Tricyclic compound as well as preparation method and application thereof

Abstract

The invention provides a tricyclic compound as well as a preparation method and application thereof. The invention specifically provides a compound as shown in a formula (I) or an isomer and pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] This disclosure belongs to the field of medicinal chemistry, specifically relating to a tricyclic compound, its preparation method, and its application. Background Technology

[0002] Human epidermal growth factor receptor 2 (HER2), also known as ErbB2, is a receptor tyrosine kinase encoded by the ERBB2 proto-oncogene located on the long arm of chromosome 17 (17q21). It is a member of the EGFR / ErbB family, which includes HER1 / EGFR, HER2, HER3, and HER4. Unlike other members of the EGFR / ErbB family, HER2 has no known ligand. It is activated through homodimerization or heterodimerization with another ligand-binding HER family member, leading to cross-phosphorylation and activation of its tyrosine kinase catalytic domain. Activated downstream signaling pathways such as ERK-MAPK, PI3K-Akt, and STAT regulate processes such as cell proliferation, survival, differentiation, and migration. Therefore, aberrant overexpression or mutations leading to upregulation of HER2 activity (including small-frame insertions or specific point mutations in exon 20) are closely associated with tumor progression.

[0003] It is currently known that HER2 alterations are closely associated with poor prognosis in tumors such as breast cancer, gastrointestinal cancer, ovarian cancer, endometrial cancer, bladder cancer, lung cancer, colon cancer, and head and neck cancer. Three types of HER2 aberrations have been identified in non-small cell lung cancer (NSCLC): HER2 gene amplification (3%); HER2 protein overexpression (2.4%–38%); and HER2 mutation (3%–6%). HER2 mutation is a major driver gene in HER2-mutant NSCLC; HER2 exon20 is the most common mutated region in the HER2 tyrosine kinase domain in NSCLC (accounting for 50–90% of all mutations), and Her2 A775_G776insYVMA is the most common mutation type in HER2 exon20. HER2 overexpression is found in approximately 15–20% of breast cancer patients, indicating a clear clinical need for intervention. Most current HER2 TKIs target both EGFR and HER2, leading to EGFR-related limiting toxicities and limited efficacy in treating HER2-positive or HER2-mutant patients. Tucatinib has good EGFR selectivity, but its inhibitory effect on mutant HER2 is limited. Therefore, there is a need to develop a TKI with good EGFR selectivity that can effectively target mutant HER2. Summary of the Invention

[0004] This disclosure provides a compound of formula (I) or an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0005]

[0006] in,

[0007] M1 is selected from N or C;

[0008] M2 is selected from N or C;

[0009] L1 is selected from bonds, -N(R5)-, and 3-6 membered heterocyclic alkyl groups;

[0010] L2 is selected from O or CH2;

[0011] Ring A is selected from 3-10 membered heterocyclic alkyl groups;

[0012] Ring B is selected from C 6-14 Aryl, 5-14 heteroaryl;

[0013] R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0014] R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the amino, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic alkyl groups are optionally replaced by deuterium, halogen, amino, hydroxyl, cyano, or C. 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Substituted with one or more of cycloalkyl groups or 3-8 membered heterocyclic alkyl groups;

[0015] R 3-1 R 3-2 R 3-3 and R 3-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl;

[0016] R 4-1 R 4-2 and R 4-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 The cycloalkyl group or 3-8 membered heterocycloalkyl group is optionally further substituted with one or more R4'; R4' is independently selected from amino, C1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 3-8 cycloalkyl), -NH (3-8 membered heterocycloalkyl), -N (C 1-6 Alkyl)(C 3-8 cycloalkyl), -N(C) 1-6 Alkyl groups (3-8 membered heterocyclic alkyl groups), 3-8 membered heterocyclic alkyl groups, wherein the amino group, C 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 3-8 cycloalkyl), -NH (3-8 membered heterocycloalkyl), -N (C 1-6 Alkyl)(C 3-8 cycloalkyl), -N(C) 1-6 Alkyl groups (3-8 membered heterocyclic alkyl groups), 3-8 membered heterocyclic alkyl groups optionally surrounded by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Substituted with one or more of cycloalkyl groups or 3-8 membered heterocyclic alkyl groups;

[0017] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0018] x is selected from 0, 1, 2, 3 or 4;

[0019] y is selected from 0, 1, 2, 3 or 4.

[0020] This disclosure provides a compound of formula (I) or an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0021]

[0022] in,

[0023] M1 is selected from N or C;

[0024] M2 is selected from N or C;

[0025] L1 is selected from bonds, -N(R5)-, and 3-6 membered heterocyclic alkyl groups;

[0026] L2 is selected from O or CH2;

[0027] Ring A is selected from 3-10 membered heterocyclic alkyl groups;

[0028] Ring B is selected from C 6-14 Aryl, 5-14 heteroaryl;

[0029] R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0030] R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the amino, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic alkyl groups are optionally replaced by deuterium, halogen, amino, hydroxyl, cyano, or C. 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Substituted with one or more of cycloalkyl groups or 3-8 membered heterocyclic alkyl groups;

[0031] R 3-1 R 3-2 R 3-3 and R 3-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0032] R 4-1 R 4-2 and R 4-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 The cycloalkyl group or 3-8 membered heterocycloalkyl group is optionally further substituted with one or more R4'; R4' is independently selected from amino, C1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 3-8 cycloalkyl), -NH (3-8 membered heterocycloalkyl), -N (C 1-6 Alkyl)(C 3-8 cycloalkyl), -N(C) 1-6 Alkyl groups (3-8 membered heterocyclic alkyl groups), 3-8 membered heterocyclic alkyl groups, wherein the amino group, C 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 3-8 cycloalkyl), -NH (3-8 membered heterocycloalkyl), -N (C 1-6 Alkyl)(C 3-8 cycloalkyl), -N(C) 1-6 Alkyl groups (3-8 membered heterocyclic alkyl groups), 3-8 membered heterocyclic alkyl groups optionally surrounded by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Substituted with one or more of cycloalkyl groups or 3-8 membered heterocyclic alkyl groups;

[0033] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0034] x is selected from 0, 1, 2, 3 or 4;

[0035] y is selected from 0, 1, 2, 3 or 4.

[0036] In some embodiments of this disclosure, when L1 is connected to a carbon atom in ring A, L1 is NH; when L1 is connected to a nitrogen atom in ring A, L1 is a bond; the definitions of other groups are the same as described in any of the technical solutions of this disclosure.

[0037] In some embodiments of this disclosure, structural fragments Selected from The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0038] In some embodiments of this disclosure, structural fragments Selected from The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0039] In some embodiments of this disclosure, ring B is selected from 6-membered heteroaryl and 5-membered heteroaryl, phenyl 5-membered heteroaryl, 5-membered heteroaryl, and 6-membered heteroaryl; the definitions of other groups are the same as those described in any technical solution of this disclosure.

[0040] In some embodiments of this disclosure, ring B is selected from... The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0041] In certain embodiments of this disclosure, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, wherein the amino, hydroxyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups and 3-6-membered heterocyclic alkyl groups are optionally replaced by deuterium, halogen, amino, hydroxyl, cyano, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 The group is substituted with one or more of cycloalkyl groups or 3-6 membered heterocycloalkyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0042] In some embodiments of this disclosure, R2 is independently selected from hydrogen, methyl, methoxy, cyclopropyl, The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0043] In some embodiments of this disclosure, R2 is independently selected from fluorine, The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0044] In some embodiments of this disclosure, R2 is independently selected from difluoromethyl and trifluoromethyl; the definitions of other groups are the same as those described in any of the technical solutions of this disclosure.

[0045] In some embodiments of this disclosure, Selected from The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0046] In some embodiments of this disclosure, Selected from The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0047] In some embodiments of this disclosure, Selected from The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0048] In certain embodiments of this disclosure, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic alkyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0049] In some embodiments of this disclosure, R1 is independently selected from hydrogen; the definitions of other groups are the same as those described in any of the technical solutions of this disclosure.

[0050] In some embodiments of this disclosure, R1 is independently selected from methyl groups; the definitions of other groups are the same as those described in any of the technical solutions of this disclosure.

[0051] In some embodiments of this disclosure, R 3-1 R 3-2 R 3-3 and R 3-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; other groups are defined as described in any of the technical solutions disclosed herein.

[0052] In some embodiments of this disclosure, R 3-1 R 3-2 R 3-3 and R 3-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic alkyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0053] In some embodiments of this disclosure, R 3-1 Selected from hydrogen; other groups are defined as described in any of the technical solutions disclosed herein.

[0054] In some embodiments of this disclosure, R 3-2 The radicals are selected from hydrogen, fluorine, and methoxy groups; the definitions of other radicals are the same as those described in any of the technical solutions disclosed herein.

[0055] In some embodiments of this disclosure, R 3-2Selected from The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0056] In some embodiments of this disclosure, R 3-3 Selected from methyl and chlorine; other groups are defined as described in any of the technical solutions disclosed herein.

[0057] In some embodiments of this disclosure, R 3-4 Selected from hydrogen and fluorine; other groups are defined as described in any of the technical solutions disclosed herein.

[0058] In some embodiments of this disclosure, R 4-1 R 4-2 and R 4-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 The cycloalkyl group or 3-6 membered heterocycloalkyl group is optionally further substituted with one or more R4'; R4' is independently selected from amino, C 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-6 cycloalkyl), -NH (3-6 membered heterocycloalkyl), -N (C 1-3 Alkyl)(C 3-6 cycloalkyl), -N(C) 1-3 Alkyl groups (3-6 membered heterocyclic alkyl groups), 3-6 membered heterocyclic alkyl groups, wherein the amino group, C 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-6 cycloalkyl), -NH (3-6 membered heterocycloalkyl), -N (C1-3 Alkyl)(C 3-6 cycloalkyl), -N(C) 1-3 Alkyl groups (3-6 membered heterocyclic alkyl groups), 3-6 membered heterocyclic alkyl groups optionally surrounded by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 The group is substituted with one or more of cycloalkyl groups or 3-6 membered heterocycloalkyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0059] In some embodiments of this disclosure, R 4-1 Selected from hydrogen, -CH2N(CH3)2, The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0060] In some embodiments of this disclosure, R 4-1 Selected from -CHF2; other groups are defined as described in any of the technical solutions disclosed herein.

[0061] In some embodiments of this disclosure, R 4-2 Selected from hydrogen; other groups are defined as described in any of the technical solutions disclosed herein.

[0062] In some embodiments of this disclosure, R 4-3 Selected from hydrogen; other groups are defined as described in any of the technical solutions disclosed herein.

[0063] In some embodiments of this disclosure, R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic alkyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0064] In some embodiments of this disclosure, R5 is selected from hydrogen or methyl; the definitions of other groups are the same as those described in any of the technical solutions of this disclosure.

[0065] In some embodiments of this disclosure, the compound is as shown in formula (II).

[0066]

[0067] The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0068] In some embodiments of this disclosure, the compound is as shown in formula (III).

[0069]

[0070] The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0071] In some embodiments of this disclosure, L2 is O; the definitions of other groups are the same as those described in any of the technical solutions of this disclosure.

[0072] In some embodiments of this disclosure, ring B is The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0073] In some embodiments of this disclosure, L2 is O, and ring B is The definitions of other functional groups are the same as those described in any of the technical solutions disclosed herein.

[0074] This disclosure also provides a compound or an isomer thereof, or a pharmaceutically acceptable salt thereof, the compound being shown below.

[0075]

[0076]

[0077] This disclosure also provides a pharmaceutical composition comprising the compound described herein or an isomer thereof, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0078] In some embodiments of this disclosure, the amount of the compound or its isomers, or pharmaceutically acceptable salts in the pharmaceutical composition is selected from 0.1 mg to 1000 mg.

[0079] In some embodiments of this disclosure, the pharmaceutically acceptable carrier in the pharmaceutical composition includes one or more of fillers, disintegrants, binders, flow aids, and lubricants.

[0080] This disclosure also provides the use of compounds or isomers thereof, pharmaceutically acceptable salts, or pharmaceutical compositions as described herein in the preparation of medicaments for treating cancer.

[0081] In some embodiments of this disclosure, the cancer is a HER2-mutated or HER2-positive cancer.

[0082] In some embodiments of this disclosure, the cancer is selected from non-small cell lung cancer, breast cancer, or colon cancer.

[0083] In some embodiments of this disclosure, the cancer is selected from HER2-mutant non-small cell lung cancer, HER2-positive breast cancer, or HER2-positive colon cancer.

[0084] Technical effect

[0085] The compounds disclosed herein exhibit good HER2 inhibitory activity and good selectivity.

[0086] Explanation and Definition

[0087] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0088] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0089] The term "pharmaceutically acceptable salt" refers to derivatives obtained from the compounds of this disclosure prepared with relatively non-toxic acids or bases. These salts can be prepared during the synthesis, isolation, and purification of the compounds, or by reacting the purified free form of the compounds with suitable acids or bases. When the compounds contain relatively acidic functional groups, they react with alkali metal, alkaline earth metal hydroxides, or organic amines to yield base addition salts, including alkali metal and alkaline earth metal-based cations, as well as non-toxic ammonium, quaternary ammonium, and amine cations, and also encompassing amino acid salts. When the compounds contain relatively basic functional groups, they react with organic or inorganic acids to yield acid addition salts.

[0090] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering a bioactive pharmaceutical agent to animals, particularly mammals. Depending on the route of administration and dosage form, this includes, for example, adjuvants, excipients, or excipients such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated based on a multitude of factors, within the scope of those skilled in the art. These include, but are not limited to, the type and nature of the formulated active pharmaceutical agent, the recipient to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as various solid and semi-solid dosage forms. In addition to the active pharmaceutical agent, such carriers include many different components and additives, and the inclusion of such additional components in the formulation for various reasons (e.g., stabilizing active pharmaceutical agents, binders, etc.) is well known to those skilled in the art.

[0091] The term "effective preventive or therapeutic dose" refers to a sufficient amount of the compound of this disclosure, its pharmaceutically acceptable salts, or its stereoisomers to provide a reasonable benefit / risk ratio for treating any medical condition and / or preventing the disorder. However, it should be understood that the total daily dose of the compound of Formula I, or its pharmaceutically acceptable salts and compositions thereof, must be determined by the attending physician within the bounds of reliable medical judgment. For any given patient, the specific effective therapeutic dose level must be determined based on a number of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors known in the medical field.

[0092] The compounds and their isomers disclosed herein are all within the scope of this disclosure, including geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, racemic mixtures and other mixtures, all of which are within the scope of this disclosure.

[0093] The compounds disclosed herein exist as “tautomers”. The term “tautomer” refers to a functional group isomer that has different connection points through one or more double bond shifts. For example, ketones and their enol forms are ket-enol tautomers.

[0094] The term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0095] The term "diastereomer" refers to a stereoisomer of a molecule that has two or more chiral centers and is not a mirror image of the molecule.

[0096] The term "cis-trans isomer" refers to the configuration in which the double bonds or single bonds of cyclic carbon atoms in a molecule cannot rotate freely.

[0097] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key Represents the relative configuration of the center of a solid.

[0098] The stereoisomers of the compounds disclosed herein can be prepared by chiral synthesis or using chiral reagents or other conventional techniques. For example, an enantiomer of a compound disclosed herein can be prepared by asymmetric catalysis or chiral derivative derivatization. Alternatively, a single stereoisomer can be obtained from a mixture using chiral resolution techniques. Alternatively, it can be prepared directly from chiral starting materials. The separation of optically pure compounds in this disclosure is typically accomplished using preparative chromatography, employing a chiral column to achieve the separation of chiral compounds.

[0099] The absolute stereoconfiguration of a compound can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction (SFC) can be used, or the absolute configuration of the compound can be confirmed by examining the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis. Alternatively, after resolution, the stereoconfiguration can be determined by comparing it with a product whose absolute configuration is known. Compounds marked "absolute configuration unknown" in this article are typically racemic compounds resolved into single isomers via chiral preparative SFC, followed by characterization and testing.

[0100] The term “optionally” means that it may or may not be substituted, unless otherwise specified. The type and number of substituents may be arbitrary on the basis of chemical feasibility. For example, the term “optionally substituted with one or more Rs” means that it may or may not be substituted with one or more Rs.

[0101] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, This indicates that the cyclopentyl group is replaced by three Rs, and each R has an independent option.

[0102] When a substituent's bond can be cross-linked to two atoms on a ring, this substituent can bond to any atom on that ring. For example, structural units. This indicates that the substituent R1 can be substituted at any position on the benzene ring.

[0103] When the listed substituents do not specify which atom they are attached to in a compound included but not specifically mentioned in the general chemical formula, such substituents can be bonded to any of their atoms. For example, pyrazole as a substituent means that any carbon or nitrogen atom on the pyrazole ring is attached to the substituted group; when the structure contains... When, it indicates that the atom is a bonding atom, for example This indicates that the N atom on the morpholine ring is a bonding atom.

[0104] Unless otherwise specified, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0105] Unless otherwise specified, the term "alkyl" refers to a branched or straight-chain saturated aliphatic alkane with a specified number of carbon atoms, minus a hydrogen-derived group. For example, "C..." 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, and C6 alkyl groups. 1-6 Alkyl", C 1-3 Alkyl; specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc.

[0106] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. C is preferred. 1-6 Halogenated alkyl, more preferably C 1-3 Alkyl halogens. Examples of alkyl halogens include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc. Alkyl groups are as defined above.

[0107] Unless otherwise specified, the term "deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by deuterium atoms. Alkyl groups are as defined above.

[0108] Unless otherwise specified, the term "hydroxyalkyl" refers to a group derived from an alkyl group by replacing one or more hydrogen atoms with a hydroxyl group, and "hydroxyalkyl" as used in this disclosure includes "C 1-6 Hydroxyalkyl, C 1-3 "Hydroxyalkyl"; specific examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, wait.

[0109] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein, in which an alkyl group is attached to another group by an oxygen atom, i.e., "alkyl-O-". This includes "C". 1-6 Alkoxy (structure is C) 1-6 alkyl-O-), "C1-3 "Alkoxy" is a suffix, specifically including but not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" in this disclosure is preferably C 1-3 Alkyl group.

[0110] Unless otherwise specified, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group with a halogen. Preferably, the "haloalkoxy" described in this disclosure is "haloC". 1-6 Alkoxy, halogenated C 1-3 Alkyl groups. Specific examples described in this disclosure include: fluoromethoxy groups (including monofluoromethoxy, difluoromethoxy, and trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkyl groups are as defined above.

[0111] Unless otherwise specified, the term "deuterated alkoxy" refers to the group obtained by replacing one or more hydrogen atoms in an alkoxy group with a deuterium atom. Alkoxy groups are as defined above.

[0112] Unless otherwise specified, the term "alkenyl" refers to a group derived from a straight-chain or branched alkene (containing at least one carbon-carbon double bond) by removing one hydrogen atom, including "C". 2-6 "alkenyl", "C" 2-5 "alkenyl", "C" 2-4 "alkenyl", "C" 2-3 "Alkenyl", specific examples include but are not limited to: -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, etc.

[0113] Unless otherwise specified, the term "alkynyl" refers to a group derived from a straight-chain or branched alkyne (containing at least one carbon-carbon triple bond) by removing one hydrogen atom, including "C". 2-6 "Alkyne", "C" 2-4 "Alkyne", "C" 2-3 "Alkyne group", specific examples include but are not limited to: -C≡CH, -C≡CHCH3, HC≡CHCH2-, HC≡CC≡C-, etc.

[0114] Unless otherwise specified, the term "cycle" refers to a saturated, partially saturated, or unsaturated monocyclic or polycyclic ring, including spirocyclic, fused, or bridged rings. A group derived from a ring by removing a hydrogen atom is called a "cycloyl group," which includes monovalent, divalent (commonly referred to as a subcyclic ring), trivalent, and tetravalent rings, with the specific valence depending on the number of substituents attached to the ring. This disclosure no longer specifically distinguishes the valence of the ring in its description of "cycloyl groups." Representative "cycloyl groups" include substituted or unsubstituted cycloalkyl, heterocyclic alkyl, cycloalkenyl, heterocyclic alkenyl, cycloynyl, heterocyclic alynyl, aryl, or heteroaryl groups.

[0115] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic alkyl group derived from a cycloalkane by removing a hydrogen atom, including monocyclic or polycyclic saturated hydrocarbon groups; the polycyclic saturated hydrocarbon group refers to a polycyclic group formed by two or more cyclic alkyl structures linked by spiro, bridging, fusion, or other means. The cycloalkyl group includes "C 3-8 cycloalkyl, C 3-6 cycloalkyl, C 3-5 "Cycloalkyl". Preferably, the cycloalkyl group is a monocyclic, saturated structure; specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0116] Unless otherwise specified, "cycloalkenyl" refers to one or more double bonds in a "cycloalkyl" group, and the cycloalkenyl group is not aromatic. The carbon atom in the cycloalkenyl group may be further oxidized, forming C(O). The cycloalkenyl group includes "3-8 membered cycloalkenyl", "3-6 membered cycloalkenyl", "3-5 membered cycloalkenyl", and "5-6 membered cycloalkenyl". Specific examples include, but are not limited to, those mentioned above.

[0117] Unless otherwise specified, the term "heterocyclic alkyl" refers to a saturated cyclic group derived from which one or more cyclic carbon atoms in a cycloalkyl group are replaced by heteroatoms and / or heteroatom groups. The heteroatoms and / or heteroatom groups are generally selected from -C(O), N, O, S, NO, SO, S(O)2, P(O), and NR; preferably, the heteroatoms are independently selected from 1-3 N and / or O atoms. Heterocyclic alkyl groups include "3-10-membered heterocyclic alkyl", "3-8-membered heterocyclic alkyl", "3-6-membered heterocyclic alkyl", "3-5-membered heterocyclic alkyl", "4-6-membered heterocyclic alkyl", and "5-6-membered heterocyclic alkyl". Specific examples include, but are not limited to, nitrogen-containing heterocyclic butyl, oxocyclic butane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, etc. wait.

[0118] Unless otherwise specified, the term "heterocyclic alkenyl" refers to one or more double bonds in a "heterocyclic alkyl" group, wherein the heterocycle is not aromatic. Preferably, the heteroatoms are independently selected from 1-3 N and / or O atoms. The heterocyclic alkenyl groups include "3-10-membered heterocyclic alkenyl," "3-8-membered heterocyclic alkenyl," "3-6-membered heterocyclic alkenyl," "3-5-membered heterocyclic alkenyl," and "5-6-membered heterocyclic alkenyl." Specific examples include, but are not limited to: wait.

[0119] Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic, hydrocarbon group, which can be a monocyclic or fused ring. The fused rings on the "aryl" group can be cycloalkenyl, heterocyclic alkenyl, or aryl, but the portion attached to the parent compound must be aromatic. C is preferred. 6-14 Aryl, C 6-10 Aryl; examples of aryl groups include, but are not limited to, phenyl, naphthyl,

[0120] The term "heteroaryl" as used in this disclosure refers to an aromatic monocyclic group having at least one heteroatom and / or heterogroup, wherein the heteroatom and / or heterogroup is generally selected from N, O, S, P, NO, SO, S(O)2, P(O), -C(O), and NR, and R is H or any possible substituent group. Preferably, the heteroatom is independently selected from 1-3 N and / or O atoms. The heteroaryl includes "5-14-membered heteroaryl", "5-10-membered heteroaryl", and "5-6-membered heteroaryl"; specific examples include, but are not limited to, pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazoleyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, pyridinyl, pyridinyl, pyrimidinyl, and so on.

[0121]

[0122] Linking substituents are described in various parts of this disclosure. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0123] The combinations of substituents and / or variables described in this disclosure are permitted only when these combinations produce stable compounds or usable synthetic intermediates. A stable compound or stable structure is a compound that is sufficiently stable to withstand chemical reactions, be isolated with useful purity, and be formulated into an effective therapeutic agent.

[0124] The preparation methods of some compounds in this disclosure reference the preparation methods of the aforementioned similar compounds. Those skilled in the art should understand that when using or referring to the referenced preparation methods, the reactant ratios, reaction solvents, reaction temperatures, etc., can be appropriately adjusted according to the different reactants.

[0125] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein. Detailed Implementation

[0126] The structures of the compounds disclosed herein were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS), or ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR determinations were performed using a Bruker Neo 400M or Bruker Ascend 400M NMR spectrometer, with solvents including deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), heavy water (D2O), and tetramethylsilane (TMS) as the internal standard.

[0127] The starting materials used in the embodiments of this disclosure are known and commercially available, or can be synthesized using methods known in the art.

[0128] Unless otherwise specified, all reactions in this disclosure are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius (°C).

[0129] I. Intermediates

[0130] Intermediate I:

[0131] 4-(methylthio)-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(7H)-carboxylic acid tert-butyl ester

[0132]

[0133] Reaction route:

[0134]

[0135] Operating steps:

[0136] Step A: 4-hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (2 g, 9.04 mmol) was dissolved in toluene (30 mL), and phosphorus oxychloride (6.93 g, 45.21 mmol) and N,N-diisopropylethylamine (2.34 g, 18.08 mmol) were added. The system was stirred at 110 °C for 16 hours.

[0137] After the reaction of the starting materials was complete, the reaction solution was added dropwise to an aqueous solution of dipotassium hydrogen phosphate (6.7 g dissolved in 30 mL of water) at 0 °C. After stirring at 25 °C for 0.5 hours, the mixture was filtered and separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.38 g of crude ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid, which was used directly in the next step without further purification.

[0138] MS(ESI)M / Z:240.1[M+H] + .

[0139] Step B: At 0°C, ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (2.38 g, 9.93 mmol) was dissolved in tetrahydrofuran (40 mL), and sodium methanethiol (990 mg, 14.12 mmol) was added in portions. The system was stirred at 25°C for 1.5 hours.

[0140] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that after the reaction of the raw materials was complete, the reaction solution was diluted with water (50 mL), extracted with a 10 / 1 dichloromethane / methanol mixture (50 mL × 2), and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether, 0-4% gradient) to obtain 1.95 g of ethyl 5-methyl-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid.

[0141] MS(ESI)M / Z:252.1[M+H] + .

[0142] 1 H NMR (400MHz, CDCl3): δ8.08 (s, 1H), 8.04 (s, 1H), 4.35 (q, J = 7.2Hz, 2H), 2.84 (s, 3H), 2.64 (s, 3H), 1.39 (t, J = 7.1Hz, 3H).

[0143] Step C: Under a nitrogen atmosphere, ethyl 5-methyl-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (1.95 g, 7.76 mmol), benzoyl peroxide (375.92 mg, 1.55 mmol), and N-bromosuccinimide (1.66 g, 9.31 mmol) were dissolved in carbon tetrachloride (40 mL). The system was stirred at 90 °C for 16 hours under a nitrogen atmosphere.

[0144] Thin-layer chromatography monitoring showed the formation of new spots, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether, 0-5% gradient) to obtain 1.74 g of ethyl 5-(bromomethyl)-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid.

[0145] 1 H NMR (400MHz, CDCl3): δ8.21 (s, 1H), 8.08 (s, 1H), 5.34 (s, 2H), 4.41 (q, J = 7.1Hz, 2H), 2.72 (s, 3H), 1.42 (t, J = 7.2Hz, 3H).

[0146] Step D: Ethyl 5-(bromomethyl)-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (1.74 g, 4.48 mmol, 85% purity) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of bis(tert-butoxycarbonyl)amine (1.07 g, 4.93 mmol) and cesium carbonate (2.92 g, 8.96 mmol). The mixture was stirred at 25 °C for 16 hours.

[0147] After the reaction of the raw materials was complete, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether, 0-15% gradient) to give 1.65 g of ethyl 5-((bis(tert-butoxycarbonyl)amino)methyl)-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid.

[0148] MS(ESI)M / Z:467.2[M+H] + .

[0149] 1 H NMR (400MHz, CDCl3): δ8.14(s,1H),8.06(s,1H),5.42(s,2H),4.34(q,J=7.0Hz,2H),2.65(s,3H),1.39(br s,3H),1.38(s,18H).

[0150] Step E: Under a nitrogen atmosphere at -78°C, ethyl 5-((bis(tert-butoxycarbonyl)amino)methyl)-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (1.65 g, 3.54 mmol) was dissolved in tetrahydrofuran (40 mL), and lithium aluminum hydride (2.5 M, 4.24 mL, 10.61 mmol) was slowly added dropwise. The system was stirred at 0°C for 1 hour.

[0151] Thin-layer chromatography monitoring showed that the reaction of the starting materials was complete. The reaction solution was quenched with a saturated sodium potassium tartrate aqueous solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol, 0-3% gradient) to obtain 410 mg of tert-butyl carbamate ((6-(hydroxymethyl)-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-5-yl)methyl)carbamate.

[0152] MS(ESI)M / Z:325.1[M+H] + .

[0153] 1 H NMR (400MHz, CDCl3): δ8.14(s,1H),7.66(s,1H),5.42(br s,1H),4.76-4.78(m,2H),4.66(d,J=6.6Hz,2H),4.37(br s,1H),2.71(s,3H),1.42(s,9H).

[0154] Step F: At 0°C, tert-butyl ((6-(hydroxymethyl)-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)carbamate (410 mg, 1.26 mmol) and N,N-diisopropylethylamine (490.04 mg, 3.79 mmol) were dissolved in dichloromethane (10 mL), and methanesulfonyl chloride (560 mg, 4.89 mmol) was added dropwise. The system was stirred at 25°C for 1 hour.

[0155] After the reaction of the starting materials was complete, as monitored by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed successively with saturated potassium bisulfate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 460 mg of crude product ((6-(chloromethyl)-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)carbamate tert-butyl ester was obtained, which was used directly in the next step without further purification.

[0156] MS(ESI)M / Z:343.1[M+H] + .

[0157] 1 H NMR (400MHz, CDCl3): δ8.14(s,1H),7.69(s,1H),4.97(br s,1H),4.87(s,2H),4.70(d,J=6.0Hz,2H),2.69(s,3H),1.45(s,9H).

[0158] Step G: At 0°C, tert-butyl ((6-(chloromethyl)-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine-5-yl)methyl)carbamate (460 mg, 1.34 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (80.50 mg, 2.01 mmol, 60% purity) was added. The system was stirred at 25°C for 2.5 hours.

[0159] After the reaction of the raw materials was complete as monitored by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether, 0-15% gradient) to give 245 mg of 4-(methylthio)-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(7H)-carboxylic acid tert-butyl ester.

[0160] MS(ESI)M / Z:307.1[M+H] + .

[0161] 1 H NMR (400MHz, CDCl3): δ8.11 (d, J = 2.5Hz, 1H), 7.43-7.52 (m, 1H), 4.77-4.87 (m, 2H), 4.67 (br d,J=16.3Hz,2H),2.66(d,J=5.5Hz,3H),1.54(d,J=5.5Hz,9H).

[0162] Intermediate II:

[0163] 4-Chloro-6,7-dihydropyrazino[1',2':1,5]pyrrolo[3,2-d]pyrimidin-8(9H)-carboxylic acid tert-butyl ester

[0164]

[0165] Reaction route:

[0166]

[0167] Operating steps:

[0168] Step A: At 25°C, N-Boc-ethanolamine (3g, 18.61mmol), imidazole (1.90g, 27.92mmol), and 4-dimethylaminopyridine (341.04mg, 2.79mmol) were dissolved in dichloromethane (40mL), and tert-butyldimethylchlorosilane (3.09g, 20.47mmol, 2.52mL) was added in portions. The system was stirred at 25°C for 12 hours.

[0169] After the reaction of the starting materials was monitored to be complete by thin-layer chromatography, the reaction solution was quenched in water (50 mL) and extracted with dichloromethane (40 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 4.6 g of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate.

[0170] 1 H NMR (400MHz, CDCl3): δ4.85 (br s, 1H), 3.66 (t, J = 5.14Hz, 2H), 3.23 (br d, J = 5.02Hz, 2H), 1.45 (s, 9H), 0.90 (s, 9H), 0.07 (s, 6H).

[0171] Step B: At 0°C, 2.6 g (9.44 mmol) of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate was dissolved in 26 mL of tetrahydrofuran, and sodium hydride (755.03 mg, 18.88 mmol, 60% purity) was added in portions. After stirring the reaction solution at 0°C for 30 minutes, tetrabutylammonium iodide (348.64 mg, 943.88 μmol) and 3-bromopropyne (3.51 g, 23.60 mmol, 80% purity) were added, and the reaction solution was stirred at 25°C for 2 hours.

[0172] Thin-layer chromatography was used to monitor the completeness of the reaction. The reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 2.1 g of tert-butyl 2-((tert-butyldimethylsilyl)oxy)ethyl)(prop-2-yn-1-yl)carbamate.

[0173] 1 H NMR (400MHz, CDCl3): δ4.14(m,2H),3.75(br s,2H),3.42(m,2H),2.19(br s,1H),1.47(s,9H),0.90(s,9H),0.06(s,6H).

[0174] Step C: 4,6-Dichloropyrimidin-5-amine (2.35 g, 14.35 mmol) and (2-((tert-butyldimethylsilyl)oxy)ethyl)(prop-2-yn-1-yl)carbamate tert-butyl ester (3 g, 9.57 mmol) were dissolved in tetrahydrofuran (30 mL). Then, bis(triphenylphosphine)palladium(II) dichloride (1.34 g, 1.91 mmol), triethylamine (4.84 g, 47.85 mmol), and cuprous iodide (364.49 mg, 1.91 mmol) were added to the solution. The mixture was stirred at 50 °C for 2 hours.

[0175] After monitoring the formation of the product by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 1 g of crude product (3-(5-amino-6-chloropyrimidin-4-yl)prop-2-yn-1-yl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate tert-butyl ester.

[0176] MS(ESI)M / Z:441.2[M+H] + .

[0177] Step D: At 0°C, (3-(5-amino-6-chloropyrimidin-4-yl)prop-2-yn-1-yl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate tert-butyl ester (1 g, 2.27 mmol) was dissolved in N-methylpyrrolidone (10 mL), and potassium tert-butoxide (1 M, 4.53 mL, 4.53 mmol) was added dropwise. The reaction solution was stirred at 0°C for 2 hours.

[0178] After liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction mixture was completely reacted, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1 g of crude (2-((tert-butyldimethylsilyl)oxy)ethyl)((4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methyl)carbamate tert-butyl ester, which was used directly in the next step without purification.

[0179] MS(ESI)M / Z:441.2[M+H] + .

[0180] Step E: Dissolve tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)((4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methyl)carbamate (950 mg, 2.15 mmol) and tetrabutylammonium fluoride (1 M, 4.31 mL) in tetrahydrofuran (15 mL) and stir at 25 °C for 2 hours.

[0181] After the reaction of the raw materials was monitored to be complete by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0 / 1) to obtain 690 mg of ((4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methyl)(2-hydroxyethyl)carbamate tert-butyl ester.

[0182] MS(ESI)M / Z:327.1[M+H] + .

[0183] Step F: Under a nitrogen atmosphere, tert-butyl ((4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methyl)(2-hydroxyethyl)carbamate (690 mg, 2.11 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of triphenylphosphine (1.11 g, 4.22 mmol) and diisopropyl azodicarbonate (853.93 mg, 4.22 mmol). The reaction mixture was stirred at 25 °C for 2 hours.

[0184] After the reaction of the raw materials was monitored to be complete by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0 / 1) to obtain 250 mg of 4-chloro-6,7-dihydropyrazino[1',2':1,5]pyrrolo[3,2-d]pyrimidine-8(9H)-carboxylic acid tert-butyl ester.

[0185] MS(ESI)M / Z:309.1[M+H] + .

[0186] 1 H NMR (400MHz, CDCl3): δ8.67 (s, 1H), 6.54 (s, 1H), 4.91 (s, 2H), 4.61 (t, J = 5.48Hz, 2H), 3.96 (t, J = 5.54Hz, 2H), 1.52 (s, 9H).

[0187] Intermediate III:

[0188] N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[3,2-d]pyrimidin-4-amine

[0189]

[0190] Reaction route:

[0191]

[0192] Operating steps:

[0193] Step A: Dissolve 150 mg (0.49 mmol) of 4-chloro-6,7-dihydropyrazino[1',2':1,5]pyrrolo[3,2-d]pyrimidin-8(9H)-carboxylic acid tert-butyl ester in 1,4-dioxane (10 mL), add 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylaniline (126.54 mg (0.49 mmol) and p-toluenesulfonic acid (8.44 mg (0.049 mmol)), and react the mixture at 100 °C for 5 hours.

[0194] Liquid chromatography-mass spectrometry (LC-MS) was used to detect a small amount of residual raw material. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 110 mg of 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)-6,7-dihydropyrazino[1',2':1,5]pyrrolo[3,2-d]pyrimidine-8(9H)-carboxylic acid tert-butyl ester.

[0195] MS(ESI)M / Z:531.2[M+H] + .

[0196] Step B: Dissolve 110 mg, 0.21 mmol of 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)-6,7-dihydropyrazino[1',2':1,5]pyrrolo[3,2-d]pyrimidine-8(9H)-carboxylic acid tert-butyl ester in methanol (10 mL), add 5 mL of 4 M dioxane hydrochloride solution, and react the system at 25 °C for 2 hours.

[0197] Liquid chromatography-mass spectrometry (LC-MS) was used to confirm the completeness of the reaction. The reaction solution was concentrated under reduced pressure to obtain 60 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[3,2-d]pyrimidine-4-amine, which was used directly in the next step without purification.

[0198] MS(ESI)M / Z:431.2[M+H] + .

[0199] Intermediate IV: 4-(methylthio)-5,6-dihydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-7(8H)-carboxylic acid tert-butyl ester

[0200]

[0201] Intermediate V: 4-(methylthio)-7,8-dihydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(5H)-carboxylic acid tert-butyl ester

[0202]

[0203] Reaction route:

[0204]

[0205] Operating steps:

[0206] Step A: At 25°C, tert-butyl 3,6-dihydropyridine-1(2H)-carboxylic acid (13g, 70.94mmol) was dissolved in dichloromethane (400mL) and water (400mL), and sodium p-toluenesulfinate (31.60g, 177.36mmol) and iodine (27.01g, 106.41mmol) were added. The reaction solution was heated to 30°C and stirred for 16 hours.

[0207] Thin-layer chromatography monitoring showed that the reaction of the starting materials was complete. The reaction solution was quenched with sodium sulfite aqueous solution and extracted with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in toluene (500 mL) at 25 °C, and 1,8-diazabicyclo[5.4.0]undec-7-ene (12.96 g, 85.13 mmol, 12.83 mL) was added. The reaction solution was heated to 30 °C and stirred for one hour.

[0208] Thin-layer chromatography monitoring showed that the reaction mixture was completely reacted. The reaction solution was quenched with potassium bisulfate aqueous solution and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (330 g silica gel column, ethyl acetate / n-hexane eluent, 0-19% gradient, 100 mL / min flow rate) to obtain a mixture of 28 g of tert-butyl 5-toluenesulfonyl-3,6-dihydropyridine-1(2H)-carboxylic acid and tert-butyl 4-toluenesulfonyl-3,6-dihydropyridine-1(2H)-carboxylic acid.

[0209] Step B: Under a nitrogen atmosphere at 0°C, a mixture of 13 g (38.53 mmol) of 5-p-toluenesulfonyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and 4-p-toluenesulfonyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran (300 mL). Sodium hydrogen (7.70 g, 192.63 mmol, 60% purity) was added in portions. After stirring for 10 minutes, ethyl isocyanate (13.07 g, 115.58 mmol, 12.64 mL) was slowly added dropwise. The reaction mixture was then heated to 30°C and stirred for 16 hours.

[0210] After the reaction of the raw materials was complete as monitored by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (330 g silica gel column, ethyl acetate / n-hexane eluent, 0-15% gradient, 100 mL / min flow rate) to obtain a mixture of 18.3 g of 5-tert-butyl-1-ethyl-2,4,6,7-tetrahydro-5H-pyrrolo[3,4-c]pyridine-1,5-dicarboxylic acid ester and 5-tert-butyl-3-ethyl-2,4,6,7-tetrahydro-5H-pyrrolo[3,4-c]pyridine-3,5-dicarboxylic acid ester.

[0211] Step C: At 0°C, a mixture (16.50 g, 56.06 mmol) of 5-tert-butyl-1-ethyl-2,4,6,7-tetrahydro-5H-pyrrolo[3,4-c]pyridine-1,5-dicarboxylic acid ester and 5-tert-butyl-3-ethyl-2,4,6,7-tetrahydro-5H-pyrrolo[3,4-c]pyridine-3,5-dicarboxylic acid ester was dissolved in N-methylpyrrolidone (300 mL), and potassium tert-butoxide (12.58 g, 112.11 mmol) was added. Then, O-p-nitrobenzoylhydroxylamine (15.31 g, 84.08 mmol) in tetrahydrofuran (150 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was heated to 20°C and stirred for two hours.

[0212] After the reaction of the raw materials was complete as monitored by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was washed with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (220 g silica gel column, ethyl acetate / n-hexane eluent, 0-22% gradient, 100 mL / min flow rate) to obtain a mixture of 13 g of 5-tert-butyl-1-ethyl-2-amino-2,4,6,7-tetrahydro-5H-pyrrolo[3,4-c]pyridine-1,5-dicarboxylic acid ester and 5-tert-butyl-3-ethyl-2-amino-2,4,6,7-tetrahydro-5H-pyrrolo[3,4-c]pyridine-3,5-dicarboxylic acid ester.

[0213] MS(ESI)M / Z:310.2[M+H] + .

[0214] Step D: At 25°C, a mixture (13 g, 42.02 mmol) of 5-tert-butyl-1-ethyl-2-amino-2,4,6,7-tetrahydro-5H-pyrrolo[3,4-c]pyridine-1,5-dicarboxylic acid ester and 5-tert-butyl-3-ethyl-2-amino-2,4,6,7-tetrahydro-5H-pyrrolo[3,4-c]pyridine-3,5-dicarboxylic acid ester was dissolved in anhydrous ethanol (130 mL), and formamidine acetate (26.25 g, 252.13 mmol) was added. The reaction mixture was heated to 100°C and stirred for 16 hours.

[0215] After the reaction of the starting materials was complete, the reaction solution was concentrated under reduced pressure by liquid chromatography-mass spectrometry (LC-MS / MS). The residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (220 g silica gel column, methanol / dichloromethane eluent, 0-3% gradient, 100 mL / min flow rate) to obtain a mixture of 9.11 g of 4-oxo-3,4,5,6-tetrahydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-7(8H)-carboxylic acid tert-butyl ester and 4-oxo-4,5,7,8-tetrahydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(3H)-carboxylic acid tert-butyl ester.

[0216] MS(ESI)M / Z:291.1[M+H] + .

[0217] Step E: At 25°C, a mixture of 4-oxo-3,4,5,6-tetrahydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-7(8H)-carboxylic acid tert-butyl ester and 4-oxo-4,5,7,8-tetrahydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(3H)-carboxylic acid tert-butyl ester (9.1 g, 31.38 mmol) and N,N-diisopropylethylamine (32.44 g, 251.04 mmol, 43.73 mL) was dissolved in anhydrous toluene (100 mL), and phosphorus oxychloride (19.25 g, 125.52 mmol, 11.70 mL) was added dropwise. The reaction mixture was heated to 110°C and stirred for 16 hours.

[0218] After liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reactants had reacted completely, the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane, slowly poured into an aqueous solution of glacial sodium bicarbonate for quenching, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude mixture of 9.69 g of tert-butyl 4-chloro-5,6-dihydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-7(8H)-carboxylic acid and tert-butyl 4-chloro-7,8-dihydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(5H)-carboxylic acid. This crude product did not require purification and was used directly in the next step.

[0219] MS(ESI)M / Z:309.3[M+H] + .

[0220] Step F: At 0°C, a mixture (9.6 g, 31.38 mmol) of 4-chloro-5,6-dihydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-7(8H)-carboxylic acid tert-butyl ester and 4-chloro-7,8-dihydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(5H)-carboxylic acid tert-butyl ester was dissolved in N,N-dimethylformamide (150 mL), and sodium methanethiol (4.86 g, 69.34 mmol, 4.42 mL) was added. The reaction mixture was heated to 20°C and stirred for 16 hours.

[0221] After the reaction of the reactants was complete, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (12g silica gel column, ethyl acetate / n-hexane eluent, 0-15% gradient, 30mL / min flow rate) and supercritical fluid chromatography (separation column: DAICL CHIRALCEL OJ (250mm×50mm, 10um); mobile phase: [CO2-ethanol (0.1% ammonia)]; B%: 25% isocratic elution) to obtain 2.5g of 4-(methylthio)-5,6-dihydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-7(8H)-carboxylic acid tert-butyl ester (intermediate IV) and 2.55g of 4-(methylthio)-7,8-dihydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(5H)-carboxylic acid tert-butyl ester (intermediate V).

[0222] Intermediate IV:

[0223] MS(ESI)M / Z:321.1[M+H] + .

[0224] 1 ¹H NMR (400MHz, DMSO-d6): δ 8.20(s, 1H), 7.83(s, 1H), 4.57(s, 2H), 3.65(t, J = 5.8Hz, 2H), 3.00(t, J = 5.8Hz, 2H), 2.62(s, 3H), 1.42(s, 9H). (2D NOESY NMR spectrum analysis showed NOE-related signals between the singlet at 4.57 Hz on the six-membered saturated carbon ring in intermediate IV and the singlet at 7.83 Hz on the intermediate pyrrole ring, indicating a spatial interaction between them. This information can be used to determine the structure of this compound.)

[0225] Intermediate V:

[0226] MS(ESI)M / Z:321.1[M+H] + .

[0227] 1 H NMR (400MHz, DMSO-d6): δ8.21(s,1H),7.79(s,1H),4.83(br s,2H),3.61(t,J=5.8Hz,2H),2.74(t,J=5.6Hz,2H),2.64(s,3H),1.43(s,9H).

[0228] II. Preparation Examples

[0229] Example 1:

[0230] 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(7H)-yl)propyl-2-en-1-one

[0231]

[0232] Reaction route:

[0233]

[0234] Operating steps:

[0235] Step A: At 0°C, 4-(methylthio)-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(7H)-carboxylic acid tert-butyl ester (45 mg, 146.88 μmol) and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (42.35 mg, 176.25 μmol) were dissolved in N,N-dimethylformamide (2 mL), and potassium tert-butoxide (49.44 mg, 440.63 μmol) was added. The system was stirred at 25°C for 0.5 hours.

[0236] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction mixture was completely quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol, 0-4% gradient) to give 65 mg of 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(7H)-carboxylic acid tert-butyl ester.

[0237] MS(ESI)M / Z:499.2[M+H] + .

[0238] Step B: Dissolve 55 mg (110.32 μmol) of 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(7H)-carboxylic acid tert-butyl ester in 2M dioxane hydrochloride solution (10 mL), and stir the system at 25 °C for 1 hour.

[0239] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the starting materials was complete, and the reaction solution was concentrated under reduced pressure. 45 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6,7-dihydro-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-4-amine hydrochloride was obtained, which was used directly in the next step without purification.

[0240] MS(ESI)M / Z:399.2[M+H] + .

[0241] Step C: At 0 °C, N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6,7-dihydro-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-4-amine hydrochloride (43 mg, 98.88 μmol) and triethylamine (100.05 mg, 988.78 μmol) were dissolved in dichloromethane (2 mL), and acryloyl chloride (8.95 mg, 98.88 μmol) was added dropwise. The reaction was stirred at 0 °C for 10 minutes.

[0242] After the reaction of the raw materials was complete as monitored by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was diluted with water (4 mL). The aqueous phase was extracted with dichloromethane (10 mL × 2). The combined organic phases were concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (column: Welch Ultimate C18 150 × 25 mm × 5 μm; mobile phase: [water (ammonia + ammonium bicarbonate) - acetonitrile]; gradient: phase B increased from 25% to 55% within 9 minutes) to obtain 18.39 mg of 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(7H)-yl)propyl-2-en-1-one).

[0243] MS(ESI)M / Z:453.2[M+H] + .

[0244] 1 H NMR (400MHz, DMSO-d6): δ9.27-8.88(m,2H),8.38(s,1H),7.95(d,J=4.5Hz,1H),7.82-7.60(m,3H),7. 31-7.14(m,1H),7.09-7.00(m,1H),6.89-6.59(m,2H),6.40-6.20(m,1H),5.94-5.66(m,1H),5.18(br s,1H),4.95(br d,J=19.6Hz,2H),4.69(s,1H),2.19(d,J=4.0Hz,3H).

[0245] The following examples are synthesized according to the preparation method of Example 1:

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263] Example 9:

[0264] (E)-4-(dimethylamino)-1-(4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(7H)-yl)but-2-en-1-one

[0265]

[0266] Reaction route:

[0267]

[0268] Operating steps:

[0269] Step A: N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-6,7-dihydro-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-4-amine hydrochloride (48 mg, 117.39 μmol) and (E)-4-(dimethylamino)butyl-2-enoate (21.39 mg, 129.13 μmol) were dissolved in N,N-dimethylformamide (1 mL), and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4-one (38.64 mg, 129.13 μmol) and triethylamine (118.79 mg, 1.17 mmol) were added. The reaction system was stirred at 25 °C for 16 hours.

[0270] After the reaction of the raw materials was complete, the reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (column: C18 150×30mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: phase B increased from 5% to 35% within 7 minutes) to obtain 14.58 mg of (E)-4-(dimethylamino)-1-(4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(7H)-yl)but-2-en-1-one formate.

[0271] MS(ESI)M / Z:484.2[M+H] + .

[0272] 1 H NMR (400MHz, DMSO-d6): δ8.89-9.27(m,1H),8.23(s,1H),8.16-8.21(m,1H),7.91(s,1H),7.68(s,1H),7.58(br d,J=6.3Hz,1H),7.48-7.55(m,1H),7.19-7.28(m,2H),6.95(dd,J=12.7,8.7Hz,1H),6.69-6.82(m,1H),6.41-6.53(m,1H),5.08(br s,1H),4.89(br s,2H),4.65(s,1H),3.08(br d,J=5.8Hz,2H),2.44(s,3H),2.21(d,J=8.3Hz,3H),2.18(d,J=0.8Hz,6H).

[0273] Examples 14 & 15:

[0274] (R)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-6,7,8,9-tetrahydropyrimidino[4,5-b]indolazin-8-yl)acrylamide

[0275] (S)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-6,7,8,9-tetrahydropyrimidino[4,5-b]indolazin-8-yl)acrylamide

[0276]

[0277] Reaction route:

[0278]

[0279] Operating steps:

[0280] Step A: At 0°C, BOC-L-propargylglycine (5 g, 23.45 mmol) and N-methylmorpholine (2.85 g, 28.14 mmol) were dissolved in dichloromethane (100 mL), and isobutyl chloroformate (3.84 g, 28.14 mmol) was added dropwise. After reacting for 1 hour, dimethylhydroxylamine hydrochloride (2.63 g, 26.97 mmol) and N-methylmorpholine (2.85 g, 28.14 mmol) were added to the above reaction solution, and the mixture was stirred at 20°C for 12 hours.

[0281] Thin-layer chromatography monitoring showed that after the reaction of the raw materials was complete, the reaction solution was quenched with water (40 mL), extracted with dichloromethane (30 mL × 2), the organic phase was concentrated under vacuum, and the crude product was purified by silica gel column separation (eluent: petroleum ether / ethyl acetate, 0-21% gradient) to obtain 3.88 g of (S)-(1-(methoxy(methyl)amino)-1-oxo-4-yn-2-yl)carbamate tert-butyl ester.

[0282] MS(ESI)M / Z:257.1[M+H] + .

[0283] 1 H NMR (400MHz, CDCl3): δ5.45(br d,J=8.2Hz,1H),4.91-4.75(m,1H),3.76(s,3H),3.23(s,3H),2.79-2.53(m,2H),2.05-2.02(m,1H),1.44(s,9H).

[0284] Step B: At -78°C, (S)-(1-(methoxy(methyl)amino)-1-oxo-4-yn-2-yl)carbamate tert-butyl ester (5.5 g, 21.46 mmol) was dissolved in tetrahydrofuran (100 mL), and diisobutylaluminum hydride (1 M, 53.65 mL) was slowly added dropwise. The reaction mixture was stirred at -78°C under nitrogen protection for 1 hour.

[0285] Thin-layer chromatography monitoring showed that after the reaction of the raw materials was complete, the reaction solution was slowly added dropwise to a saturated sodium tartrate aqueous solution (200 mL) at 0 °C under nitrogen protection to quench the reaction, and stirred for 15 minutes. Extraction was performed with ethyl acetate (100 mL × 2), and the organic layer was concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 0-9% gradient) to obtain 4.2 g of (S)-(1-oxo-4-yn-2-yl)carbamate tert-butyl ester.

[0286] MS(ESI)M / Z:198.1[M+H] + .

[0287] Step C: At 0°C, methyl methoxytriphenylphosphine chloride (8.76 g, 25.55 mmol) was dissolved in tetrahydrofuran (60 mL), and potassium tert-butoxide solution (1 M, 23.42 mL) was slowly added dropwise. After stirring for 30 minutes, a tetrahydrofuran solution (20 mL) of (S)-(1-oxo-4-yn-2-yl)carbamate tert-butyl ester (4.2 g, 21.29 mmol) was slowly added dropwise to the reaction solution. The reaction solution was stirred at 20°C for 1 hour.

[0288] Thin-layer chromatography monitoring showed that the reaction of the raw materials was complete. Saturated ammonium chloride aqueous solution (20 mL) was added dropwise to quench the reaction, followed by extraction with ethyl acetate (30 mL × 2). The organic layer was then concentrated under vacuum. The crude product was purified by a rapid silica gel column (eluent: petroleum ether / ethyl acetate, 0-7% gradient) to obtain 1.7 g of (1-methoxyhexyl-1-en-5-yn-3-yl) tert-butyl carbamate.

[0289] MS(ESI)M / Z:226.1[M+H] + .

[0290] 1 H NMR (400MHz, CDCl3): δ6.66-5.90(m,1H),4.89-4.48(m,2H),3.67-3.51(m,3H),2.60-2.36(m,2H),2.08-1.95(m,1H),1.45(s,9H).

[0291] Step D: At 0°C, tert-butyl (1.7 g, 7.55 mmol) of (1-methoxyhexyl-1-en-5-yn-3-yl)carbamate was dissolved in water (15 mL) and acetonitrile (90 mL), and trifluoroacetic acid (4.30 g, 37.73 mmol) was slowly added. The reaction solution was stirred at 20°C for 2 hours.

[0292] Thin-layer chromatography monitoring showed that the reaction of the starting materials was complete. Saturated sodium bicarbonate aqueous solution (15 mL) was slowly added dropwise to the reaction solution to adjust the pH to 6-7. Extraction was performed with ethyl acetate (30 mL × 2), and the organic layer was concentrated under vacuum. The crude product was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 0-15% gradient) to obtain 1.5 g of tert-butyl 1-oxo-5-yn-3-yl)carbamate.

[0293] MS(ESI)M / Z:212.1[M+H] + .

[0294] 1 H NMR (400MHz, CDCl3): δ9.77(t,J=1.6Hz,1H),4.93(br dd,J=1.5,4.2Hz,1H),4.31-4.18(m,1H),2.79(br d,J=6.2Hz,2H),2.54(dd,J=2.5,5.7Hz,2H),2.07(t,J=2.7Hz,1H),1.44(s,9H).

[0295] Step E: At 0°C, tert-butyl (1.5 g, 7.10 mmol) of (1-oxo-5-yn-3-yl)carbamate was dissolved in methanol (20 mL), and sodium borohydride (620 mg, 16.39 mmol) was slowly added in portions. The reaction solution was stirred at 0°C under nitrogen protection for 1 hour.

[0296] Thin-layer chromatography monitoring showed that after the reaction of the raw materials was complete, the reaction solution was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic layer was concentrated under vacuum. The crude product was purified by rapid silica gel column separation (eluent: petroleum ether / ethyl acetate, 0-30% gradient) to obtain 1.3 g of (S)-(1-hydroxyhexyl-5-yn-3-yl)carbamate tert-butyl ester.

[0297] MS(ESI)M / Z:214.1[M+H] + .

[0298] 1H NMR (400MHz, CDCl3): δ4.86 (br d, J=7.8Hz, 1H), 3.99 (br dd,J=4.9,9.4Hz,1H),3.78-3.58(m,2H),2.62-2.50(m,1H),2.48-2.35(m, 1H),2.07-2.04(m,1H),1.93-1.76(m,1H),1.73-1.60(m,1H),1.46(s,9H).

[0299] Step F: Under nitrogen protection, (S)-(1-hydroxyhexyl-5-yn-3-yl)carbamate tert-butyl ester (1.25 g, 5.86 mmol) and 5-amino-4,6-dichloropyrimidine (1.92 g, 11.72 mmol) were dissolved in tetrahydrofuran (24 mL), and triethylamine (593.07 mg, 5.86 mmol), bis(triphenylphosphine)palladium(II) dichloride (822.77 mg, 1.17 mmol) and cuprous iodide (223.25 mg, 1.17 mmol) were added sequentially. The reaction solution was stirred at 20 °C for 1 hour.

[0300] After the reaction of the raw materials was complete as monitored by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic layer was concentrated under vacuum. The crude product was purified by rapid silica gel column chromatography (eluent: dichloromethane / methanol, 0-3% gradient) to obtain 1.15 g of crude product (tert-butyl 6-(5-amino-6-chloropyrimidin-4-yl)-1-hydroxyhexane-5-yn-3-yl)carbamate.

[0301] MS(ESI)M / Z:341.1[M+H] + .

[0302] Step G: Dissolve tert-butyl (6-(5-amino-6-chloropyrimidin-4-yl)-1-hydroxyhexane-5-yn-3-yl)carbamate (1.15 g, 3.37 mmol) in N,N-dimethylformamide (20 mL), and add cuprous iodide (642.65 mg, 3.37 mmol). Under nitrogen protection, the reaction mixture is stirred at 110 °C for 0.5 hours.

[0303] After the reaction of the raw materials was complete as monitored by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (10 mL × 2), and the organic layer was concentrated under vacuum. The crude product was purified by rapid silica gel column chromatography (eluent: dichloromethane / methanol, 0-3% gradient) to obtain 315 mg of tert-butyl 1-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-4-hydroxybutane-2-yl)carbamate.

[0304] MS(ESI)M / Z:341.1[M+H] + .

[0305] 1 H NMR (400MHz, CDCl3): δ10.80-10.58(m,1H),8.85-8.57(m,1H),6.55(br s,1H),5.19-4.93(m,1H),4.48-4.10(m,1H),3.88(br d,J=3.5Hz,2H),3.52(d,J=4.9Hz,1H),3.20-3.06(m,2H),2.01-1.92(m,1H),1.74-1.63(m,1H),1.41(s,9H).

[0306] Step H: Under nitrogen protection, tert-butyl carbamate (315 mg, 924.28 μmol) and triphenylphosphine (484.85 mg, 1.85 mmol) were dissolved in tetrahydrofuran (10 mL), and diisopropyl azodicarbonate (373.80 mg, 1.85 mmol) was added dropwise. The reaction solution was stirred at 20 °C for 12 hours.

[0307] After the reaction of the raw materials was complete as monitored by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), and the organic layer was concentrated under vacuum. The crude product was purified by rapid silica gel column separation (eluent: dichloromethane / methanol, 0-3.2% gradient) to obtain 420 mg of crude product (4-chloro-6,7,8,9-tetrahydropyrimidino[4,5-b]indolazin-8-yl)carbamate tert-butyl ester.

[0308] MS(ESI)M / Z:323.1[M+H] + .

[0309] Step I: Dissolve (4-chloro-6,7,8,9-tetrahydropyrimidino[4,5-b]indolazin-8-yl) tert-butyl carbamate (193 mg, 596.98 μmol), p-toluenesulfonic acid (10.28 mg, 59.70 μmol), and 4-([1,2,4]triazol[1,5-a]pyridin-7-yloxy)-3-methylaniline (143.43 mg, 596.98 μmol) in isopropanol (8 mL). Heat the reaction solution in a microwave oven to 110 °C and react for 1 hour.

[0310] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was directly concentrated. The crude product was purified by rapid silica gel column separation (eluent: dichloromethane / methanol, 0-3.5% gradient) to obtain 298 mg of tert-butyl (4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-6,7,8,9-tetrahydropyrimidino[4,5-b]indolazin-8-yl)carbamate.

[0311] MS(ESI)M / Z:527.2[M+H] + .

[0312] 1 H NMR (400MHz, CDCl3): δ8.57-8.40(m,2H),8.22(s,1H),7.52-7.41(m,2H),7.05(d,J=8.5Hz,1H),6.90(br dd,J=2.4,7.4Hz,2H),6.83(d,J=2.3Hz,1H),6.38-6.30(m,1H),4.89-4.77(m,1H), 4.66-4.55(m,1H),4.52-4.42(m,1H),4.19-4.06(m,1H),3.39-3.29(m,1H),2.90(br dd,J=7.4,16.7Hz,1H),2.42-2.30(m,1H),2.29-2.17(m,4H),1.47(s,9H).

[0313] Step J: Dissolve tert-butyl (4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-6,7,8,9-tetrahydropyrimidino[4,5-b]indolazin-8-yl)carbamate (298 mg, 565.91 μmol) in dichloromethane (6 mL), and slowly add trifluoroacetic acid (6 mL). Stir the reaction mixture at 20 °C for 0.5 hours.

[0314] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that after the reactants had reacted completely, the reaction solution was directly concentrated. 240 mg of crude N was obtained. 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6,7,8,9-tetrahydropyrimidino[4,5-b]indoleazine-4,8-diamine, without purification, can be used directly in the next step.

[0315] MS(ESI)M / Z:427.2[M+H] + .

[0316] Step K: At 0℃, N 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6,7,8,9-tetrahydropyrimidino[4,5-b]indoleazine-4,8-diamine (240 mg, 562.76 μmol) and triethylamine (569.45 mg, 5.63 mmol) were dissolved in dichloromethane (6 mL), and acryloyl chloride (50.93 mg, 562.76 μmol) was added dropwise. The reaction mixture was stirred at 0 °C for 10 minutes.

[0317] After liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reactants had reacted completely, the reaction solution was washed with water (4 mL). The aqueous phase was extracted with dichloromethane (10 mL × 2). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: C18 150×40 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: B phase increased from 10% to 40% within 8 minutes) and separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [carbon dioxide-isopropanol (0.1% ammonia)]; B%: 45%, isocratic elution) to obtain a single configuration of 36.77 mg peak1 N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-6,7,8,9-tetrahydropyrimidino[4,5-b]indoleazine-8-yl)acrylamide (RT = 0.631 min) and 9.44 mg peak2 The single configuration of N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-6,7,8,9-tetrahydropyrimidino[4,5-b]indolazin-8-yl)acrylamide (RT = 0.882 min).

[0318] 14 & 15 - peak1 (RT = 0.631 min)

[0319] MS(ESI)M / Z:481.2[M+H] + .

[0320] 11H NMR (400 MHz, DMSO-d6): δ 8.92 (d, J = 7.5 Hz, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.26 (s, 1H), 7.61 - 7.57 (m, 2H), 7.16 - 7.10 (m, 1H), 7.01 (dd, J = 2.7, 7.5 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 6.32 - 6.22 (m, 2H), 6.18 - 6.10 (m, 1H), 5.65 - 5.59 (m, 1H), 4.76 - 4.67 (m, 1H), 4.55 - 4.43 (m, 1H), 4.23 (br t, J = 8.0 Hz, 1H), 3.29 (br s, 1H), 2.89 (dd, J = 8.4, 16.3 Hz, 1H), 2.26 (br d, J = 15.0 Hz, 1H), 2.15 (s, 3H), 2.12 - 2.02 (m, 1H).

[0321] 14&15 - peak2 (RT = 0.882 min)

[0322] MS (ESI) M / Z: 481.2 [M + H] + .

[0323] 1 1H NMR (400 MHz, DMSO-d6): δ 8.92 (d, J = 7.4 Hz, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 8.32 (d, J = 7.3 Hz, 1H), 8.26 (s, 1H), 7.62 - 7.56 (m, 2H), 7.14 (d, J = 9.5 Hz, 1H), 7.02 (dd, J = 2.6, 7.5 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 6.31 - 6.27 (m, 1H), 6.24 (d, J = 10.0 Hz, 1H), 6.17 - 6.10 (m, 1H), 5.62 (dd, J = 2.4, 10.0 Hz, 1H), 4.71 (td, J = 5.8, 11.6 Hz, 1H), 4.55 - 4.44 (m, 1H), 4.27 - 4.18 (m, 1H), 3.28 (br d, J = 5.2 Hz, 1H), 2.96 - 2.83 (m, 1H), 2.29 - 2.21 (m, 1H), 2.15 (s, 3H), 2.12 - 2.04 (m, 1H).

[0324] Example 28:

[0325] (E)-1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)-6,7-dihydropyrazino[1',2':1,5]pyrrolo[3,2-d]pyrimidin-8(9H)-yl)-4-(azacyclobutan-1-yl)but-2-en-1-one

[0326]

[0327] Reaction route:

[0328]

[0329] Operating steps:

[0330] Step A: Dissolve aziridine (0.19 g, 3.26 mmol) and triethylamine (0.49 g, 4.89 mmol) in tetrahydrofuran (5 mL), and add (E)-4-bromobut-2-enoic acid tert-butyl ester (0.36 g, 1.63 mmol) dropwise to the reaction system at 0 °C. Stir the reaction at 25 °C for 12 hours.

[0331] The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS) until it ended, and then diluted with ethyl acetate / water. The mixed solution was extracted three times with ethyl acetate, and the organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 0.16 g of (E)-4-(azacyclobutan-1-yl)but-2-enoic acid tert-butyl ester.

[0332] MS(ESI)M / Z:198.2[M+H] + .

[0333] 1 H NMR (400MHz, DMSO-d6): δ6.62 (dt, J=15.7, 5.2Hz, 1H), 5.79 (dt, J=15.7, 1.9Hz, 1H), 3.16-3.06 (m, 6H), 1.97 (p, J=7.0Hz, 2H), 1.42 (s, 9H).

[0334] Step B: Dissolve tert-butyl (E)-4-(azacyclobutane-1-yl)but-2-enoate (0.16 g, 0.81 mmol) in formic acid (3 mL), and place the reaction at 60 °C and stir for 2 hours.

[0335] The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS) until it ended. The reaction was then concentrated and lyophilized to obtain 0.1 g of (E)-4-(azacyclobutane-1-yl)butyl-2-enoic acid.

[0336] MS(ESI)M / Z:142.1[M+H] +.

[0337] Step C: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[3,2-d]pyrimidin-4-amine (0.05 g, 0.12 mmol), N,N-diisopropylethylamine (0.078 g, 0.60 mmol) and (E)-4-(azacyclobutane-1-yl)but-2-enoic acid (0.034 g, 0.24 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction was carried out at 25 °C, and then 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.055 g, 0.14 mmol) was added and stirred for 2 hours.

[0338] The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS) until it ended, and then diluted with ethyl acetate / water. The mixed solution was extracted three times with ethyl acetate, and the organic phases were combined, dried, and concentrated. The crude product was purified by preparative high-performance liquid chromatography (C18 column: 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: phase B increased from 29% to 59% within 7 minutes) to obtain 6.2 mg of (E)-1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)-6,7-dihydropyrazino[1',2':1,5]pyrrolo[3,2-d]pyrimidin-8(9H)-yl)-4-(azacyclobutan-1-yl)but-2-en-1-one formate.

[0339] MS(ESI)M / Z:554.2[M+H] + .

[0340] 1 H NMR (400MHz, DMSO-d6): δ8.97(d,J=7.4Hz,1H),8.42(d,J=9.9Hz,2H),8.24(s,2H),7.58(s,1H),7.14-6.97(m,2H),6.90(d,J=2.7Hz,1H),6.72-6 .56(m,2H),6.42(s,1H),5.03(d,J=58.3Hz,2H),4.61(s,2H),4.07(d,J= 29.6Hz,2H),3.23-3.11(m,6H),2.18-2.08(m,3H),2.01(p,J=7.1Hz,2H).

[0341] Example 51: (E)-1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-5,6-dihydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-7(8H)-yl)-4-(dimethylamino)but-2-en-1-one

[0342] Example 52: (E)-1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-7,8-dihydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(5H)-yl)-4-(dimethylamino)but-2-en-1-one

[0343]

[0344] Reaction route:

[0345]

[0346] Operating steps:

[0347] Step A: At 0°C, a mixture (0.23 g) of 4-(methylthio)-5,6-dihydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-7(8H)-carboxylic acid tert-butyl ester and 4-(methylthio)-7,8-dihydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(5H)-carboxylic acid tert-butyl ester and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylaniline (185.38 mg, 717.83 μmol) were dissolved in N,N-dimethylformamide (6 mL), and potassium tert-butoxide (109.87 mg, 979.17 μmol) was added. The reaction mixture was heated to 20°C and stirred for 0.5 hours.

[0348] After the reaction of the reactants was complete, the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (12 g silica gel column, ethyl acetate / n-hexane eluent, 0-30% gradient, 30 mL / min flow rate) to obtain 310 mg of a mixture of 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-5,6-dihydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-7(8H)-carboxylic acid tert-butyl ester and 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-7,8-dihydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(5H)-carboxylic acid tert-butyl ester).

[0349] MS(ESI)M / Z:531.2[M+H] + .

[0350] Step B: A mixture (0.31 g) of 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-5,6-dihydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-7(8H)-carboxylic acid tert-butyl ester and 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-7,8-dihydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(5H)-carboxylic acid tert-butyl ester) was dissolved in dioxane hydrochloride solution (2 M, 2 mL) and reacted at 20 °C for 2 hours.

[0351] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the starting materials was complete, and the reaction solution was directly concentrated. A crude mixture of 272 mg of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)-5,6,7,8-tetrahydropyridino[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-4-amine hydrochloride and N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)-5,6,7,8-tetrahydropyridino[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-4-amine hydrochloride was obtained. This crude product did not require purification and was used directly in the next step.

[0352] MS(ESI)M / Z:431.1[M+H]+ .

[0353] Step C: At 0°C, (E)-4-(dimethylamino)but-2-enoate salt (192.97 mg, 1.17 mmol) was dissolved in N,N-dimethylformamide (6 mL), followed by the sequential addition of 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4-one (191.75 mg, 640.83 μmol), triethylamine (589.50 mg, 5.83 mmol, 810.86 μL), and N-(4-([1,2,4]triazolo[1,5-a]pyridine). A mixture (272 mg) of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)-5,6,7,8-tetrahydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-4-amine hydrochloride and N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)-5,6,7,8-tetrahydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-4-amine hydrochloride was prepared. The reaction mixture was stirred at 20 °C for 12 hours.

[0354] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete. The reaction solution was purified by preparative high-performance liquid chromatography (HPLC) (column: 52-Welch Xtimate C18 150×30mm, 5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; gradient: phase B increased from 34% to 64% within 7.0 min) to obtain 200 mg of crude product, which was then purified by supercritical fluid chromatography (column: DAICEL CHIRALCEL). OD (250mm×30mm, 10um); mobile phase: [CO2-isopropanol (0.1% ammonia)]; B%: 60% isocratic elution) purification yielded 78.27 mg (E)-1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-5,6-dihydropyrido[4',3':3,4]pyrrolo[2,1-f][1,2,4]triazine-7(8H)-yl)-4-(dimethylamino)but-2-en-1-one (Peak) 1. Retention time 2.276 (Example 51) and 51.40 mg (E)-1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-7,8-dihydropyrido[3',4':3,4]pyrrolo[2,1-f][1,2,4]triazine-6(5H)-yl)-4-(dimethylamino)but-2-en-1-one (Peak 2, retention time 2.992, Example 52). (The two compounds were distinguished by comparing the final product obtained from intermediate IV, whose configuration was determined, with the 1H NMR spectrum of Peak 1 (Example 51) obtained by supercritical fluid chromatography.)

[0355] Example 51:

[0356] MS(ESI)M / Z:542.2[M+H] + .

[0357] 1 H NMR (400MHz, DMSO-d6): δ8.98(d,J=7.39Hz,1H),8.33-8.56(m,2H),7.87(s,1H),7.72(br s,2H),7.29(d,J=10.61Hz,1H),7.05(dd,J=7.45,2.44Hz,1H),6.91(d,J=2.03Hz,1H),6.63-6.77(m,2H),4.71-4.89(m,2H),3.91(br s,2H),3.10-3.26(m,2H),3.03-3.08(m,2H),2.17(br d,J=3.70Hz,9H).

[0358] Example 52:

[0359] MS(ESI)M / Z:542.2[M+H] + .

[0360] 1 H NMR (400MHz, DMSO-d6): δ8.90-9.04(m,1H),8.53-8.83(m,1H),8.38-8.47(m,1H),7.83-7.92(m,1H),7.48-7.71(m,2H),7.18-7.37(m,1H),7 .01-7.14(m,1H),6.88-6.99(m,1H),6.61-6.82(m,2H),4.82-5.25(m, 2H),3.74-3.89(m,2H),3.01-3.12(m,2H),2.71-2.86(m,2H),2.16(br s,9H).

[0361] The following examples were prepared using the method described above:

[0362]

[0363]

[0364] III. Bioactivity Experiment

[0365] 1. Experimental method for HER2 / EGFR enzyme activity detection

[0366] 1.1 Experimental Materials

[0367]

[0368] 1.2 Experimental Procedure

[0369] 1) Prepare 1× kinase reaction buffer: 50mM HEPES, pH 7.5, 10mM MgCl2, 2mM DTT, 0.01% Tween-20, 0.01% BSA.

[0370] 2) The compounds disclosed herein are diluted using DMSO.

[0371] 3) Transfer 200 nL of the disclosed compound to a 384 reaction plate using an Echo.

[0372] 4) Prepare a 2× kinase solution using 1× kinase reaction buffer, and transfer 10 μL of HER2 / EGFR (final concentration: 0.005 nM / 0.016 nM) solution into the corresponding well of the 384 reaction plate.

[0373] 5) Centrifuge with shaking and incubate at 25°C for 60 minutes (HER2) and 120 minutes (EGFR), respectively.

[0374] 6) Prepare a 2× substrate (final concentration: 20 nM Fluorescein-Poly GT) and ATP (final concentration: 14 μM (HER2) / 13 μM (EGFR)) mixture using kinase reaction buffer, and add 10 μL to the corresponding well of the reaction plate.

[0375] 7) Centrifuge with shaking and incubate at 25°C for 30 minutes.

[0376] 8) Prepare a 2× detection solution (final concentration: 0.5 nM Tb-PY20 antibody and 10 mM EDTA) using antibody dilution buffer, and add 20 μL to each well of the reaction plate.

[0377] 9) Centrifuge with shaking and incubate at 25°C for 60 minutes.

[0378] 10) Detect fluorescence signals at 520 nm and 495 nm using Envision.

[0379] 11) Analyze ICs using XLfit software 50 The experimental results are shown in Table 1.

[0380] Table 1. Enzymatic inhibitory activities of the compounds disclosed herein against HER2 and EGFR.

[0381]

[0382]

[0383] Note: " / " indicates that it was not detected.

[0384] The results showed that the disclosed compounds had a significant inhibitory effect on HER2 kinase, and some compounds exhibited significant selectivity. 2. HER2 TKI Cell Proliferation Inhibition Experiment

[0385] 1.1 Experimental Materials

[0386]

[0387]

[0388] 1.2 Experimental Procedure

[0389] HER2 A775_G776insYVMA / BaF3, HER2 WT / BaF3 complete medium: RPMI-1640 liquid medium, 10% FBS, 1% Pen Strep; EGFR WT (EGF Dependent) / BaF3 complete medium: RPMI-1640 liquid medium, 10% FBS, 1% Pen Strep, 100 ng / mL EGF.

[0390] 1. After seeding HER2 A775_G776insYVMA / BaF3, HER2 WT / BaF3, EGFR WT (EGFDependent) / BaF3 cells at a density of 1000 cells per well (40uL 1640Growth Media), add the drug.

[0391] 2. Using a compound dispenser, the compound was sequentially diluted nine times at a ratio of 1:3, with 10 μM as the highest initial concentration.

[0392] 3. After drug administration, cells were placed in a 37°C incubator and cultured for 6 days. After 6 days, 25 μL of CTG buffer was added to each well for CTG assay and plate reading analysis was performed using an ELISA reader.

[0393] 4. Use the CTG assay to detect the CTG readings of each well.

[0394] 5. Calculate the inhibition rate (inhibition%) of each concentration of the test compound on cells using the following formula.

[0395] Inhibition%=(bx) / (ba)*100%

[0396] a=CTG value(highest concentration)

[0397] b = CTG value (blank well)

[0398] x = CTG value(nM)

[0399] 6. Use GraphPad PRISM 8 for ICs 50 Perform the calculation.

[0400] (1) The concentrations and inhibition rates corresponding to 10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, and 1.5 nM were statistically analyzed. Log10 (A compound concentration) was used for statistical calculation.

[0401] (2) Input the data into GraphPad PRISM 8 and select Analysis.

[0402] (3) Select Nonlinear regression (curve fit)

[0403] (4) Select Log(inhibitor) vs. response — Variable slope.

[0404] (5) Select a calculation formula and calculate it according to the following formula.

[0405] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0406] X:log of dose or concentration

[0407] Y:Response,decreasing as X increases

[0408] Top and Bottom:Plateaus in same units as Y.

[0409] TIP:

[0410] -If X is not already the log of dose,go back and transform your data.

[0411] -If you have subtracted off any basal response,consider constrainingBottom to a constant value of 0.0.

[0412] (6) Fit the data to obtain IC. 50 value.

[0413] (7) Adjust the fitting conditions according to the specific data. Make appropriate adjustments to the bottom, top, and hill slope constraints to achieve the curve that best reflects the actual situation.

[0414] The experimental results are shown in Table 2.

[0415] Table 2. Cell inhibitory activities of the disclosed compounds against HER2 and EGFR.

[0416]

[0417]

[0418]

[0419] Note: " / " indicates that it was not detected.

[0420] The results showed that the disclosed compound had a significant inhibitory effect and selectivity on HER2 cells.

Claims

1. A compound of formula (I) or an isomer thereof, or a pharmaceutically acceptable salt thereof, in, M1 is selected from N or C; M2 is selected from N or C; L1 is selected from bonds, -N(R5)-, and 3-6 membered heterocyclic alkyl groups; L2 is selected from O or CH2; Ring A is selected from 3-10 membered heterocyclic alkyl groups; Ring B is selected from C 6-14 Aryl, 5-14 heteroaryl; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl; R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the amino, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic alkyl groups are optionally replaced by deuterium, halogen, amino, hydroxyl, cyano, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Substituted with one or more of cycloalkyl groups or 3-8 membered heterocyclic alkyl groups; R 3-1 R 3-2 R 3-3 and R 3-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl; R 4-1 R 4-2 and R 4-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 The cycloalkyl group or 3-8 membered heterocycloalkyl group is optionally further substituted with one or more R4'; R4' is independently selected from amino, C 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 3-8 cycloalkyl), -NH (3-8 membered heterocycloalkyl), -N (C 1-6 Alkyl)(C 3-8 cycloalkyl), -N(C) 1-6 Alkyl groups (3-8 membered heterocyclic alkyl groups), 3-8 membered heterocyclic alkyl groups, wherein the amino group, C 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 3-8 cycloalkyl), -NH (3-8 membered heterocycloalkyl), -N (C 1-6 Alkyl)(C 3-8 cycloalkyl), -N(C) 1-6 Alkyl groups (3-8 membered heterocyclic alkyl groups), 3-8 membered heterocyclic alkyl groups optionally surrounded by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Substituted with one or more of cycloalkyl groups or 3-8 membered heterocyclic alkyl groups; R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl; x is selected from 0, 1, 2, 3 or 4; y is selected from 0, 1, 2, 3 or 4.

2. The compound or its isomer, or a pharmaceutically acceptable salt, as described in claim 1, wherein, When L1 is connected to a carbon atom in ring A, L1 is NH; when L1 is connected to a nitrogen atom in ring A, L1 is a bond.

3. The compound or its isomer, or a pharmaceutically acceptable salt, as described in claim 1 or 2, wherein, Structural fragments Selected from 4. The compound or its isomer, or a pharmaceutically acceptable salt, as described in any one of claims 1 to 3, wherein, Ring B is selected from 6-membered heteroaryl and 5-membered heteroaryl, phenyl 5-membered heteroaryl, 5-membered heteroaryl, and 6-membered heteroaryl; Preferably, ring B is selected from or, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, wherein the amino, hydroxyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups and 3-6-membered heterocyclic alkyl groups are optionally replaced by deuterium, halogen, amino, hydroxyl, cyano, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 The alkyl group is substituted with one or more of the cycloalkyl and 3-6 membered heterocycloalkyl groups; preferably, R2 is independently selected from hydrogen, methyl, methoxy, cyclopropyl, fluorine, Difluoromethyl, trifluoromethyl; or, Selected from 5. The compound or its isomer, or a pharmaceutically acceptable salt, as described in any one of claims 1 to 4, wherein, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl; Preferably, R1 is independently selected from hydrogen and methyl; or, R 3-1 R 3-2 R 3-3 and R 3-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; Preferably, R 3-1 Selected from hydrogen; Or, R 3-2 Selected from hydrogen, fluorine, methoxy, Or, R 3-3 Selected from methyl, chlorine; Or, R 3-4 Selected from hydrogen and fluorine. or, R 4-1 R 4-2 and R 4-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 The cycloalkyl group or 3-6 membered heterocycloalkyl group is optionally further substituted with one or more R4'; R4' is independently selected from amino, C 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-6 cycloalkyl), -NH (3-6 membered heterocycloalkyl), -N (C 1-3 Alkyl)(C 3-6 cycloalkyl), -N(C) 1-3 Alkyl groups (3-6 membered heterocyclic alkyl groups), 3-6 membered heterocyclic alkyl groups, wherein the amino group, C 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-6 cycloalkyl), -NH (3-6 membered heterocycloalkyl), -N (C 1-3 Alkyl)(C 3-6 cycloalkyl), -N(C) 1-3 Alkyl groups (3-6 membered heterocyclic alkyl groups), 3-6 membered heterocyclic alkyl groups optionally surrounded by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Substituted with one or more of cycloalkyl groups or 3-6 membered heterocycloalkyl groups; Preferably, R 4-1 Selected from hydrogen, -CH2N(CH3)2, -CHF2; Or, R 4-2 Selected from hydrogen; Or, R 4-3 Selected from hydrogen. or, R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl; Preferably, R5 is selected from hydrogen or methyl.

6. The compound or its isomer, or a pharmaceutically acceptable salt, as described in any one of claims 1 to 5, wherein, The compounds are shown in formula (II) or formula (III).

7. The compound or its isomer, or a pharmaceutically acceptable salt, as described in any one of claims 1 to 6, wherein, The compounds are shown below:

8. A pharmaceutical composition comprising the compound or an isomer thereof as claimed in any one of claims 1-7, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

9. Use of the compound or isomer thereof, pharmaceutically acceptable salt, or pharmaceutical composition as described in any one of claims 1-7 in the preparation of a medicament for treating cancer.

10. The use as claimed in claim 9, wherein the cancer is selected from non-small cell lung cancer, breast cancer, or colon cancer.

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