Macrocyclic compound as well as pharmaceutical composition and application thereof

Abstract

The invention relates to a macrocycle-containing inhibitor, a composition and application of the macrocycle-containing inhibitor. In particular, the present invention relates to a compound represented by formula (I), a pharmaceutical composition containing the compound, and uses of the compound as an EGFR inhibitor in treatment of cancer-related diseases. # imgabs0 #

Description

Macrocyclic compound and its pharmaceutical composition and application Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a macrocyclic compound and a pharmaceutical composition and application thereof. Background Art

[0002] The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that belongs to the ErbB family of tyrosine kinase receptors. Activation of EGFR leads to autophosphorylation of the receptor tyrosine kinase, which initiates a cascade of downstream signaling pathways involved in regulating cell proliferation, differentiation, and survival. EGFR is aberrantly activated by various mechanisms, such as receptor overexpression, mutation, ligand-dependent receptor dimerization, and ligand-independent activation, and has been implicated in the development of multiple human cancers.

[0003] In the field of cancer, lung cancer is one of the malignant tumors with the highest growth in morbidity and mortality, and poses the greatest threat to human health and life. Therefore, the development of treatments for lung cancer is a major research focus for anti-tumor drugs. Because epidermal growth factor receptor (EGFR) is a major driver of lung cancer (mutations account for over 20% and are more prevalent in Asian populations), the development of EGFR inhibitors as targeted therapies for lung cancer patients has attracted widespread attention from drug researchers.

[0004] Among them, in non-small cell lung cancer (NSCLC), EGFR mutations account for approximately 12-47%, of which the two most common mutations are deletion mutations in exon 19 (del19) and point mutations in exon 21 (mainly L858R). The resulting abnormal activation of epidermal growth factor receptor (EGFR) that is independent of ligands promotes the proliferation of tumor cells, which is also the scientific basis for the development of EGFR inhibitors. The first generation (Gefitinib) used in clinical practice Erlotini and icotinib ), second generation (Afatinib Dacomitinib and Neratinib The objective response rate of first-generation and third-generation (osimertinib, AZD9291) EGFR inhibitors for NSCLC tumors with these two mutations is approximately 60-85%. However, this response does not last a lifetime. Usually, patients will develop varying degrees of drug resistance 9.2 to 14.7 months after taking first- or second-generation EGFR inhibitors. Of these drug-resistant mutations, approximately 50-70% occur at the gatekeeper site T790M on EGFR. This mutation can cause changes in the spatial conformation of EGFR, increase EGFR's affinity for ATP, and thus weaken the inhibitor's ability to bind to EGFR. Although the second-generation EGFR inhibitor Afatinib has inhibitory activity against the EGFR-T790M mutation in vitro, it has not been able to overcome the drug resistance caused by the T790M mutation in clinical application. Moreover, it is difficult for both first- and second-generation EGFR inhibitors to exclude inhibition of wild-type EGFR, resulting in significant skin toxicity (such as acne-like rash). This situation was not resolved until the emergence of the third-generation inhibitor osimertinib.

[0005] Although osimertinib addresses the T790M mutation, clinical studies have observed that in EGFR T790M-positive NSCLC patients receiving osimertinib as second-line treatment, drug resistance develops after 10 months of medication, with 20-40% of these patients harboring C797S mutations (i.e., cis or trans triple mutations of del19 / T790M / C797S or L858R / T790M / C797S). While osimertinib also has a positive effect on EGFR-sensitive mutations (del19 or L858R) and has been approved for first-line indications, drug-resistant mutations develop after approximately 19 months of use, 7% of which harbor C797S double mutations (i.e., del19 / C797S or L858R / C797S).

[0006] Currently, three generations of EGFR inhibitors have been approved for marketing. With their approval for first- and second-line indications, they are widely used clinically. However, drug resistance often develops after a period of use, resulting in a failure to significantly improve patients' effective survival. Therefore, there is an urgent need to develop next-generation EGFR inhibitors to meet more clinical needs.

[0007] Summary of the Invention

[0008] In order to solve the above problems, the present invention provides a macrocyclic compound that can serve as an inhibitor of various EGFR mutations for the treatment of cancer.

[0009] The macrocyclic compound provided by the present invention is a compound represented by formula (I), or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof:

[0010] in,

[0011] L1, L2 are independently selected from a bond, -CR h R i -、-NR h -or-O-;

[0012] Each R a 、R b The same or different, each independently selected from H, deuterium, halogen, CN, NO2, -OR e 、-SR e 、-S(O)R e 、-S(O)2R e 、-NR e R f 、C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R e and R f Optionally replaced by one or more deuterium, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR h or -NR h R i replace;

[0013] Each R1 and R2 are the same or different and are independently selected from R h ;or

[0014] R1 and R2 together with the atoms to which they are attached form a 3-14 membered heterocyclic group or a C 3-14 Carbocyclic group; wherein, the 3-14 membered heterocyclic group or C 3-14 The carbocyclyl group is optionally substituted by one or more R h replace;

[0015] M1 is selected from CR c or N;

[0016] M3, M4, M7, M8 and M9 are independently selected from CR c R c or NR c ;

[0017] M2, M5, M6 and M 10 Independently selected from absence, CR c R c 、-CR c R c -CRc R c - or NR c ;

[0018] R4 is H, deuterium, halogen, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 a halocycloalkyl group or a cyano group;

[0019] R5 is H, deuterium, halogen, -NH2, -N=S(O)R e R f ,-OH,-C(=O)OH,-C(=O)NH2,C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein said -NH2, -N=S(O)R e R f ,-OH,-C(=O)OH,-C(=O)NH2,C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R h replace.

[0020] Each R c The same or different, each independently selected from H, deuterium, halogen, CN, NO2, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6Alkylene-C 3-14 Carbocyclic group, -C 0-6 Alkylene-3-14 membered heterocyclic 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)2R e 、-S(O)NR e R f 、-S(O)2NR e R f 、-N(R e )S(O)R f 、-N(R e )S(O)2R f 、-C(O)OR e 、-OC(O)R f OR-OC(O)OR g ; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclic group, -C 0-6 Alkylene-3-14 membered heterocyclic group, R e 、R f and R g Optionally, one or more R h 、-OR h 、-NR h R i 、-C(O)OR h 、-OC(O)R h 、-COR h or -C(O)NR hR i replace;

[0021] R e 、R f 、R g 、R h 、R i are independently selected from hydrogen, deuterium, halogen, CN, OH, -NH2, -COOH, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 3-14 Cycloalkyl, -OC 3-14 Heterocyclic group, -SC 3-14 Heterocyclic group, -SC 3-14 Cycloalkyl, -SC 1-6 Alkyl, -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2, -CONH(C 2-6 alkenyl), -CON(C 2-6 alkenyl)2, -CONH(C 2-6 Alkynyl), -CON(C 2-6 Alkynyl)2, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)-C 2-6 Alkenyl, -S(O)2-C 2-6 Alkenyl, -S(O)-C 2-6 Alkynyl, -S(O)2-C 2-6 Alkynyl, -S(O)-C 3-14 Cycloalkyl, -S(O)2-C 3-14 Heterocyclic group, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C 1-6 Alkyl)2, -CHO, -C(O)-C 1-6 Alkyl, -C(O)-C 2-6 Alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclic or -C 0-6 Alkylene-3-14 membered heterocyclic group; wherein the -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 3-14 Cycloalkyl, -OC 3-14 Heterocyclic group, -SC 3-14 Heterocyclic group, -SC 3-14 Cycloalkyl, -SC 1-6 Alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2, -CONH(C 2-6 alkenyl), -CON(C 2-6 alkenyl)2, -CONH(C 2-6 Alkynyl), -CON(C 2-6 Alkynyl)2, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)-C 2-6 Alkenyl, -S(O)2-C 2-6 Alkenyl, -S(O)-C 2-6 Alkynyl, -S(O)2-C 2-6 Alkynyl, -S(O)-C 3-14 Cycloalkyl, -S(O)2-C 3-14 Heterocyclyl, -S(O)NHC 1-6 Alkyl, -S(O)N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, -C(O)-C 2-6 Alkenyl, -C0-6 alkylene-C 6-14 Aryl, -C0-6 alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Cycloalkyl and -C 0-6 Alkylene-3-14 membered heterocyclic radicals are optionally replaced by one or more hydrogen, deuterium, halogen, CN, OH, -NH2, -COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NH(C 1-6 Alkyl), -NH(C 1-6 Haloalkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 Haloalkyl)2, -N(C 1-6Alkyl)(C 1-6 Halogenated alkyl), -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)-C 2-6 Alkenyl, -S(O)2-C 2-6 Alkenyl, -S(O)-C 2-6 Alkynyl, -S(O)2-C 2-6 Alkynyl, -S(O)-C 3-14 Cycloalkyl, -S(O)2-C 3-14 Heterocyclyl, -S(O)NHC 1-6 Alkyl, -S(O)N(C 1-6 Alkyl)2, -COO(C 1-6 Alkyl), -COO(C 1-6 Halogenated alkyl), -CONH(C 1-6 alkyl), -CONH(C 1-6 Halogenated alkyl), -CON(C 1-6 alkyl)2, -CON(C 1-6 Halogenated alkyl)2, -CON(C 1-6 Alkyl)(C 1-6 haloalkyl), -C 0-6 Alkylene-NHC(=O)C 1-6 Alkyl, -C 0-6 Alkylene-NHC(=O)C 1-6 Haloalkyl, -C 0-6 Alkylene-NHC(=O)C 2-6 Alkenyl, substituted or unsubstituted -C 0-6 Alkylene-C 3-14 Carbocyclic or substituted or substituted-C 0-6 Alkylene-3-14 membered heterocyclic substitution;

[0022] m is 0, 1, 2, or 3;

[0023] n is 0, 1, 2 or 3; or

[0024] r is 0, 1, 2, 3, 4 or 5.

[0025] In some embodiments, L1 in formula (I) is selected from -CR h R i -.

[0026] In some embodiments, L1 in formula (I) is selected from -CH2-.

[0027] In some embodiments, L2 in formula (I) is a bond or -O-.

[0028] In some embodiments, R1 or R2 in formula (I) are independently selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl, halogen, -NH2, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy.

[0029] In some embodiments, R1 or R2 in formula (I) is H or C 1-3 alkyl.

[0030] In some embodiments, R1 and R2 in formula (I) together with the atoms to which they are attached form

[0031] In some embodiments, in formula (I) for

[0032] In some embodiments, R in formula (I) a H, deuterium, halogen, CN, OH, -NH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or -NH-C(O)-C 1-6 alkyl.

[0033] In some embodiments, R in formula (I) a H, deuterium, F, Cl, CN, -NH2, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy or C 1-3 Halogenated alkyl.

[0034] In some embodiments, R in formula (I) a is H or CH3.

[0035] In some embodiments, R in formula (I) b H, deuterium, halogen, CN, OH, -NH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -SC 1-6Alkyl, -S(=O)-CH3, -S(=O)2-C 1-6 Alkyl, -S(=O)2-C 3-6 Cycloalkyl or -O-3-6 membered heterocyclic group.

[0036] In some embodiments, R in formula (I) b H, deuterium, F, Cl, -OCH3, C 1-3 Alkyl, CD3, CF3, CN, -NH2, -S-CH3, -S(=O)-CH3,

[0037] In some embodiments, R in formula (I) b H or C 1-3 Alkyl; preferably, R b is H or CH3.

[0038] In some embodiments, R4 in formula (I) is H.

[0039] In some embodiments, R5 in formula (I) is H, halogen, C 1-6 Alkyl, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; wherein the C 1-6 Alkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups are optionally substituted with one or more OH, -NH2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, -S(O)2-C 1-6 Alkyl, -C 1-6 Alkyl-S(O)2-C 1-6 Alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2 substituted.

[0040] In some embodiments, R5 in formula (I) is H, F, Cl, CH3, -NH2,

[0041] In some embodiments, R5 in formula (I) is H.

[0042] In some embodiments, R in formula (I) c H, deuterium, halogen, NO2, CN, OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein said OH, -NH2, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted with one or more halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -COOH, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2, -CONH(C 2-6 alkenyl), -CON(C 2-6 alkenyl)2, -CONH(C 2-6 Alkynyl), -CON(C 2-6 Alkynyl)2, substituted or unsubstituted -CO-3-6 membered heterocyclic group, -OC 1-6 Haloalkyl, -OC(=O)NH2, -OCONH(C 1-6 alkyl) or -OCON(C 1-6 alkyl)2 substituted.

[0043] In some embodiments, R in formula (I) c H, deuterium, CH3, CD3, CH2CH3, CH(CH3)2, -C(CH3)3, OH, F, Cl, -NH2,

[0044] In some embodiments, in formula (I) for

[0045] In some embodiments, in formula (I) for

[0046] In some embodiments, in formula (I) for

[0047] In some embodiments, m in formula (I) is 0, 1 or 2.

[0048] In some embodiments, n in formula (I) is 0, 1 or 2.

[0049] In some embodiments, r in formula (I) is 2, 3 or 4.

[0050] In some embodiments, the compound of formula (I) is selected from the compound of formula (II) shown below:

[0051] Wherein, 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 above in formula (I).

[0052] In some embodiments, the compound of formula (I) is selected from the compound of formula (III) shown below:

[0053] Wherein, R in the compound of formula (III) a 、R b 、R c , R1, R2, m and n are as defined above in formula (I).

[0054] In some embodiments, the compound of formula (I) is selected from the compound of formula (IV) shown below:

[0055] Wherein, R in the compound of formula (IV) a 、R b 、R c , R1, R2, m and n are as defined above in formula (I).

[0056] In some embodiments, the compound of formula (I) is selected from the compound of formula (V) shown below:

[0057] Wherein, R in the compound of formula (V) a 、R b 、R c , R1, m and n are as defined above in formula (I).

[0058] In some embodiments, the compound represented by formula (I) is selected from the following compounds, or stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0059] 2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one;

[0060] 2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one;

[0061] (R)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0062] (R)-2 6 ,7-dimethyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0063] (R)-5 5 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0064] (R)-5 5 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0065] 2 6 ,9,9-trimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0066] (R)-5 5 -((dimethyl(oxo)-l 6 Sulfonamide)amino)-2 6 ,7-dimethyl 5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxo-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0067] (R)-1 6 -Fluorine-2 6 ,7-dimethyl 5 6 -(3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0068] (R)-1 6 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0069] (R)-2 6 , 5 5 ,7-trimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0070] (R)-2 6 , 5 5 ,7-trimethyl-5 6-(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0071] 2 6 , 5 5 -Dimethyl-5- 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0072] 5 5 -Fluorine-2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0073] 5 6 -(9-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)-3-azaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0074] (R)-1 6 ,5 5 -Difluoro-5- 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0075] 1 6 -Fluoro-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0076] 3-(9-(2 6 -methyl-3-oxo-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)propanamide;

[0077] (R)-2 6 ,7-dimethyl 5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5 -((2-(methylsulfonyl)ethyl)amino)-5-(2-methylsulfonyl)ethyl)amino)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0078] (R)-2 6 ,7-dimethyl 5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5 -(methylamino)-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0079] (R)-7-methyl-2 6 -(methyl-d3)5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0080] (R)-1 6 -Fluoro-5 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0081] 16 ,2 6 -Dimethyl-5- 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0082] 1 2 ,2 6 -Dimethyl-5- 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5-(9- ... 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0083] 1 2 -Fluorine-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0084] 1 2 -Fluorine-1 5 ,2 6 -Dimethyl-5- 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0085] 2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1 6 -(trifluoromethyl)-5-(trifluoromethyl)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0086] 1 5 ,2 6 -Dimethyl-5- 6-(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5-(9-oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0087] 1 6 -Amino-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0088] 1 6 -Fluorine-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0089] 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]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0090] 1 5 -Fluorine-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0091] 1 6 -Methoxy-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5-(9-oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)- 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0092] 1 5 -Methoxy-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5-(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0093] 2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-3-oxo-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-1 2 -carbonitrile;

[0094] 2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-3-oxo-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-1 6 -carbonitrile;

[0095] 2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-3-oxo-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-1 5 -carbonitrile;

[0096] 2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-1 5 -(oxetane-3-yloxy)-5-(oxetane-3-yloxy)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0097] 1 5 -Fluorine-1 6 -Methoxy-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0098] (R)-5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0099] (R)-2 6 ,7-dimethyl-5 6 -(9-(tetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0100] (R)-5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one;

[0101] (R)-5 6 -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0102] (R)-5 6 -(9-(4-methoxycyclohexyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0103] (R)-5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one;

[0104] (R)-5 5 -Fluoro-5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0105] (R)-5 5 -Fluoro-5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one;

[0106] (R)-5 5 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-(tetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0107] (R)-5 5 -Fluoro-5 6 -(9-(4-methoxycyclohexyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0108] (R)-5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5 -Fluorine-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0109] (R)-5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 , 5 5 ,7-trimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0110] 2 6 -methyl-5 6 -(9-(oxa-tetra-membered ring-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0111] 2 6 -methyl-5-(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridylcyclodecyl-3-one;

[0112] 5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0113] 5 6 -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 , 5 5 -Dimethyl-5- 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0114] 5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undec-3-yl)-2 6 , 5 5 -Dimethyl-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0115] 5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 , 5 5 -Dimethyl-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0116] 2 6 , 5 5 -Dimethyl-5- 6 -(9-(oxetan-3-ylmethyl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0117] 5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 , 5 5 -Dimethyl-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0118] 5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,5 5 -Dimethyl-5- 1 H-12-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocyclododecyl-3-one;

[0119] 5 5 -Fluoro-56 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0120] 5 5 -Fluorine-2 6 -methyl-5 6 -(9-(oxetan-3-ylmethyl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0121] 5 5 -Fluorine-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-51H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-bipyridocycloundecyl-3-one;

[0122] 5 5 -Fluoro-5 6 -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-26-methyl-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0123] 5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5 -Fluorine-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0124] (R)-2 6 ,7-di(methyl-d3)-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0125] 2 6 -methyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0126] (R)-5 5 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0127] 5 5 -Fluorine-2 6 -methyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0128] 2 6 , 5 5 -Dimethyl-5- 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one;

[0129] (R)-2 6 , 5 5 ,7-trimethyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0130] 2 6 -methyl-56 -(3-methyl-3-azaspiro[5.5]undec-9-yl)-5 1 H-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0131] 5 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0132] (R)-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridylcycloundecyl-3-one;

[0133] 5 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0134] 5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0135] (R)-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0136] 5 6-(9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0137] (R)-5 5 -Amino-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0138] (R)-1 6 -Fluoro-5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0139] (R)-1 6 -Fluorine-2 6 ,7-dimethyl 5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0140] (7R)-5 6 -(9-(2,2-dimethyloxetane-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]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0141] (7R)-2 6 ,7-dimethyl 5 6 -(9-(2-methyloxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0142] (R)-2 6 ,7-dimethyl 5 6 -(9-(1-methylazetidin-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0143] (R)-2 6 ,7-dimethyl 5 6 -(9-(3-methyloxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0144] (R)-5 5 -Fluoro-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0145] 5 6 -(9-(2-(dimethylamino)ethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0146] (7R)-5 6 -(9-(4-methoxy-4-methylpentan-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0147] 5 6-(9-cyclopropyl-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0148] 5 6 -(9-(4-methoxy-4-methylpentan-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0149] 5 6 -(9-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0150] 5 5 -Chloro-2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0151] (R)-5 5 -Chloro-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0152] 6'-Methyl-6'-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)spiro[cyclopropane-1,7'-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-bipyridocycloundecyl]-3'-one;

[0153] 2 6,8,8-trimethyl 5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0154] (R)-3-(9-(2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundec-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)propanamide;

[0155] (R)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5 -(Oxetane-3-ylamino)-5-(2-oxetane-3-ylamino)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0156] (R)-2-(9-(16-fluoro-2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)ethylmethylcarbamate;

[0157] (R)-3-(9-(2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)-N,N-dimethylpropionamide;

[0158] (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]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)propanamide;

[0159] (R)-1 6 ,5 5 -Difluoro-5- 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0160] (R)-3-(9-(1 6 -Fluorine-2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)-N,N-dimethylpropionamide;

[0161] (R)-2 6 ,7-dimethyl 5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-3-oxo-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-1 6 -nitrile;

[0162] (R)-5 6 -(9-(3-(azetidin-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0163] (R)-5 6 -(9-(3-(azetidin-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undec-3-yl)-1 6 -Fluorine-2 6 ,7-dimethyl-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0164] (R)-2 6 ,7-dimethyl 5 6 -(9-(2-(trifluoromethoxy)ethyl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0165] (R)-1 6 -Fluorine-2 6 ,7-dimethyl 5 6 -(9-(2-(trifluoromethoxy)ethyl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one;

[0166] (R)-5 6 -(9-(3-(3,3-dimethylazetidin-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one; or

[0167] (R)-2-(9-(2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)carbamic acid ethyl ester.

[0168] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I), or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0169] The present invention also provides the use of the above-mentioned compound and / or pharmaceutical composition in the preparation of an anti-tumor drug. In certain embodiments, the anti-tumor drug is used to treat the following conditions: 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's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, multiple myeloma, or mesothelioma.

[0170] In certain embodiments, the tumor is a malignant tumor carrying an EGFR gene mutation; preferably, the EGFR gene mutation is selected from one or more of: EGFR Del19 gene mutation, EGFR L858R gene mutation, EGFR T790M gene mutation and EGFR C797S gene mutation.

[0171] The present invention also provides a method for treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the above-mentioned compound or pharmaceutical composition, wherein the patient is preferably a mammal, and the mammal is preferably a human.

[0172] In certain embodiments, the administration during treatment comprises oral, mucosal, sublingual, ocular, topical, parenteral, rectal, intracisternal, vaginal, peritoneal, bladder, or nasal administration.

[0173] In some embodiments, the tumor comprises 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.

[0174] In certain embodiments, the tumor is a malignant tumor carrying an EGFR gene mutation; preferably, the EGFR gene mutation is selected from one or more of: EGFR Del19 gene mutation, EGFR L858R gene mutation, EGFR T790M gene mutation and EGFR C797S gene mutation.

[0175] Definition and Description

[0176] General chemical terms used in the above structural formulae have their usual meanings.

[0177] For example, unless otherwise indicated, the terms "halo" and "halogen" as used herein refer to fluorine, chlorine, bromine or iodine. Preferred halogen groups include fluorine, chlorine and bromine.

[0178] In the present invention, unless otherwise indicated, the term "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. The alkyl group used herein may optionally be substituted with one or more substituents. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "C" in "alkyl" 1-6 ” refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain.

[0179] The terms "alkenyl" and "alkynyl" include straight or branched chain alkenyl and alkynyl groups. 2-6 Alkenyl" and "C 2-6 "Alkynyl" refers to an alkenyl or alkynyl group containing 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or branched form.

[0180] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl groups.

[0181] The term "haloalkyl" refers to the aforementioned "alkyl" substituted by one or more halogens.

[0182] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

[0183] The term "aryl" in the present invention, unless otherwise specified, refers to an unsubstituted or substituted monocyclic, fused or condensed aromatic group containing carbon atoms, preferably C 6-14 Aryl, the C 6-14 Aryl is more preferably C 6-10 Examples of these aromatic rings include, but are not limited to, phenyl and naphthyl.

[0184] The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom ring member (e.g., 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms), wherein the heteroatoms are selected from N, O, and / or S. The nitrogen or sulfur heteroatom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroaryl group may be attached to any heteroatom or carbon atom to produce a stable structure. The heteroaryl group is preferably a 5-14 membered heteroaryl group, and the 5-14 membered heteroaryl group is further preferably a 5-10 membered heteroaryl group or a 5-6 membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl, or isoquinolinyl.

[0185] The term "carbocyclyl" refers to a saturated or unsaturated cyclic group that is not aromatic. Depending on its degree of saturation, it may include "cycloalkyl", "cycloalkenyl" or "cycloalkynyl". Monocyclic carbocyclyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane or cyclohexene and the like; polycyclic carbocyclyl groups include spirocyclic, fused ring, bridged ring carbocyclyl groups. The carbocyclyl is preferably C 3-14 Carbocyclic group, the C 3-14 The carbocyclic group is more preferably C 3-8 Carbocyclic group, the C 3-8 The carbocyclic group is more preferably C 3-6 Carbocyclic group, the C 3-8 The carbocyclic group is more preferably C 5-6 Carbocyclic group.

[0186] The term "cycloalkyl" refers to saturated monocyclic and polycyclic ring systems containing only carbon atoms in the ring and may be optionally substituted with one or more substituents. "Cycloalkyl" may have ring systems including bridged rings, fused rings, and spiro rings. Non-limiting examples of cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.4]octyl, bicyclo[2.2.1]heptane, and the like. The cycloalkyl is preferably C 3-14 Cycloalkyl, the C 3-14 The cycloalkyl group is more preferably C 3-8 Cycloalkyl, the C 3-8 The cycloalkyl group is more preferably C 3-6 Cycloalkyl, the C 3-8 The cycloalkyl group is more preferably C 5-6 Cycloalkyl.

[0187] The term "heterocyclyl" in the present invention, unless otherwise indicated, refers to unsubstituted or substituted monocyclic and polycyclic ring systems consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S, and includes saturated or unsaturated ring systems and polycyclic ring systems with unsaturated and / or aromatic moieties. The nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. The heterocyclyl can be attached to any heteroatom or carbon atom to form a stable structure. It should be understood that the polycyclic heterocycloalkyl group can have a ring system including fused rings, bridged rings and spirocycles. The heterocyclyl is preferably a 3-14 membered heterocyclyl, and the 3-14 membered heterocyclyl is further preferably a 3-8 membered heterocyclyl or a 5-10 membered heterocyclyl, and the 3-8 membered heterocyclyl is further preferably a 3-6 membered heterocyclyl, and the 3-6 membered heterocyclyl is further preferably a 5-6 membered heterocyclyl. The heterocycloalkyl group used herein may optionally be substituted with one or more substituents. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxetane, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinylsulfoxide, thiomorpholinylsulfone, and tetrahydrooxadiazolyl.

[0188] However, in no case will heterocyclyls and carbocyclyls intersect or include each other. Thus, according to the above definition, if at least one all-carbocycle is fused with a heterocyclyl to form a bi-, poly- or spiro-ring, it will still be defined as a heterocyclyl.

[0189] Additionally, if a heteroaryl group is fused with a heterocyclyl group to form a bi-, poly-, or spiro-ring, it will be defined as a heterocyclyl group rather than a heteroaryl group.

[0190] The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C 1-8 Alkyl, C 3-12 Cycloalkyl, -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, nitro, -S(O)2R 1 、-OS(O2)OR1 、-OS(O)2R 1 、-OP(O)(OR 1 )(OR 2 ); where R 1 and R 2 Independently selected from -H, C 1-6 Alkyl, C 1-6 In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethylamino, methylthio, sulfonyl, and acetyl.

[0191] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable base or acid. When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable base, including inorganic bases and organic bases.

[0192] As used herein, "deuterated" refers to a compound or chemical group formed when some or all of the hydrogen atoms in its structure are replaced by its isotope, deuterium. Any position specifically designated as "D" or "deuterium" is understood to have a deuterium enrichment of 50%, 80%, 90%, 95%, 98%, or 99%. "Deuterium enrichment" is a molar percentage determined by dividing the number of deuterium-containing compounds at the designated position by the total number of all compounds. When a position is designated as "H" or "hydrogen," hydrogen is present at its natural abundance at that position. When a position is silent regarding the presence of hydrogen or deuterium, hydrogen is present at its natural abundance at that position. A specific alternative embodiment relates to compounds of the present disclosure 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 compound described herein can be replaced with deuterium to provide the corresponding labeled or enriched compound.

[0193] The "deuterated C 1-6 "Alkyl" refers to "C 1-6 "Deuterated methyl" refers to a group in which the hydrogen atoms in the methyl structure are partially or completely replaced by their isotopes deuterium; "deuterated methyl" refers to a group in which the hydrogen atoms in the methyl structure are partially or completely replaced by their isotopes deuterium. CD3 is a group in which the hydrogen atoms in the methyl structure are completely replaced by their isotopes deuterium. The deuterated C 1-6 The alkyl group is preferably a deuterated C 1-3 Alkyl; the deuterated C1-3 The alkyl group is preferably a deuterated methyl group.

[0194] Since the compound represented by formula (I) is to be used as a medicine, it is preferably used with a certain purity, for example, at least 60% purity, more preferably at least 75% purity, and particularly preferably at least 98% purity (% is weight ratio).

[0195] Prodrugs of the compounds of the present invention are included within the scope of the present invention. Generally, the prodrug refers to a functional derivative that is easily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of the compounds of the present invention, which, upon administration to a recipient, can directly or indirectly provide the compounds of the present invention or their pharmaceutically active metabolites or residues. Particularly preferred derivatives or prodrugs are those that can increase the bioavailability of the compounds of the present invention when administered to a patient (e.g., by making orally administered compounds more readily absorbed into the blood), or those that promote the delivery of the parent compound to biological organs or sites of action (e.g., the brain or lymphatic system). Therefore, the term "administration" in the treatment methods provided herein refers to the administration of the compounds of the present invention that can treat various diseases, or, although not explicitly disclosed, can be converted into the compounds of the present invention in vivo upon administration to a subject. Conventional methods for selecting and preparing suitable prodrug derivatives are described in books such as "Design of Prodrugs" (ed. H. Bundgaard, Elsevier, 1985).

[0196] Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of the definition of any other position in the molecule. It is readily understood that one skilled in the art can select substituents or substitution patterns for the compounds of the present invention using existing techniques and the methods described herein to obtain chemically stable and readily synthesized compounds.

[0197] The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0198] The above formula (I) does not precisely define the stereostructure of a particular position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. During the synthetic process for preparing such compounds, or using racemization or epimerization processes known to those skilled in the art, the resulting product may be a mixture of stereoisomers.

[0199] When the compound represented by formula (I) exists in tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0200] When the compound represented by formula (I) and its pharmaceutically acceptable salt exist in solvates or polymorphs, 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.

[0201] The term "composition," as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product produced, directly or indirectly, from combination of the specified ingredients in the specified amounts. Thus, pharmaceutical compositions containing a compound of the invention as an active ingredient, as well as methods for preparing the compounds of the invention, are also part of this invention.

[0202] In addition, some crystalline forms of the compound can exist as polymorphs, and such polymorphs are included in the present invention. In addition, some compounds can form solvates with water (i.e. hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.

[0203] The pharmaceutical composition provided by the present invention includes a compound shown in formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient and other optional therapeutic components or adjuvants. Although in any given case, the most suitable active ingredient administration method depends on the specific subject, subject property and severity of the disease to be administered, the pharmaceutical composition of the present invention includes a pharmaceutical composition suitable for oral, rectal, local and parenteral (including subcutaneous administration, intramuscular injection, intravenous administration) administration. The pharmaceutical composition of the present invention can be conveniently prepared in any unit dosage form known in the art and any preparation method known in the pharmaceutical field.

[0204] The pharmaceutical compositions of the present invention can be prepared by any pharmaceutical method. Generally, such methods include the step of combining the active ingredient with a carrier comprising one or more essential ingredients. Typically, the pharmaceutical compositions are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or a mixture thereof. Furthermore, the product can be readily prepared to a desired appearance.

[0205] Therefore, 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, pharmaceutically acceptable salts, or prodrugs. Combinations of the compound represented by formula (I) or its pharmaceutically acceptable salts with one or more other therapeutically active compounds are also included in the pharmaceutical composition of the present invention.

[0206] The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gaseous carrier. DETAILED DESCRIPTION

[0207] To make the above content clearer and more specific, the present invention will further illustrate the technical solutions of the present invention with 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 intended to limit the scope of protection 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 art.

[0208] Unless otherwise indicated, all parts and percentages herein are by weight and all temperatures are in degrees Celsius.

[0209] The following abbreviations are used in the examples:

[0210] AcOH: glacial acetic acid;

[0211] (Boc)2O: di-tert-butyl dicarbonate;

[0212] CNBr: cyanogen bromide;

[0213] CMBP: cyanomethylenetri-n-butylphosphine;

[0214] DCM: dichloromethane;

[0215] DIEA / DIPEA: N,N-diisopropylethylamine;

[0216] Dioxane: dioxane;

[0217] DMAP: 4-dimethylaminopyridine;

[0218] DMF: N,N-dimethylformamide;

[0219] EA / EtOAc: ethyl acetate;

[0220] EtOH: ethanol;

[0221] Fe: iron powder;

[0222] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0223] LC-MS or LCMS: liquid chromatography-mass spectrometry;

[0224] Ruphos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl;

[0225] STAB: sodium triacetoxyborohydride;

[0226] t-BuONa: sodium tert-butoxide;

[0227] TBAF: tetrabutylammonium fluoride;

[0228] TEA: triethylamine;

[0229] TFA: trifluoroacetic acid;

[0230] THF: tetrahydrofuran;

[0231] TLC: thin layer chromatography;

[0232] Na2CO3: sodium carbonate;

[0233] K2CO3: potassium carbonate;

[0234] Pd(Amphos)Cl2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride;

[0235] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium;

[0236] Pd / C: palladium on carbon;

[0237] PE: petroleum ether;

[0238] Prep-HPLC: high performance liquid chromatography;

[0239] PLC: preparative liquid chromatography;

[0240] Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0241] The raw materials and reagents used in the examples can be obtained from commercial sources or prepared by conventional methods in the art.

[0242] Example 1 Synthesis of Compound 1

[0243] 2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0244] Step 1: Synthesis of compound 1-1

[0245] Dissolve 3-bromo-4-hydroxypyridine (1 g, 5.75 mmol) and benzyl bromide (1.03 g, 6.03 mmol) in acetonitrile (20 mL) and DMF (5 mL), and add sodium carbonate (1.22 g, 11.49 mmol). Heat the oil bath to 80°C and react for 3 hours. LCMS monitoring indicates the reaction is complete. Cool to room temperature. Add 100 mL of ethyl acetate and wash with 4×30 mL of saturated brine. Dry the organic phase, filter, and concentrate. Purify by column chromatography (DCM / MeOH = 15 / 1). The product compound 1-1 (1.20 g, yield 79.05%) is obtained. MS: 263.99 [M+H] + .

[0246] Step 2: Synthesis of compound 1-2

[0247] Compound 1-1 (500 mg, 1.89 mmol), methyl 2-chloro-6-methylisonicotinate (1.05 g, 5.68 mmol), pinacol diboronate (1.45 g, 5.68 mmol), Pd(Amphos)Cl2 (135 mg, 0.19 mmol), and sodium carbonate (502 mg, 4.73 mmol) were dispersed in acetonitrile (15 mL) and water (3 mL). Under nitrogen protection, the mixture was heated to 100°C in an oil bath and reacted for 2 hours. LCMS monitoring confirmed the reaction was complete. The mixture was cooled to room temperature. 30 mL of water was added and the mixture was extracted with 50 mL of ethyl acetate. The organic phase was dried, filtered, and concentrated. Purification was performed by column chromatography (DCM / MeOH = 20 / 1). The product, compound 1-2 (200 mg, yield 31.60%), was obtained. MS: 335.13 [M+H] + .

[0248] Step 3: Synthesis of compound 1-3

[0249] Compound 1-2 (200 mg, 0.6 mmol) was dissolved in methanol (6 mL), and lithium hydroxide (51 mg, 1.2 mmol) and water (2 mL) were added. The reaction was allowed to react at room temperature for 1 hour. LCMS monitoring indicated the reaction was complete. 6 mL of water was added and the methanol was removed by concentration. The pH was adjusted to 6 with 2 mol / L dilute hydrochloric acid. The system was concentrated and purified by reverse phase column chromatography (A: 0.1% formic acid aqueous solution, B: acetonitrile; acetonitrile was adjusted from 10% to 40% over 15 min). Product 1-3 (110 mg, yield: 57.41%) was obtained. MS: 321.12 [M+H] + .

[0250] Step 4: Synthesis of Compound 1-4

[0251] In a reaction flask, 4-bromo-2-fluoro-1-nitrobenzene (1.00 g, 4.55 mmol), 5-aminopentan-1-ol (0.52 g, 5.00 mmol), potassium carbonate (1.88 g, 13.64 mmol), and DMF (10 mL) were mixed and stirred overnight at room temperature. The reaction mixture was poured into 50 mL of ice water and filtered. The filter cake was rinsed with 3 x 15 mL of water and dried under vacuum to obtain the product compound 1-4 (1.2 g, yield: 87.01%). MS: 303.03, 305.03 [M+H] +

[0252] Step 5: Synthesis of Compound 1-5

[0253] In a reaction flask, compound 1-4 (24.00 g, 90.91 mmol), 2-methyl-2,7-diazaspiro[3.5]nonane (15.61 g, 92.78 mmol), and anhydrous potassium carbonate (25.64 g, 185.55 mmol) were dissolved in DMF (200 mL) and heated to 120°C with stirring for 6.5 h. LCMS monitoring indicated that the starting material reaction was complete and stirring was stopped. The reaction solution was cooled to room temperature and poured into 1 L of water. The mixture was stirred at room temperature for 1 h, filtered, and the filter cake was collected. The filtrate was extracted twice with ethyl acetate. The organic phases were combined, washed three times with water, washed once with saturated brine, dried, filtered, and concentrated. The residue and filter cake were combined, slurried with 200 mL of ethyl acetate, filtered, and the filter cake was rinsed with ethyl acetate. The filter cake was collected and dried to obtain compound 1-5 (24.15 g, yield: 75.35%) as a yellow solid. MS: 391.26 [M+H] +

[0254] Step 6: Synthesis of Compound 1-6

[0255] Compound 1-5 (16.00 g, 40.97 mmol) and imidazole (5.58 g, 61.46 mmol) were dissolved in dichloromethane (240 mL) in a 500 mL single-necked bottle. TBDMSCl (9.26 g, 61.46 mmol) was added dropwise under an ice bath. After addition, the mixture was warmed to room temperature and stirred for 12 h. LCMS monitoring indicated that the reaction was complete and stirring was stopped. The reaction solution was quenched by adding 300 mL of water. The layers were separated by stirring. The DCM phase was collected, washed once with water and once with saturated brine, dried, filtered, and concentrated. The residue was mixed with silica gel and purified on a flash silica gel column (A: DCM, B: MeOH, phase elution from 0-20% over 15 min). Compound 1-6 (19.64 g, yield: 94.96%) was obtained as a yellow oil. MS: 505.35 [M+H] +

[0256] Step 7: Synthesis of Compound 1-7

[0257] Compound 1-6 (15.00 g, 29.72 mmol) was dissolved in DCM / MeOH / H2O (100 mL / 100 mL / 150 mL) in a 1000 mL single-necked flask. Zinc powder (10.00 g, 297.16 mmol) and ammonium chloride (15.89 g, 297.16 mmol) were added under an ice bath and allowed to react at room temperature for 3 h. LCMS monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. Filtered through a pad of Celite, the filter cake was rinsed with dichloromethane, and the filtrate was collected. The layers were separated and the dichloromethane phase was collected. The phase was washed twice with water and once with saturated brine, dried, filtered, and concentrated to afford compound 1-7 (13.26 g, yield: 94.00%). MS: 475.38 [M+H] +

[0258] Step 8: Synthesis of Compound 1-8

[0259] In a 250 mL single-necked flask, compound 1-7 (8.00 g, 16.85 mmol) was dissolved in anhydrous ethanol (100 mL). Solid cyanogen bromide (3.14 g, 20.22 mmol) was added under ice-cooling and stirred for 2 h. LCMS confirmed the complete reaction of the starting material. Aqueous potassium carbonate (0.5 N) and DCM were added to the reaction mixture, and the layers were separated by stirring. The dichloromethane phase was collected, washed twice with water and once with saturated brine, dried, filtered, and concentrated. The residue was purified on a Flash C18 reverse-phase column (A: 0.1% formic acid in water, B: acetonitrile; acetonitrile increased from 0% to 50% over 15 mins) to afford compound 1-8 (3.80 g, yield: 45.12%). MS: 500.37 [M+H] +

[0260] Step 9: Synthesis of Compound 1-9

[0261] Compound 1-3 (90 mg, 0.28 mmol), compound 1-8 (141 mg, 0.28 mmol), and HATU (118 mg, 0.31 mmol) were dissolved in DCM (3 mL). Stir and cool. DIEA (91 mg, 0.70 mmol) was added at 0°C. After the addition was complete, the mixture was allowed to warm to room temperature and react for 2 hours. LCMS monitoring confirmed the reaction was complete. 30 mL of DCM was added and the mixture was washed with 20 mL of saturated brine. The organic phase was dried, filtered, and concentrated to obtain crude compound 1-9 (300 mg). MS: 802.48 [M+H] + .

[0262] Step 10: Synthesis of Compound 1-10

[0263] Compound 1-9 (300 mg, 0.37 mmol) was dissolved in THF (8 mL) and TBAF (1 mL) was added. The mixture was heated to 60°C in an oil bath and reacted for 6 hours. LCMS monitoring confirmed the completion of the reaction. The system was directly concentrated and purified on a Flash C18 reverse phase column (A: 0.1% formic acid in water, B: acetonitrile; acetonitrile from 0% to 100% in 20 mins). Product 1-10 (200 mg, yield 77.74%) was obtained. MS: 688.39 [M+H] + .

[0264] Step 11: Synthesis of Compound 1-11

[0265] Compound 1-10 (170 mg, 0.25 mmol) was dissolved in methanol (6 mL) and THF (2 mL), and palladium on carbon (132 mg) was added. The hydrogen atmosphere was replaced. The reaction was allowed to react at room temperature for 12 hours. LCMS monitoring indicated the reaction was complete. The system was filtered through a celite pad. The filtrate was concentrated. Purification was performed on a Flash C18 reverse phase column (A: 0.1% formic acid aqueous solution, B: acetonitrile; acetonitrile from 0% to 80% in 15 mins) to obtain the product compound 1-11 (100 mg, yield: 67.70%). MS: 598.34 [M+H] + .

[0266] Step 12: Synthesis of Compound 1

[0267] Compound 1-11 (100 mg, 0.17 mmol) was dissolved in toluene (2 mL) and CMBP (130 mg, 0.54 mmol) was added. The mixture was heated to 130°C in an oil bath and reacted for 1 hour. LCMS monitoring confirmed the reaction was complete. The temperature was cooled to room temperature. The system was directly concentrated. Purification was performed by Prep-HPLC using a Luna C18 column, 30 x 250 mm, and a mobile phase (A: 0.1% formic acid in water, B: acetonitrile; acetonitrile was adjusted from 17% to 50% over 20 min). The product, Compound 1 (15 mg, yield: 16%), was obtained. MS: 580.33 [M+H] + .

[0268] 1 H NMR(500MHz,DMSO-d6)δ12.49(s,1H),9.25(s,1H),9.04(s,1H),8.46(d,J=5.8Hz,1H),7.71(s,1H), 7.36(d,J=8.6Hz,1H),7.19(d,J=5.8Hz,1H),7.14(s,1H),7.06(d,J=2.2Hz,1H),6.91(dd,J=8.8,2. 2Hz,1H),4.23(dt,J=44.5,5.3Hz,4H),3.16(dd,J=11.4,5.7Hz,3H),2.81(s,3H),2.64(s,3H),2.57 (s,1H),2.53(s,3H),2.01(h,J=7.3Hz,2H),1.91(dp,J=19.3,6.8,5.6Hz,4H),1.61(d,J=6.1Hz,9H).

[0269] Example 2 Synthesis of Compound 2

[0270] 2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-4-Aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0271] Step 1: Synthesis of compound 2-2

[0272] In a 250 mL single-necked bottle, compound 2-1 (5.0 g, 51.46 mmol), (Boc)2O (13.48 g, 61.75 mmol), TEA (15.62 g, 154 mmol), and DMAP (1.26 g, 10.29 mmol) were added to 1,4-dioxane (80 mL) and stirred at room temperature for 5 h. The reaction was monitored for completion by TLC, concentrated, and purified by column chromatography (dichloromethane:methanol = 40:1). Compound 2-2 (9.83 g, yield: 96.85%) was obtained. MS: 198.14 [M+H] + Step 2: Synthesis of compound 2-3

[0273] In a 250 mL reaction flask, compound 2-2 (9.83 g, 49.84 mmol), 3-bromo-4-iodopyridine (16.98 g, 59.81 mmol), bis(triphenylphosphine)palladium dichloride (7.00 g, 9.97 mmol), CuI (4.75 g, 24.92 mmol), and DMF (80 mL) were mixed uniformly and heated to 100°C under nitrogen for 4 h. After cooling, the reaction solution was added with 200 mL of EA and extracted with 200 mL of water. The layers were separated, and the organic layer was washed with saturated brine (200 mL x 3), dried, filtered, and the filtrate concentrated. The residue was purified by column chromatography using PE:EA = 2:1 as the eluent. The eluate was concentrated to give compound 2-3 (13.81 g, yield: 78.42%). MS: 353.08, 355.08 [M+H] +

[0274] Step 3: Synthesis of compound 2-4

[0275] In a 250 mL reaction bottle, compound 2-3 (10.0 g, 28.31 mmol), methyl 2-bromo-6-methylisonicotinate (14.32 g, 62.27 mmol), Pd(Amphos)2Cl2 (1.60 g, 2.26 mmol), B2Pin2 (14.38 g, 56.62 mmol), sodium carbonate (9.00 g, 84.93 mmol), acetonitrile (100 mL), and water (20 mL) were mixed evenly, heated to 100 ° C under nitrogen protection for 2 h, cooled, and the solvent was evaporated under reduced pressure. The residue was washed with 200 mL of ethanol. The product was dissolved in DCM and washed sequentially with water (200 mL) and saturated brine (200 mL). The organic layer was dried, filtered, and the filtrate was concentrated. The residue was separated and purified by column chromatography using DCM:MeOH = 25:1 as eluent. The eluate was concentrated to obtain the product compound 2-4 (5.18 g, yield: 43.22%). MS: 424.22 [M+H] +

[0276] Step 4: Synthesis of compound 2-5

[0277] Compound 2-4 (5.00 g, 11.81 mmol) was added to DCM (20 mL) and stirred to dissolve. A 4 M solution of hydrogen chloride in 1,4-dioxane (30 mL) was added dropwise. After addition, the mixture was stirred at room temperature for 1 hour. LCMS was used to monitor the reaction until completion. The mixture was concentrated to obtain crude compound 2-5 (4.10 g), which was used directly in the next step. MS: 324.16 [M+H] +

[0278] Step 5: Synthesis of compound 2-6

[0279] In a 100 mL reaction flask, compound 2-5 (4.10 g, 11.81 mmol), 4-bromo-2-fluoro-1-nitrobenzene (3.12 g, 14.17 mmol), potassium carbonate (4.90 g, 35.43 mmol), and DMF (20 mL) were mixed uniformly and heated to 50°C overnight. The mixture was cooled, and 100 mL of EA was added to the reaction solution, followed by extraction with 100 mL of water. The organic layer was separated and washed with saturated brine (100 mL x 3), dried, filtered, and the filtrate concentrated. The residue was purified by column chromatography using DCM:MeOH = 18:1 as eluent. The eluate was concentrated to give compound 2-6 (5.45 g, yield: 88.2%). MS: 523.09, 525.09 [M+H] +

[0280] Step 6: Synthesis of Compound 2-7

[0281] In a 100 mL single-necked flask, compound 2-6 (2.48 g, 4.73 mmol) was dissolved in DCM / MeOH / H2O (20 mL / 10 mL / 20 mL). Zinc powder (2.47 g, 37.84 mmol) and ammonium chloride (5.06 g, 94.6 mmol) were added under ice-cooling. The mixture was allowed to warm to room temperature and allowed to react for 4 h. LCMS monitoring indicated that the starting material had reacted completely, and the reaction was stopped. Post-treatment: Filtration was performed, and the filter cake was rinsed with dichloromethane and methanol. The filtrate was collected and separated. The organic phase was collected, washed twice with water and once with saturated brine, dried, filtered, and concentrated to afford compound 2-7 (2.22 g, yield: 95.20%). MS: 493.12, 495.12 [M+H] +

[0282] Step 7: Synthesis of compound 2-8

[0283] In a 100 mL single-necked flask, compound 2-7 (2.22 g, 4.50 mmol) was dissolved in anhydrous methanol (30 mL) and water (6 mL). Solid cyanogen bromide (0.52 g, 4.95 mmol) was added at 20°C and stirred at this temperature for 4 h. LCMS confirmed the complete reaction. Aqueous sodium bicarbonate (0.5 N) and DCM were added to the reaction mixture, stirred, and the layers separated. The organic phase was collected, washed twice with water and once with saturated brine, dried, filtered, and concentrated. The residue was mixed with silica gel and purified by flash column chromatography (eluent: DCM:MeOH = 12:1) to afford compound 2-8 (1.99 g, yield: 85.4%). MS: 518.11, 520.11 [M+H] +

[0284] Step 8: Synthesis of compound 2-9

[0285] Compound 2-8 (1.99 g, 3.84 mmol) was dissolved in methanol (8 mL) and tetrahydrofuran (8 mL), and sodium hydroxide (0.31 g, 7.68 mmol) and water (8 mL) were added. The reaction was allowed to react at room temperature for 2 hours. LCMS monitoring indicated that the reaction was complete. The methanol and tetrahydrofuran were removed by concentration. The pH was adjusted to 7 with 2N dilute hydrochloric acid. The system was concentrated. Purification was performed on a Flash C18 reverse phase column (A: 0.1% formic acid aqueous solution, B: acetonitrile; acetonitrile was adjusted from 10% to 100% in 20 mins). The product compound 2-9 (1.89 g, yield: 97.8%) was obtained. MS: 504.10, 506.10 [M+H] + Step 9: Synthesis of compound 2-10

[0286] Compound 2-9 (1.89 g, 3.75 mmol) was dissolved in DCM (30 mL). Stir and cool. HATU (1.43 g, 3.75 mmol) and DIEA (3.1 mL, 18.75 mmol) were added at 0°C. After the addition was complete, stirring was continued at this temperature for 2 hours. LCMS monitoring indicated the reaction was complete. 30 mL of DCM was added and the mixture was washed sequentially with 50 mL of water and 50 mL of saturated brine. The organic phase was dried, filtered, and concentrated. The residue was mixed with silica gel and passed through a flash column chromatography (eluent: DCM:MeOH = 15:1) to obtain compound 2-10 (0.99 g, yield: 54.32%). MS: 486.09, 488.09 [M+H] +

[0287] Step 10: Synthesis of compound 2-11

[0288] Compound 2-10 (0.99 g, 2.03 mmol) was added to a reaction flask, followed by anhydrous dioxane (20 mL) as solvent. 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) were then added sequentially. The atmosphere was purged with nitrogen and the reaction was allowed to proceed at 100°C for 3 hours. The reaction was monitored by LCMS. Heating was discontinued, the solvent was evaporated under reduced pressure, and the residue was mixed with silica gel and purified by flash column chromatography (eluent: DCM:MeOH = 12:1) to afford compound 2-11 (0.81 g, yield: 69.45%). MS: 574.32 [M+H] +

[0289] Step 11: Synthesis of Compound 2

[0290] Compound 2-11 (100 mg, 0.174 mmol) was added to MeOH (8 mL), followed by 15% Pd / C (15 mg). After addition, the atmosphere was replaced with hydrogen three times and the reaction was stirred at room temperature for 2 hours. LCMS was used to monitor the reaction until completion. The reaction was stopped, filtered, and the filter cake was rinsed with methanol. The filtrate was concentrated and subjected to Prep-HPLC using a Luna C18 column, 30*250 mm, and a mobile phase (A: 0.1% formic acid in water, B: acetonitrile; acetonitrile was adjusted from 17% to 50% over 20 mins) to obtain the product, compound 2 (53 mg, 52.34%), with MS: 578.35 [M+H]. +

[0291] Example 3 Synthesis of Compound 3

[0292] (R)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0293] Step 1: Synthesis of compound 3-1

[0294] Disperse 4-hydroxy-3-iodopyridine (15 g, 67.87 mmol), methyl 2-chloro-6-methylisonicotinate (25 g, 135.74 mmol), pinacol diboronate (52 g, 203.61 mmol), Pd(amphos)Cl2 (4.7 g, 6.8 mmol), and sodium carbonate (28 g, 203 mmol) in acetonitrile (900 mL) and water (90 mL). Heat to 100°C in an oil bath under nitrogen for 2 hours. LCMS monitoring indicates the reaction is complete. Cool to room temperature. Add 1 L of water, adjust the pH to neutral with 1 N dilute hydrochloric acid, and extract three times with 500 mL of ethyl acetate. Combine the organic phases, dry, and concentrate. Purify by column chromatography (DCM / MeOH = 10 / 1). Obtain product 3-1 (10 g, 62% yield). MS: 245.08 [M+H] + .

[0295] Step 2: Synthesis of compound 3-2

[0296] Compound 3-1 (10 g, 40.98 mmol) was added to methanol (100 mL), and an aqueous solution of NaOH (3.28 g, 81.97 mmol, dissolved in 20 mL of water) was added dropwise. The mixture was allowed to react at room temperature for 1 h. LCMS monitored the reaction to completion. The pH was adjusted to 4 with 1N HCl. A large amount of solid precipitated, which was filtered and dried to obtain the product, compound 3-2 (7.22 g, yield: 76%). MS: 231.07 [M+H] +

[0297] Step 3: Synthesis of compound 3-3

[0298] The synthesis method of compound 3-3 is the same as that of compound 1-4, except that 5-aminopentane-1-ol is replaced by (R)-5-amino-4-methylpentane-1-ol. MS of compound 3-3: 317.04, 319.04 [M+H] + Step 4: Synthesis of compound 3-4

[0299] Compound 3-3 (2.90 g, 9.14 mmol), iron powder (2.55 g, 45.72 mmol), ammonium chloride (2.45 g, 45.72 mmol), ethanol (30 mL), and H2O (10 mL) were mixed and reacted at 60°C for 1 h. The reaction was complete after LCMS monitoring. The mixture was filtered, dried, and purified by column chromatography using DCM / MeOH = 10 / 1 to obtain the product compound 3-4 (2.60 g, yield: 99%). MS: 287.07, 289.07 [M+H] +

[0300] Step 5: Synthesis of compound 3-5

[0301] Compound 3-4 (2.60 g, 9.05 mmol), cyanogen bromide (1.15 mg, 10.86 mmol), methanol (30 mL), and water (6 mL) were mixed and reacted at 60°C for 0.5 h. The reaction was monitored by LCMS. The pH was adjusted to 8, and the mixture was extracted with 3 x 50 mL of DCM. The product compound 3-5 (2.70 mg, yield: 95%) was obtained by spin drying. MS: 312.06, 314.06 [M+H] +

[0302] Step 6: Synthesis of Compound 3-6

[0303] Compound 3-5 (0.40 g, 1.28 mmol), compound 3-2 (0.35 g, 1.54 mmol), and DIEA (1.06 mL, 6.41 mmol) were added to DMF (8 mL), followed by HOBt (0.26 mg, 1.92 mmol) and EDCI (0.37 g, 1.92 mmol). The mixture was reacted at 60°C for 1 h. The reaction was complete as monitored by LCMS. 200 mL of water was added to quench the reaction, and the mixture was extracted with 3 x 10 mL of DCM. The mixture was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The mixture was purified by PTLC (DCM / MeOH = 15 / 1) to give the product compound 3-6 (0.16 g, yield: 23.8%). MS: 524.12, 526.12 [M+H] +

[0304] Step 7: Synthesis of Compound 3-7

[0305] Compound 3-6 (150 mg, 0.29 mmol) was added to dioxane (4 mL), followed by CMBP (1380 mg, 5.72 mmol). The mixture was heated to 110°C in an oil bath and reacted for 2 hours. LCMS monitoring confirmed the reaction was complete. The mixture was cooled to room temperature and concentrated. Purification was performed by PTLC (DCM / MeOH = 15 / 1). The product, compound 3-7 (70 mg, yield: 48%), was obtained. MS: 506.11, 508.11 [M+H] +

[0306] Step 8: Synthesis of compound 3

[0307] The synthesis method of compound 3 was the same as that of compound 2-11, except that compound 2-10 was replaced by compound 3-7. The crude product was purified by prep-HPLC using a Luna C18 column, 30*250 mm, and a mobile phase (A: 0.1% formic acid aqueous solution, B: acetonitrile; acetonitrile was adjusted from 17% to 50% over 20 mins) to obtain compound 3. MS: 594.35 [M+H] +

[0308] Example 4 Synthesis of Compound 4

[0309] (R)-2 6 ,7-dimethyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0310] Step 1: Synthesis of compound 4-1

[0311] The synthesis method of compound 4-1 is the same as that of compound 3, except that 3-methyl-3,9-diazaspiro[5,5]undecane is replaced with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate to obtain compound 4-1. MS: 636.36 [M+H] +

[0312] Step 2: Synthesis of compound 4-2

[0313] Compound 4-1 (7.2 g, 10.59 mmol) and DCM (70 mL) were added to a 100 mL reaction flask. A dioxane hydrochloride solution (26.48 mL, 105.91 mmol, 4 M) was added dropwise at room temperature. The mixture was allowed to react for 2 h. LCMS monitoring indicated that the reaction was complete, and stirring was stopped. The reaction solution was filtered directly, and the filter cake was rinsed twice with dichloromethane and once with n-hexane. The filter cake was collected and dried to obtain the product, compound 4-2 (6.50 g, yield: 99.6%). MS: 580 [M+H] +

[0314] Step 3: Synthesis of compound 4

[0315] In a 100 mL single-necked flask, compound 4-2 (3.50 g, 5.68 mmol) was dissolved in anhydrous methanol (30 mL). Triethylamine (1.72 g, 17.04 mmol), 3-oxetanone (4.09 g, 56.80 mmol), and sodium cyanoborohydride (7.14 g, 113.60 mmol) were then added sequentially. The mixture was stirred and heated to 60°C for 1 h. LCMS monitored the complete reaction and the stirring was stopped. The reaction solution was cooled to room temperature and dichloromethane (150 mL) was added. The mixture was washed twice with saturated sodium carbonate solution, once with water, and once with saturated brine. The mixture was dried and filtered. The filtrate was concentrated. Acetonitrile was added twice during the concentration process and then the filter cake was rinsed with a small amount of acetonitrile. The filter cake was collected and dried to obtain the product, compound 4 (1.91 g, yield: 47.84%). MS: 636 [M+H] +

[0316] 1 H NMR (500MHz, DMSO-d6) δ12.53(s,1H),9.14(s,1H),8.97(s,1H),8.45(d,J=5.8Hz,1H),7.75(s,1H),7.36(d,J=8.7Hz,1H),7.19(d,J= 5.9Hz,1H),7.06(d,J=2.2Hz,1H),6.88(dd,J=8.8,2.2Hz,1H),4.51(t,J=6.5Hz,2H),4.40(t,J=6.1Hz,2H),4.23(td,J=10.8,6.8Hz,2 H),4.08(dd,J=14.0,2.8Hz,1H),4.00(dd,J=13.8,6.6Hz,1H),3.38(q,J=6.4Hz,1H),3.12(t,J=5.7Hz,4H),2.63(s,3H),2.30–2.22( m,2H),2.19(q,J=8.3,5.7Hz,4H),2.03(d,J=12.6Hz,1H),1.72(d,J=4.4Hz,0H),1.70(s,1H),1.56(t,J=5.7Hz,5H),1.48(d,J=5.7Hz, 4H),0.93(d,J=6.5Hz,3H).

[0317] Example 5 Synthesis of Compound 5

[0318] (R)-5 5 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0319] Step 1: Synthesis of compound 5-1

[0320] The synthesis method of compound 5-1 is the same as that of compound 3-3, except that 4-bromo-2-fluoro-1-nitrobenzene is replaced by 4-bromo-2,5-difluoronitrobenzene. The MS of compound 5-1 is 335.03, 337.03 [M+H] +

[0321] Step 2: Synthesis of compound 5-2

[0322] In a 500 mL single-necked flask, compound 5-1 (10.25 g, 30.58 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (11.67 g, 45.87 mmol), and anhydrous potassium carbonate (10.57 g, 76.45 mmol) were dissolved in DMF (200 mL) and heated to 100°C with stirring for 8 h. LCMS monitoring indicated complete reaction of the starting materials, and stirring was stopped. The reaction solution was cooled to room temperature and poured into 600 mL of water. Stir at room temperature for 1 h, filtered, and the filter cake was collected and purified by column chromatography using DCM:MeOH = 50:1 to 15:1 to obtain compound 5-2 (13.00 g, yield: 83.58%) as a yellow solid. MS: 509.31 [M+H] +

[0323] Step 3: Synthesis of compound 5-3

[0324] In a 100 mL single-necked bottle, compound 5-2 (2.00 g, 3.93 mmol) and imidazole (0.54 g, 7.86 mmol) were dissolved in dichloromethane (50 mL). TBDMSCl (0.71 g, 4.72 mmol) was added under ice-cooling. After addition, the mixture was warmed to room temperature and stirred overnight. LCMS monitoring indicated that the reaction was complete, and stirring was stopped. The reaction solution was poured into 100 mL of water to quench the reaction. The layers were separated by stirring. The DCM phase was collected, washed once with water and once with saturated brine, dried, filtered, and concentrated. The residue was mixed with silica gel and purified on a flash silica gel column (A: PE, B: EtOAc, phase B from 0-30% over 15 min). Compound 5-3 (2.10 g, yield: 85.74%) was obtained. MS: 623.39 [M+H] +

[0325] Step 4: Synthesis of compound 5-4

[0326] The synthesis method of compound 5-4 is the same as that of compound 1-7, except that compound 1-6 is replaced by compound 5-3. The MS of compound 5-4 is 593.42 [M+H] +

[0327] Step 5: Synthesis of compound 5-5

[0328] The synthesis method of compound 5-5 is the same as that of compound 1-8, except that compound 1-7 is replaced by compound 5-4. The MS of compound 5-5 is 618.41 [M+H] +

[0329] Step 6: Synthesis of compound 5-6

[0330] Compound 5-5 (1.70 g, 2.75 mmol), compound 3-2 (0.63 g, 2.75 mmol), EDCI (1.58 g, 8.25 mmol), HOBt (1.12 g, 8.25 mmol), DIEA (1.78 g, 13.76 mmol), and DMF (15 mL) were mixed and reacted at 40°C for 2 h. The reaction was monitored by LCMS for completion. The reaction system was poured into 100 mL of ice water and extracted with DCM (3 x 50 mL). The product was then purified by column chromatography using a DCM / MeOH (30 / 1) column to obtain compound 5-6 (1.70 g, yield: 74.44%). MS: 830.47 [M+H] +

[0331] Step 7: Synthesis of Compound 5-7

[0332] Compound 5-6 (1.60 g, 1.93 mmol), TBAF (5.78 mL, 1 mol / L), and THF (10 mL) were mixed uniformly and reacted at 70°C for 4 h. The reaction was monitored by LCMS for completion. The mixture was spin-dried, slurried with 50 mL of water three times, filtered, and the filter cake was rinsed with 15 mL of water (3 x 15 mL). The filter cake was then dried under vacuum to obtain the product compound 5-7 (1.15 g, yield: 83.35%). MS: 716.39 [M+H] +

[0333] Step 8: Synthesis of Compound 5-8

[0334] Compound 5-7 (300 mg, 0.42 mmol) was dissolved in DMF (3 mL), and CMBP (1011 mg, 4.19 mmol) was added. The mixture was heated to 110°C in an oil bath and reacted for 2 hours. LCMS monitoring confirmed the reaction was complete. The temperature was cooled to room temperature and the system was directly concentrated. Purification was performed by Prep-HPLC using a Luna C18 column, 30 x 250 mm, and a mobile phase (A: 0.1% formic acid in water, B: acetonitrile; acetonitrile was adjusted from 17% to 40% over 20 mins) to obtain compound 5-8. MS: 698.38 [M+H] + .

[0335] Step 9: Synthesis of compound 5-9

[0336] Compound 5-8 (220 mg, 0.31 mmol) was dissolved in DCM (4 mL) and TFA (2 mL) was added. The reaction was allowed to react at room temperature for 1 hour. LCMS monitoring indicated the reaction was complete. The system was directly concentrated, and the concentrate was dissolved in 20 mL of DCM. The pH was adjusted to alkaline with saturated aqueous potassium carbonate solution. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 5-9 (156 mg, yield: 85.37%). MS: 598.32 [M+H] + .

[0337] Step 10: Synthesis of compound 5

[0338] Compound 5-9 (50 mg, 0.08 mmol), 0.5 mL of formaldehyde solution, 1 drop of HOAc, and 3 mL of MeOH were mixed thoroughly. NaBH3CN (52.60 mg, 0.84 mmol) was added at room temperature and allowed to react for 1 h. The reaction solution was directly prepped for HPLC using a Luna C18 column, 30 x 250 mm, and a mobile phase (A: 0.1% formic acid in water, B: acetonitrile; acetonitrile increased from 17% to 50% over 20 mins) to obtain the product, compound 5 (11.20 mg, yield: 21.87%). MS: 612.34 [M+H] +

[0339] Example 6 Synthesis of Compound 6

[0340] (R)-5 5 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0341] Step 1: Synthesis of compound 6

[0342] Compound 5-9 (100 mg, 0.17 mmol) was dissolved in anhydrous methanol (4 mL), followed by the addition of glacial acetic acid (100 mg, 1.67 mmol), 3-oxetanone (121 mg, 1.67 mmol), and sodium cyanoborohydride (105 mg, 1.67 mmol). The mixture was stirred and allowed to react at room temperature for 2 h. LCMS monitored the reaction until complete, and stirring was stopped. The reaction solution was added to dichloromethane (15 mL), washed twice with saturated sodium carbonate solution, once with water, and once with saturated brine, dried, filtered, and concentrated. The product was prepared by Prep-HPLC using a Luna C18 column, 30 x 250 mm, and a mobile phase (A: 0.1% formic acid solution, B: acetonitrile; acetonitrile increased from 17% to 50% over 20 mins) to obtain the product, compound 6 (22.90 mg, yield: 19.56%). MS: 654.35 [M+H] +

[0343] 1 H NMR (500MHz, DMSO-d6) δ12.67(s,1H),9.14(s,1H),8.98(s,1H),8.46(d,J=5.8Hz,1H),7.75(d,J=1.2Hz,1H ),7.32–7.25(m,2H),7.20(d,J=5.9Hz,1H),4.52(t,J=6.4Hz,2H),4.41(t,J=6.1Hz,2H),4.26(d,J=11.6Hz ,2H),4.15–4.00(m,2H),3.39(p,J=6.4Hz,1H),2.96(dt,J=17.3,6.7Hz,4H),2.64(s,3H),2.24(d,J=32.8H z,6H),2.03(s,1H),1.76–1.70(m,1H),1.60(t,J=5.9Hz,5H),1.53(d,J=5.8Hz,4H),0.93(d,J=6.5Hz,3H).

[0344] Example 7 Synthesis of Compound 7

[0345] 2 6 ,9,9-trimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-51 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0346] Step 1: Synthesis of compound 7-1

[0347] Mix 4-bromo-2-fluoro-1-nitrobenzene (2.00 g, 9.09 mmol), 5-amino-2,2-dimethylpentan-1-ol (1.31 g, 10.00 mmol), potassium carbonate (3.77 g, 27.27 mmol), and DMF (20 mL). Stir overnight at room temperature, add 60 mL of ethyl acetate, wash with 3 x 40 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry to obtain compound 7-1 (3.00 g, yield: 99.6%). MS: 331.06 [M+H] +

[0348] Step 2: Synthesis of compound 7-2

[0349] Compound 7-1 (2.10 g, 6.97 mmol), triethylamine (2.91 mL, 20.91 mmol), and DCM (20 mL) were mixed uniformly. TBDMSCl (1.58 g, 10.46 mmol) was added at room temperature and the mixture was allowed to react for 2 h. The reaction solution was dried and column chromatography using PE / EA = 10 / 1 afforded compound 7-2 (3.00 g, yield: 96.6%). MS: 445.14 [M+H] +

[0350] Step 3: Synthesis of compound 7-3

[0351] Compound 7-2 (1.50 g, 3.37 mmol), Zn (2.20 g, 33.67 mmol), ammonium chloride (1.80 g, 33.67 mmol), DCM (10 mL), H2O (10 mL), and MeOH (10 mL) were added to a reaction flask and reacted at 40°C for 1 h. The reaction was monitored by LCMS. The mixture was filtered, separated, dried over anhydrous sodium sulfate, filtered, and dried in a spin dryer to obtain the product, compound 7-3 (0.90 g, yield: 64%). MS: 415.17 [M+H] +

[0352] Step 4: Synthesis of compound 7-4

[0353] Compound 7-3 (0.90 g, 2.17 mmol), anhydrous ethanol (20 mL), and cyanogen bromide (0.25 g, 2.38 mmol) were mixed and allowed to react at room temperature for 1 h. LCMS monitored the reaction completion, and the product was directly spin-dried and used in the next reaction. Compound 7-4 (0.60 g, yield: 95%). MS: 440.17 [M+H] +

[0354] Step 5: Synthesis of compound 7-5

[0355] Compound 7-4 (0.90 g, 2.04 mmol), compound 3-2 (0.56 g, 2.45 mmol), EDCI (0.78 g, 4.09 mmol), HOBT (0.55 g, 4.09 mmol), DIEA (1.69 mmol, 10.22 mmol), and DMF (10 mL) were mixed and reacted at 70°C for 30 min. LCMS monitored the reaction completion. 30 mL of ethyl acetate was added, and the mixture was washed with saturated brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and dried to afford compound 7-5 (1.20 g, 90% yield). MS: 652.22 [M+H] +

[0356] Step 6: Synthesis of compound 7-6

[0357] Compound 7-5 (900 mg, 1.38 mmol) and TBAF (10 mL, 1 M) were mixed and reacted at 70°C for 1 h. The reaction was monitored for completion by LCMS and then directly purified by Flash C18 reverse chromatographic analysis. Mobile phase A: 0.05% formic acid in water; mobile phase B: MeOH; gradient: 60-100% B over 20 min. The product, compound 7-6, was obtained by spin drying (560 mg, 95% yield). MS: 538.14 [M+H] +

[0358] Step 7: Synthesis of compound 7-7

[0359] Compound 7-6 (560 mg, 1.04 mmol), CMBP (2.51 g, 10.40 mmol), and DMF (10 mL) were mixed and reacted at 130°C for 4 h. The reaction was monitored for completion by LCMS and then directly purified by reverse phase chromatography (mobile phase A: 0.05% formic acid in water; mobile phase B: MeOH; gradient: 60-100% B over 20 min). The product, compound 7-7, was obtained by spin drying (120 mg, yield: 22%). MS: 520.13 [M+H] +

[0360] Step 8: Synthesis of compound 7

[0361] 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), and lithium tert-butoxide (32 mg, 0.40 mmol) were mixed and reacted at 100°C for 1 h under nitrogen. Direct Prep-HPLC was performed using a Luna C18 column, 30 x 250 mm, and a mobile phase (A: 0.1% formic acid in water, B: acetonitrile; acetonitrile increased from 17% to 50% over 20 mins) to yield the product, compound 7 (26 mg, 0.02 mmol, 60%). MS: 608.36 [M+H] +

[0362] 1 H NMR(500MHz,DMSO-d6)δ12.50(s,1H),9.11(s,1H),9.03(s,1H),8.46 (d,J=5.7Hz,1H),7.75(s,1H),7.35(d,J=8.8Hz,1H),7.21(d,J=5.8Hz,1H),7.12(d ,J=2.1Hz,1H),6.90(dd,J=8.8,2.3Hz,1H),4.21–4.15(m,2H),3.94(s,2H),3.15(t, J=5.7Hz,4H),2.64(s,3H),2.46(s,4H),2.27(s,3H),2.11(dd,J=11.2,6.2Hz,2H), 1.83(s,2H),1.58(t,J=5.7Hz,4H),1.53(t,J=5.8Hz,4H),1.23(s,2H),0.90(s,6H).

[0363] Example 8 Synthesis of Compound 8

[0364] (R)-5 5 -((dimethyl(oxo)-l 6 Sulfonamide)amino)-2 6 ,7-dimethyl 5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-Oxo-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0365] Step 1: Synthesis of compound 8-1

[0366] 1-Bromo-2-chloro-4-fluoro-5-nitrobenzene (0.60 g, 2.36 mmol), (R)-5-amino-4-methylpentan-1-ol (0.33 g, 2.83 mmol), potassium carbonate (1.30 g, 9.43 mmol), and DMF (6 mL) were mixed uniformly and reacted at 60°C for 1 h under nitrogen. LCMS monitored the reaction completion. The reaction mixture was cooled to room temperature, poured into 50 mL of ice water, filtered, rinsed with 3 x 15 mL of water, and the filter cake dried under vacuum to afford compound 8-1 (0.8 g, 2.27 mmol, yield: 96.48%). MS: 351.00, 353.00 [M+H] +

[0367] Step 2: Synthesis of compound 8-2

[0368] Compound 8-1 (0.8 g, 2.27 mmol), 3-methyl-3,9-diazaspiro[5,5]undecane (0.50 g, 2.96 mmol), potassium carbonate (1.26 g, 9.10 mmol), and DMF (8 mL) were mixed uniformly and reacted at 100°C for 18 h under nitrogen. LCMS monitored the reaction completion. The reaction mixture was cooled to room temperature and poured into 50 mL of ice water. The mixture was filtered, rinsed with 3 x 15 mL of water, and the filter cake was dried under vacuum to obtain the product, compound 8-2 (1.0 g, 2.07 mmol, yield: 96.48%). MS: 483.19, 485.19 [M+H] +

[0369] Step 3: Synthesis of compound 8-3

[0370] Compound 8-2 (1.0 g, 2.07 mmol), imidazole (0.51 g, 7.45 mmol), and DCM (20 mL) were added to a reaction flask. TBDMSCl (0.56 g, 3.72 mmol) was added at 0°C and the reaction was continued for 1 h. The reaction was monitored by LCMS until complete. The product was dried and then purified by column chromatography using PE / EA = 1 / 1 to obtain the product compound 8-3 (1.20 g, 2.00 mmol, yield: 80.88%). MS: 597.28, 599.28 [M+H] +

[0371] Step 4: Synthesis of compound 8-4

[0372] Compound 8-3 (1.90 g, 4.40 mmol), zinc powder (1.09 g, 16.73 mmol), ammonium chloride (0.89 g, 16.73 mmol), ethanol (20 mL), and H2O (10 mL) were mixed and reacted at 55°C for 1 h. The reaction was complete after LCMS monitoring. The mixture was filtered, cooled, and dried by spin chromatography. The product compound 8-4 (0.95 g, 1.69 mmol, yield: 99%) was obtained by column chromatography using DCM / MeOH = 10 / 1. MS: 567.30, 569.30 [M+H] +

[0373] Step 5: Synthesis of compound 8-5

[0374] Compound 8-4 (0.95 g, 1.69 mmol), cyanogen bromide (0.21 mg, 2.03 mmol), methanol (5 mL), and water (1 mL) were mixed evenly and reacted at 15°C for 1 h. The reaction was monitored by LCMS for completion. The pH was adjusted to 8, and the mixture was extracted with 3 x 50 mL of DCM. The product, compound 8-5 (0.90 g, 1.52 mmol, yield: 89.79%), was obtained by spin drying. MS: 592.30, 594.29 [M+H] +

[0375] Step 6: Synthesis of compound 8-6

[0376] Compound 8-5 (0.90 g, 1.52 mmol), 4'-hydroxy-6-methyl-[2,3'-bipyridine]-4-carboxylic acid (0.30 g, 1.29 mmol), EDCI (0.58 g, 3.04 mmol), HOBt (0.41 g, 3.04 mmol), DIEA (0.79 g, 6.07 mmol), and DMF (10 mL) were mixed and reacted at 60°C for 12 h. The reaction was monitored by LCMS for completion. The reaction system was poured into 500 mL of ice water and extracted with 3 x 50 mL of DCM. The product was then spin-dried and purified by column chromatography using a DCM / MeOH ratio of 10 / 1 to obtain compound 8-6 (0.8 g, 0.93 mmol, yield: 65.46%). MS: 804.36, 806.35 [M+H] +

[0377] Step 7: Synthesis of compound 8-7

[0378] Compound 8-6 (0.8 g, 0.93 mmol), TBAF (1.57 mL, 3.98 mmol), and THF (5 mL) were mixed and reacted at 70°C for 4 h. The reaction was completed after LCMS monitoring. The mixture was spin-dried and slurried with 5 mL of water three times. The mixture was filtered, rinsed with 3 x 5 mL of water, and the filter cake was dried under vacuum to obtain the product compound 8-7 (0.5 g, 0.72 mmol, yield: 72.83%). MS: 690.27, 692.27 [M+H] +

[0379] Step 8: Synthesis of compound 8-8

[0380] Compound 8-7 (0.5 g, 0.72 mmol), CMBP (2.62 g, 10.86 mmol), and DMF (10 mL) were mixed and reacted at 100°C for 4 h. The reaction was monitored by LCMS. The mixture was dried and purified by column chromatography using DCM / MeOH = 10 / 1 to obtain the product compound 8-8 (300 mg, 4.46 mmol, yield: 61.61%). MS: 672.26, 674.26 [M+H] +

[0381] Step 9: Synthesis of compound 8

[0382] Compound 8-8 (300 mg, 4.46 mmol), dimethylsulfenyl imide (82.95 mg, 0.90 mmol), Pd2(dba)3 (108.5 mg, 0.12 mmol), Xphos (112.98 mg, 0.24 mmol), t-BuONa (170.8 mg, 1.76 mmol), and 1,4-dioxane (5 mL) were mixed and reacted at 110°C for 4 h. The reaction was monitored by LCMS. The mixture was dried and prepared by Prep-HPLC using a Luna C18 column, 30*250 mm, and a mobile phase (A: 0.1% formic acid aqueous solution, B: acetonitrile; acetonitrile increased from 17% to 40% in 20 mins) to obtain the product compound 8 (30 mg, 0.59 mmol, yield: 6.09%). MS: 685.36, 686.36 [M+H] +

[0383] Example 9 Synthesis of Compound 9

[0384] (R)-1 6 -Fluorine-2 6 ,7-dimethyl 5 6 -(3,9-diazaspiro[5.5]undec-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0385] Step 1: Synthesis of compound 9-1

[0386] Methyl 2-bromo-6-methylisonicotinate (3.50 g, 15.21 mmol), hexamethyltin (5.48 g, 16.73 mg), tetrakistriphenylphosphine palladium (1.76 g, 1.52 mmol), and dioxane (20 mL) were mixed uniformly and reacted at 100°C under nitrogen for 40 min. 5-bromo-2-fluoro-4-methoxypyridine (2.82 g, 13.69 mmol) was added and the mixture was allowed to react overnight. Completion of the reaction was monitored by LCMS. The mixture was cooled to room temperature, dried, and purified by column chromatography using a PE / EA (2 / 1) ratio to afford compound 9-1 (1.70 g, 40% yield). MS: 277.09 [M+H] +

[0387] Step 2: Synthesis of compound 9-2

[0388] Compound 9-1 (1.70 g, 6.15 mmol) was added to a BBr3 solution in DCM (30 mL, 1 M) and reacted for 10 min in an ice bath. 30 mL of water was added, and the mixture was extracted with 3 x 20 mL of DCM. The mixture was dried over anhydrous sodium sulfate, filtered, and dried to give a crude product, compound 9-2 (2.0 g). MS of compound 9-2: 263.08 [M+H] + Step 3: Synthesis of compound 9-3

[0389] Compound 9-2 (1.60 g, 6.10 mmol) was dissolved in MeOH (30 mL), and a solution of NaOH (1.22 g, 30.51 mmol) in water (20 mL) was added at room temperature. The mixture was kept warm for 30 min. The reaction was monitored by LCMS for completion. The organic solvent was dried by spin drying, and the aqueous phase was extracted with 20 mL of DCM. The pH of the aqueous phase was adjusted to 4, filtered, and dried under vacuum to obtain the product compound 9-3 (1.00 g, 66%). MS of compound 9-3: 249.06 [M+H] +

[0390] Step 4: Synthesis of compound 9-7

[0391] Compound 9-7 was prepared using the same synthetic method as compound 8-5. MS of compound 9-7: 600.42 [M+H] +

[0392] Step 5: Synthesis of compound 9-8

[0393] Compound 9-3 (0.52 g, 2.10 mmol), compound 9-7 (1.20 g, 2.00 mmol), EDCI (0.96 g, 5.00 mmol), HOBT (0.68 g, 5.00 mmol), DIEA (1.29 g, 10.00 mmol), and DMF (15 mL) were mixed and reacted at 70°C for 30 min. LCMS monitored the reaction completion, and 30 mL of ethyl acetate was added. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to give the crude product, compound 9-8. MS of compound 9-8: 830.47 [M+H] +

[0394] Step 6: Synthesis of compound 9-9

[0395] Compound 9-9 was prepared using the same synthetic method as compound 5-7, except that the raw material compound 5-6 was replaced by compound 9-8. MS of compound 9-9: 716.39 [M+H] +

[0396] Step 7: Synthesis of Compounds 9-10

[0397] Compound 9-10 was prepared using the same synthetic method as compound 5-8, except that the starting compound 5-7 was replaced by compound 9-9. MS of compound 9-10: 698.38 [M+H] +

[0398] Step 8: Synthesis of compound 9

[0399] Compound 9-10 (1.20 g, 1.72 mmol) was dissolved in DCM (10 mL) and TFA (3 mL) was added at room temperature. The reaction was allowed to react for 1 h at room temperature. The reaction was monitored by LCMS for completion. Saturated aqueous sodium carbonate solution was added to adjust the pH to 8. The mixture was extracted with a mixed solvent of DCM / MeOH (10 / 1) (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and dried to obtain the product compound 9. MS: 598.32 [M+H] +

[0400] Example 10 Synthesis of Compound 10

[0401] (R)-1 6 -Fluorine-2 6 ,7-dimethyl-5 6-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0402] Step 1: Synthesis of compound 10

[0403] Compound 9 (20 mg, 0.03 mmol), 0.1 mL of formaldehyde solution, 1 drop of HOAc, and 2 mL of MeOH were mixed thoroughly. NaBH3CN (4 mg, 0.06 mmol) was added at room temperature and the mixture was allowed to react at 60°C for 1 h. The reaction solution was directly prepped for HPLC using a Luna C18 column, 30 x 250 mm, and a mobile phase (A: 0.1% formic acid in water, B: acetonitrile; acetonitrile increased from 17% to 50% over 20 mins) to obtain the product. Compound 10 had an MS of 612.34 [M+H] +

[0404] Example 11 Synthesis of Compound 11

[0405] (R)-2 6 , 5 5 ,7-trimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0406] The synthesis method of compound 11 is the same as that of compound 5, except that 4-bromo-2,5-difluoronitrobenzene is replaced by 2-bromo-4-fluoro-5-nitrotoluene. The synthesis route is as follows. The MS of compound 11 is 608.36 [M+H] +

[0407] Example 12 Synthesis of Compound 12

[0408] (R)-2 6 , 5 5 ,7-trimethyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0409] Step 1: Synthesis of compound 12

[0410] The synthesis method of compound 12 is the same as that of compound 6, except that compound 5-9 is replaced by compound 11-9. MS of compound 12: 650.37 [M+H] +

[0411] Example 13 Synthesis of Compound 13

[0412] 2 6 , 5 5 -Dimethyl-5- 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0413] Step 1: Synthesis of compound 13-1

[0414] In a 250 mL single-necked flask, 2-bromo-4-fluoro-5-nitrotoluene (5 g, 21.0 mmol) was dissolved in DMF (50 mL). Potassium carbonate (5.81 g, 42.0 mmol) and 5-aminopentan-1-ol (2.38 g, 23.10 mmol) were added and allowed to react overnight at room temperature. After the disappearance of the starting material as monitored by TLC, the reaction solution was poured into 300 mL of water. A large amount of orange-red solid precipitated. The solid was filtered, rinsed with 100 mL of water twice, and the filter cake was dried under vacuum to obtain the product, compound 13-1 (6.1 g, yield: 92%). MS: 317.04, 319.03 [M+H] +

[0415] Step 2: Synthesis of compound 13

[0416] The other synthetic steps of compound 13 are the same as those of compound 11, except that compound 11-1 is replaced by compound 13-1. MS of compound 13: 594.35 [M+H] + .

[0417] Example 14 Synthesis of Compound 14

[0418] 5 5 -Fluorine-2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0419] The synthesis steps of compound 14 are the same as those of compound 13, except that 2-bromo-4-fluoro-5-nitrotoluene is replaced by 4-bromo-2,5-difluoronitrobenzene. MS of compound 14: 598.32 [M+H] + .

[0420] 1 H NMR (500MHz, DMSO-d6) δ12.62(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,4 H),2.34(s,3H),2.01(s,2H),1.91(s,4H),1.59(dt,J=19.8,5.4Hz,8H).

[0421] Example 15 Synthesis of Compound 15

[0422] 5 6 -(9-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)-3-azaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0423] Step 1: Synthesis of compound 15-1

[0424] In a 50 mL single-necked bottle, 3-Boc-9-oxo-3-azaspiro[5.5]undecane (0.50 g, 1.87 mmol) was dissolved in DCM (10 mL). (3R,4S)-3-fluoro-4-methoxypiperidine (0.25 g, 1.87 mmol) and sodium triacetylborohydride (1.19 g, 5.61 mmol) were added. The mixture was allowed to react overnight at room temperature. LCMS monitored the completion of the reaction. The reaction solution was poured into 20 mL of aqueous sodium bicarbonate solution, the layers were separated, and the organic phase was concentrated and subjected to column chromatography using DCM:MeOH = 30:1 to 10:1 to obtain product 15-1 (0.62 g, yield: 86%). MS: 385.28 [M+H] + Step 2: Synthesis of compound 15-2

[0425] The synthesis method of compound 15-2 is the same as that of compound 4-2, except that compound 4-1 is replaced by compound 15-1. MS of compound 15-2: 285.23 [M+H] +

[0426] Step 3: Synthesis of compound 15

[0427] The synthesis method of compound 15 is the same as that of compound 3, except that compound 3-3 is replaced by compound 1-4. MS of compound 15: 696.40 [M+H] +

[0428] Example 16 Synthesis of Compound 16

[0429] (R)-1 6 ,5 5 -Difluoro-5- 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0430] Step 1: Synthesis of compound 16

[0431] The synthesis method of compound 16 is the same as that of compound 6, except that 3-oxetanone is replaced by 3-methoxypropanal. MS of compound 16: 688.37 [M+H] +

[0432] Example 17 Synthesis of Compound 17

[0433] 1 6 -Fluoro-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0434] The synthesis method of compound 17 is the same as that of compound 16, except that compound 5-1 is replaced by compound 1-4. The synthesis route is as follows. The MS of compound 17 is 656.36 [M+H] +

[0435] Example 18 Synthesis of Compound 18

[0436] 3-(9-(2 6 -methyl-3-oxo-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)propanamide

[0437] Step 1: Synthesis of compound 18

[0438] In a 50 mL single-necked vial, compound 17-8 (50 mg, 0.09 mmol) was dissolved in DMF (2 mL). 3-Bromopropionamide (27 mg, 0.18 mmol) and potassium carbonate (40 mg, 0.27 mmol) were added. The mixture was reacted at 70°C for 2 h under nitrogen atmosphere. LCMS monitoring revealed the disappearance of the starting material. The filtrate was filtered and concentrated. Prep-HPLC was performed using a Luna C18 column, 30 x 250 mm, and a mobile phase (A: 0.1% formic acid in water, B: acetonitrile; acetonitrile increased from 15% to 40% over 20 mins) to afford compound 18 (30.8 mg, 55% yield). MS: 637.35 [M+H] +

[0439] Example 19 Synthesis of Compound 19

[0440] (R)-2 6 ,7-dimethyl 5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5-((2-(methylsulfonyl)ethyl)amino)-5-(2-methylsulfonyl)ethyl)amino)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0441] Step 1: Synthesis of compound 19-1

[0442] In a 100 mL reaction flask, compound 8-1 (5.60 g, 16.00 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (4.88 g, 19.19 mmol), potassium carbonate (4.42 g, 31.99 mmol), and DMF (25 mL) were mixed uniformly and heated to 100°C for 8 h. After cooling, the reaction solution was added with 100 mL of EA and extracted with 50 mL of water. The layers were separated, and the organic layer was washed with saturated brine (50 mL x 3), dried, filtered, and the filtrate concentrated. The residue was purified by column chromatography using DCM:MeOH = 20:1 as the eluent. The eluate was concentrated to give compound 19-1 (9.11 g, 99% yield). MS: 569.23, 571.23 [M+H] +

[0443] Step 2: Synthesis of compound 19-2

[0444] Compound 19-1 (9.11 g, 16 mmol), triethylamine (4.45 mL, 32.01 mmol), and DCM (100 mL) were added to a reaction flask. p-Toluenesulfonyl chloride (3.97 g, 20.80 mmol) was added portionwise under an ice bath. After addition, the temperature was raised to room temperature and the reaction was allowed to react for 22 h. LCMS monitored the reaction to be nearly complete. The reaction solution was extracted with 100 mL of water and separated. The organic layer was washed with saturated brine (50 mL x 2), dried, filtered, and the filtrate concentrated. The residue was purified by column chromatography using a 3:1 ratio of PE:DCM as the eluent. The eluate was concentrated to give compound 19-2 (10.19 g, yield: 88.05%). MS: 723.22, 723.22 [M+H] +

[0445] Step 3: Synthesis of compound 19-3

[0446] In a 100 mL reaction flask, compound 19-2 (4.55 g, 6.30 mmol), compound 3-1 (2.00 g, 8.19 mmol), potassium carbonate (1.74 g, 12.60 mmol), and DMF (20 mL) were mixed uniformly and heated to 100°C for 2 h. After cooling, the reaction solution was added with 100 mL of EA and extracted with 50 mL of water. The layers were separated, and the organic layer was washed with saturated brine (50 mL x 3), dried, filtered, and the filtrate concentrated. The residue was purified by column chromatography using DCM:MeOH = 25:1 as the eluent. The eluate was concentrated to give compound 19-3 (3.88 g, yield: 77%). MS: 795.30, 797.30 [M+H] +

[0447] Step 4: Synthesis of compound 19-4

[0448] Compound 19-3 (3.76 g, 4.73 mmol) was dissolved in DCM / MeOH / H2O (20 mL / 10 mL / 20 mL) in a 100 mL single-necked flask. Zinc powder (2.47 g, 37.84 mmol) and ammonium chloride (5.06 g, 94.6 mmol) were added under ice-cooling. The mixture was allowed to warm to room temperature and allowed to react for 3 h. LCMS monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. Post-treatment: Filter through Celite, rinse the filter cake with dichloromethane, collect the filtrate, separate the layers, collect the dichloromethane phase, wash twice with water, once with saturated brine, dry, filter, and concentrate to give compound 19-4 (3.58 g, yield: 99%). MS: 765.32, 767.32 [M+H] +

[0449] Step 5: Synthesis of compound 19-5

[0450] In a 100 mL single-necked flask, compound 19-4 (2.15 g, 2.82 mmol) was dissolved in anhydrous ethanol (30 mL). Solid cyanogen bromide (0.31 g, 2.96 mmol) was added under ice-cooling and stirred for 2 h. LCMS monitored the complete reaction of the starting material. Aqueous potassium carbonate solution (0.5 N) and DCM were added to the reaction solution, stirred, and the layers separated. The dichloromethane phase was collected, washed twice with water and once with saturated brine, dried, filtered, and concentrated. The residue was mixed with silica gel and purified by flash column chromatography (eluent: DCM:MeOH = 13:1) to obtain compound 19-5 (1.74 g, yield: 79%). MS: 790.32, 792.32 [M+H] +

[0451] Step 6: Synthesis of compound 19-6

[0452] Compound 19-5 (1.74 g, 2.21 mmol) was dissolved in methanol (8 mL), and sodium hydroxide (0.18 g, 4.42 mmol) and water (8 mL) were added. The reaction was allowed to react at room temperature for 1 hour. LCMS monitoring indicated that the reaction was complete. The methanol was removed by concentration. The pH was adjusted to 7 with 2 mol / L dilute hydrochloric acid. The system was concentrated and purified by Flash C18 reverse phase column chromatography (A: 0.1% formic acid aqueous solution, B: acetonitrile; acetonitrile was adjusted from 0% to 100% in 20 mins). The product compound 19-6 (1.68 g, yield: 98%) was obtained. MS: 776.31, 778.31 [M+H] + .

[0453] Step 7: Synthesis of compound 19-7

[0454] Compound 19-6 (1.64 g, 2.11 mmol) was dissolved in DCM (17 mL). Stir and cool. HATU (0.84 g, 2.21 mmol) and DIEA (0.70 mL, 4.21 mmol) were added at 0°C. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was allowed to proceed for 2 hours. LCMS monitoring confirmed the completion of the reaction. 30 mL of DCM was added and the mixture was washed with 20 mL of saturated brine. The organic phase was dried, filtered, and concentrated. The residue was mixed with silica gel and passed through a flash column chromatography (eluent: DCM:MeOH = 25:1) to obtain compound 19-7 (1.57 g, yield: 98%). MS: 758.29, 760.30 [M+H] +

[0455] Step 8: Synthesis of compound 19-8

[0456] Compound 19-7 (257 mg, 0.34 mmol), 2-methylsulfonylethylamine hydrochloride (108 mg, 0.68 mmol), sodium tert-butoxide (98 mg, 1.02 mmol), bis(tri-tert-butylphosphine)palladium (36 mg, 0.07 mmol) and toluene (10 mL) were added sequentially to a single-necked flask. The atmosphere was purged with nitrogen three times. Microwave-treated at 100°C for 2 h. The reaction was monitored by LCMS. The solvent was evaporated under reduced pressure, and the residue was filtered through a silica gel flash column chromatography (eluent: DCM:MeOH = 40:1) to afford compound 19-8 (166 mg, yield: 61%). MS: 801.40 [M+H] + Step 9: Synthesis of compound 19-9

[0457] Compound 19-8 (128 mg, 0.16 mmol) was added to DCM (4 mL) and stirred to dissolve. Trifluoroacetic acid (2 mL) was added dropwise. After addition, the mixture was stirred at room temperature for 2 hours. LCMS was used to monitor the reaction until completion. The mixture was concentrated to obtain crude product 19-9 (124 mg, 111%), which was used directly in the next reaction. MS: 701.35 [M+H] + Step 10: Synthesis of compound 19

[0458] The crude product, compound 19-9 (100 mg, 0.14 mmol), from the previous step was dissolved in MeOH (5 mL). Formaldehyde (5.09 mg, 0.18 mmol) and sodium triacetoxyborohydride (36 mg, 0.18 mmol) were added sequentially and allowed to react at room temperature for 1 h. The reaction was monitored for completion by LCMS. Prep-HPLC was performed using a Luna C18 column, 30 x 250 mm, and a mobile phase (A: 0.1% formic acid in water, B: acetonitrile; acetonitrile increased from 17% to 50% over 20 min) to yield the product, compound 19 (21 mg, 20.6%). MS: 715.37 [M+H] +

[0459] Example 20 Synthesis of Compound 20

[0460] (R)-2 6 ,7-dimethyl 5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5 -(methylamino)-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0461] The synthesis method of compound 20 is the same as that of compound 19, except that 2-(methylsulfonyl)ethylamine hydrochloride is replaced by methylamine hydrochloride. The synthesis route is as follows. MS of compound 20: 623.37 [M+H]

[0462] Example 21 Synthesis of Compound 21

[0463] (R)-7-methyl-2 6 -(methyl-d3)5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0464] Step 1: Synthesis of compound 21-1

[0465] In a 50 mL single-necked flask, methyl 2,6-dichloroisonicotinate (2.06 g, 10 mmol) was dissolved in THF (10 mL). Deuterated methylmagnesium iodide (1 mol / L) (30 mL, 30 mmol) was added dropwise at -78°C. The reaction was allowed to proceed for 2 hours at -20°C. LCMS monitoring confirmed the reaction was complete. The system was quenched by pouring ammonium chloride solution and extracted with ethyl acetate. The product was concentrated and purified by column chromatography (PE / EA = 5 / 1). The product, compound 21-1 (0.45 g, 24% yield), was obtained, with MS: 189.04 [M+H] + .

[0466] Step 2: Synthesis of compound 21-2

[0467] Disperse 4-hydroxy-3-iodopyridine (15 g, 67.87 mmol), compound 21-1 (25 g, 135.74 mmol), pinacol diboronate (52 g, 203.61 mmol), Pd(amphos)Cl2 (4.7 g, 6.8 mmol), and sodium carbonate (28 g, 203 mmol) in acetonitrile (900 mL) and water (90 mL). Heat the mixture to 100°C in an oil bath under nitrogen for 2 hours. LCMS monitoring confirmed the completion of the reaction. Cool the mixture to room temperature. Add 1 L of water, adjust the pH to neutral with 1 N dilute hydrochloric acid, and extract three times with 500 mL of ethyl acetate. Combine the organic phases, dry, and concentrate. Purify the product by column chromatography (DCM / MeOH = 10 / 1). The product, compound 21-2 (10 g, 62% yield), was obtained. MS: 248.10 [M+H] + .

[0468] Step 3: Synthesis of compound 21-3

[0469] The synthesis method of compound 21-3 is the same as that of compound 3-2, except that the raw material is replaced by compound 21-2 instead of compound 3-1. The MS of compound 21-3 is 234.09 [M+H] +

[0470] Step 4: Synthesis of compound 21-4

[0471] The synthesis method of compound 21-4 is the same as that of compound 1-6, except that the raw material is replaced by compound 3-5 from compound 1-5. The MS of compound 21-4 is 426.15, 428.15 [M+H] +

[0472] Step 5: Synthesis of compound 21-5

[0473] The synthesis method of compound 21-5 is the same as that of compound 1-9, except that the raw materials are replaced by compound 21-3 and compound 21-4 instead of compound 1-3 and compound 1-8. The MS of compound 21-5 is 641.23, 643.23 [M+H] +

[0474] Step 6: Synthesis of compound 21-6

[0475] The synthesis method of compound 21-6 is the same as that of compound 1-10, except that the raw material is replaced by compound 21-5 from compound 1-9. The MS of compound 21-6 is 527.14, 529.14 [M+H] +

[0476] Step 7: Synthesis of compound 21-7

[0477] The synthesis method of compound 21-7 is the same as that of compound 5-8, except that the raw material 5-7 is replaced by 21-6. The MS of compound 21-7 is 509.13, 511.13 [M+H] +

[0478] Step 8: Synthesis of compound 21

[0479] The synthesis method of compound 21 is the same as that of compound 3, except that the raw material is replaced by compound 21-7 from compound 3-7, and the raw material is replaced by 3-methyl-3,9-diazaspiro[5,5]undecane from 3-methyl-3,9-diazaspiro[5,5]undecane from 3-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane. The MS of compound 21 is 639.38 [M+H] +

[0480] Example 22 Synthesis of Compound 22

[0481] (R)-1 6 -Fluoro-5 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one

[0482] Step 1: Synthesis of compound 22

[0483] Compound 9 (50 mg, 0.08 mmol), 1-bromo-2-methoxyethane (14 mg, 0.10 mmol), K2CO3 (35 mg, 0.25 mmol), and DMF (2 mL) were mixed and reacted at 60°C for 3 h. The reaction was monitored by LCMS for completion, and the reaction solution was directly prepared by Prep-HPLC using a Luna C18 column, 30 x 250 mm, and a mobile phase (A: 0.1% formic acid in water, B: acetonitrile; acetonitrile increased from 17% to 50% over 20 mins) to obtain the product. Compound 22 had an MS of 656.36 [M+H] +

[0484] The following examples shown in Table 1 were prepared in a similar manner to the above compounds.

[0485] Table 1

[0486] Example 77: 11H NMR (500 MHz, DMSO-d6) δ 12.53 (s, 1H), 9.14 (s, 1H), 8.97 (s, 1H), 8.46 (d, J = 5.7 Hz, 1H), 7.77–7.73 (m, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 5.9 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 6.89 (dd, J = 8.9, 2.2 Hz, 1H), 4.25 (dt, J = 10.5, 7.2 Hz, 2H), 4.12–4.05 (m, 1H), 4.00 (dd, J = 13.9, 6.5 Hz, 1H), 3.34 (t, J = 6.3 Hz, 2H), 3.22 (s, 3H), 3.13 (t, J = 5.6 Hz, 4H), 2.90 (q, J = 7.2 Hz, 2H), 2.63 (s, 3H), 2.56 (dt, J = 22.9, 6.4 Hz, 6H), 2.29–2.23 (m, 1H), 2.03 (s, 1H), 1.72 (p, J = 6.4 Hz, 2H), 1.56 (dt, J = 22.6, 5.5 Hz, 9H), 0.93 (d, J = 6.5 Hz, 3H).

[0487] Example 87: 1 1H NMR (500 MHz, 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 (d, J = 1.2 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 5.8 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.91 (dd, J = 9.0, 2.1 Hz, 1H), 4.28 (t, J = 4.8 Hz, 2H), 4.19 (s, 2H), 3.14 (t, J = 5.6 Hz, 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 = 9.2 Hz, 1H), 1.58 (t, J = 5.6 Hz, 4H), 1.51 (t, J = 5.6 Hz, 4H), 1.23 (s, 2H).

[0488] Example 89: 1¹H NMR (500 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.24 (s, 1H), 9.05 (s, 1H), 8.46 (d, J = 5.8 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.36 (dd, J = 8.8, 5.3 Hz, 1H), 7.20 (d, J = 5.9 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.91 (dd, J = 8.7, 2.3 Hz, 1H), 4.28 (t, J = 4.9 Hz, 2H), 4.19 (t, J = 5.7 Hz, 2H), 3.14 (t, J = 5.9 Hz, 4H), 2.64 (s, 3H), 2.53 (d, J = 5.4 Hz, 2H), 2.04–1.97 (m, 3H), 1.95–1.87 (m, 5H), 1.60 (dt, J = 25.7, 6.3 Hz, 5H), 1.52 (s, 1H), 1.44 (t, J = 5.7 Hz, 3H), 1.23 (s, 2H), 0.39 (dt, J = 6.1, 3.0 Hz, 1H), 0.29–0.23 (m, 1H).

[0489] Example 90: 1 ¹H NMR (500 MHz, 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), 7.36 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 5.8 Hz, 1H), 7.05 (s, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.28 (d, J = 5.4 Hz, 2H), 4.19 (s, 2H), 3.14 (t, J = 5.5 Hz, 4H), 3.08 (s, 3H), 2.88 (d, J = 9.4 Hz, 1H), 2.64 (s, 5H), 2.54 (s, 1H), 2.01 (s, 2H), 1.92 (s, 4H), 1.74 (dd, J = 13.8, 4.8 Hz, 1H), 1.60–1.56 (m, 4H), 1.52 (s, 5H), 1.39 (dd, J = 14.3, 6.4 Hz, 1H), 1.13 (d, J = 4.5 Hz, 6H), 1.04 (d, J = 6.6 Hz, 3H).

[0490] Example 91: 1H NMR (500MHz, DMSO-d6) δ12.48(s,1H),9.24(s,1H),9.05(s,1H),8.46(d,J=5.7Hz,1H),7.71(s,1H),7.35(d,J=8.7H z,1H),7.20(d,J=5.9Hz,1H),7.05(d,J=2.2Hz,1H),6.90(dd,J=8.9,2.1Hz,1H),4.28(t,J=4.9Hz,2H),4.22–4.15(m ,2H),3.39(dt,J=10.9,6.3Hz,2H),3.13(t,J=5.5Hz,3H),2.64(s,3H),2.55(q,J=9.2,5.5Hz,4H),2.05–1.85(m,6H) ,1.79–1.72(m,2H),1.57(t,J=5.6Hz,4H),1.49(d,J=5.8Hz,4H),1.23(s,1H),1.13–1.05(m,7H),1.06–0.98(m,2H).

[0491] Control compound 1

[0492] The following control compound 1 was prepared as described in Example I-021 on page 129 of WO2020260252.

[0493] Reference compound 1 (BI-4020)

[0494] Control compound 2

[0495] According to Example 51 on page 47 of CN114163454A, the following control compound 2 was prepared.

[0496] Control compound 2

[0497] Pharmacological experiments

[0498] Example A: Cell proliferation inhibitory activity assay

[0499] Suspension cells overexpressing various EGFR mutations, Ba / F3 (EGFR Del19 / T790M / C797S), Ba / F3 (EGFR L858R / T790M / C797S), Ba / F3 (EGFR Del19 / C797S), and Ba / F3 (EGFR L858R / C797S), were cultured in PRMI 1640 medium supplemented with 10% FBS and 1% PS. Adherent A431 cells carrying WT EGFR were cultured in DMEM supplemented with 10% FBS and 1% PS. Compound activity assays were performed as follows:

[0500] (1) Obtain adherent cells in the logarithmic growth phase, digest them with trypsin, count them, and seed them into a 96-well plate at a certain density. Incubate them overnight at 37°C and 5% CO2 to allow them to adhere. Obtain suspension cells in the logarithmic growth phase, count them, and seed them into a 96-well plate at a certain density.

[0501] (2) Compound preparation: The compound was serially diluted 3-fold using DMSO and then diluted 100-fold using culture medium to obtain a 10× working solution.

[0502] (3) 10× working solution containing different concentrations of compounds was added to each well, and the cells were incubated in a 37°C, 5% CO2 incubator for 72 h;

[0503] (4) Take out the 96-well cell culture plate, add 50 μL of CTG reagent to each well, shake for 2 minutes, react for 10 minutes, and read the luminescence signal value Lum using a PerkinElmer reader;

[0504] (5) Calculate the cell survival inhibition rate of each well, analyze the data using GraphPad Prism 6.0 software, and use nonlinear regression equation to fit the data to obtain the dose-effect curve and calculate the compound IC 50 : Cell survival inhibition rate (%) = (1-(Lum test compound-Lum culture medium control) / (Lum cell control-Lum culture medium control)) × 100% Y = minimum value + (maximum value - minimum value) / (1 + 10^((LogIC50-X)*slope));

[0505] X: logarithm of compound concentration; Y: cell survival inhibition rate.

[0506] Cell proliferation inhibitory activity IC 50 The results are shown in Table 2.

[0507] Table 2

[0508] The above experiments show that the compounds of the present invention have good proliferation inhibitory activity against Ba / F3 (EGFR Del19 / C797S), Ba / F3 (EGFR L858R / C797S), Ba / F3 (EGFR L858R / T790M / C797S) double-mutation or triple-mutation cell lines, and have weaker inhibitory effects on the EGFR wild-type cell line A431, indicating that the compounds of the present invention have good cell inhibitory activity and selectivity.

[0509] Example B: Pharmacokinetic study in mice

[0510] Mouse PK studies were conducted using female BALB / c mice (20-30 g). Compounds were prepared immediately prior to use. Administered via intravenous injection or oral gavage, blood was collected from the mouse orbital venous plexus, with 100 μL of whole blood transferred to a K2-EDTA tube at each time point.

[0511] After intravenous administration of 1 mg / kg, whole blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, and 24 hours. After oral administration of 5 mg / kg, whole blood was collected at 0.25, 0.5, 1, 2, 4, 6, and 24 hours after dosing in different batches, or mice were sacrificed simultaneously at 2, 4, and 6 hours to obtain brain samples. Whole blood samples were centrifuged to separate plasma. Brain tissue samples were homogenized with 4 volumes of buffer and stored at -80°C until further use. After protein precipitation with acetonitrile, the supernatant of these plasma and brain tissue samples was collected and mixed with water in a 1:1 ratio. 10 μL of the supernatant was analyzed by LC-MS / MS. Pharmacokinetic data for oral plasma are shown in Table 3.

[0512] Table 3

[0513] Example C: Pharmacokinetics in rats

[0514] Rat PK studies were conducted using male Sprague-Dawley rats (200-300 g). Compounds were prepared immediately prior to use. Administration was via intravenous injection or oral gavage. Blood was collected from the rats' orbital venous plexus, with 100 μL of whole blood collected into K2-EDTA tubes at each time point.

[0515] After intravenous administration of 1 mg / kg, whole blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 7, 24, 48, and 72 hours. After oral administration of 5 mg / kg, whole blood was collected at 0.25, 0.5, 1, 2, 4, 7, 24, 48, and 72 hours after dosing in different batches. Alternatively, rats were sacrificed and brains were obtained at 4 and 24 hours. Brain tissue samples were homogenized with 4 volumes of buffer and stored at -80°C until further use. After protein precipitation with acetonitrile, the supernatant of these whole blood and brain tissue samples was collected and mixed with water in a 1:2 ratio. 10 μL of the supernatant was analyzed by LC-MS / MS. Pharmacokinetic data for oral plasma are shown in Table 4.

[0516] Table 4

[0517] The experiments in Examples B and C show that the compounds of the present invention exhibit excellent pharmacokinetic properties and are significantly superior to the control compounds 1 and 2.

[0518] Example D: Liver microsome metabolic stability assay

[0519] The liver microsomal metabolic stability of the compound was studied using human, rat, mouse, and dog liver microsomes. The specific experimental steps are as follows:

[0520] (1) Add 40 μL MgCl2 and 306 μL PBS to each well of a 96-well plate, and then add 4 μL of compound. The final concentration of DMSO should be ≤0.5%. A blank well without compound should be set up at the same time.

[0521] (2) Add 10 μL of 20 mg / mL liver microsomes to each well and incubate at 37°C for 10 min;

[0522] (3) Add 40 μL of NADPH working solution to each well to start the reaction, and set up a control well without NADPH;

[0523] (4) At 0, 5, 15, and 45 min after the start of the reaction, 50 μL of sample was taken out, the termination solution was added, and the mixture was shaken for 5 min.

[0524] (5) The sample was then centrifuged at 3,220 g for 10 min, and 50 μL of the supernatant was removed and added to 200 μL of water for dilution and LC-MS / MS analysis.

[0525] In vitro intrinsic clearance (CL int , in μL / min / mg) was calculated from the in vitro half-life t using the following equation (average of replicates). 1 / 2 (Minutes) Conversion:

[0526] In vitro clearance rate = 0.693 / in vitro half-life t 1 / 2 ×[incubation volume (μL) / (protein amount (mg)]

[0527] The results are shown in Table 5.

[0528] Table 5

[0529] Experiments show that the compound of the present invention exhibits excellent metabolic stability in liver microsomes.

[0530] Although the present invention has been fully described through its embodiments, it is noteworthy that various changes and modifications are 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 a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof: in, L1, L2 are independently selected from a bond, -CR h R i -、-NR h -or-O-; Each R a 、R b The same or different, each independently selected from H, deuterium, halogen, CN, NO2, -OR e 、-SR e 、-S(O)R e 、-S(O)2R e 、-NR e R f 、C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R e and R f Optionally replaced by one or more deuterium, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR h or -NR h R i replace; Each R1 and R2 are the same or different and are independently selected from R h ;or R1 and R2 together with the atoms to which they are attached form a 3-14 membered heterocyclic group or a C 3-14 Carbocyclic group; wherein the 3-14 membered heterocyclic group or C 3-14 The carbocyclyl group is optionally substituted by one or more R h replace; M1 is selected from CR c or N; M3, M4, M7, M8 and M9 are independently selected from CR c R c or NR c ; M2, M5, M6 and M 10 Independently selected from absence, CR c R c 、-CR c R c -CR c R c - or NR c ; R4 is H, deuterium, halogen, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 a halocycloalkyl group or a cyano group; R5 is H, deuterium, halogen, -NH2, -N=S(O)ReR f ,-OH,-C(=O)OH,-C(=O)NH2,C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein said -NH2, -N=S(O)ReR f ,-OH,-C(=O)OH,-C(=O)NH2,C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R h replace. Each R c The same or different, each independently selected from H, deuterium, halogen, CN, NO2, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclic group, -C 0-6 Alkylene-3-14 membered heterocyclic 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)2R e 、-S(O)NR e R f 、-S(O)2NR e R f 、-N(R e )S(O)R f 、-N(R e )S(O)2R f 、-C(O)OR e 、-OC(O)R f OR-OC(O)OR g ; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclic group, -C 0-6 Alkylene-3-14 membered heterocyclic group, R e 、R f and R g Optionally, one or more R h 、-OR h 、-NR h R i 、-C(O)OR h 、-OC(O)R h 、-COR h 、-C(O)NR h R i replace; R e 、R f 、R g 、R h 、R i are independently selected from hydrogen, deuterium, halogen, CN, OH, NH2, -COOH, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 3-14 Cycloalkyl, -OC 3-14 Heterocyclic group, -SC 3-14 Heterocyclic group, -SC 3-14 Cycloalkyl, -SC 1-6 Alkyl, -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2, -CONH(C 2-6 alkenyl), -CON(C 2-6 alkenyl)2, -CONH(C 2-6 Alkynyl), -CON(C 2-6 Alkynyl)2, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)-C 2-6 Alkenyl, -S(O)2-C 2-6 Alkenyl, -S(O)-C 2-6 Alkynyl, -S(O)2-C 2-6 Alkynyl, -S(O)-C 3-14 Cycloalkyl, -S(O)2-C 3-14 Heterocyclic group, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C 1-6 Alkyl)2, -CHO, -C(O)-C 1-6 Alkyl, -C(O)-C 2-6 Alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclic or -C 0-6 Alkylene-3-14 membered heterocyclic group; wherein the -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 3-14 Cycloalkyl, -OC 3-14 Heterocyclic group, -SC 3-14 Heterocyclic group, -SC 3-14 Cycloalkyl, -SC 1-6 Alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2, -CONH(C 2-6 alkenyl), -CON(C 2-6 alkenyl)2, -CONH(C 2-6 Alkynyl), -CON(C 2-6 Alkynyl)2, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)-C 2-6 Alkenyl, -S(O)2-C 2-6 Alkenyl, -S(O)-C 2-6 Alkynyl, -S(O)2-C 2-6 Alkynyl, -S(O)-C 3-14 Cycloalkyl, -S(O)2-C 3-14 Heterocyclyl, -S(O)NHC 1-6 Alkyl, -S(O)N(C 1-6 Alkyl)2, -C(O)-C 1-6 Alkyl, -C(O)-C 2-6 Alkenyl, -C0-6 alkylene-C 6-14 Aryl, -C0-6 alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Cycloalkyl and -C 0-6 Alkylene-3-14 membered heterocyclic radicals are optionally replaced by one or more hydrogen, deuterium, halogen, CN, OH, NH2, -COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NH(C 1-6 Alkyl), -NH(C 1-6 Haloalkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 Haloalkyl)2, -N(C 1-6 Alkyl)(C 1-6 Halogenated alkyl), -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)-C 2-6 Alkenyl, -S(O)2-C 2-6 Alkenyl, -S(O)-C 2-6 Alkynyl, -S(O)2-C 2-6 Alkynyl, -S(O)-C 3-14 Cycloalkyl, -S(O)2-C 3-14 Heterocyclyl, -S(O)NHC 1-6 Alkyl, -S(O)N(C 1-6 Alkyl)2, -COO(C 1-6 Alkyl), -COO(C 1-6 Halogenated alkyl), -CONH(C 1-6 alkyl), -CONH(C 1-6 Halogenated alkyl), -CON(C 1-6 alkyl)2, -CON(C 1-6 Halogenated alkyl)2, -CON(C 1-6 Alkyl)(C 1-6 haloalkyl), -C 0-6 Alkylene-NHC(=O)C 1-6 Alkyl, -C 0-6 Alkylene-NHC(=O)C 1-6 Haloalkyl, -C 0-6 Alkylene-NHC(=O)C 2-6 Alkenyl, substituted or unsubstituted -C 0-6 Alkylene-C 3-14 Carbocyclyl, substituted or substituted-C 0-6 Alkylene-3-14 membered heterocyclic substitution; m is 0, 1, 2, or 3; n is 0, 1, 2 or 3; or r is 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1, or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form, characterized in that: L1 is selected from -CR h R i -.

3. The compound according to any one of claims 1 or 2, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: L1 is selected from -CH2-.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: L2 is a bond or -O-.

5. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R1 or R2 are independently selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl, halogen, -NH2, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R1 or R2 is H or C 1-3 alkyl.

7. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R1 and R2 together with the atoms to which they are attached form 8. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: for 9. The compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R a H, deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or -NH-C(O)-C 1-6 alkyl.

10. The compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R a H, deuterium, F, Cl, CN, NH2, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy or C 1-3 Halogenated alkyl.

11. The compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R a is H or CH3.

12. The compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R b H, deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -SC 1-6 Alkyl, -S(=O)-CH3, -S(=O)2-C 1-6 Alkyl, -S(=O)2-C 3-6 Cycloalkyl or -O-3-6 membered heterocyclic group.

13. The compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R b H, deuterium, F, Cl, -OCH3, C 1-3 Alkyl, CD3, CF3, CN, NH2, -S-CH3, -S(=O)-CH3, 14. The compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R b H or C 1-3 Alkyl; preferably, R b is H or CH3.

15. The compound according to any one of claims 1 to 14, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R4 is H.

16. The compound according to any one of claims 1 to 15, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R5 is H, halogen, C 1-6 Alkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; wherein, the C 1-6 Alkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups are optionally substituted with one or more OH, NH2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, -S(O)2-C 1-6 Alkyl, -C 1-6 Alkyl-S(O)2-C 1-6 Alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2 substituted.

17. The compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R5 is H, F, Cl, CH3, -NH2, 18. The compound according to any one of claims 1 to 17, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R5 is H.

19. The compound according to any one of claims 1 to 18, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R c H, deuterium, halogen, NO2, CN, OH, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein said -OH, NH2, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted with one or more halogen, C 1-6 Alkyl, C 1-6 Alkoxy, NH2, -COOH, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2, -CONH(C 2-6 alkenyl), -CON(C 2-6 alkenyl)2, -CONH(C 2-6 Alkynyl), -CON(C 2-6 Alkynyl)2, substituted or unsubstituted CO-3-6 membered heterocyclic group, -OC 1-6 Haloalkyl, -OC(=O)NH2, -OCONH(C 1-6 alkyl) or -OCON(C 1-6 alkyl)2 substituted.

20. The compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: R c H, deuterium, CH3, CD3, CH2CH3, CH(CH3)2, -C(CH3)3, OH, F, Cl, NH2, 21. The compound according to any one of claims 1 to 20, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: for 22. The compound according to any one of claims 1 to 21, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: for 23. The compound according to any one of claims 1 to 22, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: for 24. The compound according to any one of claims 1 to 23, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: m is 0, 1 or 2.

25. The compound according to any one of claims 1 to 24, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: n is 0, 1 or 2.

26. The compound according to any one of claims 1 to 25, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: r is 2, 3 or 4.

27. The compound according to any one of claims 1 to 26, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: The compound of formula (I) is selected from the compounds of formula (II) shown below: Wherein, 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 any one of claims 1-26.

28. The compound according to any one of claims 1 to 26, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: The compound of formula (I) is selected from the compounds of formula (III) shown below: Wherein, R in the compound of formula (III) a 、R b 、R c , R1, R2, m and n are as defined in any one of claims 1-26.

29. The compound according to any one of claims 1 to 26, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, characterized in that: The compound of formula (I) is selected from the compound of formula (IV) shown below: Wherein, R in the compound of formula (IV) a 、R b 、R c , R1, R2, m and n are as defined in any one of claims 1-26.

30. The compound according to any one of claims 1 to 26, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, wherein: The compound of formula (I) is selected from the compounds of formula (V) shown below: Wherein, R in the compound of formula (V) a 、R b 、R c , R1, m and n are as defined in any one of claims 1-26.

31. The compound according to claim 1, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, wherein: The compound is selected from: 2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one; 2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one; (R)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-2 6 ,7-dimethyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 5 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11- Oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one; (R)-5 5 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 2 6 ,9,9-trimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 5 -((dimethyl(oxo)-l 6 Sulfonamide)amino)-2 6 ,7-dimethyl 5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxo-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-1 6 -Fluorine-2 6 ,7-dimethyl 5 6 -(3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-1 6 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-2 6 , 5 5 ,7-trimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-2 6 , 5 5 ,7-trimethyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 2 6 , 5 5 -Dimethyl-5- 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 5 -Fluorine-2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)-3-azaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-1 6 ,5 5 -Difluoro-5- 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 1 6 -Fluoro-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11- Oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 3-(9-(2 6 -methyl-3-oxo-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)propanamide; (R)-2 6 ,7-dimethyl 5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5 -((2-(methylsulfonyl)ethyl)amino)-5-(2-methylsulfonyl)ethyl)amino)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-2 6 ,7-dimethyl 5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5 -(methylamino)-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-7-methyl-2 6 -(methyl-d3)5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-1 6 -Fluoro-5 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 1 6 ,2 6 -Dimethyl-5- 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 1 2 ,2 6 -Dimethyl-5- 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5-(9-oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 1 2 -Fluorine-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 1 2 -Fluorine-1 5 ,2 6 -Dimethyl-5- 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1 6 -(trifluoromethyl)-5-(trifluoromethyl)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridine Cycloundecyl-3-one; 1 5 ,2 6 -Dimethyl-5- 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5-(9-oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 1 6 -Amino-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 1 6 -Fluorine-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-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]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 1 5 -Fluorine-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 1 6 -Methoxy-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5-(9-oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 1 5 -Methoxy-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-5-(9-oxetane-3-yl)-3,9-diazaspiro[5.5]undecane-3-yl)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-3-oxo-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-1 2 -carbonitrile; 2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-3-oxo-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-1 6 -carbonitrile; 2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-3-oxo-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecane Alkyl-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-(oxetane-3-yloxy)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 1 5 -Fluorine-1 6 -Methoxy-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-2 6 ,7-dimethyl-5 6 -(9-(tetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one (R)-5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one; (R)-5 6 -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 6 -(9-(4-methoxycyclohexyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 5 -Fluoro-5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 5 -Fluoro-5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one; (R)-5 5 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-(tetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 5 -Fluoro-5 6 -(9-(4-methoxycyclohexyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5 -Fluorine-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 , 5 5 ,7-trimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 2 6 -methyl-5 6 -(9-(oxa-tetra-membered ring-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 2 6 -methyl-5-(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridylcyclodecyl-3-one; 5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 , 5 5 -Dimethyl-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undec-3-yl)-2 6 , 5 5 -Dimethyl-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-(3-methoxycyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 , 5 5 -Dimethyl-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 2 6 , 5 5 -Dimethyl-5- 6 -(9-(oxetan-3-ylmethyl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 , 5 5 -Dimethyl-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,5 5 -Dimethyl-5- 1 H-12-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocyclododecyl-3-one; 5 5 -Fluoro-5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 5 -Fluorine-2 6 -methyl-5 6 -(9-(oxetan-3-ylmethyl)-3,9-diazaspiro[5.5]undecane-3- Base)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 5 -Fluorine-2 6 -methyl-5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-51H-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-bipyridocycloundecyl-3-one; 5 5 -Fluoro-5 6 -(9-(3-fluorocyclobutyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5 -Fluorine-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-2 6 ,7-di(methyl-d3)-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 2 6 -methyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 5 -Fluorine-2 6 ,7-dimethyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 5 -Fluorine-2 6 -methyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 2 6 , 5 5 -Dimethyl-5- 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-2 6 , 5 5 ,7-trimethyl-5 6 -(9-(methyl-d3)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 2 6 -methyl-5 6 -(3-methyl-3-azaspiro[5.5]undec-9-yl)-5 1 H-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridylcycloundecyl-3-one; 5 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 5 -Amino-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-1 6 -Fluoro-5 6 -(9-(2-fluoroethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-1 6 -Fluorine-2 6 ,7-dimethyl 5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (7R)-5 6 -(9-(2,2-dimethyloxetane-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]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (7R)-2 6 ,7-dimethyl 5 6 -(9-(2-methyloxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one (R)-2 6 ,7-dimethyl 5 6 -(9-(1-methylazetidin-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-2 6 ,7-dimethyl 5 6 -(9-(3-methyloxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 5 -Fluoro-5 6 -(9-(3-methoxypropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-(2-(dimethylamino)ethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (7R)-5 6 -(9-(4-methoxy-4-methylpentan-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-cyclopropyl-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-(4-methoxy-4-methylpentan-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 6 -(9-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 -methyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 5 5 -Chloro-2 6 -methyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 5 -Chloro-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; 6'-Methyl-6'-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)spiro[cyclopropane-1,7'-11-oxa-4-aza-5(2,1)-benzo[d]imidazol-1(3,4),2(2,4)-bipyridocycloundecyl]-3'-one; 2 6 ,8,8-trimethyl 5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-3-(9-(2 6 ,7-dimethyl-3-oxo-5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazole oxazole-1(3,4),2(2,4)-bipyridocycloundecane-5-yl)-3,9-diazaspiro[5.5]undecane-3-yl)propionamide; (R)-2 6 ,7-dimethyl-5 6 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5 5 -(Oxetane-3-ylamino)-5-(2-oxetane-3-ylamino)- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-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]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)ethylmethylcarbamate; (R)-3-(9-(2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)-N,N-dimethylpropionamide; (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]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)propanamide; (R)-1 6 ,5 5 -Difluoro-5- 6 -(9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-3-(9-(1 6 -Fluorine-2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)-N,N-dimethylpropionamide; (R)-2 6 ,7-dimethyl 5 6 -(9-(oxetane-3-yl)-3,9-diazaspiro[5.5]undec-3-yl)-3-oxo-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-1 6 -nitrile; (R)-5 6 -(9-(3-(azetidin-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 6 -(9-(3-(azetidin-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undec-3-yl)-1 6 -Fluorine-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-2 6 ,7-dimethyl 5 6 -(9-(2-(trifluoromethoxy)ethyl)-3,9-diazaspiro[5.5]decane -3-alkyl)-5- 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-1 6 -Fluorine-2 6 ,7-dimethyl 5 6 -(9-(2-(trifluoromethoxy)ethyl)-3,9-diazaspiro[5.5]undec-3-yl)-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-dipyridocycloundecyl-3-one; (R)-5 6 -(9-(3-(3,3-dimethylazetidin-1-yl)-3-oxopropyl)-3,9-diazaspiro[5.5]undec-3-yl)-2 6 ,7-dimethyl-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecyl-3-one; or (R)-2-(9-(2 6 ,7-dimethyl-3-oxo-5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-1(3,4),2(2,4)-bipyridocycloundecane-5-ol 6 -yl)-3,9-diazaspiro[5.5]undec-3-yl)carbamic acid ethyl ester.

32. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises 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 substance thereof and at least one pharmaceutically acceptable excipient.

33. Use of a compound according to any one of claims 1 to 31, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated form thereof, or the pharmaceutical composition according to claim 32 in the preparation of an anti-tumor drug; preferably, the anti-tumor drug is used to treat the following conditions: 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's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma.

34. The use according to claim 33, characterized in that The tumor is a malignant tumor carrying an EGFR gene mutation: preferably, the EGFR gene mutation is selected from one or more 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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