Macrocyclic compounds and their pharmaceutical compositions and uses

Abstract

The present invention relates to macrocyclic inhibitors, compositions and their use. In particular, the present invention relates to compounds represented by formula (I), pharmaceutical compositions comprising the compounds of the present invention, and their use as EGFR inhibitors in the treatment of cancer-related diseases. [Chemical 1] JPEG2025524014000184.jpg26125

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a macrocyclic compound, its pharmaceutical composition, and its use.

Background Art

[0002] Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein and belongs to the ErbB family of tyrosine kinase receptors. Activation of EGFR results in autophosphorylation of the receptor tyrosine kinase. The autophosphorylated receptor tyrosine kinase activates a series of downstream signaling pathways involved in the regulation of cell proliferation, differentiation, and survival. EGFR is abnormally activated by various mechanisms such as receptor overexpression, mutation, ligand-dependent receptor dimerization, and ligand-independent activation, and is associated with the development of various human cancers.

[0003] In the field of cancer, lung cancer has the highest increase in morbidity and mortality and is one of the most threatening malignant tumors to people's health and lives. Therefore, treatment methods for lung cancer are the main research focus of anti-tumor drugs. Among them, since epidermal growth factor receptor (EGFR) is a major lung cancer driver (with a mutation rate exceeding 20% and being more prevalent in Asians), the development of EGFR inhibitors for targeted treatment of lung cancer patients has attracted the attention of drug researchers.

[0004] Here, EGFR mutations account for approximately 12 - 47% of non-small cell lung cancer (NSCLC). The two most common mutations are the deletion mutation in exon 19 (del19) and the point mutation in exon 21 (mainly L858R). The resulting abnormal ligand-independent activation of the epidermal growth factor receptor (EGFR) promotes the proliferation of tumor cells. This also serves as the scientific basis for the development of EGFR inhibitors. The objective response rates of first-generation (gefitinib "Iressa (registered trademark)", erlotinib "Tarceva (registered trademark)", and icotinib "Conmana (registered trademark)"), second-generation (afatinib "Gilotrif (registered trademark)", dacomitinib "Vizimpro (registered trademark)", and neratinib "Nerlynx (registered trademark)"), and third-generation (osimertinib, AZD9291) EGFR inhibitors used clinically for NSCLC tumors with these two mutations are approximately 60 - 85%. However, this efficacy does not last forever. Patients usually develop varying degrees of drug resistance 9.2 - 14.7 months after taking first-generation or second-generation EGFR inhibitors. Approximately 50 - 70% of these drug-resistant mutations occur at the gatekeeper T790M of EGFR. This mutation can cause a change in the three-dimensional structure of EGFR, increase the affinity of EGFR for ATP, and thereby potentially weaken the ability of the inhibitor to bind to EGFR. Afatinib, a second-generation EGFR inhibitor, has inhibitory activity against the EGFR-T790M mutation in vitro, but in clinical applications, it still cannot overcome the drug resistance caused by the T790M mutation. Moreover, both first-generation and second-generation EGFR inhibitors have difficulty excluding the inhibition of wild-type EGFR and thus cause obvious skin toxicity (such as acne-like rashes). This situation was not resolved until the emergence of osimertinib, a third-generation inhibitor.

[0005] Osimertinib has solved the problem of the T790M mutation. However, in EGFRT790M-positive NSCLC patients who received second-line treatment with osimertinib, drug resistance has been clinically observed to occur 10 months after administration. Among them, 20-40% is due to the C797S mutation (i.e., cis-type or trans-type triple mutations including del19 / T790M / C797S or L858R / T790M / C797S). At the same time, osimertinib also shows excellent effects on EGFR-sensitive mutations (del19 or L858R) and is approved for use as a first-choice drug. However, about 19 months after the start of use drug-resistant mutations occur, and 7% of them are C797S double mutations, namely del19 / C797S or L858R / C797S.

[0006] Currently, third-generation EGFR inhibitors have been approved and launched. They are approved for use as first-choice and second-choice drugs and are widely used in clinical practice. However, after being used for a certain period, drug resistance often occurs, and the effective survival period of patients cannot be significantly improved. Therefore, the development of next-generation EGFR inhibitors that can meet more clinical needs is urgently needed.

Summary of the Invention

[0007] To solve the above problems, the present invention provides a macrocyclic compound that can be used for the treatment of cancer as an inhibitor of various mutations of EGFR.

[0008] The macrocyclic compound provided by the present invention is a compound represented by formula (I), or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative,

Chemical formula

[0009] In some embodiments, L1 in formula (I) is -CR h R i - selected from.

[0010] In some embodiments, L1 in formula (I) is -CH2.

[0011] In some embodiments, L2 in formula (I) is a bond or -O-.

[0012] In some embodiments, R1 or R2 in formula (I) are each independently H, C 1-6 (alkyl group), deuterium-substituted C 1-6 (alkyl group), hydroxy group, C 1-6 (haloalkyl group), halogen, -NH2, C 1-6 (alkoxy group) and C 1-6 (haloalkoxy group) selected from the group consisting of.

[0013] In some embodiments, R1 or R2 in formula (I) is H, or a C 1-3 alkyl group.

[0014] In some embodiments, R1 and R2 in formula (I), together with the atoms to which they are attached,

Chemical formula

[0015] In some embodiments,

Chemical formula

Chemical formula

[0016] In some embodiments, R in formula (I) a is H, deuterium, halogen, CN, OH, -NH2, C 1-6 alkyl group, deuterium-substituted C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, or -NH-C(O)-C 1-6 alkyl group.

[0017] In some embodiments, R in formula (I) a is H, deuterium, F, Cl, CN, -NH2, C 1-3 alkyl group, deuterium-substituted C 1-3 alkyl group, C 2-4 alkynyl group, C 1-3 alkoxy group, or C 1-3 haloalkyl group.

[0018] In some embodiments, R in formula (I) a is H or CH3.

[0019] In some embodiments, R in formula (I) b is H, deuterium, halogen, CN, OH, -NH2, C 1-6 alkyl group, deuterium-substituted C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 haloalkoxy group, -S-C 1-6 alkyl group, -S(=O)-CH3, -S(=O)2-C 1-6 alkyl group, -S(=O)2-C 3-6 cycloalkyl group, or -O-3-6 membered heterocyclyl group.

[0020] In some embodiments, R in formula (I) b is H, deuterium, F, Cl, -OCH3, C 1-3 alkyl group, CD3, CF3, CN, -NH2, -S-CH3, -S(=O)-CH3,

Chemical formula

[0021] In some embodiments, R in formula (I) b is H or C 1-3 alkyl group, preferably, R b is H or CH3.

[0022] In some embodiments, R4 in formula (I) is H.

[0023] In some embodiments, R5 in formula (I) is H, halogen, C 1-6 alkyl group, NH2, -NH(C 1-6 alkyl group), -N(C 1-6 alkyl group)2, C 3-6It is a cycloalkyl group or a 4- to 6-membered heterocyclyl group, and the C 1-6 alkyl group, -NH2, -NH(C 1-6 alkyl group), -N(C 1-6 alkyl group)2, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclyl group are optionally substituted by one or more selected from the group consisting of OH, -NH2, oxo, C 1-6 alkyl group, C 1-6 alkoxy group, -S(O)2-C 1-6 alkyl group, -C 1-6 alkyl group-S(O)2-C 1-6 alkyl group, -NH(C 1-6 alkyl group), and -N(C 1-6 alkyl group)2.

[0024] In some embodiments, R5 in formula (I) is H, F, Cl, CH3, -NH2,

Chemical formula

[0025] In some embodiments, R5 in formula (I) is H.

[0026] In some embodiments, R c in formula (I) is H, deuterium, halogen, NO2, CN, OH, -NH2, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, or a 3- to 6-membered heterocyclyl group, and the OH, -NH2, C 1-6 alkyl group, C2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group and the 3- to 6-membered heterocyclyl group are optionally halogen, C 1-6An alkyl group, C 1-6 an alkoxy group, -NH2, -COOH, -NH(C 1-6 alkyl group), -N(C 1-6 alkyl group)2, C 3-6 a cycloalkyl group, a 3- to 6-membered heterocyclyl group, -CONH2, -CONH(C 1-6 alkyl group), -CON(C 1-6 alkyl group)2, -CONH(C 2-6 alkenyl group), -CON(C 2-6 alkenyl group)2, -CONH(C 2-6 alkynyl group), -CON(C 2-6 alkynyl group)2, a substituted or unsubstituted -CO-3- to 6-membered heterocyclyl group, -O-C 1-6 a haloalkyl group, -OC(=O)NH2, -OCONH(C 1-6 alkyl group), and -OCON(C 1-6 alkyl group)2, and is substituted by one or more selected from the group consisting of.

[0027] In some embodiments, R in formula (I) c is H, deuterium, CH3, CD3, CH2CH3, CH(CH3)2, -C(CH3)3, OH, F, Cl, -NH2,

Chemical formula

[0028] In some embodiments,

Chemical formula

Chemical formula

[0029] In some embodiments,

Chemical formula

[0030] In some embodiments, [Chem.] is [Chem.] .

[0031] In some embodiments, m in formula (I) is 0, 1, or 2.

[0032] In some embodiments, n in formula (I) is 0, 1, or 2.

[0033] In some embodiments, r in formula (I) is 2, 3, or 4.

[0034] In some embodiments, the compound represented by formula (I) is selected from the compounds represented by formula (II) shown below, [Chem.] wherein the definitions of L1, L2, R a , R b , R1, R2, R4, R5, M1, M2, M3, M4, M5, M6, M7, M8, M9, M 10 , m, n, and r are as defined in formula (I) above.

[0035] In some embodiments, the compound represented by formula (I) is selected from the compounds represented by formula (III) shown below, [Chem.] Here, R in the compound represented by formula (III) a , R b , R c , R1, R2, m, and n are defined as in the aforementioned formula (I).

[0036] In some embodiments, the compound represented by formula (I) is selected from the compounds represented by formula (IV) shown below, [Chemical formula] Here, R in the compound represented by formula (IV) a , R b , R c , R1, R2, m, and n are defined as in the aforementioned formula (I).

[0037] In some embodiments, the compound represented by formula (I) is selected from the compounds represented by formula (V) shown below, [Chemical formula] Here, R in the compound represented by formula (V) a , R b , R c , R1, m, and n are defined as in the aforementioned formula (I).

[0038] In some embodiments, the compound represented by formula (I) is 2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 2 6 -methyl-5 6-(9-Methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-4-Aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 6 ,7-Dimethyl-5 6 -(9-Methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 6 ,7-Dimethyl-5 6 -(9-(Oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 5 -Fluoro-2 6 ,7-Dimethyl-5 6 -(9-Methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 5 -Fluoro-2 6 ,7-Dimethyl-5 6 -(9-(Oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 2 6 ,9,9-Trimethyl-5 6 -(9-Methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 5 -((dimethyl(oxo)-1 6 sulfaniliden)amino)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-1 6 -fluoro-2 6 ,7-dimethyl-5 6 -(3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-1 6 -fluoro-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-2 6 ,5 5 ,7-trimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-2 6 ,5 5 ,7-trimethyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 2 6 ,5 5 -dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 5 -fluoro-2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 6 -(9-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)-3-azaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-1 6 ,5 5 -difluoro-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 6 -fluoro-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 3-(9-(2 6 -methyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-5 6 -yl)-3,9-diazaspiro[5.5]undecan-3-yl)propanamide, (R)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 5 -((2-(methylsulfonyl)ethyl)amino)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 5 -(methylamino)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-7-methyl-2 6 -(methyl-d3)-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-1 6 -fluoro-5 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 6 ,2 6 -dimethyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaph ane-3-one, 1 2 ,2 6 -dimethyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 2 -fluoro-2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 2 -fluoro-1 5 ,2 6 -dimethyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-1 6 -(trifluoromethyl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 5 ,2 6 -dimethyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 6 -amino-2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 6 -fluoro-2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 6 -chloro-2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 5 -fluoro-2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 6 -methoxy-2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 5 -methoxy-2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-1 2 -carbonitrile, 2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5. 5]undecan-3-yl)-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-1 6 -carbonitrile, 2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-3-oxo-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-1 5 -carbonitrile, 2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-1 5 -(oxetan-3-yloxy)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 1 5 -fluoro-1 6 -methoxy-2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-2 6 ,7-dimethyl-5 6 -(9-(tetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 6 -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 6 -(9-(4-methoxycyclohexyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 5 -fluoro-5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 5 -fluoro-5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 5 -fluoro-2 6 ,7-dimethyl-5 6 -(9-(tetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2 (2,4)-dipyridinacycloundecaphane-3-one, (R)-5 5 -fluoro-5 6 -(9-(4-methoxycyclohexyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 5 -fluoro-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,5 5 ,7-trimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 2 6 -methyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 2 6 -methyl-5-(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacyclodecaphane-3-one, 5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 6 -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,5 5 -dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,5 5 -dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,5 5 -dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 2 6 ,55 -dimethyl-5 6 -(9-(oxetan-3-ylmethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,5 5 -dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,5 5 -dimethyl-5 1 H-12-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacyclododecafan-3-one, 5 5 -fluoro-5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5. 5]undecan-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 5 -fluoro-2 6 -methyl-5 6 -(9-(oxetan-3-ylmethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 5 -fluoro-2 6 -methyl-5 6-(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 5 -fluoro-5 6 -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undecan-3-yl)-26-methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 5 -fluoro-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-2 6 ,7-bis(methyl-d3)-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 2 6 -methyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 5 -fluoro-2 6 ,7-dimethyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 5 -fluoro-2 6 -methyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 2 6 ,5 5 -dimethyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-2 6 ,5 5 ,7-trimethyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 2 6 -methyl-5 6 -(3-methyl-3-azaspiro[5.5]undecan-9-yl)-5 1 H-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1 H-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 6-(9-(3-Methoxypropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-4-Aza-5(2,1)-benzo [d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 6 -(9-(2-Methoxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 6 -(9-(3-Methoxypropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 6 -(9-(3-Methoxypropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 6 -(9-(2-Fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 5 -amino-2 6 ,7-dimethyl-5 6 -(9-Methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-1 6 -fluoro-5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-1 6 -fluoro-2 6 ,7-dimethyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (7R)-5 6 -(9-(2,2-dimethyloxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (7R)-2 6 ,7-dimethyl-5 6 -(9-(2-methyloxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one (R)-2 6 ,7-dimethyl-5 6 -(9-(1-methylazetidin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-2 6 ,7-dimethyl-5 6 -(9-(3-methyloxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 5 -fluoro-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 6 -(9-(2-(dimethylamino)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (7R)-5 6 -(9-(4-methoxy-4-methylpentan-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, 56 -(9-(4-methoxy-4-methylpentan-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benz[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 6 -(9-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benz[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 5 -chloro-2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benz[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 5 -chloro-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benz[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 6’-methyl-6’-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)spiro[cyclopropane-1,7’-11-oxa-4-aza-5(2,1)-benz[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan]-3’-one, 2 6 ,8,8-trimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-3-(9-(2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-5-yl)-3,9-diazaspiro[5.5]undecane-3-yl)propanamide, (R)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 5 -(oxetan-3-ylamino)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-2-(9-(16-fluoro-2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-5 6 -yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethylmethylcarbamate, (R)-3-(9-(2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-5 6 -yl)-3,9-diazaspiro[5.5]undecane- 3-yl)-N,N-dimethylpropanamide, (R)-3-(9-(1 6 ,5 5 -difluoro-2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-56 -yl)-3,9-diazaspiro[5.5]undecan-3-yl)propanamide, (R)-1 6 ,5 5 -difluoro-5 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benz[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-3-(9-(1 6 -fluoro-2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benz[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-5 6 -yl)-3,9-diazaspiro[5.5]undecan-3-yl)-N,N-dimethylpropanamide, (R)-2 6 ,7-dimethyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benz[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-1 6 -carbonitrile, (R)-5 6 -(9-(3-(azetidin-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benz[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 6 -(9-(3-(azetidin-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-1 6 -fluoro-2 6,7-Dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-2 6 ,7-Dimethyl-5 6 -(9-(2-(Trifluoromethoxy)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-1 6 -Fluoro-2 6 ,7-Dimethyl-5 6 -(9-(2-(Trifluoromethoxy)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, (R)-5 6 -(9-(3-(3,3-Dimethylazetidin-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-Dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one, and (R)-2-(9-(2 6 ,7-Dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-5 6 -yl)-3,9-diazaspiro[5.5]undecan-3-yl)ethylcarbamate, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative thereof.

[0039] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound represented by the above formula (I), or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0040] Furthermore, the present invention provides the use of the above compound and / or pharmaceutical composition in the preparation of an antitumor drug. In some embodiments, the antitumor drug is used for head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma.

[0041] In some embodiments, the tumor is a malignant tumor having an EGFR gene mutation, preferably, the EGFR gene mutation is at least one selected from the group consisting of EGFR Del19 gene mutation, EGFR L858R gene mutation, EGFR T790M gene mutation, and EGFR C797S gene mutation.

[0042] The present invention also provides a method for treating a tumor in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the above compound or pharmaceutical composition, the patient is preferably a mammal, and the mammal is preferably a human.

[0043] In some embodiments, the administration method during treatment includes oral, mucosal, sublingual, ocular, topical, parenteral, rectal, intracerebroventricular, vaginal, peritoneal, intravesical, intranasal administration.

[0044] In some embodiments, the tumor includes head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma.

[0045] In some embodiments, the tumor is a malignant tumor having an EGFR gene mutation, and preferably, the EGFR gene mutation is at least one selected from the group consisting of an EGFR Del19 gene mutation, an EGFR L858R gene mutation, an EGFR T790M gene mutation, and an EGFR C797S gene mutation.

[0046] Definitions and Explanations The general chemical terms used in the above structural general formula have a general meaning.

[0047] For example, as used herein, the terms "halo" and "halogen" refer to fluorine, chlorine, bromine or iodine, unless otherwise specified. Preferred halogen groups include fluorine, chlorine and bromine.

[0048] As used herein, unless otherwise specified, the term "alkyl group" includes a straight-chain or branched-chain monovalent saturated hydrocarbon group. The alkyl groups used herein may optionally be substituted by one or more substituents. Non-limiting examples of alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, 3-(2-methyl)butyl group, 2-pentyl group, 2-methylbutyl group, neopentyl group, n-hexyl group, 2-hexyl group, 2-methylpentyl group, etc. Similarly, "C 1-6 " in "C 1-6 alkyl group" refers to a group arranged in a straight-chain or branched-chain containing 1, 2, 3, 4, 5 or 6 carbon atoms.

[0049] The terms "alkenyl group" and "alkynyl group" include linear or branched alkenyl groups and alkynyl groups. Similarly, "C 2-6 alkenyl group" and "C 2-6 alkynyl group" refer to alkenyl groups or alkynyl groups arranged in a linear or branched chain containing 2, 3, 4, 5, or 6 carbon atoms.

[0050] The term "alkoxy group" refers to the oxygen ether form of the linear or branched alkyl group. refer to.

[0051] The term "haloalkyl group" refers to the one in which the above-mentioned "alkyl group" is substituted by one or more halogens.

[0052] In the present invention, "one", "1", "one", "the", "at least one" and "one or more" can be used interchangeably. Thus, for example, a composition containing "one" pharmaceutically acceptable excipient can be interpreted to mean that the composition contains "one or more" pharmaceutically acceptable excipients.

[0053] The term "aryl group" refers to an unsubstituted or substituted monocyclic, polycyclic or fused-ring aromatic group containing carbon atoms in the present invention unless otherwise specified. The aryl group is preferably a C 6-14 aryl group, and the C 6-14 aryl group is more preferably a C 6-10 aryl group. Specific examples of these aromatic rings include, but are not limited to, phenyl group and naphthyl group.

[0054] The term "heteroaryl group" refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom (e.g., 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms), wherein the heteroatom is selected from the group consisting of N, O, and / or S. Also, nitrogen or sulfur may optionally be oxidized, and nitrogen may optionally be quaternized. The heteroaryl group can be attached to any heteroatom or carbon atom to form a stable structure. The heteroaryl group is preferably a 5- to 14-membered heteroaryl group, and more preferably the 5- to 14-membered heteroaryl group is a 5- to 10-membered heteroaryl group or a 5- to 6-membered heteroaryl group. Specific examples of the heteroaryl group include, but are not limited to, thienyl group, furanyl group, imidazolyl group, isoxazolyl group, oxazolyl group, pyrazolyl group, pyrrolyl group, thiazolyl group, thiadiazolyl group, triazolyl group, pyridinyl group, pyridazinyl group, indolyl group, azaindolyl group, indazolyl group, benzimidazolyl group, benzofuranyl group, benzothienyl group, benzisoxazolyl group, benzoxazolyl group, benzopyrazolyl group, benzothiazolyl group, benzothiadiazolyl group, benzotriazolyl adeninyl group, quinolinyl group, or isoquinolinyl group.

[0055] The term "carbocyclic group" refers to a saturated or unsaturated cyclic group that is not aromatic. Depending on the degree of saturation, it may include "cycloalkyl group", "cycloalkenyl group", or "cycloalkynyl group". Monocyclic carbocyclic groups include, but are not limited to, similar groups such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, or cyclohexene. Polycyclic carbocyclic groups include spirocyclic, fused cyclic, and bridged cyclic carbocyclic groups. The carbocyclic group is preferably a C 3-14 carbocyclic group, and the C 3-14 carbocyclic group is a C 3-8 carbocyclic group is more preferably, and the C 3-8 carbocyclic group is a C 3-6 carbocyclic group is even more preferably, and the C3-8 The carbocyclic group is C 5-6 More preferably, it is a carbocyclic group.

[0056] The term "cycloalkyl group" refers to a saturated monocyclic and polycyclic structure containing only carbon atoms in the ring, and the cycloalkyl group may be optionally substituted with one or more substituents. The "cycloalkyl group" may have a cyclic structure including a bridged ring, a fused ring, and a spiro ring. Non-limiting specific examples of the cycloalkyl group include, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a spiro[3.4]octyl group, bicyclo[2.2.1]heptane, and the like. The cycloalkyl group is C 3-14 Preferably, it is a cycloalkyl group, and the C 3-14 The cycloalkyl group is C 3-8 More preferably, it is a cycloalkyl group, and the C 3-8 The cycloalkyl group is C 3-6 Even more preferably, it is a cycloalkyl group, and the C 3-8 The cycloalkyl group is C 5-6 Even more preferably, it is a cycloalkyl group.

[0057] As used herein, the term "heterocyclyl group" refers to an unsubstituted or substituted monocyclic and polycyclic structure composed of 1 to 3 heteroatoms selected from the group consisting of N, O, and S and carbon atoms, and includes saturated or unsaturated cyclic structures, and polycyclic structures having unsaturated moieties and / or aromatic moieties. Here, nitrogen or sulfur may be optionally oxidized, and nitrogen may be optionally quaternized. The heterocyclyl group can be bonded to any heteroatom or carbon atom to form a stable structure. It should be understood that the polycyclic heterocycloalkyl group may have a cyclic structure including fused rings, bridged rings, and spiro rings. The heterocyclyl group is preferably a 3- to 14-membered heterocyclyl group, more preferably the 3- to 14-membered heterocyclyl group is a 3- to 8-membered heterocyclyl group or a 5- to 10-membered heterocyclyl group, still more preferably the 3- to 8-membered heterocyclyl group is a 3- to 6-membered heterocyclyl group, and still more preferably the 3- to 6-membered heterocyclyl group is a 5- to 6-membered heterocyclyl group. The heterocycloalkyl group used herein may optionally be substituted by one or more substituents. Specific examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxetane, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl.

[0058] However, in any case, the heterocyclyl group and the carbocyclyl group do not intersect or include each other. Therefore, according to the above definition, even when at least one all-carbon ring is condensed with the heterocyclyl group to form a di-, poly-, or spiro-ring, it is still defined as a heterocyclyl group.

[0059] In addition, when a heteroaryl group is fused with a heterocyclyl group to form a di-, poly-, or spiro-ring, it is defined as a heterocyclyl group rather than a heteroaryl group.

[0060] The term "substituted" refers to the situation where one or more hydrogen atoms in a group are each substituted by the same or different substituents. Typical substituents are halogen (F, Cl, Br or I), C 1-8 alkyl group, C 3-12 cycloalkyl group, -OR 1 , -SR 1 , =O, =S, -C(O)R 1 , -C(S)R 1 , =NR 1 , -C(O)OR 1 , -C(S)OR 1 , -NR 1 R 2 , -C(O)NR 1 R 2 , cyano group, nitro group, -S(O)2R 1 , -O-S(O2)OR 1 , -O-S(O)2R 1 , -OP(O)(OR 1 )(OR 2 ), but are not limited thereto, where R 1 and R 2 are each independently selected from the group consisting of -H, C 1-6 alkyl group, C 1-6 haloalkyl group. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, methyl group, ethyl group, -OH, trifluoromethoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, -SCH3, -SC2H5, formaldehyde group, -C(OCH3), cyano group, nitro group, -CF3, -OCF3, amino group, dimethylamino group, methylthio group, sulfonyl group, and acetyl group.

[0061] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable bases or acids. When the compounds provided by the present invention are acids, the corresponding salts can be conveniently prepared from pharmaceutically acceptable bases including inorganic bases and organic bases.

[0062] As used herein, the term "deuterated derivative" refers to a compound or group produced when a hydrogen atom in the structure of a compound or chemical group is partially or completely replaced by deuterium, which is an isotope thereof. Positions specifically designated as "D" or "deuterium" are understood to have a deuterium enrichment of 50%, 80%, 90%, 95%, 98% or 99%. "Deuterium enrichment" is the mole percentage determined by dividing the number of deuterium-containing compounds at a designated position by the total number of all compounds. When a position is designated as "H" or "hydrogen", hydrogen is naturally abundant at that position. When the presence of hydrogen or deuterium at a position is not specified, the hydrogen at that position is naturally abundant. Certain alternative embodiments relate to compounds of the invention having a deuterium enrichment of at least 5%, 10%, 25%, 50%, 80%, 90%, 95%, 98% or 99% at one or more positions not specifically designated as "D" or "deuterium". In some embodiments, one or more hydrogen atoms of any of the compounds described herein can be replaced with deuterium to obtain the corresponding labeled or enriched compound.

[0063] As used in the present invention, the term "deuterium-substituted C 1-6 alkyl group" refers to a group obtained by partially or completely replacing the hydrogen atoms in the structure of a "C 1-6 alkyl group" with deuterium, which is an isotope thereof. "Deuterium-substituted methyl" refers to a group obtained by partially or completely replacing the hydrogen atoms in the methyl structure with deuterium, which is an isotope thereof. CD3 is a group obtained by completely replacing the hydrogen atoms in the methyl structure with deuterium, which is an isotope thereof. The deuterium-substituted C 1-6 alkyl group is a deuterium-substituted C 1-3It is preferably an alkyl group, and the deuterium-substituted C 1-3 The alkyl group is preferably a deuterium-substituted methyl group.

[0064] Since the compound represented by formula (I) is used as a pharmaceutical, it is preferably used at a certain purity. For example, it is used at a purity of at least 60%, more preferably at least 75%, and particularly preferably at least 98% (the % is by weight).

[0065] The prodrugs of the compounds of the present invention are included in the protection scope of the present invention. Generally, the prodrug refers to a functional derivative that can be easily converted into a compound required in the body. For example, any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of the compound of the present invention can directly or indirectly provide the compound of the present invention or its pharmaceutically active metabolite or residue after administration to a recipient. Particularly preferred derivatives or prodrugs are compounds that can enhance the bioavailability of the compounds of the present invention (for example, compounds that can more easily absorb an orally administered compound into the blood) when administered to a patient, or compounds that can promote the delivery of the parent compound to a biological organ or site of action (such as the brain or lymphatic system). Therefore, the term "administration" in the treatment method provided by the present invention refers to administering a compound disclosed by the present invention that can treat different diseases, or administering a compound that, although not explicitly disclosed, can be converted into the compound disclosed by the present invention in the body after administration to a person undergoing testing. Conventional methods for selecting and preparing appropriate prodrug derivatives have already been described in books such as "Design of Prodrugs" (ed. H. Bundgaard, Elsevier, 1985).

[0066] Obviously, the definition of any substituent or variable at a specific position in a molecule is independent of the definitions at other positions in the molecule. As can be understood, a person skilled in the art can select the substituents and substitution forms of the compounds in the present invention by the methods described in the prior art and the present invention in order to obtain chemically stable and easily synthesized compounds.

[0067] The compounds described in the present invention can contain one or more asymmetric centers, thereby making it possible to generate diastereomers and optical isomers. The present invention includes all possible diastereomers and their racemic mixtures, these substantially pure separated enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

[0068] The above formula (I) does not clearly define the steric structure at a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and their pharmaceutically acceptable salts. Furthermore, mixtures of stereoisomers and separated specific stereoisomers are also included in the present invention. The synthetic process for preparing such compounds, or the products obtained by the racemization or epimerization processes known to those skilled in the art, may be mixtures of stereoisomers.

[0069] When there are tautomers in the compound represented by formula (I), unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and mixtures thereof.

[0070] When there are solvates or polymorphs in the compound represented by formula (I) and its pharmaceutically acceptable salts, the present invention includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable.

[0071] As used herein, the term "composition" refers to a product containing a specific amount of a specific component, and a product consisting directly or indirectly of a combination of specific amounts of specific components. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods for preparing the compounds of the present invention are also part of the present invention.

[0072] In addition, some crystals of the compound may exist as polymorphs, and such polymorphs are also included in the present invention. Note that some compounds may form hydrates (i.e., hydrates) or solvates with common organic solvents, and such solvates are also included within the scope of the present invention.

[0073] The pharmaceutical compositions provided by the present invention contain a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient, and any other optional therapeutic component or adjuvant. In any given case, the optimal mode of administering the active ingredient depends on the specific subject to be administered, the nature of the subject, and the severity of the medical condition, but the pharmaceutical compositions of the present invention include pharmaceutical compositions suitable for administration by oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) routes. The pharmaceutical compositions of the present invention can conveniently exist as unit dosage forms known in the art and can be prepared by any preparation method known in the pharmaceutical art.

[0074] The pharmaceutical compositions of the present invention may be prepared by any pharmaceutical method. Under normal circumstances, this method includes the step of combining the active ingredient with a carrier constituting one or more necessary components. Under normal circumstances, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. Note that the product can conveniently be prepared in the desired appearance.

[0075] Accordingly, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (I) or its stereoisomers, tautomers, polymorphs, solvates, its pharmaceutically acceptable salts, and its prodrugs. The combination of the compound represented by formula (I) or its pharmaceutically acceptable salts with one or more other compounds having therapeutic activity is also included in the pharmaceutical composition of the present invention.

[0076] The pharmaceutical carrier employed in the present invention may be, for example, a solid carrier, a liquid carrier, or a gas carrier.

Mode for Carrying Out the Invention

[0077] To make the above content clearer, the present invention further describes the technical solution of the present invention using the following examples. The following examples are only used to illustrate the specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not used to limit the protection scope of the present invention. In the specific embodiments of the present invention, technical means or methods not specifically described are conventional technical means or methods in the technical field.

[0078] Unless otherwise specified, all parts and percentages of the present invention are by weight, and all temperatures refer to degrees Celsius.

[0079] In the examples, the following abbreviations are used.

[0080] AcOH: Glacial acetic acid; (Boc)2O: Di-tert-butyl dicarbonate; CNBr: Cyanogen bromide; CMBP: Cyanomethylene tri-n-butylphosphine; DCM: Dichloromethane; DIEA / DIPEA: N,N-Diisopropylethylamine; Dioxane: Dioxane; DMAP: 4-Dimethylaminopyridine; DMF: N,N-Dimethylformamide; EA / EtOAc: Ethyl acetate; EtOH: Ethanol; Fe: Iron powder; HATU: O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; LC-MS or LCMS: Liquid chromatography mass spectrometry; Ruphos: 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl; STAB: Sodium triacetoxyborohydride; t-BuONa: Sodium tert-butoxide; TBAF: Tetrabutylammonium fluoride; TEA: Triethylamine; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; TLC: Thin layer chromatography; Na2CO3: Sodium carbonate; K2CO3: Potassium carbonate; Pd(Amphos)Cl2: Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium; Pd / C: Palladium on carbon; PE: Petroleum ether; Prep-HPLC: High performance liquid chromatography; PLC: Preparative liquid chromatography; Xphos: 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl.

[0081] The raw materials and reagents used in the examples can all be obtained from commercial sources or prepared by conventional methods in the art.

Examples

[0082] Example 1 Synthesis of Compound 1 2 6-Methyl-5 6 -(9-Methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-Oxa-4-aza-5(2,1)-benzod[1,2]imidazol-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chemical formula

[0083] Step 1: Synthesis of Compound 1-1

Chemical formula

[0084] Step 2: Synthesis of Compound 1-2

Chemical formula

[0085] Step 3: Synthesis of Compound 1-3

Chemical Structure

[0086] Step 4: Synthesis of Compound 1-4

Chemical Structure

[0087] Step 5: Synthesis of compound 1-5

Chemical formula

[0088] Step 6: Synthesis of compound 1-6

Chemical formula

[0089] Step 7: Synthesis of compound 1-7

Chemical formula

[0090] Step 8: Synthesis of compound 1-8

Chemical formula

[0091] Step 9: Synthesis of compound 1-9

Chemical formula

[0092] Step 10: Synthesis of compound 1-10

Chemical formula

[0093] Step 11: Synthesis of Compound 1-11

Chem.

[0094] Step 12: Synthesis of Compound 1

Chem.

[0095] 1 HNMR (500 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.25 (s, 1H), 9.04 (s, 1H), 8.46 (d, J = 5.8 Hz, 1H), 7.71 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 5.8 Hz, 1H), 7.14 (s, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.91 (dd, J = 8.8, 2.2 Hz, 1H), 4.23 (dt, J = 44.5, 5.3 Hz, 4H), 3.16 (dd, J = 11.4, 5.7 Hz, 3H), 2.81 (s, 3H), 2.64 (s, 3H), 2.57 (s, 1H), 2.53 (s, 3H), 2.01 (h, J = 7.3 Hz, 2H), 1.91 (dp, J = 19.3, 6.8, 5.6 Hz, 4H), 1.61 (d, J = 6.1 Hz, 9H).

[0096] Example 2 Synthesis of Compound 2 2 6 -Methyl-5 6 -(9-Methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-4-Aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chemical Structure

[0097] Step 1: Synthesis of Compound 2-2

Chemical Structure

[0098] Step 2: Synthesis of compound 2-3

Chemical Structure

[0099] Step 3: Synthesis of compound 2-4

Chemical Structure

[0100] Step 4: Synthesis of compound 2-5

Chemical Structure

[0101] Step 5: Synthesis of compound 2-6

Chemical Structure

[0102] Step 6: Synthesis of compound 2-7

Chemical formula

[0103] Step 7: Synthesis of compound 2-8

Chemical formula

[0104] Step 8: Synthesis of compound 2-9

Chemical formula

[0105] Step 9: Synthesis of compound 2-10

Chemical formula

[0106] Step 10: Synthesis of Compounds 2-11 [ka] Compound 2-10 (0.99 g, 2.03 mmol) was added to the reaction bottle, and anhydrous distilled water was used as the solvent. Oxane (20 mL) was added, followed by sodium tert-butoxide (0.39 g, 4.06 mmol), Xphos (195 mg, 0.41 mmol), Pd2(dba)3 (183 mg, 0.2 mmol), and 3-methyl-3,9-diazaspiro[5,5]undecane (0.68 g, 4.06 mmol) in that order, and the mixture was purged with nitrogen gas and reacted at 100°C for 3 hours. The reaction was monitored by LCMS, heating was stopped, the solvent was evaporated under reduced pressure, and the residue was mixed with silica gel and subjected to flash column chromatography (eluent was DCM:MeOH=12:1) to obtain compound 2-11 (0.81 g, yield: 69.45%). MS: 574.32 [M+H] +

[0107] Step 11: Synthesis of Compound 2 [ka] Compound 2-11 (100 mg, 0.174 mmol) was added to MeOH (8 mL), and then 15% Pd / C (15 mg) was added. After the addition was complete, the mixture was purged with hydrogen gas three times and stirred at room temperature for 2 hours for reaction. The reaction was monitored by LCMS and allowed to proceed to completion. The reaction was stopped, filtered, and the filter cake was washed with methanol. The filtrate was concentrated and prepared by Prep-HPLC (chromatography column: luna C18, 30 * 250 mm, mobile phase (A: 0.1% aqueous formic acid solution, B: acetonitrile, acetonitrile 17 - 50%, 20 minutes)) to obtain the product, compound 2 (53 mg, 52.34%). MS: 578.35 [M+H] +

[0108] Example 3 Synthesis of Compound 3 (R)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chemical formula

[0109] Step 1: Synthesis of compound 3-1

Chemical formula

[0110] Step 2: Synthesis of compound 3-2

Chemical formula

[0111] Step 3: Synthesis of compound 3-3

Chemical formula

[0112] Step 4: Synthesis of compound 3-4

Chemical formula

[0113] Step 5: Synthesis of compound 3-5

Chemical formula

[0114] Step 6: Synthesis of compound 3-6

Chemical formula

[0115] Step 7: Synthesis of compound 3-7

Chemical Structure

[0116] Step 8: Synthesis of compound 3

Chemical Structure

[0117] Example 4 Synthesis of Compound 4 (R)-2 6 ,7-dimethyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chemical formula

[0118] Step 1: Synthesis of Compound 4-1

Chemical formula

[0119] Step 2: Synthesis of Compound 4-2

Chemical formula

[0120] Step 3: Synthesis of Compound 4 [Chem.] Dissolve compound 4-2 (3.50 g, 5.68 mmol) in anhydrous methanol (30 mL) in a 100 mL single-neck flask, then sequentially add triethylamine (1.72 g, 17.04 mmol), 3-oxetanone (4.09 g, 56.80 mmol), and sodium cyanoborohydride (7.14 g, 113.60 mmol), stir to mix uniformly, heat to 60 °C and react for 1 hour, monitor by LCMS until the raw materials are completely reacted, and then stop stirring. Cool the reaction solution to room temperature, wash twice with dichloromethane (150 mL) and saturated sodium carbonate aqueous solution, wash once with water, wash once with saturated brine, dry, filter, concentrate the filtrate. During the concentration process, add acetonitrile and evaporate twice, filter, wash the filter cake with a small amount of acetonitrile, collect the filter cake, dry, and obtain the product compound 4 (1.91 g, yield: 47.84%). MS: 636 [M+H] +

[0121] 1HNMR(500MHz, DMSO-d6) δ 12.53 (s, 1H), 9.14 (s, 1H), 8.97 (s, 1H), 8.45 (d, J = 5.8 Hz, 1H), 7.75 (s, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 5.9 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 8.8, 2.2 Hz, 1H), 4.51 (t, J = 6.5 Hz, 2H), 4.40 (t, J = 6.1 Hz, 2H), 4.23 (td, J = 10.8, 6.8 Hz, 2H), 4.08 (dd, J = 14.0, 2.8 Hz, 1H), 4.00 (dd, J = 13.8, 6.6 Hz, 1H), 3.38 (q, J = 6.4 Hz, 1H), 3.12 (t, J = 5.7 Hz, 4H), 2.63 (s, 3H), 2.30 - 2.22 (m, 2H), 2.19 (q, J = 8.3, 5.7 Hz, 4H), 2.03 (d, J = 12.6 Hz, 1H), 1.72 (d, J = 4.4 Hz, 0H), 1.70 (s, 1H), 1.56 (t, J = 5.7 Hz, 5H), 1.48 (d, J = 5.7 Hz, 4H), 0.93 (d, J = 6.5 Hz, 3H).

[0122] Example 5 Synthesis of Compound 5 (R)-5 5 -fluoro-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chemical Structure

[0123] Step 1: Synthesis of Compound 5-1

Chemical Structure

[0124] Step 2: Synthesis of Compound 5-2

Chemical Structure

[0125] Step 3: Synthesis of Compound 5-3

Chemical Structure

[0126] Step 4: Synthesis of compound 5-4

Chemical formula

[0127] Step 5: Synthesis of compound 5-5

Chemical formula

[0128] The synthesis method of compound 5-5 was the same as that of compound 1-8, except that compound 1-7 was replaced with compound 5-4. MS of compound 5-5: 618.41 [M+H] +

[0129] Step 6: Synthesis of compound 5-6

Chemical formula

[0130] Step 7: Synthesis of Compound 5-7

Chemical Structure

[0131] Step 8: Synthesis of Compound 5-8

Chemical Structure

[0132] Step 9: Synthesis of Compound 5 - 9

Chemical Structure

[0133] Step 10: Synthesis of Compound 5

Chemical Structure

[0134] Example 6 Synthesis of Compound 6 (R)-5 5 -fluoro-2 6 ,7-dimethyl-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chemical formula

[0135] Step 1: Synthesis of Compound 6

Chemical formula

[0136] 1HNMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.14 (s, 1H), 8.98 (s, 1H), 8.46 (d, J = 5.8 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.20 (d, J = 5.9 Hz, 1H), 4.52 (t, J = 6.4 Hz, 2H), 4.41 (t, J = 6.1 Hz, 2H), 4.26 (d, J = 11.6 Hz, 2H), 4.15 - 4.00 (m, 2H), 3.39 (p, J = 6.4 Hz, 1H), 2.96 (dt, J = 17.3, 6.7 Hz, 4H), 2.64 (s, 3H), 2.24 (d, J = 32.8 Hz, 6H), 2.03 (s, 1H), 1.76 - 1.70 (m, 1H), 1.60 (t, J = 5.9 Hz, 5H), 1.53 (d, J = 5.8 Hz, 4H), 0.93 (d, J = 6.5 Hz, 3H).

[0137] Example 7 Synthesis of Compound 7 2 6 , 9,9 - trimethyl - 5 6 -(9 - methyl - 3,9 - diazaspiro[5.5]undecan - 3 - yl)-5 1 H - 11 - oxa - 4 - aza - 5(2,1)-benzo[d]imidazola - 1(3,4),2(2,4)-dipyridinacycloundecafan - 3 - one

Chemical Structure

[0138] Step 1: Synthesis of Compound 7 - 1

Chemical Structure

[0139] Step 2: Synthesis of compound 7-2

Chemical formula

[0140] Step 3: Synthesis of compound 7-3

Chemical formula

[0141] Step 4: Synthesis of compound 7-4

Chemical formula

[0142] Step 5: Synthesis of Compound 7-5

Chemical Structure

[0143] Step 6: Synthesis of Compound 7-6

Chemical Structure

[0144] Step 7: Synthesis of Compound 7-7 [ka] Compound 7-6 (560 mg, 1.04 mmol), CMBP (2.51 g, 10.40 mmol), and DMF (10 mL) were mixed homogeneously and reacted at 130 °C for 4 hours. The reaction was monitored by LCMS to ensure complete reaction and was directly purified by reverse phase column chromatography (A: 0.05% formic acid aqueous solution, B: MeOH, gradient 60-100% B, 20 min). Spin-dried to obtain the product compound 7-7 (120 mg, yield: 22%). MS: 520.13 [M+H] +

[0145] Step 8: Synthesis of compound 7 [ka] Compound 7-7 (35 mg, 0.07 mmol), 2-methyl-2,7-diazaspiro[3.5]nonane (45.30 mg, 0.27 mmol), Pd2(dba)3 (25 mg, 0.03 mmol), dioxane (2 mL), Ruphos (19 mg, 0.04 mmol), ol) and lithium tert-butoxide (32 mg, 0.40 mmol) were mixed homogeneously and reacted at 100 °C for 1 hour under nitrogen gas protection. The product was directly purified by Prep-HPLC (chromatography column: lunaC18, 30*250 mm, mobile phase (A: 0.1% formic acid aqueous solution, B: acetonitrile, acetonitrile 17-50%, 20 min)) to obtain compound 7 (26 mg, 0.02 mmol, 60%). MS: 608.36 [M+H] +

[0146] 1HNMR (500 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.11 (s, 1H), 9.03 (s, 1H), 8.46 (d, J = 5.7 Hz, 1H), 7.75 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 5.8 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.90 (dd, J = 8.8, 2.3 Hz, 1H), 4.21 - 4.15 (m, 2H), 3.94 (s, 2H), 3.15 (t, J = 5.7 Hz, 4H), 2.64 (s, 3H), 2.46 (s, 4H), 2.27 (s, 3H), 2.11 (dd, J = 11.2, 6.2 Hz, 2H), 1.83 (s, 2H), 1.58 (t, J = 5.7 Hz, 4H), 1.53 (t, J = 5.8 Hz, 4H), 1.23 (s, 2H), 0.90 (s, 6H).

[0147] Example 8 Synthesis of Compound 8 (R)-5 5 -((Dimethyl(oxo)-1 6 sulfanilylidene)amino)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzod[1,2]imidazolo[1,5-a][1,2,4]dipyridino[2,1-f][1,5,9]triazacycloundecan-3-one

Chemical Structure

[0148] Step 1: Synthesis of Compound 8-1

Chemical Structure

[0149] Step 2: Synthesis of compound 8-2

Chemical formula

[0150] Step 3: Synthesis of compound 8-3

Chemical formula

[0151] Step 4: Synthesis of compound 8-4

Chemical Structure

[0152] Step 5: Synthesis of compound 8-5

Chemical Structure

[0153] Step 6: Synthesis of Compound 8-6

Chem.

[0154] Step 7: Synthesis of Compound 8-7

Chem.

[0155] Step 8: Synthesis of Compound 8-8

Chem.

[0156] Step 9: Synthesis of Compound 8

Chemical Structure

[0157] Example 9 Synthesis of Compound 9 (R)-1 6 -fluoro-2 6 ,7-dimethyl-5 6 -(3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one

Chemical Structure

[0158] Step 1: Synthesis of Compound 9-1

Chem.

[0159] Step 2: Synthesis of Compound 9-2

Chem.

[0160] Step 3: Synthesis of Compound 9-3

Chem.

[0161] Step 4: Synthesis of compound 9-7

Chemical formula

[0162] Step 5: Synthesis of compound 9-8

Chemical formula

[0163] Step 6: Synthesis of compound 9-9

Chemical formula

[0164] Step 7: Synthesis of compound 9-10

Chemical formula

[0165] Step 8: Synthesis of compound 9

Chemical formula

[0166] Example 10 Synthesis of Compound 10 (R)-1 6 -fluoro-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chemical formula

[0167] Step 1: Synthesis of Compound 10 [Chemical formula] Compound 9 (20 mg, 0.03 mmol), 0.1 mL of aqueous formaldehyde solution, 1 drop of HOAc, and MeOH (2 mL) were uniformly mixed, and NaBH3CN (4 mg, 0.06 mmol) was added at room temperature, followed by reaction at 60 °C for 1 hour. The reaction solution was directly prepared by Prep-HPLC (chromatography column: luna C18, 30 * 250 mm, mobile phase (A: 0.1% aqueous formic acid solution, B: acetonitrile, 17 - 50% acetonitrile, 20 minutes)) to obtain the product, Compound 10. MS of Compound 10: 612.34 [M + H] +

[0168] Example 11 Synthesis of Compound 11 (R)-2 6 ,5 5 ,7-trimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one [Chemical formula] The synthesis method of Compound 11 was the same as that of Compound 5, except that 4-bromo-2,5-difluoronitrobenzene was replaced with 2-bromo-4-fluoro-5-nitrotoluene. The synthesis route is as follows. MS of Compound 11: 608.36 [M + H] + [Chemical formula]

[0169] Example 12 Synthesis of Compound 12 (R)-2 6 ,5 5 ,7-trimethyl-5 6-(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chem.

[0170] Step 1: Synthesis of Compound 12

Chem.

[0171] Example 13 Synthesis of Compound 13 2 6 ,5 5 -dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chem.

[0172] Step 1: Synthesis of Compound 13-1

Chem.

[0173] Step 2: Synthesis of Compound 13

Chemical formula

[0174] Example 14 Synthesis of Compound 14 5 5 -fluoro-2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzod[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one

Chemical formula

[0175] 1HNMR(500MHz, DMSO-d6) δ 12.62(s, 1H), 9.24(s, 1H), 9.04(s, 1H), 8.46(d, J = 5.6Hz, 1H), 7.71(s, 1H), 7.28(t, J = 9.1Hz, 2H), 7.20(d, J = 5.8Hz, 1H), 4.28(s, 2H), 4.20(s, 2H), 2.98(t, J = 5.3Hz, 4H), 2.64(s, 3H), 2.56(s, 4H), 2.34(s, 3H), 2.01(s, 2H), 1.91(s, 4H), 1.59(dt, J = 19.8, 5.4Hz, 8H).

[0176] Example 15 Synthesis of Compound 15 5 6 -(9 - ((3S,4R)-3 - fluoro - 4 - methoxypiperidin - 1 - yl)-3 - azaspiro[5.5]undecan - 3 - yl)-2 6 - methyl - 5 1 H - 11 - oxa - 4 - aza - 5(2,1)-benzo[d]imidazol - 1(3,4),2(2,4)-dipyridinacycloundecaphane - 3 - one

Chem.

[0177] Step 1: Synthesis of Compound 15 - 1

Chem.

[0178] Step 2: Synthesis of Compound 15-2

Chem.

[0179] Step 3: Synthesis of Compound 15

Chem.

[0180] Example 16 Synthesis of Compound 16 (R)-1 6 ,5 5 -Difluoro-5 6 -(9-(3-Methoxypropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-Dimethyl-5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chem.

[0181] Step 1: Synthesis of Compound 16

Chem.

[0182] Example 17 Synthesis of Compound 17 1 6 -fluoro-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzod]imidazo[1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chemical Structure

Chemical Structure

[0183] Example 18 Synthesis of Compound 18 3-(9-(2 6 -methyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzod]imidazo[1(3,4),2(2,4)-dipyridinacycloundecaphane-5 6 -yl)-3,9-diazaspiro[5.5]undecan-3-yl)propanamide

Chemical Structure

[0184] Step 1: Synthesis of Compound 18

Chemical Structure

[0185] Example 19 Synthesis of Compound 19 (R)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 5 -((2-(methylsulfonyl)ethyl)amino)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one

Chemical formula

[0186] Step 1: Synthesis of compound 19-1

Chemical formula

[0187] Step 2: Synthesis of compound 19-2

Chemical formula

[0188] Step 3: Synthesis of compound 19-3

Chemical formula

[0189] Step 4: Synthesis of compound 19-4

Chemical formula

[0190] Step 5: Synthesis of compound 19-5

Chemical formula

[0191] Step 6: Synthesis of compound 19-6

Chemical formula

[0192] Step 7: Synthesis of compound 19-7

Chemical formula

[0193] Step 8: Synthesis of Compound 19-8

Chemical Structure

[0194] Step 9: Synthesis of Compound 19-9

Chemical Structure

[0195] Step 10: Synthesis of Compound 19

Chemical Structure

[0196] Example 20 Synthesis of Compound 20 (R)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-5 5 -(methylamino)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chemical Structure

Chemical Structure

[0197] Example 21 Synthesis of Compound 21 (R)-7-Methyl-2 6 -(methyl-d3)-5 6 -(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chemical Structure

[0198] Step 1: Synthesis of Compound 21-1

Chemical Structure

[0199] Step 2: Synthesis of Compound 21-2

Chemical Structure

[0200] Step 3: Synthesis of Compound 21-3

Chemical formula

[0201] Step 4: Synthesis of Compound 21-4

Chemical formula

[0202] Step 5: Synthesis of Compound 21-5

Chemical formula

[0203] Step 6: Synthesis of Compound 21-6

Chemical formula

[0204] Step 7: Synthesis of Compound 21-7

Chemical formula

[0205] Step 8: Synthesis of Compound 21

Chemical formula

[0206] Example 22 Synthesis of Compound 22 (R)-1 6 -fluoro-5 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-dipyridinacycloundecaphane-3-one

Chemical formula

[0207] Step 1: Synthesis of Compound 22

Chemical formula

[0208]

Table 1-1

[0209]

Table 1-2

[0210]

Table 1-3

[0211]

Table 1-4

[0212]

Table 1-5

[0213]

Table 1-6

[0214]

Table 1-7

[0215]

Table 1-8

[0216]

Table 1-9

[0217]

Table 1-10

[0218]

Table 1-11

[0219]

Table 1-12

[0220]

Table 1-13

[0221]

Table 1-14

[0222] Example 77: 1 HNMR(500MHz, DMSO-d6) δ 12.53(s, 1H), 9.14(s, 1H), 8.97(s, 1H), 8.46(d, J = 5.7Hz, 1H), 7.77 - 7.73(m, 1H), 7.36(d, J = 8.7Hz, 1H), 7.1 9(d, J = 5.9Hz, 1H), 7.07(d, J = 2.1Hz, 1H), 6.89(dd, J = 8.9, 2.2Hz, 1H), 4.25(dt, J = 10.5, 7.2Hz, 2H), 4.12 - 4.05(m, 1H), 4.00(dd, J = 13.9, 6.5Hz, 1H), 3.34(t, J = 6.3Hz, 2H), 3.22(s, 3H), 3.13(t, J = 5.6Hz, 4H), 2.90(q, J = 7.2Hz, 2H), 2.63(s, 3H), 2.56(dt, J = 22.9, 6.4Hz, 6H), 2.29 - 2.23(m, 1H), 2.03(s, 1H), 1.72(p, J = 6.4Hz, 2H), 1.56(dt, J = 22.6, 5.5Hz, 9H), 0.93(d, J = 6.5Hz, 3H).

[0223] Example 87: 1 HNMR(500MHz, DMSO-d6) δ 12.48(s, 1H), 9.24(s, 1H), 9.05(s, 1H), 8.46(d, J = 5.7Hz, 1H), 7.71(d, J = 1.2Hz, 1H), 7.36(d, J = 8.7Hz, 1H), 7.20(d, J = 5.8Hz, 1H), 7.06(d, J = 2.2Hz, 1H), 6.91(dd, J = 9.0, 2.1Hz, 1H), 4.28(t, J = 4.8Hz, 2H), 4.19(s, 2H), 3.14(t, J = 5.6Hz, 4H), 2.64(s, 3H), 2.48(s, 5H), 2.25(s, 6H), 2.04 - 1.97(m, 3H), 1.92(s, 3H), 1.91(t, J = 9.2Hz, 1H), 1.58(t, J = 5.6Hz, 4H), 1.51(t, J = 5.6Hz, 4H), 1.23(s, 2H).

[0224] Example 89: 1 HNMR(500MHz, DMSO-d6) δ 12.48(s, 1H), 9.24(s, 1H), 9.05(s, 1H), 8.46(d, J = 5.8Hz, 1H), 7.71(d, J = 1.2Hz, 1H), 7.36(dd, J = 8.8, 5.3Hz, 1H), 7.20(d, J = 5.9Hz, 1H), 7.06(d, J = 2.3Hz, 1H), 6.91(dd, J = 8.7, 2.3Hz, 1H), 4.28(t, J = 4.9Hz, 2H), 4.19(t, J = 5.7Hz, 2H), 3.14(t, J = 5.9Hz, 4H), 2.64(s, 3H), 2.53(d, J = 5.4Hz, 2H), 2.04 - 1.97(m, 3H), 1.95 - 1.87(m, 5H), 1.60(dt, J = 25.7, 6.3Hz, 5H), 1.52(s, 1H), 1.44(t, J = 5.7Hz, 3H), 1.23(s, 2H), 0.39(dt, J = 6.1, 3.0Hz, 1H), 0.29 - 0.23(m, 1H).

[0225] Example 90: 1 HNMR(500MHz, DMSO-d6) δ 12.48(s, 1H), 9.24(s, 1H), 9.05(s, 1H), 8.46(d, J = 5.7Hz, 1H), 7.71(s, 1H), 7.36(d, J = 8.7Hz, 1H), 7.20(d, J = 5.8Hz, 1H), 7.05(s, 1H), 6.91(d, J = 8.8Hz, 1H), 4.28(d, J = 5.4Hz, 2H), 4.19(s, 2H), 3.14(t, J = 5.5Hz, 4H), 3.08(s, 3H), 2.88(d, J = 9.4Hz, 1H), 2.64(s, 5H), 2.54(s, 1H), 2.01(s, 2H), 1.92(s, 4H), 1.74(dd, J = 13.8, 4.8Hz, 1H), 1.60 - 1.56(m, 4H), 1.52(s, 5H), 1.39(dd, J = 14.3, 6.4Hz, 1H), 1.13(d, J = 4.5Hz, 6H), 1.04(d, J = 6.6Hz, 3H).

[0226] Example 91: 1HNMR(500MHz, DMSO-d6) δ 12.48 (s, 1H), 9.24 (s, 1H), 9.05 (s, 1H), 8.46 (d, J = 5.7 Hz, 1H), 7.71 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 5.9 Hz, 1H), 7.05 (d, J = 2.2 Hz, 1H), 6.90 (dd, J = 8.9, 2.1 Hz, 1H), 4.28 (t, J = 4.9 Hz, 2H), 4.22 - 4.15 (m, 2H), 3.39 (dt, J = 10.9, 6.3 Hz, 2H), 3.13 (t, J = 5.5 Hz, 3H), 2.64 (s, 3H), 2.55 (q, J = 9.2, 5.5 Hz, 4H), 2.05 - 1.85 (m, 6H), 1.79 - 1.72 (m, 2H), 1 .57 (t, J = 5.6 Hz, 4H), 1.49 (d, J = 5.8 Hz, 4H), 1.23 (s, 1H), 1.13 - 1.05 (m, 7H), 1.06 - 0.98 (m, 2H).

[0227] Comparative Compound 1 As described in Example I - 021 on page 129 of Patent WO2020260252, the following Comparative Compound 1 was prepared. [Chemical Formula]

[0228] Comparative Compound 2 As described in Example 51 on page 47 of CN114163454A, the following Comparative Compound 2 was prepared. [Chemical Formula]

[0229] Pharmacological Experiments Example A: Measurement of Cell Proliferation Inhibitory Activity Suspension cells Ba / F3 (EGFR Del19 / T790M / C797S), Ba / F3 (EGFR L858R / T790M / C797S), Ba / F3 (EGFR Del19 / C797S), and Ba / F3 (EGFR (L858R / C797S) was cultured in RPMI 1640 containing 10% FBS and 1% PS, and adherent cells A431 with EGFR WT were cultured in DMEM containing 10% FBS and 1% PS. The experimental procedure for detecting compound activity is as follows.

[0230] (1) Adherent cells in the logarithmic growth phase were collected, digested with trypsin, counted, and then inoculated into 96-well plates at a certain density and cultured overnight at 37°C and 5% CO2 to allow adhesion. Suspended cells in the logarithmic growth phase were collected, counted, and then inoculated into 96-well plates at a certain density.

[0231] (2) Preparation of the compound: The compound was diluted in DMSO in a 3-fold gradient and then diluted 100-fold with the medium to obtain a 10× working solution.

[0232] (3) A 10× working solution containing different concentrations of the compound was added to each well, and the cells were incubated in an incubator at 37°C and 5% CO2 for 72 hours.

[0233] (4) The 96-well cell culture plate was taken out, 50 μL of CTG reagent was added to each well, shaken for 2 minutes, reacted for 10 minutes, and then the luminescence signal value Lum was read using a PerkinElmer reader.

[0234] (5) The cell survival inhibition rate of each well was calculated, the data was analyzed using GraphPad Prism 6.0 software, and the data was fitted using a non-linear regression equation to obtain a dose-response curve, and the IC 50 of the compound was calculated.

Number

Number

[0235] IC of cell growth inhibitory activity50 The results are shown in Table 2.

[0236] Table 2

Table 2-1

Table 2-2

Table 2-3

[0237] From the above experiments, it is shown that the compound of the present invention has good growth inhibitory activity against double or triple mutant cell lines of Ba / F3(EGFRDel19 / C797S), Ba / F3(EGFRL858R / C797S), Ba / F3(EGFRL858R / T790M / C797S) and Ba / F3(EGFRDel19 / T790M / C797S), but has a weak inhibitory effect on the wild-type cell line A431 with EGFR. From this it can be seen that the compound of the present invention has good cell inhibitory activity and selectivity.

[0238] Example B: Pharmacokinetic study in mice Female BALB / c mice (20 - 30 g) were used to conduct a mouse PK study. The compound was prepared immediately before use. The drug was administered by intravenous injection or forced oral administration, and blood was collected from the orbital venous plexus of the mice. 100 μL of whole blood at each time point was transferred to a K2-EDTA tube.

[0239] 1 mg / kg was administered intravenously, and whole blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, and 24 hours after administration. 5 mg / kg was administered by forced oral administration, and after administration in different batches, whole blood was collected at 0.25, 0.5, 1, 2, 4, 6, and 24 hours, or the mice were sacrificed at 2, 4, and 6 hours to collect the brain. The whole blood samples were centrifuged to separate the plasma, and the brain tissue samples were homogenized by adding four times the volume of buffer. The plasma and brain tissue samples were stored in an -80 °C refrigerator for later use. After precipitating the proteins in the above plasma and brain tissue samples with acetonitrile, the supernatant was collected, mixed with water at a ratio of 1:1, and 10 μL was collected for LC-MS / MS detection. Here, the pharmacokinetic data of the orally administered plasma are shown in Table 3.

[0240] Table 3

Table 3

[0241] 1 mg / kg was administered intravenously, and whole blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 7, 24, 48, and 72 hours after administration. 5 mg / kg was administered by forced oral administration, and after administration in different batches, whole blood was collected at 0.25, 0.5, 1, 2, 4, 7, 24, 48, and 72 hours, or the rats were sacrificed at 4 and 24 hours to collect the brain. The brain tissue samples were homogenized by adding four times the volume of buffer. The whole blood and brain tissue samples were stored in an -80 °C refrigerator for later use. After precipitating the proteins in the above whole blood and brain tissue samples with acetonitrile, the supernatant was collected, mixed with water at a ratio of 1:2, and 10 μL was collected for LC-MS / MS detection. Here, the pharmacokinetic data of the orally administered plasma are shown in Table 4.

[0242]

Table 4

[0243] Example D: Measurement of Metabolic Stability of Liver Microsomes Using human, rat, mouse, and dog liver microsomes, the metabolic stability of the compounds in liver microsomes was investigated. The specific experimental procedures are as follows.

[0244] (1) Add 40 μL of MgCl2 and 306 μL of PBS to each well of a 96-well plate, then add 4 μL of the compound, ensuring that the final concentration of DMSO is ≤ 0.5%. At the same time, prepare a blank well without the compound.

[0245] (2) Add 10 μL of 20 mg / mL liver microsomes to each well and incubate at 37 °C for 10 minutes.

[0246] (3) Add 40 μL of the working solution of NADPH to each well to start the reaction. At the same time, prepare a control well without NADPH.

[0247] (4) After the start of the reaction, collect 50 μL of the sample at 0, 5, 15, and 45 minutes respectively, add the reaction stop solution, and shake for 5 minutes.

[0248] (5) Then, centrifuge the sample at 3220 g for 10 minutes, take out 50 μL of the supernatant, add 200 μL of water, mix and dilute, and analyze by LC-MS / MS.

[0249] In vitro intrinsic clearance (in vitro CL int , unit: μL / min / mg) was calculated from the in vitro half-life t 1 / 2 (minutes) using the following formula (average value measured repeatedly).

Equation

[0250] The results are shown in Table 5.

[0251] [Table 5] From this experiment, it can be seen that the compound of the present invention exhibits excellent hepatic microsomal metabolic stability.

[0252] Although the present invention has been fully described through its embodiments, it should be noted that various changes and modifications will be obvious to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims of the present invention.

Claims

1. A compound represented by formula (I), or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, 【Chemistry 1】 Here, L １ , L ２ These are, independently, combined, -CR ｈ R ｉ -, -NR ｈ Selected from the group consisting of - and -O-, Each R ａ and R ｂ are the same or different and each independently is H, deuterium, halogen, CN, NO ２ , -OR ｅ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -NR ｅ R ｆ , C １－６ alkyl group, C ２－６ alkenyl group and C ２－６ alkynyl group selected from the group consisting of, said C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, R ｅ and R ｆ are optionally substituted by one or more selected from the group consisting of deuterium, halogen, CN, oxo, C １－６ alkyl group, C １－６ haloalkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, -OR ｈ and -NR[[ID=Z]] ｈ R ｉ and is substituted by one or more selected from the group consisting of Each R １ and R ２ They are the same or different, and each is independent of R. ｈ Selected from, or, R １ and R ２ These, along with the atoms to which they are bonded, are 3-14 membered heterocyclyl groups or C ３－１４ A carbocykryl group is formed, and the 3-14 membered heterocyclyl group or C ３－１４ The carbocyclyl group may optionally consist of one or more R groups. ｈ Replaced by, M １ CR ｃ Selected from the group consisting of and N, M ３ M ４ M ７ M ８ and M ９ Each of them operates independently, CR ｃ R ｃ and NR ｃ Selected from the group consisting of, M ２ M ５ M ６ and M １０ These are, independently, non-existent, CR ｃ R ｃ , -CR ｃ R ｃ -CR ｃ R ｃ - and NR ｃ Selected from the group consisting of, R ４ H, deuterium, halogen, -NH ２ , C １－６ alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Haloalkenyl group, C ２－６ Alkynyl group, C ２－６ Haloalkynyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C ３－６ Cycloalkyl groups, C ３－６ It is a halocycloalkyl group or a cyano group. R ５ is H, deuterium, halogen, -NH ２ , -N=S(O)ReR ｆ , -OH, -C(=O)OH, -C(=O)NH ２ , C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ alkoxy group, -NH(C １－６ alkyl group), -N(C １－６ alkyl group) ２ , C ３－８ cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ aryl group or 5-10 membered heteroaryl group, and the -NH ２ , -N=S(O)ReR ｆ , -OH, -C(=O)OH, -C(=O)NH ２ , C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ alkoxy group, -NH(C １－６ alkyl group), -N(C １－６ alkyl group) ２ , C ３－８ cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ aryl group and 5-10 membered heteroaryl group are optionally substituted by one or more R ｈ s, Each R ｃ These are the same or different, and each is independently H, deuterium, halogen, CN, NO ２ , oxo, C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -C ０－６ Alkylene-C ６－１４ Aryl group, -C ０－６ Alkylene-5-14 membered heteroaryl group, -C ０－６ Alkylene-C ３－１４ Carbocyclyl group, -C ０－６ Alkylene-3-14 member heterocyclyl group, -OR ｅ , -NR ｅ R ｆ ,-SR ｅ , -C(O)R ｅ , -N(R ｅ ) C(O)R ｆ , -C(O)NR ｅ R ｆ , -N(R ｅ ) C(O)OR ｆ , -OC(O)NR ｅ R ｆ , -N(R ｅ ) C(O)NR ｆ R ｇ , -S(O)R ｅ , -S(O)(=NR ｅ ) R ｆ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -N(R ｅ ) S(O)R ｆ , -N(R ｅ ) S(O) ２ R ｆ , -C(O)OR ｅ , -OC(O)R ｆ and -OC(O)OR ｇ Selected from the group consisting of the above C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -C ０－６ Alkylene-C ６－１４ Aryl group, -C ０－６ Alkylene-5-14 membered heteroaryl group, -C ０－６ Alkylene-C ３－１４ Carbocyclyl group, -C ０－６ Alkylene-3-14 member heterocyclyl group, R ｅ , R ｆ and R ｇ R is optional. ｈ , -OR ｈ , -NR ｈ R ｉ , -C(O)OR ｈ , -OC(O)R ｈ , -COR ｈ and -C(O)NR ｈ R ｉ Replaced by one or more selected from the group consisting of, R ｅ , R ｆ , R ｇ , R ｈ , R ｉ These are, independently, hydrogen, deuterium, halogen, CN, OH, and NH. ２ , -COOH, -NH(C １－６ Alkyl alkyl group), -N(C １－６ (Alkyl group) ２ , oxo, C １－６ alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -O-C ３－１４ Cycloalkyl groups, -O-C ３－１４ Heterocyclyl group, -S-C ３－１４ Heterocyclyl group, -S-C ３－１４ Cycloalkyl groups, -S-C １－６ Alkyl, -CONH ２ , -CONH(C １－６ Alkyl(alkyl group), -CON(C １－６ (Alkyl group) ２ , -CONH(C ２－６ Alkenyl group), -CON (C ２－６ Alkenyl group) ２ , -CONH(C ２－６ Alkynyl group), -CON (C ２－６ Alkynyl group) ２ , -S(O)-C １－６ Alkyl alkyl group, -S(O) ２ -C １－６ Alkyl alkyl group, -S(O)-C ２－６ Alkenyl group, -S(O) ２ -C ２－６ Alkenyl group, -S(O)-C ２－６ Alkynyl group, -S(O) ２ -C ２－６ Alkynyl group, -S(O)-C ３－１４ Cycloalkyl group, -S(O) ２ -C ３－１４ Heterocyclyl group, -S(O)NH ２ , -S(O)NHC １－６ Alkyl alkyl group, -S(O)N(C) １－６ (Alkyl group) ２ , -CHO, -C(O)-C １－６ Alkyl alkyl group, -C(O)-C ２－６ Alkenyl group, -C ０－６ Alkylene-C ６－１４ Aryl group, -C ０－６ Alkylene-5-14 membered heteroaryl group, -C ０－６ Alkylene-C ３－１４ Carbocyclyl group, and -C ０－６ Selected from the group consisting of alkylene-3-14 membered heterocyclyl groups, the -NH(C １－６ Alkyl alkyl group), -N(C １－６ (Alkyl group) ２ , C １－６ alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -O-C ３－１４ Cycloalkyl groups, -O-C ３－１４ Heterocyclyl group, -S-C ３－１４ Heterocyclyl group, -S-C ３－１４ Cyclo Alkyl alkyl group, -S-C １－６ Alkyl alkyl, -CONH(C １－６ Alkyl(alkyl group), -CON(C １－６ (Alkyl group) ２ , -CONH(C ２－６ Alkenyl group), -CON (C ２－６ Alkenyl group) ２ , -CONH(C ２－６ Alkynyl group), -CON (C ２－６ Alkynyl group) ２ , -S(O)-C １－６ Alkyl alkyl group, -S(O) ２ -C １－６ Alkyl alkyl group, -S(O)-C ２－６ Alkenyl group, -S(O) ２ -C ２－６ Alkenyl group, -S(O)-C ２－６ Alkynyl group, -S(O) ２ -C ２－６ Alkynyl group, -S(O)-C ３－１４ Cycloalkyl group, -S(O) ２ -C ３－１４ Heterocyclyl group, -S(O)NHC １－６ Alkyl alkyl group, -S(O)N(C) １－６ (Alkyl group) ２ , -C(O)-C １－６ Alkyl alkyl group, -C(O)-C ２－６ Alkenyl group, -C ０ - ６ Alkylene-C ６－１４ Aryl group, -C ０ - ６ Alkylene-5-14 membered heteroaryl group, -C ０－６ Alkylene-C ３－１４ Cycloalkyl groups, and -C ０－６ The alkylene-3-14 member heterocyclyl group can optionally contain hydrogen, deuterium, halogen, CN, OH, or NH. ２ ,-COOH, oxo, C １－６ alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Haloalkenyl group, C ２－６ Alkynyl group, C ２－６ Haloalkynyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, -NH(C) １－６ Alkyl alkyl group), -NH(C １－６ Haloalkyl group), -N(C １－６ (Alkyl group) ２ , -N(C １－６ (Halogen) ２ , -N(C １－６ (Alkyl alkyl group) (C １－６ Haloalkyl group), -S(O)-C １－６ Alkyl alkyl group, -S(O) ２ -C １－６ Alkyl alkyl group, -S(O)-C ２－６ Alkenyl group, -S(O) ２ -C ２－６ Alkenyl group, -S(O)-C ２－６ Alkynyl group, -S(O) ２ -C ２－６ Alkynyl group, -S(O)-C ３－１４ Cycloalkyl group, -S(O) ２ -C ３－１４ Heterocyclyl group, -S(O)NHC １－６ Alkyl alkyl group, -S(O)N(C) １－６ (Alkyl group) ２ , -COO(C １－６ Alkyl alkyl group), -COO(C １－６ Haloalkyl group), -CONH(C １－６ Alkyl(alkyl group), -CONH(C １－６ Haloalkyl group), -CON(C １－６ (Alkyl group) ２ , -CON(C １－６ (Halogen) ２ , -CON(C １－６ (Alkyl alkyl group) (C １－６ Haloalkyl group), -C ０－６ Alkylene-NHC(=O)C １－６ Alkyl alkyl group, -C ０－６ Alkylene-NHC(=O)C １－６ Haloalkyl group, -C ０－６ Alkylene-NHC(=O)C ２－６ Alkenyl group, substituted or unsubstituted -C ０－６ Alkylene-C ３－１４ Carbocyclyl group, and substituted or unsubstituted -C ０－６ Substituted by one or more selected from the group consisting of alkylene-3-14 membered heterocyclyl groups, m is 0, 1, 2, or 3. n is 0, 1, 2, or 3, or A compound represented by formula (I), or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, where r is 0, 1, 2, 3, 4, or 5.

2. L １ Ha-CR ｈ R ｉ A compound according to claim 1, characterized by being selected from the following, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative thereof.

3. L １ ha-CH ２ The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized by being -.

4. L ２ The compound according to claim 1, characterized in that the bond is -O-, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative thereof.

5. R １ or R ２ These are H and C, which are independent of each other. １－６ Alkyl and deuterium-substituted C １－６ Alkyl group, hydroxyl group, C １－６ Haloalkyl groups, halogens, -NH ２ , C １－６ Alkoxy groups and C １－６ A compound according to claim 1, characterized by being selected from the group consisting of haloalkoxy groups, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative thereof.

6. R １ or R ２ is H, or C １－３ The compound according to claim 1, characterized by being an alkyl group, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative.

7. R １ and R ２ Along with the atoms to which they are bonded, 【Chemistry 2】 The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized by forming a compound. 【Request Item 8】 【Chemistry 3】 teeth, 【Chemistry 4】 The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that it is such.

9. R ａ H, deuterium, halogen, CN, OH, NH ２ , C １－６ Alkyl and deuterium-substituted C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Haloalkyl groups, or -NH-C(O)-C １－６ The compound according to claim 1, characterized by being an alkyl group, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative.

10. R ａ H, deuterium, F, Cl, CN, NH ２ , C １－３ Alkyl and deuterium-substituted C １－３ alkyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, or C １－３ The compound according to claim 1, characterized by being a haloalkyl group, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative.

11. R ａ is H or CH ３ The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that it is such.

12. R ｂ H, deuterium, halogen, CN, OH, NH ２ , C １－６ Alkyl and deuterium-substituted C １－６ alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, -S-C １－６ Alkyl alkyl group, -S(=O)-CH ３ , -S (=O) ２ -C １－６ Alkyl alkyl group, -S (=O) ２ -C ３－６ The compound according to claim 1, characterized by being a cycloalkyl group or an -O-3-6 membered heterocyclyl group, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative thereof.

13. R ｂ H, deuterium, F, Cl, -OCH ３ , C １－３ Alkyl alkyl group, CD ３ CF ３ , CN, NH ２ , -S-CH ３ , -S(=O)-CH ３ , 【Transformation 5】 The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that it is such.

14. R ｂ is H or C １－３ It is an alkyl group, preferably R ｂ is H or CH ３ The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that it is such.

15. R ４ The compound according to claim 1, characterized in that is H, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative.

16. R ５ H, halogen, C １－６ Alkyl, -NH ２ ,-NH(C １－６ Alkyl alkyl group), -N(C １－６ (Alkyl group) ２ , C ３－６ The C is a cycloalkyl group or a 4-6 membered heterocyclyl group. １－６ Alkyl, -NH ２ ,-NH(C １－６ Alkyl alkyl group), -N(C １－６ (Alkyl group) ２ , C ３－６ Cycloalkyl groups and 4-6 membered heterocyclyl groups may optionally be OH, NH ２ , oxo, C １－６ alkyl group, C １－６ Alkoxy group, -S(O) ２ -C １－６ Alkyl alkyl group, -C １－６ Alkyl-S(O) ２ -C １－６ Alkyl alkyl, -NH(C) １－６ alkyl groups), and -N(C １－６ (Alkyl group) ２ The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative, characterized by being substituted by one or more selected from the group consisting of the above.

17. R ５ H, F, Cl, CH ３ , -NH ２ , 【Transformation 6】 The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that it is such.

18. R ５ The compound according to claim 1, characterized in that is H, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative.

19. R ｃ H, deuterium, halogen, NO ２ , CN, OH, NH ２ , C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C ３－６ It is a cycloalkyl group or a 3-6 membered heterocyclyl group, and the -OH, NH ２ , C １－６ alkyl group, C ２ - ６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C ３－６ Cycloalkyl groups and 3-6 The member heterocyclyl group may optionally contain a halogen, C １－６ alkyl group, C １－６ Alkoxy group, NH ２ , -COOH, -NH(C １－６ Alkyl alkyl group), -N(C １－６ (Alkyl group) ２ , C ３－６ Cycloalkyl group, 3-6 membered heterocyclyl group, -CONH ２ , -CONH(C １－６ Alkyl(alkyl group), -CON(C １－６ (Alkyl group) ２ , -CONH(C ２－６ Alkenyl group), -CON (C ２－６ Alkenyl group) ２ , -CONH(C ２－６ Alkynyl group), -CON (C ２－６ Alkynyl group) ２ , substituted or unsubstituted -CO-3-6 membered heterocyclyl group, -O-C １－６ Haloalkyl groups, -OC(=O)NH ２ , -OCONH(C １－６ Alkyl alkyl groups), and -OCON(C １－６ (Alkyl group) ２ The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative, characterized by being substituted by one or more selected from the group consisting of the above.

20. R ｃ H, deuterium, CH ３ CD ３ ,CH ２ CH ３ , CH (CH ３ ) ２ , -C(CH ３ ) ３ , OH, F, Cl, NH ２ , 【Transformation 7】 The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that it is such. 【Request Item 21】 【Chemistry 8】 teeth, 【Chemistry 9】 The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that it is such. 【Request Item 22】 【Chemistry 10】 teeth, 【Chemistry 11】 The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that it is such. 【Request Item 23】 【Chemistry 12】 teeth, 【Chemistry 13】 The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that it is such.

24. The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that m is 0, 1, or 2.

25. The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that n is 0, 1, or 2.

26. The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative, characterized in that r is 2, 3, or 4.

27. The compound represented by formula (I) above is selected from the compounds represented by formula (II) shown below, 【Chemistry 14】 Here, L in the compound represented by formula (II) １ , L ２ , R ａ , R ｂ , R １ , R ２ , R ４ , R ５ M １ M ２ M ３ M ４ M ５ M ６ M ７ M ８ M ９ M １０ The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative, characterized in that the definitions of m, n and r are as defined in claim 1.

28. The compound represented by formula (I) above is selected from the compounds represented by formula (III) shown below, 【Chemistry 15】 Here, R in the compound represented by formula (III) ａ , R ｂ , R ｃ , R １ , R ２ The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative, characterized in that the definitions of m and n are as defined in claim 1.

29. The compound represented by formula (I) above is selected from the compounds represented by formula (IV) shown below, 【Chemistry 16】 Here, R in the compound represented by formula (IV) ａ , R ｂ , R ｃ , R １ , R ２ The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative, characterized in that the definitions of m and n are as defined in claim 1.

30. The compound represented by formula (I) above is selected from the compounds represented by formula (V) shown below, 【Chemistry 17】 Here, R in the compound represented by formula (V) ａ , R ｂ , R ｃ , R １ The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative, characterized in that the definitions of m and n are as defined in claim 1.

31. The aforementioned compound, 2 ６ -Methyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 2 ６ -Methyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 ６ ,7-dimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 ６ ,7-dimethyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ５ -Fluoro-2 ６ ,7-dimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ５ -Fluoro-2 ６ ,7-dimethyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipy Rigina Cyclo Undeca Fan-3-On, 2 ６ ,9,9-trimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ５ -((dimethyl(oxo)-1 ６ Sulfanylidene(amino)-2 ６ ,7-dimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-1 ６ -Fluoro-2 ６ ,7-dimethyl-5 ６ - (3,9-diazaspiro[5.5]undekan-3-il)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-1 ６ -Fluoro-2 ６ ,7-dimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 ６ , 5 ５ ,7-trimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 ６ , 5 ５ ,7-trimethyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 2 ６ , 5 ５ -Dimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ５ -Fluoro-2 ６ -Methyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-((3S,4R)-3-fluoro-4-methoxypiperidine-1-yl)-3-azaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-1 ６ , 5 ５ -Difluoro-5 ６ -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ６ -Fluoro-5 ６ -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 3-(9-(2 ６ -methyl-3-oxo-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafane-5 ６ -yl)-3,9-diazaspiro[5.5]undecane-3-yl)propanamide, (R)-2 ６ ,7-dimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 ５ -((2-(methylsulfonyl)ethyl)amino)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 ６ ,7-dimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 ５ -(methylamino)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-7-methyl-2 ６ -(methyl-d) ３ )-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-1 ６ -Fluoro-5 ６ -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ６ ,2 ６ -Dimethyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ２ ,2 ６ -Dimethyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ２ -Fluoro-2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl]-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ２ -Fluoro-1 ５ ,2 ６ -Dimethyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl]-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl]-1 ６ -(trifluoromethyl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ５ ,2 ６ -Dimethyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ６ -amino-2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl]-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ６ -Fluoro-2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl]-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ６ -Chloro-2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ５ -Fluoro-2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ６ - Methoxy-2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ５ - Methoxy-2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-3-oxo-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafane-1 ２ -Carbonitrile, 2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-3-oxo-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafane-1 ６ -Carbonitrile, 2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-3-oxo-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafane-1 ５ -Carbonitrile, 2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-1 ５ -(oxetane-3-yloxy)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 1 ５ -Fluoro-1 ６ - Methoxy-2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl]-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ６ -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 ６ ,7-dimethyl-5 ６ -(9-(tetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ６ -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ６ -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ６ -(9-(4-methoxycyclohexyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza 5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ６ -(9-cyclopropyl-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ５ -Fluoro-5 ６ -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ５ -Fluoro-5 ６ -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ５ -Fluoro-2 ６ ,7-dimethyl-5 ６ -(9-(tetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ５ -Fluoro-5 ６ -(9-(4-methoxycyclohexyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ６ -(9-cyclopropyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 ５ -Fluoro-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ６ -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ , 5 ５ ,7-trimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 2 ６ -methyl-5-(9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacyclodecafan-3-one, 5 ６ -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ , 5 ５ -Dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-cyclopropyl-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ , 5 ５ -Dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ , 5 ５ -Dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 2 ６ , 5 ５ -Dimethyl-5 ６ -(9-(oxetan-3-ylmethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ , 5 ５ -Dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ , 5 ５ -Dimethyl-5 １ H-12-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacyclododecafan-3-one, 5 ５ -Fluoro-5 ６ -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ５ -Fluoro-2 ６ -Methyl-5 ６ -(9-(oxetan-3-ylmethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ５ -Fluoro-2 ６ -Methyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ５ -Fluoro-5 ６ -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-cyclopropyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 ５ -Fluoro-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 ６ ,7-bis(methyl-d ３ )-5 ６ -(9-(methyl-d ３ )-3,9-diazaspiro[5.5]undecan-3-il)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 2 ６ -Methyl-5 ６ -(9-(methyl-d ３ )-3,9-diazaspiro[5.5]undecan-3-il)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ５ -Fluoro-2 ６ ,7-dimethyl-5 ６ -(9-(methyl-d ３ )-3,9-diazaspiro[5.5]undecan-3-il)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ５ -Fluoro-2 ６ -Methyl-5 ６ -(9-(methyl-d ３ )-3,9-diazaspiro[5.5]undecan-3-il)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundekaph Fan-3-on, 2 ６ , 5 ５ -Dimethyl-5 ６ -(9-(methyl-d ３ )-3,9-diazaspiro[5.5]undecan-3-il)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 ６ , 5 ５ ,7-trimethyl-5 ６ -(9-(methyl-d ３ )-3,9-diazaspiro[5.5]undecan-3-il)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 2 ６ -Methyl-5 ６ -(3-methyl-3-azaspiro[5.5]undecane-9-yl)-5 １ H-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ６ -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ６ -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ５ -amino-2 ６ ,7-dimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-1 ６ -Fluoro-5 ６ -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-1 ６ -Fluoro-2 ６ ,7-dimethyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (7R)-5 ６ -(9-(2,2-dimethyloxetan-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-di Pyridinacycloundecafan-3-one, (7R)-2 ６ ,7-dimethyl-5 ６ -(9-(2-methyloxetan-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one (R)-2 ６ ,7-dimethyl-5 ６ -(9-(1-methylazetidine-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 ６ ,7-dimethyl-5 ６ -(9-(3-methyloxetan-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ５ -Fluoro-5 ６ -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-(2-(dimethylamino)ethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (7R)-5 ６ -(9-(4-methoxy-4-methylpentan-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-cyclopropyl-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-(4-methoxy-4-methylpentan-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ６ -(9-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ -Methyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 5 ５ -Chloro-2 ６ -Methyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ５ -Chloro-2 ６ ,7-dimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, 6'-methyl-6'-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)spiro[cyclopropane-1,7'-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan]-3'-one, 2 ６ ,8,8-trimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d] Imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-3-(9-(2) ６ ,7-dimethyl-3-oxo-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-5-yl)-3,9-diazaspiro[5.5]undecane-3-yl)propanamide, (R)-2 ６ ,7-dimethyl-5 ６ -(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-5 ５ -(oxetane-3-ylamino)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2-(9-(16-fluoro-2 ６ ,7-dimethyl-3-oxo-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafane-5 ６ -yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethylmethylcarbamate, (R)-3-(9-(2) ６ ,7-dimethyl-3-oxo-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafane-5 ６ -yl)-3,9-diazaspiro[5.5]undecane-3-yl)-N,N-dimethylpropanamide, (R)-3-(9-(1) ６ , 5 ５ -Difluoro-2 ６ ,7-dimethyl-3-oxo-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafane-5 ６ -yl)-3,9-diazaspiro[5.5]undecane-3-yl)propanamide, (R)-1 ６ , 5 ５ -Difluoro-5 ６ -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-3-(9-(1) ６ -Fluoro-2 ６ ,7-dimethyl-3-oxo-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafane-5 ６ -yl)-3,9-diazaspiro[5.5]undecane-3-yl)-N,N-dimethylpropanamide, (R)-2 ６ ,7-dimethyl-5 ６ -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-3-oxo-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafane-1 ６ -Carbonitrile, (R)-5 ６ -(9-(3-(azetidine-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ６ -(9-(3-(azetidine-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undecane-3-yl)-1 ６ -Fluoro-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-2 ６ ,7-dimethyl-5 ６ -(9-(2-(trifluoromethoxy)ethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-1 ６ -Fluoro-2 ６ ,7-dimethyl-5 ６ -(9-(2-(trifluoromethoxy)ethyl)-3,9-diazaspiro[5.5]undecane-3-yl)-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, (R)-5 ６ -(9-(3-(3,3-dimethylazetidine-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2 ６ ,7-dimethyl-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafan-3-one, and (R)-2-(9-(2) ６ ,7-dimethyl-3-oxo-5 １ H-11-oxa-4-aza-5(2,1)-benzo[d]imidazola-1(3,4),2(2,4)-dipyridinacycloundecafane-5 ６ -yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethylcarbamate A compound according to claim 1, characterized by being selected from the group consisting of the following, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated derivative thereof.

32. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 31, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative thereof, and at least one pharmaceutically acceptable excipient.

33. The use of a compound according to any one of claims 1 to 31, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated derivative, in the preparation of an antitumor drug, The aforementioned antitumor drug is used for head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, multiple myeloma, or mesothelioma. use.

34. Use of the pharmaceutical composition according to claim 32 in the preparation of an antitumor drug, The aforementioned antitumor drug is used for head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, multiple myeloma, or mesothelioma. use.

35. The use according to claim 33, wherein the tumor is a malignant tumor having an EGFR gene mutation, and preferably the EGFR gene mutation is at least one selected from the group consisting of an EGFR Del19 gene mutation, an EGFR L858R gene mutation, an EGFR T790M gene mutation, and an EGFR C797S gene mutation.

36. The use according to claim 34, wherein the tumor is a malignant tumor having an EGFR gene mutation, and preferably the EGFR gene mutation is at least one selected from the group consisting of an EGFR Del19 gene mutation, an EGFR L858R gene mutation, an EGFR T790M gene mutation, and an EGFR C797S gene mutation.

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