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-4 alkyl-C (O) NR 13 R 14 and-C 0-4 alkyl-N (R) 13 )-C(O)R 12 Or, when n is greater than or equal to 2, two adjacent R 2 In direct phase with itThe joined parts together forming a C 4-8 Cycloalkyl or 5-8 membered heterocyclyl;
    R 3 and R 4 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;
    R 5 selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 13 R 14 ；
    R 6 And R 8 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 10 、 -O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, = O, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 10 、-C 0-4 alkyl-O-R 11 、-C 0-4 alkyl-C (O) OR 11 、-C 0-4 alkyl-C (O) R 12 、-C 0-4 alkyl-O-C (O) R 12 、-C 0-4 alkyl-NR 13 R 14 、-C 0-4 alkyl-C (= NR) 13 )R 12 、-C 0-4 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-4 alkyl-C (O) NR 13 R 14 and-C 0-4 alkyl-N (R) 13 )-C(O)R 12 Provided that when ring A is
    Figure PCTCN2021132029-APPB-100005
    When R is 8 Not being unsubstituted or halogen-substituted C 1-4 An alkoxy group;
    R 7 selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
    R 9 Selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-6 CycloalkanesAnd 3-6 membered heterocyclyl;
    wherein, X 1 、X 2 Y, Z, ring A, m, n, R 10 、R 11 、R 12 、R 13 、R 14 And r is as defined in claim 1.
  3. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, according to claim 1, wherein the compound of formula (I) is a compound of formula (iia):
    Figure PCTCN2021132029-APPB-100006
    wherein Z is NR 9 Or O;
    ring a is a 3-12 membered nitrogen containing heterocyclyl group, preferably selected from the group consisting of:
    Figure PCTCN2021132029-APPB-100007
    Figure PCTCN2021132029-APPB-100008
    R 1a selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
    R 1b Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
    R 2 Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
    R 3 Selected from hydrogen, deuterium, halogen and C 1-4 An alkyl group;
    R 5 selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 13 R 14 ；
    R 8 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, -O-R 11 、-O-C(O)R 12 、-NR 13 R 14 、-N(R 13 )-C(＝NR 14 )R 12 and-N (R) 13 )-C(O)R 12 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, = O, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 10 、-C 0-4 alkyl-O-R 11 、-C 0-4 alkyl-C (O) OR 11 、-C 0-4 alkyl-C (O) R 12 、-C 0-4 alkyl-O-C (O) R 12 、-C 0-4 alkyl-NR 13 R 14 、-C 0-4 alkyl-C (= NR) 13 )R 12 、-C 0-4 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-4 alkyl-C (O) NR 13 R 14 and-C 0-4 alkyl-N (R) 13 )-C(O)R 12 Provided that when the ring is substitutedA is
    Figure PCTCN2021132029-APPB-100009
    When R is 8 Not being unsubstituted or halogen-substituted C 1-4 An alkoxy group;
    R 9 selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;
    wherein R is 10 、R 11 、R 12 、R 13 、R 14 And r is as defined in claim 1.
  4. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 3, wherein Z is NH or O;
    R 1a selected from the group consisting of hydrogen, deuterium, fluoro, chloro, bromo, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteromethyl;
    R 1b selected from the group consisting of hydrogen, deuterium, fluoro, chloro, bromo, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteromethyl;
    R 2 selected from hydrogen, deuterium, fluorine, chlorine, bromine and cyano;
    R 3 selected from hydrogen, deuterium and fluorine;
    R 5 selected from hydrogen, deuterium and methyl.
  5. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that ring a is selected from the following groups:
    Figure PCTCN2021132029-APPB-100010
  6. a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 3, wherein R is 8 Is selected from C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-6 Cycloalkyl radical C 1-4 Alkoxy and 3-6 membered heterocycloalkyl C 1-4 Alkoxy, the above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 Substituted with a substituent of (a); wherein R is 10 、R 11 、R 12 、R 13 、R 14 And r is as defined in claim 1.
  7. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 6, wherein R is 8 Is selected from
    Figure PCTCN2021132029-APPB-100011
    Figure PCTCN2021132029-APPB-100012
    The above-mentioned
    Figure PCTCN2021132029-APPB-100013
    Figure PCTCN2021132029-APPB-100014
    Each independently optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, methoxy, cyano and nitro.
  8. A compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 3, wherein R is 8 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkynyl, C 1-2 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and-NR 13 R 14 Independently, the above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 Provided that when ring A is
    Figure PCTCN2021132029-APPB-100015
    When R is 8 Not being unsubstituted or halogen-substituted C 1-2 An alkoxy group; wherein R is 10 、R 11 、R 12 、R 13 、R 14 And r is as defined in claim 1.
  9. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 8, wherein R is 8 <xnotran> , , , , , , , , , , , , , , , , ,3- - , ,2- , </xnotran>
    Figure PCTCN2021132029-APPB-100016
    Figure PCTCN2021132029-APPB-100017
    The described
    Figure PCTCN2021132029-APPB-100018
    Each independently optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, methoxy, cyano and nitro, with the proviso that when ring A is
    Figure PCTCN2021132029-APPB-100019
    When R is 8 Is not methoxy, ethoxy, monofluoromethoxy or trifluoroethoxy.
  10. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, according to claim 1, wherein the compound of formula (I) is a compound of formula (lib) as follows:
    Figure PCTCN2021132029-APPB-100020
    wherein Z is NR 9 Or O;
    ring a is a 3-12 membered nitrogen containing heterocyclyl group, preferably selected from the group consisting of:
    Figure PCTCN2021132029-APPB-100021
    Figure PCTCN2021132029-APPB-100022
    R 1a selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
    R 1b Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
    R 2 Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
    R 3 Selected from hydrogen, deuterium, halogen and C 1-4 An alkyl group;
    R 5 selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 13 R 14 ；
    R 9 Selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;
    wherein R is 10 、R 11 、R 12 、R 13 、R 14 And r is as defined in claim 1.
  11. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 10, wherein Z is O;
    R 1a selected from the group consisting of hydrogen, deuterium, fluoro, chloro, bromo, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteromethyl;
    R 1b selected from the group consisting of hydrogen, deuterium, fluoro, chloro, bromo, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteromethyl;
    R 2 selected from hydrogen, deuterium, fluorine, chlorine, bromine and cyano;
    R 3 selected from hydrogen, deuterium and fluorine;
    R 5 selected from hydrogen, deuterium and methyl.
  12. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 10, characterized in that ring a is selected from the following groups:
    Figure PCTCN2021132029-APPB-100023
  13. the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, according to claim 1, wherein each R is 10 Independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl and-NR 13 R 14 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, = O, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 A cycloalkyl group, a,C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 13 R 14 Substituted with the substituent(s);
    each R 11 Independently selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, = O, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 13 R 14 Substituted with a substituent of (a);
    each R 12 Independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 13 R 14 Independently, the above groups are optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, = O, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 13 R 14 Substituted with a substituent of (a);
    each R 13 And R 14 Each independently selected fromHydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-4 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, = O, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Substituted by alkanoyl group;
    or, R 13 And R 14 Together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl, said 4-8 membered heterocyclyl or 5-8 membered heteroaryl being optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, = O, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Substituted by alkanoyl group.
  14. A compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, according to any one of claims 1 to 13, wherein it is selected from the following compounds:
    Figure PCTCN2021132029-APPB-100024
    Figure PCTCN2021132029-APPB-100025
    Figure PCTCN2021132029-APPB-100026
    Figure PCTCN2021132029-APPB-100027
    Figure PCTCN2021132029-APPB-100028
  15. a process for the preparation of a compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, according to claim 1, comprising the steps of:
    Figure PCTCN2021132029-APPB-100029
    Figure PCTCN2021132029-APPB-100030
    wherein X is halogenPreferably selected from fluorine, chlorine and bromine; ring A, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 1 、X 2 Y, Z, m and n are as defined in claim 1.
  16. A pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-14, and a pharmaceutically acceptable carrier.
  17. Use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 14, for the manufacture of a medicament for the treatment and/or prevention of a cancer, a tumor, or a metastatic disease that is at least partially associated with an EGFR exon 20 insertion or deletion mutation.
  18. Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, for the preparation of a medicament for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and cell death-inducing disorders.
  19. Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, in the manufacture of a medicament for the prevention and/or treatment of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndromes, malignant lymphomas, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinus rhinoinverted papillomas or sinus rhinosquamous cell carcinoma associated with sinus rhinosinus inverted papillomas associated at least in part with EGFR exon 20 insertion or deletion mutations.
  20. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14, for use in the treatment and/or prevention of squamous cell carcinoma of the nasal cavity associated at least in part with mutations in the insertion or deletion of EGFR exon 20, lung cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukaemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumours, thoracic tumours, gastrointestinal tumours, endocrine tumours, breast and other gynaecological tumours, urological tumours, skin tumours, sarcomas, inverted papillomas of the nasal sinuses or squamous cell carcinoma of the nasal sinuses associated with inverted papillomas of the nasal sinuses.
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